Update - Gastroenterology and Hepatology

The latest clinical guidelines on HEPATITIS C AND MICROSCOPIC COLITIS

IE Prescribing Information: Targaxan 550mg (rifaximin-α)

REFER TO FULL SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) BEFORE PRESCRIBING

Presentation:

Film-coated tablet containing rifaximin 550 mg.

Uses:

Targaxan is indicated for the reduction in recurrence of episodes of overt hepatic encephalopathy in patients ≥ 18 years of age.

Dosage and administration:

Recommended dose: 550mg twice daily as long term treatment for the reduction in recurrence of overt episodes of overt hepatic encephalopathy.

In the pivotal study, 91% of patients were using concomitant lactulose.

TARGAXAN can be administered with a glass of water, with or without food.

No dosage changes are necessary in the elderly or those with hepatic insufficiency. Use with caution in patients with renal impairment.

The safety and efficacy in paediatric patients (aged less than 18 years) have not been established.

Contraindications:

Contraindicated in hypersensitivity to rifaximin, rifamycinderivatives or to any of the excipients and in cases of intestinal obstruction.

Warnings and precautions for use:

The potential association of rifaximin treatment with Clostridium difficile associated diarrhoea and pseudomembranous colitis cannot be ruled out.

The administration of rifaximin with other rifamycins is not recommended.

Rifaximin may cause a reddish discolouration of the urine.

Use with caution in patients with severe (Child-Pugh C) hepatic impairment and in patients with MELD (Model for End-Stage Liver Disease) score > 25.

In hepatic impaired patients, rifaximin may decrease the exposure of concomitantly administered CYP3A4 substrates (e.g. warfarin, antiepileptics, antiarrhythmics, oral contraceptives).

Both decreases and increases in international normalized ratio

(in some cases with bleeding events) have been reported in patients maintained on warfarin and prescribed rifaximin. If co-administration is necessary, the international normalized ratio should be carefully monitored with the addition or withdrawal of treatment with rifaximin. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

Ciclosporin may increase the rifaximin Cmax

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Pregnancy and lactation:

Rifaximin is not recommended during pregnancy.

The benefits of rifaximin treatment should be assessed against the need to continue breastfeeding.

Side effects:

Common effects reported in clinical trials are dizziness, headache, depression, dyspnoea, upper abdominal pain, abdominal distension, diarrhoea, nausea, vomiting, ascites, rashes, pruritus, muscle spasms, arthralgia and peripheral oedema.

At home they are still at risk; …TARGAXAN® rifaximin-α reduces the risk of recurrence of overt hepatic encephalopathy.2

Other effects that have been reported include:

Clostridial infections, urinary tract infections, candidiasis, pneumonia cellulitis, upper respiratory tract infection and rhinitis. Blood disorders (e.g. anaemia, thrombocytopenia).

Anaphylactic reactions, angioedemas, hypersensitivity. Anorexia, hyperkalaemia and dehydration. Confusion, sleep disorders, balance disorders, convulsions, hypoesthesia, memory impairment and attention disorders. Hypotension, hypertension and fainting. Hot flushes. Breathing difficulty, pleural effusion, COPD. Gastrointestinal disorders and skin reactions. Liver function test abnormalities. Dysuria, pollakiuria and proteinuria. Oedema. Pyrexia. INR abnormalities.

Prescribers should consult the SmPC in relation to all adverse reactions.

IRELAND

Legal category: Prescription only

Cost: €262.41 for 56 tablets

Marketing Authorisation holder: Norgine B.V. Antonio

Vivaldistraat 150, 1083 HP, Amsterdam, Netherlands

Marketing Authorisation number: PA 1336/009/001

Long-term prophylaxis in hepatic encephalopathy (HE)2

For further information contact: Norgine Pharmaceuticals Limited Norgine House Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, UK Telephone: +44 (0)1895 826 606

E-mail: Medinfo@norgine.com

Ref: IE-HEP-XIF-2100010

Date of preparation: April 2021

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance. Website: www.hpra.ie. Adverse events should also be reported to Medical Information at Norgine Pharmaceuticals Ltd on: Tel. +44 (0)1895 826 606 Email. Medinfo@norgine.com

References:

1. National Institute for Health and Care Excellence. Rifaximin for preventing episodes of overt hepatic encephalopathy: appraisal guidance TA337 for rifaximin. Available from: http://www.nice.org.uk/guidance/ta337

2. TARGAXAN® 550 Summary of Product Characteristics. Available for Ireland from: www.medicines.ie

Product under licence from Alfasigma S.p.A. TARGAXAN is a registered trademark of the Alfasigma group of companies, licensed to the Norgine group of companies. NORGINE and the sail logo are registered trademarks of the Norgine group of companies.

IE-HEP-XIF-2100007

Date of preparation: May 2021.

The only licensed treatment for the reduction in recurrence of episodes of overt hepatic encephalopathy ≥ 18 years1

Focusing on catching up and keeping up

A message from Priscilla Lynch, Editor

Welcome to the latest edition of Update

Gastroenterology and Hepatology

As our health services continue to adjust to the new ‘normal’ enforced by the Covid-19 pandemic, gastroenterology and liver services face unprecedented pressure and challenges in how to ensure timely expert care for patients against record-breaking waiting lists and inadequate senior staffing levels.

Patient demand has never been higher with clinicians facing burnout and dread about the inevitably difficult winter ahead. A detailed catch-up plan with a ringfenced budget and clinician input to highlight the areas in most need of extra support would go a long way towards addressing the unsustainable pressure our health service is experiencing.

Meanwhile, new ways of delivering care that have been accelerated by the pandemic, such as telemedicine, can help. Better collaboration between doctors and other key healthcare professionals is also essential, as a very interesting article in this edition of Update, which looks at the key role dietitians can play in helping reduce gastroenterology lists, shows.

This edition features a wide range of specialist clinical articles on the latest treatment approaches across a broad range of disease areas, including irritable bowel syndrome (IBS), Coeliac disease, diverticulitis and diverticular disease, the latest European guidelines on microscopic colitis, an update on the work of BowelScreen, and a detailed CPD article

on the diagnosis and management of inflammatory bowel disease (IBD), as well as a separate expert piece on treatment targets in IBD.

There is also a special focus on the role of nutrition in gastroenterology, including dietary strategies in treating IBD and IBS, and a public health overview of the impact of food on gastrointestinal and overall health. status.

Conference wise, there is a round-up of the most topical research updates from the 2021 International Liver Congress, convened by the European Association for the Study of the Liver (EASL). Leading hepatology researchers showcased a number of important developments in the treatment of non-alcoholic fatty liver disease (NAFLD), which is now one of the fastest growing diseases globally, including new data on trials involving RNAi therapeutics, antivirals and structurally engineered fatty acids. There was also exciting earlystage data on antiviral treatment for hepatitis B and D, as well as encouraging phase 2 data on the use of hepatic arterial infusion chemotherapy in combination with PD-1 inhibitor sintilimab for earlystage hepatocellular carcinoma (HCC). Unsurprisingly, there were also many research studies on the topic of Covid-19, with one study showing that chronic liver disease increases the odds of Covid-19 death by 80 per cent, and another showing that advanced fibrosis with decreased steatosis are risk factors for a lower Covid-19 vaccine response.

Closer to home, there is full coverage of the recent Irish Society of Gastroenterology (ISG) Summer Meeting, where leading national and international experts covered topics such as the latest knowledge of IBS and haemochromatosis, prevention of post-

operative Chron’s disease complications, how to use faecal immunochemical testing (FIT) for symptomatic patients, management strategies for the gastrointestinal consequences of pelvic radiation disease, endoscopic treatment of pre-neoplastic and early cancers, and evidence-based management of ascites.

There is also an article highlighting the latest European clinical guidance on diagnosing and treating hepatitis C. Almost 6,000 people with hepatitis C have been successfully treated with direct-acting antivirals (DAAs) in Ireland since the national treatment programme was established in 2015. Last year saw a significant decrease in the numbers of people commencing treatment compared to 2019 due to the impact of the coronavirus pandemic as well as a lack of ‘new’ untreated patients, with a similar downward trend this year. The progress made in tackling this disease in Ireland must not be taken for granted and ensuring wider access to treatment in the community, as well as increased awareness and promotion of testing for hepatitis C to pick up undiagnosed cases, is key to reversing this trend, according to those working in the area.

So all-in-all, this is a packed issue that should hopefully prove interesting and useful to all our readers.

Thank you to all our expert contributors for taking the time to share their knowledge and advice for the betterment of patient care.

We always welcome new contributors and suggestions for future content, as well as any feedback on our content to date. Please contact me at priscilla@mindo.ie if you wish to comment or contribute an article. ■

modified-release mesalazine

Abbreviated Prescribing Information

ASACOLON®1600 mg modified-release tablets: Red-brown, oblong, film-coated tablets each containing 1600 mg mesalazine.

INDICATIONS: Ulcerative colitis. For the treatment of mild-to-moderate acute disease. For the maintenance of remission.

DOSAGE AND ADMINISTRATION: Oral use. To be swallowed whole (not chewed, crushed, or broken) with water, with or without food. Acute ulcerative colitis: Adults and elderly: Adjust the dosage to the severity of the disease and tolerance. During exacerbation, the dose may be increased to 4800 mg daily, once daily or in 2-3 divided doses. Once remission is achieved, reduce the dose gradually to the maintenance dose. Monitor by week 8. Maintenance of remission: 1600 mg once daily. Elderly: As for adults, provided renal or hepatic function is not severely impaired. No study data. Children: Not for use in children or adolescents.

CONTRAINDICATIONS: Hypersensitivity to salicylates, mesalazine or any excipient. Severe hepatic or renal (GFR < 30 mL/min/1.73 m²) impairment.

SPECIAL WARNINGS AND PRECAUTIONS: Conduct blood count, liver function tests, serum creatinine and urinary status (dip stick) prior to and during treatment. Follow up after 14 days, then every 4 weeks for 12 weeks, 3 monthly thereafter or immediately if signs appear. Not for use in patients with renal impairment. Stop treatment immediately if signs of renal impairment develop, or if there is suspicion or evidence of blood dyscrasia. Nephrolithiasis has been reported: ensure adequate fluid intake. Caution in patients with hepatic impairment, gastric or duodenal ulcer. Not for use in patients with a history of mesalazine-induced cardiac hypersensitivity. Caution in patients with any previous myo- and pericarditis of allergic background. Monitor closely: Patients with pulmonary disease, particularly asthma; patients sensitive to sulfasalazine. Stop treatment immediately if acute symptoms of intolerance (e.g. abdominal cramps, acute abdominal pain, fever, severe headache and rash). Caution in elderly; use subject to renal and hepatic function. Limited data in children.

INTERACTIONS: Caution recommended for the concomitant use of mesalazine with known nephrotoxic agents, including NSAIDs and azathioprine, or methothrexate as these may increase the risk of renal adverse reactions. Mesalazine can increase the myelosuppressive effects of azathioprine, 6 mercaptopurine, or thioguanine. Life threatening infection can occur. Monitor closely for signs of infection and myelosuppression. Haematological parameters, especially the leukocyte, thrombocyte and lymphocyte cell counts should be monitored weekly, especially at initiation of combination therapy. May decrease the anticoagulant effect of warfarin.

USE DURING PREGNANCY AND LACTATION: Limited data on use in pregnancy. One case of neonatal renal failure was reported. Mesalazine crosses the placental barrier; use only if benefit outweighs risk. Limited data on lactation are available. N-acetyl-5-aminosalicylic acid and mesalazine are excreted in breast milk. The clinical significance has not been determined. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Use only if the benefit outweighs the risk. If the infant develops diarrhoea, discontinue breast-feeding.

UNDESIRABLE EFFECTS: Common: Headache, abdominal pain, ulcerative colitis, dyspepsia, rash, haematuria, proteinuria. Uncommon: Eosinophilia (as part of an allergic reaction), paresthesia, urticaria, pruritus, pyrexia and chest pain. Rare: Dizziness, myocarditis, pericarditis, diarrhoea, flatulence, nausea and vomiting, photosensitivity. Very rare: Altered blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia), blood dyscrasia, hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis, peripheral neuropathy, allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia, eosinophilic pneumonia, lung disorder, acute pancreatitis, changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis, alopecia, myalgia, arthralgia, impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, nephrotic syndrome, renal failure which may be reversible on early withdrawal, oligospermia (reversible). Frequency not known: nephrolithiasis, lupus-like syndrome, changes in weight and blood parameters. Refer to Summary of Product Characteristics for details.

LEGAL CATEGORY: POM.

MARKETING AUTHORISATION NUMBER: ASACOLON® 1600 mg MR Tablets PA 2018/4/1.

MA HOLDER: TILLOTTS PHARMA GMBH, Warmbacher Strasse 80, DE- 79618 Rheinfelden, Germany.

DATE OF PREPARATION: May 2021

CODE: 2021/8

FULL PRESCRIBING INFORMATION AVAILABLE ON REQUEST FROM THE MARKETING AUTHORISATION HOLDER OR FROM TILLOTTS PHARMA LIMITED, 25 SANDYFORD OFFICE PARK, DUBLIN 18, IRELAND, TEL: (00 353 1) 294 2015.

ASACOLON® is a trademark.

References:

1. https://www.hpra.ie/homepage/medicines/medicines-information/finda-medicine/results?query=MESALAZINE&field=ACTIVESUBSTANCES downloaded on 29th April 2021

2. ASACOLON® 1600 mg modified-release tablets, Summary of Product Characteristics available at www.medicines.ie

Editor Priscilla Lynch priscilla@mindo.ie

Sub-editor Emer Keogh emer@greenx.ie

Creative Director Laura Kenny laura@greenx.ie

Advertisements Graham Cooke graham@greenx.ie

Administration Daiva Maciunaite daiva@greenx.ie

Update is published by GreenCross Publishing Ltd, Top Floor, 111 Rathmines Road Lower, Dublin 6 Tel +353 (0)1 441 0024 greencrosspublishing.ie

© Copyright GreenCross Publishing Ltd 2021

The contents of Update are protected by copyright. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form by any means – electronic, mechanical or photocopy recording or otherwise – whole or in part, in any form whatsoever for advertising or promotional purposes without the prior written permission of the editor or publisher.

Disclaimer

The views expressed in Update are not necessarily those of the publishers, editor or editorial advisory board. While the publishers, editor and editorial advisory board have taken every care with regard to accuracy of editorial and advertisement contributions, they cannot be held responsible for any errors or omissions contained.

GreenCross Publishing is owned by Graham Cooke graham@greenx.ie

By getting on with their stero d t t t *

For induction and maintenance of remission of autoimmune hepatitis

tFor induction and maintenance of remission of microscopic colitis

*granules are licensed for induction of remission only

Eff icacy localised at the sites of the diseases1-5

Limiting the risk of systemic side effects1-5

Prescribing Information (Please refer to full SPC before prescribing)

Presentation: Budenofalk® gastro-resistant capsules, each containing 3mg budesonide, 240mg sucrose and 12mg lactose monohydrate Budenofalk® gastro-resistant granules, each sachet contains 9mg budesonide, 828mg sucrose, 36mg lactose monohydrate and 900mg sorbitol Indications: Capsules: Induction of remission of mild to moderate active Crohn’s disease affecting the ileum and/or the ascending colon Microscopic colitis Autoimmune hepatitis Granules: Induction of remission of mild to moderate active Crohn’s disease affecting the ileum and/or the ascending colon Induction of remission in patients with active microscopic colitis in adults aged ≥18 years

Dosage: All - take with a glass of water half an hour before meals Take once-daily doses in the morning Adults: Capsules: Crohn’s disease: 9mg once daily or 3mg three times a day Microscopic colitis: Induction of remission: 9mg once daily

Maintenance: lowest effective dose - 6mg once daily or 6mg once daily alternating with 3mg once daily

Autoimmune hepatitis: induction of remission: 3mg three times a day

Maintenance: 3mg twice a day Increase back to 9mg daily if ALAT &/or

ASAT increase Granules: Crohn’s disease and induction of remission in microscopic colitis: 9mg once daily in the morning Duration of treatment: Induction: Crohn’s disease, microscopic colitis: 8 weeks

Autoimmune hepatitis - until remission is achieved then maintenance for at least 24 months Do not stop any treatment abruptly but taper gradually Contra-indications: hypersensitivity to any constituent Hepatic cirrhosis Warnings/Precautions: Change from other steroids may result in symptoms due to reduced systemic steroids Use with caution in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataracts or family history of glaucoma or diabetes or any condition in which glucocorticosteroids may have undesirable effects Not appropriate for upper GI Crohn’s or extraintestinal symptoms. Prolonged, high dose use may result in glucocorticosteroid systemic effects Infection: suppression of the inf lammatory response and immune function increases susceptibility to infections and their severity Clinical presentation of infections may be atypical and presentation of serious infections may be masked

Chickenpox and herpes zoster are of particular concern Passive immunisation needed within 10 days in exposed non-immune patients taking systemic glucocorticosteroids Urgent specialist care required on confirmed chickenpox Give normal immunoglobulin immediately after measles exposure Do not give live vaccines to those with chronic glucocorticosteroid use Antibody response to other vaccines may be diminished With severe liver function disorders: increased systemic bioavailability expected Central serous chorioretinopathy or other causes may result in blurred vision/visual disturbances Consider referral to ophthalmologist Suppression of the HPA axis and reduced stress response: supplementary systemic glucocorticoid treatment may be needed Avoid concomitant treatment with CYP3A4 inhibitors Do not use in patients with galactose or fructose intolerance, glucose –galactose malabsorption, sucrase – isomaltase insufficiency or total lactase deficiency or congenital lactase deficiency In autoimmune hepatitis evaluate transaminase levels every 2 weeks for the first month and then every 3 months Interactions: Co-treatment with CYP3A inhibitors including cobicistat containing products may increase side effects and should be avoided where possible Beware concomitant administration of cardiac glycosides and saluretics CYP3A4 inducers: may reduce systemic and local exposure, necessitating dose adjustment of budesonide CYP3A4 substrates: may compete with budesonide increasing plasma concentrations depending on relative affinities Small, non-significant effect of cimetidine on budesonide kinetic effects Oestrogens/oral contraceptives (not oral low dose combination contraceptives) may elevate plasma concentrations and enhance corticosteroid effects Steroid-binding compounds and antacids may reduce budesonide efficacy; administer at least 2 hours apart Because adrenal function may be supressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values) Use in pregnancy and lactation: Avoid use in pregnancy unless essential Do not breastfeed during Budenofalk treatment Undesirable effects: Cushing’s syndrome, growth retardation in children, glaucoma, cataracts, blurred vision, dyspepsia, abdominal pain, constipation, gastric or duodenal ulcers, pancreatitis,

Together

For induction of remission of mild to moderate active ileo-caecal Crohn’s disease

increase in risk of infections, muscle and joint pain and weakness and twitching, osteoporosis, osteonecrosis, headache, pseudotumor cerebri (including papilloedema) in adolescents, depression, irritability and euphoria, psychomotor hyperactivity, anxiety, aggression, allergic exanthema, petechiae, ecchymosis, contact dermatitis, delayed wound healing, increased risk of thrombosis, vasculitis (after withdrawal from long-term treatment), fatigue, malaise Side effects characteristic of systemic glucocorticosteroid therapy may occur Exacerbation or reappearance of extraintestinal manifestations when switching from systemically acting glucocorticosteroids may occur Frequency is likely to be lower than with equivalent dosage of prednisolone Legal category: POM Costs: UK NHS: 60 sachets £135; 100 capsules £75 05 Ireland (PtW): 60 sachets: €146 06; 100 capsules: €78 96 Licence holder: Dr Falk Pharma GmbH, Leinenweberstr 5, D-79108 Freiburg, Germany Licence numbers: (granules) PL08637/0020 (UK) PA573/2/3 (IE) (capsules) PL08637/0002 (UK) PA573/2/1 (IE) Prepared: March 2021

References:

1 Bar-Meir S et al Gastroenterology 1998; 115(4): 835-40

2 Miehlke S et al Gastroenterology 2014; 146(5): 1222-30

3 Miehlke S et al Gastroenterology 2018; 155(6): 1795-1804 e3

4 Münch A et al Gut 2016; 65(1): 47-56

5 Manns MP et al Gastroenterology 2010; 139(4): 1198e206

UI--2100074

Date of preparation: July 2021

The only oral budesonide indicated in liver and GI diseases

Irish Society of Gastroenterology Summer Meeting 2021 Virtual ISG Summer Meeting a great success

The 2021 Irish Society of Gastroenterology (ISG) Summer Meeting was held virtually on 18 June, and featured a stellar line up of internationally renowned speakers from the US, Portugal, UK, and Ireland.

Key themes included lower GI issues such as how to use faecal immunochemical testing (FIT) for symptomatic patients, plus managing gastrointestinal consequences of pelvic radiation disease. In the area of liver disease there was an expert update on evidence-based management of ascites, while upper gastrointestinal themes covered included endoscopic treatment of preneoplastic and early cancers and an update on what is new in surgery for gastric cancer.

One of the most common presentations in gastroenterology, irritable bowel syndrome (IBS) was also covered, as well as the prevention of post-operative Crohn’s, and the latest knowledge in haemochromatosis.

This meeting was the last as ISG President for Dr Tony Tham, Consultant Physician and Gastroenterologist, Ulster Hospital, Belfast.

“I wish to thank you and the Society for giving me the honour and privilege to be your President for the last two years,” he said.

“It has truly been the highlight of my career. I would also like to thank our industry colleagues

Managing ascites in cirrhosis

The choice of treatment for ascites in cirrhosis should be primarily guided by what helps patients feel and function better, and survive longer, Prof Guru Aithal, Professor of Hepatology and Head of Division for Digestive Diseases, University of Nottingham, UK, told the 2021 ISG Summer Meeting.

Prof Aithal was the lead author of the recent guidelines on the management of ascites in cirrhosis produced by the British Society of Gastroenterology in collaboration with the British Association for the Study of the Liver.

Over the years, there has been a substantial improvement in care and survival of patients with liver cirrhosis, including those with ascites, despite higher age and more medically complex disease.

Addressing ISG delegates, Prof Aithal said the timely diagnosis of spontaneous bacterial peritonitis, which has a prevalence of 1.5-to-

3.5 per cent in outpatients and up to 11 per cent in inpatients, is key, as one study has shown that each hour of delay in diagnostic paracentesis is associated with a 3.3 per cent increase in in-hospital mortality adjusting for MELD score.

The use of human albumin solution (HAS) has long been the standard treatment in large volume paracentesis (LVP), with robust data now on its effectiveness, he noted. A meta-analysis of 16 studies has shown that compared to other alternatives (including vasoconstrictors), the use of HAS has led to 57-100 fewer patients dying per 1,000 paracentesis.

Transjugular intrahepatic portosystemic shunt (TIPS) is an alternative to paracentesis for refractory ascites, and also has good quality data supporting its effectiveness; with the now standard use of polytetrafluoroethylene (PTFE)-covered stents seeing a long-term

and friends who have continued to support us during the pandemic. Without them, it would not be possible to hold this meeting. I would like to thank the outstanding effort of our Chief Executive Michael Dineen and also Cora Gannon for organising this meeting. I would like to thank the ISG Board for their support and guidance as always and Dr Garret Cullen and our co-chairs.”

At the close of the meeting, Dr Tham handed over the chains of office to incoming ISG President Prof Deirdre McNamara, Associate Professor of Gastroenterology, Trinity College Dublin, and Consultant Gastroenterologist, Tallaght University Hospital.

patency at one year of 92 per cent, and 89 per cent at two years. While it has good outcomes and mortality data for patients on transplant lists, “careful patient selection is critical”, cautioned Prof Aithal. Data also supports TIPS as being more cost-effective and scoring higher on QALY than LVP, he added.

The Alfa pump, a subcutaneously-implanted device that pumps ascitic fluid from the peritoneal cavity into the bladder, is another option for refractory ascites. Studies have shown good results, with improvement in quality-of-life. However, it is expensive and requires surgical skill, as well as being associated with acute kidney injury in some patients, Prof Aithal said.

Long-term abdominal drainage is another option to palliate ascites, for those who are unsuitable for transplantation and wish to stay at home, with data showing reduced need for paracentesis and hospitalisation, he concluded.

Good uptake of new haemochromatosis venesection service in general practice

The long-awaited roll-out of the HSE general practice venesection service for haemochromatosis patients has been very successful to date, with high uptake especially in more rural and peripheral areas, according to Prof Suzanne Norris, Consultant Hepatologist, St James’s Hospital, Dublin.

Prof Norris gave an update on the condition at the virtual ISG 2021 Summer Meeting, where she presented data on the GP therapeutic phlebotomy service for eligible haemochromatosis patients, which only formally launched in 2020, following its approval in the HSE’s 2017 Model of Care for hereditary

rural and peripheral areas outside the Dublin north-east region.

Prof Norris presented an overview of various studies on the impact of HH, and the arguments for screening to enable earlier detection and morbidity risk reduction. Ireland has a very high prevalence of HH compared to most countries, at 1.5 per cent (1:83) for HH c282Y mutation.

The Hemochromatosis and Iron Overload Screening (HEIRS) study, which evaluated the prevalence, genetic and environmental determinants, and potential clinical, personal, and

consequences of late diagnosis can be very severe, it is such a simple and easy disease to diagnose with cheap, widely available tests, and the treatment is very simple”.

On the other hand, arguments against screening include that “despite its prevalence in Ireland very few people will develop life-threatening disease”, she noted.

“Many patients with haemochromatosis may never need venesection, probably about 50 per cent. And there is an argument that the health system has higher priorities, and there is the argument about genetic discrimination against those who are diagnosed as having homozygosity who will never develop iron overload, but could experience discrimination in terms of life insurance, mortgage approval, and so on.”

haemochromatosis (HH), and the necessary GP contract negotiations in 2018. Despite the impact of the pandemic, a total of 5,887 HH phlebotomy claims were made by 720 GPs for 2,175 patients in 2020.

“This is a fantastic first year of the primary care programme for venesection services being provided by our GP colleagues. This is hugely beneficial for patients. It means venesection is being provided close to where you live. When you look at the geographical spread of where these GPs are located and providing the services, there is a huge number of patients accessing the services in CHO 2, which is Mayo, Galway, and Roscommon, and also CHO 4, which is Kerry and Cork…,” as well as other more

societal effects of iron overload and haemochromatosis in a multicentre, multi-ethnic sample of 101,168 primary care adults (25 years+) in the US and Canada, showed that women with ferritin >1,000 were three times more likely to have significant liver disease, while men with ferritin >1,000 were six times more likely to have significant liver disease. Further research from the same group showed that patients with HH had a much higher risk of diabetes, liver disease, and liver cancer, but no increased risk of stroke and heart disease, she reported.

Arguments in favour of screening for haemochromatosis, Prof Norris said, include “the fact that Ireland has the highest prevalence of any country, the

However, there is good evidence for targeted screening in higher at-risk populations, including those with type 2 diabetes or cardiac disease (atypical arthropathy) or male sexual dysfunction, close relatives of HH patients, those with abnormal LFTs with raised iron markers, etc, though Prof Norris pointed out that elevations in ferritin levels are common, and in type 2 diabetics can be due to liver fat.

Meanwhile, separate research presented at the meeting showed that in a large sample of haemochromatosis patients in Ireland, age at diagnosis appears to be associated with death.

Carried out by researchers from the Hepatology Unit, Beaumont Hospital, Dublin, a total of 1,043 patients with HH were identified and assessed for factors associated with mortality. Of the total cohort, 65 per cent were male.

There is good evidence for targeted screening in higher at-risk populations, including those with type 2 diabetes or cardiac disease...

Fatigue was the most common presenting complaint (37 per cent), with family history (22 per cent), incidental finding of raised iron (16 per cent), and screening programmes (13 per cent) being other common causes of referral.

Homozygosity for C282Y was the most common HFE genetic mutation in this cohort (68 per cent) with

compound HFE heterozygosity accounting for 26 per cent.

At the time of assessment, 0.03 per cent (30/1043) of patients had died, with a median follow up time of 10 years (range 0.06-26). Of those that died, 70 per cent were male, 43 per cent were homozygous for C282Y, and 36 per cent were compound heterozygotes. Median

ferritin at diagnosis was 265ug/L (dead) vs 264ug/L (alive).

Median age at diagnosis was significantly higher in those that died, 63.9 years vs 49.1 years for those alive at follow up (p<0.0001).

No significant difference was observed between groups based on gender, HFE genotype, or serum ferritin at diagnosis.

IBS patients do not have increased premature mortality risk

Having irritable bowel syndrome (IBS) does not put one at increased risk of premature mortality, the ISG 2021 Summer Meeting heard.

The last speaker of the day, Dr Kyle Staller, Gastroenterologist/ Neurogastroenterologist Director, Gastrointestinal (GI) Motility Laboratory, Massachusetts General Hospital, Boston, US, gave a tour-de-force update on the latest approaches in IBS.

IBS affects an estimated 10-15 per cent of the population with substantial impacts on quality-of-life and work productivity, and is one of the most common presentations to gastroenterologists, he noted.

Fear about the potential serious nature of bowel symptoms may underlie much of the explanation for seeking care for IBS, and the literature suggests that more than half of IBS patients fear that their illness will shorten their lifespan.

Despite clear diagnostic criteria, such as the Rome IV definition, which Dr Staller feels can be too strict, most clinicians consider IBS a diagnosis of exclusion, and over 50 per cent of patients with IBS will undergo colonoscopy at some point in their diagnostic workup given fears over missing something more serious like cancer.

To address this issue, Dr Staller and colleagues used a nationwide Swedish histopathology register to conduct a matched population-based cohort study to examine the overall risk of death in individuals with IBS (over 45,000 people) undergoing colorectal biopsy compared to matched reference individuals. In a secondary cohort, they examined mortality in IBS patients without biopsy.

After adjustment for confounders, IBS was not linked to mortality (HR=0.96; 95% CI=0.92-1.00). Risk estimates were neutral when IBS patients were compared to their siblings. Underlying

breaking, but what I think it tells us is that we need to spend more time focusing on what is the diagnosis, rather than what is it not, and what treatment options can we offer these long-suffering patients,” Dr Staller commented.

In that regards, the recommended diagnostic approach in IBS should include faecal calprotectin testing in those with diarrhoea symptoms, Coeliac testing, for those due a colonoscopy; random colon biopsies to assess for microscopic colitis, and malabsorption bile acid testing, he said. Small intestinal bacterial overgrowth

mucosal appearance on biopsy had only a marginal impact on mortality, and IBS patients without colorectal biopsy were at no increased risk of death (HR=1.02; 95% CI=0.99-1.06). There was no link to increased cancer-related death either.

“Now this is not scientifically ground-

(SIBO) testing should be retired he said, based on the latest data, while routine colonocopy is unnecessary for those with standard IBS symptoms.

Alarm symptoms for further testing include iron-deficiency anaemia, blood in the stools, older age, unintentional

IBS affects an estimated 10-15 per cent of the population with substantial impacts on quality-of-life and work productivity, and is one of the most common presentations to gastroenterologists

weight loss, palpable abdominal mass, and family history of organic GI disease.

Dr Staller shared interesting data showing the association between psychological conditions and symptoms (anxiety, early life trauma, etc), and the development of IBS and disease severity; and he reminded delegates of the biopsychosocial model (and brain/gut axis) of GI disease.

Regarding treatment, beyond motility agents, he cited data for gluten-free and FODMAP diets, which showed that FODMAP diets show good results in addressing symptoms, while probiotics are likely to provide some benefit with, on the whole, products containing Bifidobacterium (either alone or in a combination) showing good efficacy. Though he noted that the quality of data

on probiotics remains inadequate and contradictory.

While there is a lot of interest in faecal microbiota transplantation (FMT), it has shown mixed results to date “and it is not necessarily benign either”, so the jury is still out, Dr Staller reported, adding that there is a lot more to learn about the role of the microbiome in relation to IBS.

Neuromodulators (“so off-label use of antidepressants like SSRIs”) can have a role in some patients, he said.

Looking at non-pharmacological approaches for the treatment of IBS symptoms, Dr Staller said that cognitive behavioural therapy (CBT) and hypnotherapy have been shown to be effective in studies. “Of course, the problem in Ireland and the US is a lack

of available therapists who are skilled in managing IBS.” That said, he noted that there are new apps that provide CBT support for IBS symptoms with more in development.

For those with severe IBS symptoms, Dr Staller said “a multidisciplinary approach really targeting the brain/gut axis” is necessary, and commented that he is seeing a lot of younger females recently with significant symptoms and disability.

“Probably the best thing we can do for our patients is invest time upfront, and explain what’s going on, what IBS is, with this visceral hypersensitivity, and allow them to understand about the abnormal brain signals in the brain/gut axis so they can start to believe in some of the treatments that may be most beneficial for them,” he concluded.

Optimising management of post-operative Crohn’s disease

Speaking about preventing recurrence of post-operative Crohn’s disease (CD), Dr David Kevans, Consultant Gastroenterologist, St James’s Hospital, Dublin, said a carefully managed approach, including regular disease monitoring and medical therapies for higher-risk patients, can be effective in reducing the risk of further surgery.

He noted that the cumulative risk of surgery in CD is 33 per cent at five years and 47 per cent at 10 years, with disease recurrence being common. “Postoperative CD requiring another intestinal resection occurs in approximately 25 per cent of patients at five years. Therefore strategies to reduce post-operative occurrence are a high priority.”

Challenges include that post-operative CD patients often experience a more severe

course and have a history of failure of multiple therapies, and that the efficacy of CD therapies in these patients is understudied, Dr Kevans told the meeting. Furthermore, in these patients there is a discrepancy between clinical symptoms and endoscopic inflammation.

Looking at the data on a variety of therapies for post-operative CD recurrence, he said there is good evidence for nitroimidazole, 5-aminosalicylates, thiopurines, and anti-TNFs, but not for budesonide and probiotics, while the jury is still out on vedolizumab/ustekinumab.

“It is also important to remember non-inflammatory mechanisms of GI symptoms like fat malabsorption, bilesalt mediated diarrhoea, IBS, vitamin deficiencies (b12), and small bowel bacterial overgrowth.”

There are two key treatment strategies for these patients – early post-operative medical therapies based on clinical risk factors, and endoscopy guided postoperative therapies.

Studies have shown that smoking is a high risk factor, so smoking cessation advice is key, Dr Kevans noted.

Summarising his own approach for high-risk post-operative CD patients, he prescribes thiopurine or biologic therapy; nothing for low-risk patients, conducts an ileocolonoscopy at sixto-12 months in both low- and highrisk patients, taking a decision on introducing or stepping up therapy at that stage depending on results; and also performs faecal calprotectin testing six-monthly and repeat ileocolonoscopy at 24-months.

Management of pelvic radiation disease

Pelvic radiation can cause significant gastrointestinal (GI) morbidity in patients who have recovered from gynaecological/ urological/colorectal cancers, which can be poorly recognised and treated, but much can be done to help these patients, the ISG 2021 Summer Meeting heard.

Prof Jervoise Andreyev, Consultant Gastroenterologist in Pelvic Radiation Disease at the Royal Marsden, UK, said that up to 30 serious GI symptoms, such as incontinence; diarrhoea; abdominal pain; fatigue; flatulence; rectal bleeding; sexual dysfunction; and other IBStype symptoms can develop in the months after pelvic radiotherapy. These symptoms develop because radiation can induce changes in one or more specific physiological functions in widely separated parts of the GI tract that lie in the path of the radiotherapy beam. Furthermore, pre-existing subclinical disease might be destabilised because of minor GI changes induced by radiotherapy, while new diseases might manifest after radiotherapy and be confused with symptoms induced by radiotherapy. “Any insult can cause pathological changes… and pelvic radiation can cause progressive ischaemia, which leads to fibrosis.”

These issues are substantially more common than generally recognised and are frequently poorly managed, Prof Andreyev commented. Despite the huge impact on quality-of-life, there are virtually no studies on what can be done for these patients.

They are often “fobbed off and told they are lucky to be alive and to stop complaining”.

However, much can be done, he maintained, with a step-by-step approach. This includes a wide range of appropriate standard tests to assess each individual symptom and the impact of diet, vitamin

deficiencies, stress, etc, so that obvious treatment options emerge.

“Once you grasp that symptoms are due to ‘physiological upset’ then the management of complex symptoms becomes relatively straightforward.”

Sometimes simple diet changes can make a big impact: “Studies show that people are less able to tolerate fibre after pelvic radiotherapy, but they are not told this and believe that more fibre is good for them, for example… while people can have developed lactose intolerance or bileacid malabsorption.”v

Following a checklist and algorithm for assessing and treating these patients is not complex, he explained. It can be done using a multidisciplinary approach in conjunction with specialist nurses, dietitians, and urology, etc. This is costeffective and can significantly improve the underlying issues, Prof Andreyev said, citing supporting data.

“So, actually, if you follow a checklist and algorithm, if you’re very systematic with this group, you can make them better, whereas if you take a punt and guess you usually get it wrong.”

Looking at the latest approaches to try to pro-actively address these issues, he said there seems to be some promise in hyperbaric oxygen therapy.

However, more data is needed, while there are a number of drugs that could be useful if tested. “Because this is such a large problem for so many patients it is really important that these studies happen.”

In conclusion, Prof Andreyev said that as well as using the aforementioned checklists and algorithms and rolling out referral pathways, new preventative strategies, biomarkers of normal tissue toxicity, and better disease-modifying

therapies are also needed to optimise care for post-pelvic radiation patients.

Meanwhile, other speakers at the meeting included Mr Paul Carroll, Oesophagogastric and General Surgeon, Galway University Hospital, who spoke about ‘Gastric Surgery – The future’. He showcased the latest developments in minimally invasive surgical techniques with robotic surgery representing the next big step forward.

Prof Mario Dinis-Ribeiro, Consultant

Gastroenterologist, Head of Gastroenterology Department, Portuguese Oncology, Institute of Porto, discussed early gastric cancers and pre-cancer detection and management. He noted that there is an increase in these cancers, with a growing ageing population, “and if we don’t change what we do, the cases will continue to be diagnosed at a late state and the deaths will rise”. He said better stratifying and surveillance of high-risk patients, including assessing H.pylori status, is key in this regard.

Dr Eamonn Quigley, Past President of the World Gastroenterology Organisation and Chief of Gastroenterology and Hepatology at Houston Methodist Hospital, Texas, US, gave a practical update on managing oesophageal dysmotility, including the increasingly useful role of highresolution manometry in diagnosis; while Prof Ramesh Arasaradnam, Consultant Gastroenterologist, University of Warwick, UK, discussed using faecal immunochemical testing (FIT) in symptomatic disease.

“FIT clearly has a role; we just need to decide in what setting and what is the optimal cut-off. Because without doubt if FIT is used wisely it can release a lot of colonoscopy capacity which can be better directed to support bowel cancer screening, which is where we aim for early detection, and so improve five- and 10-year colon cancer survival.”

doctor CPD.ie

TRUE/FALSE QUESTIONS

Q1 Ulcerative colitis can affect anywhere in the gastrointestinal tract

True or false?

Q2 5-aminosalicylate therapy is an effective treatment for Crohn’s disease

True or false?

Q3 Cortiment is an approved treatment for an acute flare of ulcerative colitis

True or false?

Q4 5-aminosalicylate suppositories are an effective therapy for patients with UC proctitis

True or false?

Q5 Anti-TNF therapy is not indicated for treatment of moderate to severe ulcerative colitis or Crohn’s disease

True or false?

Q6 A pre-biologic screen for opportunistic

infections is required before commencing patients on biologic therapy

True or false?

Q7 Leukopaenia and hepatotoxicity are possible side-effects of treatment with azathioprine or 6-mercaptopurine

True or false?

Q8 Ustekinumab and vedolizumab are approved for the treatment of Crohn’s disease

True or false?

Q9 A patient with a perianal abscess should be kept on immunosuppressive therapy until the abscess is drained

True or false?

Q10 Yearly routine endoscopy is advised for all patients with IBD to assess for polyps or dysplastic lesions

True or false?

To complete this module and earn free CPD points, go to www.doctorCPD.ie and answer the 10 true or false questions and complete the five MCQs based on this case study.

The spectrum of treatment for inflammatory bowel disease

The term inflammatory bowel disease (IBD) refers to two main subtypes of disease, Crohn’s disease (CD) and ulcerative colitis (UC), which are immune mediated diseases characterised by chronic inflammation of the gastrointestinal tract.

In this review we will give a brief summary of the pathology, epidemiology and diagnosis of IBD and discuss in more detail current treatment and management of IBD.

Pathology and epidemiology

The pathogenesis of both CD and UC is complex and is felt to be secondary to an interplay between genetic susceptibility, environmental factors and an altered gut microbiota.

CD can affect almost any part of the digestive tract whereas UC only affects the large intestine primarily involving the rectum and can extend in a continuous fashion to involve other parts, or all parts of the colon. CD exhibits histologically a thickened submucosa, transmural inflammation, fissuring ulceration, and granulomas, whereas the inflammation in UC is limited to the mucosa and submucosa with cryptitis and crypt abscess formation.

IBD is considered one of the most prevalent gastrointestinal diseases with accelerating incidence in newlyindustrialised countries. The highest prevalence of IBD is reported in Europe and North America. The incidence of CD in Ireland is approximately 5.9 per 100,000 population, while the incidence

of UC is approximately 14.9 per 100,000 population. The peak of IBD's occurrence usually happens in the second to fourth decade of life with a second, smaller peak during the fifth to seventh decades.

often a continuum of disease progression. Perianal disease can occur in a subset of patients with CD with fistula and abscess formation developing in 21-to-54 per cent of CD patients.

If patients have a convincing history, screening tests for IBD including serology and non-invasive stool tests including a faecal calprotectin (FCP) level are performed.

The diagnosis of IBD is based on a combination of a detailed clinical history and examination along with biochemical, endoscopic and histological findings. European Crohn's and Colitis Organisation (ECCO) guidelines advise an ileocolonoscopy for all patients with suspected IBD except in the case of ASUC in which sigmoidoscopy is sufficient.

Treatment

Symptoms and diagnosis

The symptoms of IBD vary depending on which part of the intestine is affected and severity of the disease.

The predominant symptom of UC is diarrhoea which is frequently bloody. Over the course of their lifetime 15 per cent of patients with UC develop acute severe ulcerative colitis (ASUC), which presents with severe diarrhoea and associated systemic dysfunction, such as fevers or tachycardia requiring hospitalisation.

Active CD can cause diffuse abdominal pain, anorexia, diarrhoea, and weight loss. CD can be sub-classified into inflammatory, stenotic or fistulating disease and these different forms are

Once a diagnosis of IBD is established treatment is focused around a combination of medication, sometimes surgery and nutritional optimisation. The overall goal of therapy is to induce remission in the short term and maintain remission in the long term. In addition to improving symptoms, mucosal healing is another goal of therapy for all patients with IBD. Mucosal healing is associated with fewer hospitalisations, reduced need for surgery, and lower rates of disease complications.

Medications used for the treatment of UC and CD differ somewhat depending on disease location and severity of disease. Along with medication and/or surgical treatments all patients with IBD should be

CD can affect almost any part of the digestive tract whereas UC only affects the large intestine primarily involving the rectum and can extend in a continuous fashion to involve other parts, or all parts of the colon

encouraged to stop smoking, nutritional deficiencies should be corrected and appropriate surveillance for vaccinations, osteoporosis, and sun protection should be implemented as per the ECCO guidelines.

Management of UC Steroids

Steroids are used for induction of remission in patients with UC. For patients with UC with mild/moderate symptoms a locally acting steroid, such as Cortiment can be used. Cortiment contains budesonide as an active ingredient along with multimatrix (MMX) that releases the drug in a controlled manner along the colon and not in the small bowel therefore Cortiment is used to treat mainly UC or colonic CD.

If a patient develops a severe flare of colitis a course of prednisolone is the best treatment option and in certain cases patients require hospitalisations for intravenous steroids especially patients with ASUC.

Steroids only induce remission and patients normally need a maintenance therapy to keep their disease in remission and prevent further flares.

Mild-to-moderate UC

Patients with UC with mild to moderate disease may achieve disease remission with 5-aminosalicylate (5-ASA) therapy.

5-ASA therapy can be given as an oral medication or in topical forms, such as enemas or suppositories for more distal disease. For patients with proctitis treatment with topical 5ASA suppositories is often sufficient to keep a patient’s disease in remission. 5-ASA suppositories taken once daily is the preferred initial treatment for mild or moderately active proctitis. If patients have mild to moderate left sided colitis or extensive colitis, treatment with a 5-ASA enema combined with oral mesalamine is more effective than oral or topical 5-ASA alone.

Moderate-to-severe UC

Patients who experience frequent disease relapse or are resistant to or dependent on steroids may require treatment escalation with immunomodulators or biologic therapy or a combination of both.

Immunomodulators include purine antimetabolites, such as azathioprine (AZA) or its metabolite 6-mercaptopurine (6-MP). Immunomodulators tend to be used in UC for patients with mild/ moderate disease activity who have experienced early or frequent relapses while taking 5-ASAs at optimal doses or who are intolerant of 5-ASAs. Patients with low thiopurine S-methyltransferase (TPMP) levels are at increased risk of leukopaenia from immunomodulators

vaccination or could be re-activated once therapy is commenced. The screen includes testing for HIV, hepatitis B&C, EBV/CMV serology, VZV titres as well as a QuantiFERON test and chest x-ray to assess for latent TB.

Infliximab was the first biologic therapy approved for the treatment of IBD. Infliximab is an anti-TNF agent, which is given intravenously. It is recommended for the treatment of moderate to severe UC and is often used as a rescue therapy for patients admitted with ASUC to help prevent the need for colectomy. There are two other anti-TNF agents approved for the treatment of UC: adalimumab and golimumab, which are both given subcutaneously. Infliximab in combination with a thiopurine is recommended for patients with moderateto-severe UC, however, combination therapy with a thiopurine is not recommended for patients treated with adalimumab starting on therapy.

and 0.3 per cent of Europeans are TPMT deficient. TPMT levels can be checked prior to commencing immunomodulators, however even patients with normal levels can develop leukopaenia or hepatotoxicity therefore weekly bloods for eight weeks (FBC and liver profile) after commencing thiopurines is required to screen for these side-effects. Methotrexate or tacrolimus can be used if a patient is intolerant to AZA/6-MP. Patients with moderate colitis refractory to thiopurines should be treated with an anti-TNF therapy.

Biologic therapies have revolutionised the management of IBD over the past two decades. Before commencing biologic therapy, all patients need a full prebiologic screen to screen for opportunistic infections which can be prevented by

Other biologic agents used for the treatment of UC include vedolizumab, an anti-integrin inhibitor licensed for moderate to severe UC. Vedolizumab blocks trafficking of neutrophils and lymphocytes to sites of inflammation. As vedolizumab is a gut specific anti-integrin it is associated with less systemic sideeffects compared to anti-TNF agents.

Unfortunately, over time patients treated with biologic therapies can lose response to treatment with up to 50 per cent of patients developing loss of response to anti-TNF therapy in one study. Loss of response to therapy can often be secondary to the development of antibodies to the drug and serum trough drug levels and specific drug antibodies levels can be tested, called therapeutic drug monitoring (TDM). TDM is recommended for symptomatic patients treated with anti-TNF therapy. Proactive drug monitoring in asymptomatic patients is not recommended to date. If patients have low levels of a drug and are symptomatic, options include

As seen with UC, patients with CD who are having a severe flare of colitis often require a course of prednisolone

reducing the interval of the biologic medication, or if a patient has developed high antibodies with low drug levels an immunomodulator can be introduced to help reduce and overcome these antibodies, thereby increasing available drug levels. Sometimes, despite the above changes, patients do not regain response and often require a switch to an alternative biologic. In cases of treatment failure in UC, a different anti-TNF agent or vedolizumab should be considered.

Most recently new targets including Janus kinase (JAK) inhibitors have been approved for medically-refractory UC. Tofacitinib is an oral, non-selective JAK inhibitor that is effective and safe for patients with moderately to severely active UC and is approved by the European Medicines Agency (EMA) for management of moderate to severe UC refractory to other medical therapies.

If patients with UC fail multiple medical therapies, develop ASUC unresponsive to medical therapy, or develop a malignancy or dysplasia in the colon, subtotal colectomy is often necessary with an end ileostomy. The European Collaborative Study Group on Inflammatory Bowel Disease reported a cumulative 10-year colectomy rate of 8.7 per cent for patients with UC. Most patients post-surgery for medically refractory UC have an end ileostomy. If patients are content with an end ileostomy and do not want their stoma reversed, a completion proctectomy is advised as there is still a risk of developing malignancy in the remnant rectum. If patients wish to have their ileostomy reversed, they can subsequently have an Ileal pouch-anal anastomosis (IPAA). Occasionally some of these patients develop pouchitis (inflammation of the reconstituted ileal reservoir (pouch)), which responds well to courses of antibiotics or anti-TNF therapy.

Management of Crohn’s disease Steroids

For CD patients, steroids are often prescribed for induction of remission and

for those with an acute disease flare. For patients with CD affecting the ileum and/ or ascending colon locally active steroids such as oral Entocort or Budenofalk are advised for patients with mild/moderate symptoms. Budesonide is the active ingredient in Entocort and Budenofalk. Neither Entocort nor Budenofalk contain MMX and therefore target the small bowel and right colon.

As seen with UC, patients with CD who are having a severe flare of colitis often require a course of prednisolone. Steroids are only a short-term treatment and maintenance treatment is often needed to treat active disease and prevent progression of disease. Steroids should be avoided in patients with CD if there are concerns regarding abscess formation.

be of some benefit to patients with CD isolated to the colon.

Moderate-severe CD

The use of thiopurines as monotherapy for the induction of remission of moderate-to-severe luminal CD is contraindicated. Biologic therapies are the most commonly used medication for moderate to severe CD to treat the inflammatory burden and prevent stricture formation.

Anti-TNF therapies used for the treatment of CD are similar to those used in UC. Infliximab and adalimumab are recommended for induction and maintenance of remission in patients with moderate-to-severe CD who do not respond to conventional therapy.

Mild CD

Management of mild CD can often be difficult especially if disease is isolated to a very short segment in the small bowel. Decision to start treatment often depends on the severity of disease and if patients are symptomatic. For patients with persistent or recurrent symptoms treatment options include an immunomodulator such as azathioprine or 6-mercaptopurine. As mentioned above, screening for leukopaenia and liver toxicity is essential once thiopurines are commenced.

If patients have very mild disease and are asymptomatic no treatment is sometimes an option and patients are monitored closely in outpatient clinics. If their disease flares again then escalation of therapy can be considered. Aminosalicylates are no longer recommended in CD, however, they may

Ustekinumab, an interleukin inhibitor (IL12/IL23) that blocks the inflammatory response is currently licensed for moderate to severe CD. Guidelines advise either the use of vedolizumab or ustekinumab for the treatment of moderate-to-severe active luminal CD in patients who have previously failed anti-TNF therapy.

For patients with severe CD with a high inflammatory burden, a combination of infliximab and an immunomodulator can be used to help obtain disease remission and mucosal healing, however, combination therapy is not recommended with adalimumab. Loss of response to biologic therapy is frequently seen in CD also and monitoring drug levels for symptomatic patients can help improve response by alterations in medication prescribing as described above.

While gastroenterologists and patients often strive to manage disease medically and avoid intestinal resection, surgery is crucial in certain clinical settings in achieving disease control

While gastroenterologists and patients often strive to manage disease medically and avoid intestinal resection, surgery is crucial in certain clinical settings in achieving disease control. Surgery is more common in patients with CD than UC. One systematic review found that while rates of surgery have decreased since the introduction of biologic therapies, the risk of surgery five years after diagnosis of CD was 33 per cent, and 47 per cent at 10 years after diagnosis. Early treatment with thiopurines and antiTNF therapy is associated with reduced risk of surgery. Current smoking, penetrating and stricturing disease behaviour, early steroid use, ileal disease, jejunal disease, and young age at diagnosis are risk factors for surgery in CD.

Indications for surgery in CD tend to be secondary to stricture formation resulting in recurrent episodes of bowel obstruction or development of fistulas. Surgery is the preferred option in patients with localised ileo-caecal CD with obstructive symptoms, but no significant evidence of active inflammation. Other indications include failure to respond to medical treatment, or development of dysplastic or malignant changes. The range of surgeries performed for CD is varied and depends on disease location and disease behaviour. These include colectomy, small bowel resection with or without ileostomy, ileocaecectomy, and fistulotomy.

Management of fistulating perianal disease in CD can be complex requiring a combination of medical therapies and surgery. Perianal disease can be managed with anti-TNF therapy including infliximab or adalimumab. Monotherapy with thiopurines is not advised for fistulae closure in patients with perianal CD. The aim of medical therapy is to reduce the inflammatory burden in the perianal area allowing the fistula to heal and close up over time. If there are concerns that a patient has developed a perianal abscess, which presents with symptoms including perianal pain, fever or chills then patients need their immunosuppressive agents held and review by a surgical colleague to examine

for an abscess. If patients develop an abscess this requires incision and drainage prior to re-commencing immunosuppression. For patients with severe fistulating perianal disease, setons can be inserted by colorectal surgeons to assist healing of fistula tracts. If perianal disease can’t be managed by the above treatments it can ultimately require surgery, which might be a proctectomy and permanent ileostomy to alleviate symptoms.

to infliximab in certain indications, these data are supportive of the framework and scientific principles applied by the EMA in biosimilar development to ensure no significant difference between reference medicines and their biosimilars.

As per the HSE’s Guidance for Biological Medicines in Acute Hospitals, for a biological medicine with a biosimilar available for the same licensed indication,

Biosimilars

Biosimilars are biologic products that are highly similar to previously approved reference biologic drugs in terms of safety, purity, and efficacy and certain biosimilars are approved for the treatment of IBD. Biosimilars for infliximab and for adalimumab are licensed by the EMA. Biological medicines consistently feature in the ‘top 10’ of drug expenditure reports in secondary care in Ireland. Given this cost, the Acute Hospital Drug Management Programme set a target rate of 50 per cent for biosimilar uptake in February 2018 for biological medicines with a biosimilar available. The uptake rates and use of biosimilars vary widely both nationally and within hospital groups ranging from 0 to 100 per cent for different hospitals.

There is a vast amount of evidence to support switching of reference medicines to biosimilars. The NOR-SWITCH study is one of the largest randomised switch trials to date. NOR-SWITCH results showed that a single switch from reference infliximab (Remicade) to the biosimilar infliximab (Inflectra, Remsima) in inflammatory arthropathies, IBD, and psoriasis was non-inferior in terms of safety, efficacy and immunogenicity. Although specific

the best value biological medicine should be prescribed (provided that this is the most clinically appropriate biological medicine for the patient). It is recommended all treatment-naïve patients should be initiated on the best value biological medicine (whether biosimilar or reference medicine). All non-naïve patients currently on treatment with the reference medicine should be considered for a switch to a biosimilar if the biosimilar is the best value biological medicine.

Before switching a patient’s therapy it is essential to discuss this with your patient in clinic and explain the reasoning behind this decision. It is important patients are informed that based on evidence from controlled trials and real-world experience in IBD, data supports the use of biosimilars for both treatment initiation and switching as safe, effective, and potentially cheaper alternatives to the originator biologic.

Clinical nutrition in IBD

Dietary management in IBD focuses on maximising nutritional status, maintaining adequate intake, and avoiding foods that can exacerbate symptoms. Malnutrition can occur in UC and CD, but is a considerably greater problem in CD given its capacity to affect any part of the GI tract.

In both UC and CD malnutrition may be the result of reduced oral intake, increased nutrient requirements and increased gastrointestinal losses of nutrients

In both UC and CD malnutrition may be the result of reduced oral intake, increased nutrient requirements and increased gastrointestinal losses of nutrients. The severity of malnutrition in IBD is influenced by the activity, duration and extent of the disease, and particularly by the magnitude of the inflammatory response. Patients with CD remain at risk even when their disease appears quiescent, whereas patients with UC generally develop problems only when the disease is active. There is no IBD diet that can be generally recommended to promote remission in IBD patients with active disease. However, adequate calorie and protein intake and monitoring for malnutrition are recommended. The energy requirements of patients with IBD are similar to those of the healthy population, however, protein requirements are increased in active IBD, and intake should be increased during a flare. Iron supplementation is recommended in all IBD patients with iron deficiency anaemia. Oral iron should be considered as first-line treatment in patients with mild anaemia and those whose disease is clinically inactive. In IBD patients with active disease and those who are steroidtreated, serum calcium and 25 (OH) vitamin D should be monitored and supplemented if required to help prevent low bone mineral density. IBD patients with severe diarrhoea or a high output jejunostomy or ileostomy should have fluid output and urine sodium monitored, and fluid input adapted accordingly.

In CD patients with intestinal strictures or stenosis in combination with obstructive symptoms, a diet with adapted texture including a low-fibre diet can be considered.

Oral nutrition supplements are the first step when artificial nutrition is indicated in IBD, but generally are a minor supportive therapy used in addition to normal food.

If oral feeding is not sufficient then tube feeding should be considered as supportive therapy. Parenteral nutrition is indicated

in IBD only when oral or tube feeding is not sufficiently possible, (eg, when the GI tract is dysfunctional or in CD patients with short bowel syndrome), when there is an obstructed bowel where there is no possibility of placement of a feeding tube beyond the obstruction or when other complications occur, such as an anastomotic leak or a high output intestinal fistula.

Novel therapies

Although significant progress has been made in the treatment of IBD, current options achieve remission in only a portion of patients affected. Research continues to unveil novel mechanisms of action and new approaches using approved therapies such as leucocyte adhesion inhibitors, JAK inhibitors and other novel therapies. Other treatments currently being looked at for treatment of IBD include faecal microbiota transplants (FMT) with promising results in numerous trials. Novel therapies in development offer alternatives to existing therapies for IBD with the hope that in the near future more patients can attain disease remission.

Assessment and monitoring

Any patient with IBD needs to be followed up regularly by a gastroenterologist for monitoring for disease progression and surveillance for colorectal cancer. In many hospitals in Ireland specialised IBD clinics have been established with multidisciplinary teams including gastroenterologists, specialist IBD nurses, colorectal surgeons, dietitians, and psychologists in certain centres.

In patients with UC who clinically respond to medical therapy, mucosal healing should be assessed endoscopically or by FCP three to six months after treatment initiation. Clinical and biochemical response to treatment of CD should be determined within 12 weeks following initiation of therapy. Endoscopic or transmural response to therapy should be evaluated within six months following initiation of therapy. For patients with IBD on a combination of both a biologic agent and immunomodulator, withdrawal of the immunomodulator can

be considered after 18-to-24 months once a patient is in disease remission confirmed by a normal FCP or normal endoscopy.

For patients in remission, routine endoscopy to monitor disease activity is not required. Serum markers of inflammation including CRP, FBC and albumin are monitored biannually. If a patient has symptoms of a disease flare, non-invasive surrogate markers of intestinal inflammation in the form of FCP are increasingly used to assess disease activity without the need for endoscopy.

Surveillance colonoscopy is recommended after eight-to-10 years to assess disease activity, extent, and to screen for early dysplastic changes and then surveillance is required thereafter every one-to-five years depending on disease-related factors.

Patients treated with aminosalicylates should have their renal function checked every three months. Patients treated with immunosuppressive agents should have routine bloods including FBC, renal/liver/ bone profile and CRP every three months. Any patient treated with steroids should have vitamin D levels checked and treated with calcium supplements. All patients diagnosed with IBD should be referred to the IBD clinical nurse specialist for education and be provided with written material regarding their diagnosis.

Conclusion

The aim of treatment in IBD should be to alleviate patients’ symptoms and enable them to achieve a good quality of life. Patients should be actively involved in their management plan. Treatment modalities over the past two decades for the management of IBD have become more complex and overall in this era patients require a multidisciplinary approach to treating and managing their IBD from gastroenterologists, IBD nurse specialists, colorectal surgeons, dietitians, psychologists and pathologists. ■

References on request

*Go to www.doctorcpd.ie to earn free CPD points for completing an assessment on this module

AND even more convenient

Unique amongst 5-ASAs, only PENTASA's wide range of formulations have ethyl cellulose coated microgranules.1–10 These release mesalazine throughout the entire colon, independent of pH.1–5 Adding to its uniqueness, PENTASA once-daily (OD) sachets can now be added to yoghurt; providing your mild to moderate UC patients with a simple dosing regimen that can fit easily into their daily routine. 1–3

Are associated with significantly improved adherence vs. twice daily (BD) dosing11

Are significantly faster at achieving remission and more effective at maintaining remission than BD PENTASA dosing

Improve the rate of mucosal healing vs. BD PENTASA dosing

*Included OD PENTASA rectal suspension for the first four weeks.12,13

PENTASA ABBREVIATED PRESCRIBING INFORMATION

Please consult the Summary of Product Characteristics (SmPC) for full details before prescribing

Name of product(s): Pentasa Sachet prolonged release granules 1g, 2g and 4g; Pentasa prolonged release Tablets 500mg and 1g; Pentasa Rectal Suspension 10mg/ml; Pentasa Suppository 1g. Indication: Sachets:The treatment of mild to moderate exacerbations of ulcerative colitis and for the maintenance of remission of ulcerative colitis. Tablets:The treatment of mild to moderate ulcerative colitis.

RectalSuspension: Management of active ulcerative colitis. Suppository:

Treatment of ulcerative proctitis. Dosage and administration: Sachets:Active Disease (Adults): up to 4g once daily or in 2–4 divided doses. Maintenance Treatment

(Adults): 2g once daily. SachetsandTablets:Active Disease (Paediatric; 6 years≥): Determine individually, start with 30-50mg/kg/day in divided doses. Maximum dose: 75mg/kg/day in divided doses. Total dose should not exceed 4g/day. Maintenance treatment (Paediatric; 6 years≥): Determine individually, start with 15-30mg/kg/day in divided doses. Total dose should not exceed 2g/day. Tablets:Active Disease (Adults): up to 4g once daily or in 2–3 divided doses. Maintenance Treatment (Adults) 2g once daily. RectalSuspension : (Adults) 1g/100ml rectal suspension at bedtime. Suppository:Active Disease (Adults): 1g twice daily for 2-4 weeks. Maintenance

Treatment (Adults) : 1-2g daily. The granules must not be chewed. The contents of the sachet should be emptied onto the tongue and washed down with some water or orange juice. Alternatively, the entire content of the sachet can be taken with yogurt and consumed immediately. Contraindications: Hypersensitivity to mesalazine, any of the excipients, or salicylates. Severe liver and/or renal impairment.

Warnings and Precautions: Caution is recommended when treating patients

allergic to sulphasalazine (risk of allergy to salicylates). In case of acute symptoms of intolerance e.g. abdominal cramps, abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately. Caution is recommended in patients with impaired liver function. Liver function parameters like ALT or AST should be assessed prior to and during treatment, at the discretion of the treating physician. The drug is not recommended for use in patients with impaired renal function and in patients with haemorrhagic diathesis. The renal function should be regularly monitored (e.g. serum creatinine), especially during the initial phase of treatment. Mesalazine induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. The concurrent use of other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions. Caution is recommended in patients with active peptic ulcer. Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment; please refer to section 4.8. Mesalazine-induced cardiac hypersensitivity reactions (myo-and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely with mesalazine (see section 4.5). Blood tests for differential blood counts is recommended prior to and during treatment, at the discretion of the treating physician. Treatment should be discontinued on suspicion or evidence of these adverse reactions. Cases of nephrolithiasis have been reported with the use of mesalazine including stones with a 100% mesalazine content. It is recommended to ensure adequate fluid intake during treatment. As a guideline, follow-up tests are recommended 14 days after commencement of treatment, then a further two to three tests at intervals of four weeks. If the findings are normal, follow-up tests should be carried out every three months. If additional symptoms occur, these tests should be performed immediately. Severe

cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Pentasa should be discontinued at the first appearance of signs and symptoms of severe skin reactions. Interactions: No interaction studies have been performed. Combination therapy with Pentasa and azathioprine or 6-mercaptopurine or thioguanine have shown a higher frequency of myelosuppressive effects, and an interaction cannot be ruled out, however, the mechanism behind the interaction is not established.

Regular monitoring of white blood cells is recommended and the dosage regimen of thiopurine should be adjusted accordingly. There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin. Driving and using machines: Pentasa has no or negligible influence on the ability to drive or use machines. Adverse reactions: Common side effects (≥ 1/100 to <1/10).

AllFormulations:Headache, diarrhoea, abdominal pain, vomiting, flatulence, nausea and rash (incl. urticaria, erythematous rash). RectalSuspension10mg/mland PentasaSuppository1g:Anal discomfort/irritation at the application site, pruritus (anal), rectal tenesmus. Prescribers should consult the SmPC for further information and for a full list of all side effects. Presentation: Pentasasachet1gis presented in packs of 50 aluminium foil sachets. Pentasasachet2gis presented in packs of 60 aluminium foil sachets. Pentasasachet4gis presented in packs of 30 aluminium foil sachets. PentasaTablet500mgis presented in packs of 100 aluminium foil blisters. PentasaTablet1gis presented in packs of 60 aluminium foil blisters. PentasaRectalSuspension10mg/mlis presented in cartons containing 7x100ml bottles. PentasaSuppository1gis presented in cartons of 28 suppositories. Legal category: Product subject to prescription which may be renewed (B). Marketing Authorisation Number: 1g sachet: PA1009/6/1, 2g sachet: PA1009/6/6, 4g sachet:

Prescribe PENTASA to give your mild to moderate UC patients the freedom to enjoy life.

PA1009/6/8, 500mg Tablet: PA1009/6/5, 1g Tablet: PA1009/6/7, 1g Suppository: PA1009/6/2, 10mg/ml Rectal Suspension: PA1009/6/3. Further information is available from the Marketing Authorisation Holder: Ferring Ireland Ltd., United Drug House, Magna Drive, Magna Business Park, Citywest Road, Dublin 24. Tel: (01) 4637355; Email: enquiries.ireland@ferring.com UK-PA-2000061

Date of preparation: January 2021

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Website: www.hpra.ie.

References:

3. Pentasa Sachet 4 g. SmPC.

Pentasa Slow Release Tablets 500 mg. SmPC.

5. Pentasa Slow Release Tablets 1 g. SmPC. 6. Tillotts Pharma Mesalazine 400 mg Gastro-resistant Tablets. SmPC. 7. Shire Pharmaceuticals Mesalazine 1200 mg, Gastro-resistant, Prolonged Release Tablets. SmPC. 8. Dr Falk Mesalazine 500 mg Gastro-resistant Prolonged Release Granules. SmPC. 9. Pfizer Sulfasalazine En-Tabs. SmPC. 10. Pfizer Sulfasalazine Tablets SmPC.

11. Dignass AU, etal.Clin.GastroenterolHepatol.2009;7(7):762–9.

13. Pentasa Rectal Suspension g. SmPC.

12. Flourie B, etal.AlimentPharmacolTher.2013;37(8):767–75.

PENTASA sachets now indicated for use with yoghurt.1–3

The 5-ASA that stands out from the crowd so your UC patients don’t have to.

Nutritional considerations in IBD

Nutrition is high on the agenda for those with, and those treating, inflammatory bowel disease (IBD). The Irish Society of Colitis and Crohn’s (ISCC) surveyed their members in 2015 and the results showed that 34 per cent were using some form of alternative non-medical treatment. Of this 34 per cent, 71 per cent were using dietary management and 57 per cent felt diet could be a trigger of their symptoms. Furthermore, 61 per cent believed that IBD specialists disregarded the importance of diet, which is a worrying statistic given that many IBD patients still do not have access to a dietitian.

In 2009 the UK IBD standards group stated that “all IBD patients should have access to a dietitian with a specialist interest in IBD”. This had not been met when reviewed in 2013. In 2006 they audited 75 per cent of UK hospitals where the median number of dietitian sessions dedicated to gastroenterology was two per week. Only 52 per cent of patients admitted with Crohn’s disease (CD) were weighed and only 37 per cent were seen by a dietitian. The standards recommend minimum staffing of 0.5WTE dietitian per 250,000 population. This works out at a caseload of 1,000 per 0.5WTE for the 240,000 patients with IBD in the UK which seems grossly inadequate given the aforementioned nutritional consequences of this disease.

At the time of writing there are only three clinical specialist dietitian posts currently dedicated to the roll-out of dietitian-led functional GI disorders (FGIDs) services and a handful of senior dietitians specialised in gastroenterology in Ireland. This staffing is clearly insufficient to deal with the rising incidence of IBD.

Role of diet in IBD

Diet has two major roles in IBD – adjuvant and primary therapy. Basic nutrition support is used as an adjuvant or supportive

therapy to prolong effects of drug therapy and prevent and treat malnutrition in both CD and ulcerative colitis (UC). Both exclusive enteral nutrition (EEN) and partial enteral nutrition (PPN) can be used as primary therapy instead of medication to achieve remission in certain patients with an acute exacerbation of CD. Nutritional intervention is tailored to each individual and depends on disease type, location, phase, surgical history, comorbidities, therapeutic goals, patient preference, and team consensus. There are many variables.

Malnutrition

It is well documented that there is an increased risk of developing malnutrition in IBD. Studies show that up to 85 per cent of hospitalised patients suffer from protein energy malnutrition (PEM). A wide variation in rates of malnutrition is reported in the literature due to differences in assessment criteria, disease type, severity, and phenotype. CD appears to have a greater nutritional insult than UC with higher rates attributed to it when we look at each condition separately – CD 80 per

The limitations of diet should be outlined to patients to address any misconceptions. Diet can contribute to or ease symptoms, but it does not cause a flare. It can induce remission in carefully selected cases, but it must not replace medications if they are prescribed. It cannot cure IBD but there is evidence to show diet may prevent IBD developing in the first instance. A better understanding of the gastrointestinal microbiota may provide some clues between diet and the aetiology of IBD also. Using visual aids of the gastrointestinal tract (GIT) can help patients understand how IBD impacts nutrition and vice versa.

Not all dietary therapies used by patients are evidence-based. Due to gaps in research patients are seeking their own ‘cure’. Interest in diet, such as the specific carbohydrate diet (SCD), gut and psychology syndrome (GAPS), and paleo diet is growing along with glutenfree and low FODMAP.

cent, UC 18-to-62 per cent. Up to 75 per cent of our patients experience weight loss and 50 per cent present in negative nitrogen balance. Healthcare professionals caring for patients with IBD should be aware of these risks and know when to refer their patients to a CORU-registered dietitian.

It is very easy for these patients to slip into a malnourished state. In the active phase, IBD is an anorexigenic disease due to increased proinflammatory cytokines IL-18 and TNF alpha which, along with altered GI hunger hormones GLP and leptin, make it counterintuitive to eat. Food aversions and fear of eating, otherwise known as sitophobia, can occur which is understandable given that diet and the GIT are inextricably linked. Self-imposed dietary restrictions in an effort to control GI symptoms can compound malnutrition further. Fatigue is extreme and extra GI manifestations such as arthritis can hinder food preparation. Odynophagia due to oral

The limitations of diet should be outlined to patients to address any misconceptions. Diet can contribute to or ease symptoms, but it does not cause a flare

aphthous ulcers can also reduce oral intake. It can be helpful to measure and monitor food related quality-of-life (FRQol) at each consultation. Increased nutrient, fluid and electrolyte losses due to malabsorptive symptoms, like diarrhoea, high output stomas or fistulae, lead to wide-ranging deficiencies and deficits.

Osteoporosis

Lean body mass (LBM) and muscle function are significantly reduced in all stages of disease, a known predictor for the development of osteoporosis. Body fat distribution differs too – a depletion of visible fat and increase in intra-abdominal fat over time may play a role in the inflammatory process. Screening tools and BMI do not detect these changes. Useful anthropometric methods include skinfold thickness, mid upper arm circumference (MUAC), dynamometry, and newer generation bioelectrical impedance analysis (BIA) technology. The use of DEXA reports and CT should be explored for this purpose too given that many IBD

patients undergo these investigations routinely. Positive or negative changes in body composition may be due to IBD medications. Steroids increase fat mass, fluid retention, and create a false appetite.

Weight gain

Infliximab (IFX) determines weight gain by achieving remission. It is important that patients receive counselling on these side effects prior to starting, particularly in those who are already overweight or obese and are keen to reduce or maintain weight.

Consequences of undernutrition in IBD

Consequences of undernutrition in IBD are similar to other chronic diseases. Patients should be optimised at all times but particular emphasis should be put on their status pre-surgery to ensure best outcomes. PEM leads to increased septic complications following GI resections, and post-operative anastomotic leakage has been cited in those who lose more than 5kgs weight prior to surgery. So if

malnutrition is identified at pre-surgical assessment, the dietitian must recommend that surgery is delayed for seven-to-14 days for intensive nutrition support to prevent such consequences. If, however, surgery cannot be delayed, as is the reality for cases of toxic megacolon, total obstruction, ischaemia, or other such emergency indications, nutrition support should be given immediately post-op.

Malnutrition occurs in quiescent disease or remission too with approximately 40 per cent of patients overweight. This trend is a concern and patients should no longer be encouraged to have a buffer of excess weight between flares. Studies show those with high BMIs are more prone to developing active CD and requiring surgery sooner than those in the ideal range. It is important to recommend healthy eating for weight management and be explicit when prescribing exercise. A twice-weekly programme of resistance training is required to correct changes in body composition. IBD patients require

ongoing and regular monitoring of their nutritional status after they are discharged from hospital. This currently takes place in specialist hospital outpatient clinics if a dietitian service exists. Alternative models of care in primary care should be explored.

Micronutrients

Assessment of micronutrients should be carried out routinely due to the impact deficiencies can have on outcomes. Supplementation is required due to some drug-food interactions such as sulfasalazine. Low vitamin D is associated with increased risk of surgery and hospitalisation in IBD. The literature also mentions that deficiency alters efficacy of medication. Vitamin D was the most common micronutrient deficiency noted in an Irish cohort followed closely by haematinics such as iron, folate and B12. Optimising zinc levels may improve gut integrity in CD. One caveat in the interpretation of micronutrients is the degree of inflammation at time of sampling, so not only should a clinician check if inflammatory markers such as CRP are raised, but note how much they are raised. An accurate Vitamin D level, for example, may not be attained until CRP is less than 10, which for many with acute IBD will not be during an inpatient stay. Similar CRP thresholds are suggested for other micronutrients. Seek and treat all deficiencies using local guidelines. Calcium should also be supplemented if intake is low. Beware of the possibility of transient lactose intolerance in those with small bowel CD and recommend dairy alternatives to meet calcium needs until resolved.

Iron deficiency

Iron deficiency anaemia (IDA) increases morbidity and mortality but treating it improves quality-of-life independent of disease activity. The anaemia seen in IBD patients is usually a combination of IDA and anaemia of chronic disease (ACD). ACD is caused by blood loss, disease severity or phenotype and focus should be on resolving the underlying cause such as giving RCC or treating the disease, not giving iron. Iron supplementation should be given in cases of IDA alone – no evidence in IBD (but

extrapolated from management of IDA in other conditions like heart failure). Excess iron is not absorbed in inflammatory states. CRP is a surrogate marker for hepcidin – a peptide that regulates iron absorption. If high, give IV as enteral absorption is blocked, hence difficulties tolerating oral iron. IDA recurs quickly following IV replacement so restart when ferritin <100 or HB <12. Check levels three-monthly in active disease. There is a useful reference table for iron requirements based on weight and haemoglobin level cited in ESPEN guidelines 2017.

follow healthy eating and lifestyle advice to maintain nutritional status between flares. If nutrition is chosen as the primary treatment for CD, EEN in the form of a polymeric formula is administered orally or via nasogastric tube for a minimum of 10 days for a duration of four-to-six weeks with close dietetic supervision. EEN can be used as a bridging treatment until a medication takes effect or during medication-free periods pre and perioperatively. Parenteral nutrition (PN) should not be used as primary treatment of inflammatory luminal CD. Bowel rest has not been proven to be more efficacious than nutrition per se. The most common indication is the presence of short bowel syndrome. PN is indicated for those who are malnourished, have inadequate or unsafe oral intake, or a non-functioning, inaccessible or perforated gut. Specific indications include obstruction, high intestinal or fistulae output.

In summary

Levels of albumin are important to assess response to medical treatment and the inflammatory process rather than nutritional status. It is unknown if patients lose response to biologics due to reduced nutritional status or vice versa, but we know that biologics are carried on albumin. For example, enteral nutrition providing more than 600kcals of nutritional requirements daily leads to a sustained response to IFX.

Nutrition approaches

In the acute phase and if malnourished, a high-calorie high-protein diet is recommended for most with careful consideration of hydration and micronutrients. Fibre may be restricted temporarily or long term in the case of stricturing disease. In remission and in well-nourished states there are no blanket restrictions and patients are advised to

One size does not fit all and nutritional intervention must be tailored to the individual. Dietary advice depends on type of IBD, phenotype, location, severity, previous surgeries, symptoms, nutritional status, and comorbidities. As in other chronic diseases, obesity is the new face of IBD. We are seeing less of the classic underweight presentations; therefore it is harder to spot malnutrition, but it is there and most certainly worsening the disease course of our patients. Implementing nutrition-focused physical findings as part of NCP will only help to identify patients most in need of our care. Assessment of nutritional status at regular intervals regardless of disease phase or care setting is key to optimising the patient throughout the course of their disease. Emerging research in areas such as fibre, pre and probiotics, curcumin and emulsifiers mean advancements in the nutritional management of IBD are on the horizon. Service infrastructure needs to be improved, however, so that all those with IBD can access a CORUregistered dietitian. ■

References on request

One size does not fit all and nutritional intervention must be tailored to the individual. Dietary advice depends on type of IBD, phenotype, location, severity, previous surgeries, symptoms, nutritional status, and comorbidities

mesalazine suppositorie s

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Advancing BowelScreen

BowelScreen is planning to extend screening to 59-year-olds in 2022, Clinical Director Prof Pádraic MacMathuna has informed Update.

While a welcome development, it falls far short of a recommendation in the National Cancer Strategy 2017-2026, which said the HSE should ensure “appropriate” capacity to expand colorectal cancer screening to “all” 55-to-74-yearolds by the end of 2021.

Launched in October 2012, BowelScreen was established to provide screening initially to all eligible men and women aged 60-to-69 and ultimately to the full 55-to-74 age group. No expansion of screening in the identified age range has been implemented to date.

A home faecal immunochemical test (FIT) kit is sent by post every two years to the eligible population who consent to participate and the vast majority receive a negative result. Those who receive a positive FIT result are referred for screening colonoscopy.

Currently, 14 endoscopy units are participating in BowelScreen with University Hospital Waterford the most recent addition in late 2020. A further three units are set to join BowelScreen in the coming months.

Prof MacMathuna, a Consultant

Gastroenterologist at the Mater Misericordiae Hospital, Dublin, said that “there is an enthusiasm in several units to come on board”. The units’ infrastructure – principally the colonoscopy capacity – is the key consideration. BowelScreen can provide support for equipment and manpower in these units.

Initially, the screening programme plans to extend age eligibility downwards, which will be implemented gradually. Given the parallel demand for urgent and routine colonoscopies in the symptomatic service, screening expansion is a delicate act. “We’d like to do it right down to 55 [sooner], but the colonoscopy capacity is the core issue,” said Prof MacMathuna.

The national capacity for endoscopy needs to be increased to meet the requirements of both symptomatic and screened populations, he stated.

The programme decided to first expand age eligibility downwards, because colon polyp formation generally begins in the 50s. Furthermore, many individuals reaching 70-plus will already have been invited to participate (and a proportion have participated) in BowelScreen.

Participation

Colorectal cancer is one of the most common cancers diagnosed in Ireland and the second most common cause of cancer death overall (third most common in females). Annually, an average of 1,633 men and 1,186 women are diagnosed with colorectal cancer, according to National Cancer Registry Ireland (NCRI) figures. In Ireland it is often detected at an advanced stage.

A Lancet Oncology study published in 2019 found that, of seven high-income countries, survival figures for Irish patients were second lowest for colon and rectal cancer, although survival rates were improving (five-year survival for colon cancer diagnosed from 2010-2014 was 61.8 per cent; and 62.4 per cent for rectal cancer).

BowelScreen aims to detect colorectal cancer as early as possible and identify and remove polyps in the colon before they may develop into cancers. In the programme’s second screening round from 2016 to 2017, it invited 546,767 eligible people, screened 226,374 clients, performed 6,523 colonoscopies and detected 410 cancers.

This represented a screening uptake rate of 41.4 per cent and a cancer detection rate of 1.81 per 1,000 people screened. Some 12,367 adenomas or polyps were removed and these individuals are offered further surveillance colonoscopies to detect and treat any adenoma recurrence at a later date

(over 1,700 surveillance colonoscopies were performed in round two).

In addition, 879 sessile serrated lesions (SSLs) were detected. SSLs are flat, pre-cancerous polyps that can develop into bowel cancer and may be difficult to visualise at colonoscopy. BowelScreen is one of the first international bowel screening services to report on these lesions, according to the programme’s report on the second screening round.

Population-based bowel cancer screening aims to reduce deaths from colorectal cancer by 36 per cent after 10 years of offering FIT screening to people aged 55-to-74.

In order to make a significant indent on mortality at population level, the extension of age eligibility and higher participation levels are required. “If you send 100 FIT tests, to make the maximum impact on mortality you should have really a 65-70 per cent uptake,” outlined Prof MacMathuna. “Our uptake is just under 45 per cent, which is not too bad. It started at 38-to-39 [per cent]; it is going in the right direction. This is common in all European experiences where it takes a while to make an impact and get a profile.”

The communications unit at the HSE National Screening Service has sought to raise public awareness, including during bowel cancer awareness month (April).

The messaging has emphasised that colorectal cancer is an ‘equal opportunity cancer’, affecting both men and women. BowelScreen is the first cancer prevention screening programme involving men, while women are generally more familiar with cancer screening through BreastCheck and CervicalCheck.

“The participation of men is increasing and there are broader cultural issues about men, particularly middle-aged men, going to their doctors and that is a generic challenge in the healthcare system. But we are trying to

emphasise more and more that this is a cancer that affects men and women pretty equally and that men need to be more aware of it,” stated Prof MacMathuna.

BowelScreen has engaged with GP and pharmacist organisations as part of heightening the profile of bowel cancer and the screening initiative.

Pandemic

The pandemic and cyber-attack on the HSE have significantly impacted the programme and work is ongoing to restore activity levels.

In this regard, Prof MacMathuna paid tribute to BowelScreen Programme Manager Ms Hilary Coffey Farrell; Deputy Programme Manager Ms Mary Sheedy, and all the programme team, as well as endoscopy staff, for their enormous efforts.

The challenge presented by the pandemic “remains significant” and BowelScreen has adjusted the FIT invitations to accommodate reduced capacity. “We anticipate that the BowelScreen programme will gradually regain lost ground by late 2021 into early 2022.”

Documents obtained by the Medical Independent under Freedom of Information law show BowelScreen has been highly constrained in its ability to deliver colonoscopies during 2020 and early 2021. The pandemic led to a pause in screening invitation activity from March to August 2020.

“One of the major problems that the pandemic had, in terms of colonoscopy and GI [gastrointestinal] services, was that the nursing personnel were transferred into high intensity Covid wards,” commented Prof MacMathuna, adding that physical distancing and extra infection control requirements affected patient throughput.

By late 2020, colonoscopy capacity was operating at 40-to-70 per cent in BowelScreen units. In early 2021, the programme was impacted by the ‘third wave’ of Covid-19 cases.

As of early March 2021, five units were operating at reduced capacity; six units advised that they

continued doing BowelScreen cases at reduced capacity, but would give clinical prioritisation to index clients; and three units were not doing BowelScreen colonoscopies. Last year 132,597 screening invitations were issued, representing just 46 per cent of total invitations in 2019.

Asked about the issue of delayed diagnoses of colorectal cancer due to the pandemic, Prof MacMathuna said the main concern related to people with symptoms.

“The major impact I think would be in symptomatic patients – in other words, the patients who are going to their doctor with symptoms and that is for all cancers and all diseases, where we are seeing patients presenting later.”

The IMO recently highlighted to the Oireachtas Health Committee that in the first quarter of 2021, some 450 people per month were not seen within the recommended four weeks for an urgent colonoscopy (in the symptomatic service) compared to 15 per month pre-Covid. In September 2020, 36.2 per cent of people were waiting less than 13 weeks for routine colonoscopy, against a target 65 per cent, states HSE performance data.

In the screening cohort, some international data has indicated that a six-month delay in accessing a colonoscopy after a positive FIT test does not affect outcomes – a matter noted at a meeting of BowelScreen’s colorectal clinical advisory group (CAG) in January.

A study in the journal Endoscopy in 2020 (Zorzi et al), involving an Italian regional screening programme using biennial FIT, found that an increased colorectal cancer prevalence at colonoscopy was observed for a time to colonoscopy of ≥ 270 days (approximately nine months), whereas it was stable for waiting times of < 180 days (approximately six months). The colorectal cancer stage was stable in relation to a waiting time of < 270 days.

Potential changes

BowelScreen is continuing with the current two-yearly FIT invite cycle, but this will be monitored and potentially extended pending the international experience.

According to Prof MacMathuna, international experience has documented that a repeat colonoscopy prompted by a repeat FIT-positive test, two years after normal index colonoscopy, is associated with “minimal polyp detection and hence cancer prevention potential”.

Additionally, an increase in the time interval for surveillance colonoscopy following polypectomy is being considered, such that it would align with international guidelines for the symptomatic cohort. In turn, this would release some colonoscopy capacity.

All aspects of BowelScreen are monitored and quality assured in line with the programme’s Guidelines for Quality Assurance in Colorectal Screening.

Performance data on endoscopy services is also collected by the HSE/RCPI/RCSI National GI Endoscopy Quality Improvement Programme through the national quality assurance and improvement system (NQAIS) for endoscopy.

Under BowelScreen’s key performance indicators (KPIs), at least 90 per cent of clients should be offered a colonoscopy appointment date that occurs within 20 working days from being deemed clinically suitable following pre-assessment.

As reported by the Medical Independent in 2019, this KPI has come under strong scrutiny at the programme’s CAG. In April of that year, the CAG noted that this standard was set when BowelScreen was established.

“However, setting this standard for screening clients at the level [of] urgent symptomatic cases is likely [to be] inappropriate and may be putting unwarranted pressure on screening unit resources without any significant clinical gain,” outlined minutes of the CAG meeting in April 2019. The minutes further noted Prof MacMathuna as confirming there were “no international standards requiring a screening client to have a colonoscopy within 20 days”. The CAG agreed to propose that this KPI be changed to 30 working days.

Prof MacMathuna told Update such a change has not yet been finalised. He said there was no

The first 1 litre PEG bowel preparation1-3

Improve the efficacy cut the volume vs MOVIPREP®1

PLENVU® PM/AM dosing was superior to MOVIPREP® in the per protocol population (successful overall cleansing 97.3% vs 92.2%, p=0.014)

Safety profile comparable to MOVIPREP® 1,4-6

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IE PRESCRIBING INFORMATION: Plenvu powder for oral solution (Macrogol 3350 + Sodium ascorbate + Ascorbic acid + Sodium sulfate anhydrous + Potassium chloride + Sodium chloride) Please refer to the full Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Plenvu powder for oral solution is administered in two doses. Dose one is made up of 1 sachet containing: macrogol 3350 100g, sodium sulfate anhydrous 9g, sodium chloride 2g, potassium chloride 1g. Dose 2 is made up of 2 sachets (A and B). Sachet A contains: macrogol 3350 40g, sodium chloride 3.2g, potassium chloride 1.2g. Sachet B contains: sodium ascorbate 48.11g, ascorbic acid 7.54g. Indication: For bowel cleansing in adults, prior to any procedure requiring a clean bowel.

Dosage and administration: For oral use. Adults and elderly: A course of treatment consists of two separate non-identical 500ml doses of Plenvu. At least 500ml of additional clear fluid must be taken with each dose. Treatment can be taken according to a two-day or one-day dosing schedule. Two-day dosing schedule: First dose taken the evening before the procedure. Second dose in the early morning of the day of the procedure. Morning only dosing schedule: Both doses taken the morning of the procedure. The two doses should be separated by a minimum of 1 hour. Day before dosing schedule: Both doses taken the evening before the procedure. The two doses should be separated by a minimum of 1 hour. No solid food should be taken from the start of the course of treatment until after the clinical procedure. Consumption of all fluids should be stopped at least 2 hours prior to a procedure under general anaesthesia or 1 hour prior to a procedure without general anaesthesia.

Children: Not recommended for use in children below 18 years of age. Patients with renal or hepatic impairment: No special dosage adjustment is deemed necessary in patients with mild to moderate renal or hepatic impairment.

Patients should be advised to allow adequate time after bowel movements have subsided to travel to the clinical unit.

Contraindications: Hypersensitivity to the active substances or to any of the excipients, gastrointestinal obstruction or perforation, ileus, disorders of gastric emptying (gastroparesis, gastric retention), phenylketonuria, glucose-6-phosphate dehydrogenase deficiency, toxic megacolon.

Warnings and precautions: The fluid content of reconstituted Plenvu does not replace regular fluid intake. Adequate fluid intake must be maintained. As with other macrogol containing products, allergic reactions including rash, urticaria, pruritus, angioedema and anaphylaxis

www.medicines.ie.

Powder for Oral Solution

PEG 3350, Sodium Ascorbate, Sodium Sulfate, Ascorbic Acid, Sodium Chloride, and Potassium Chloride

are a possibility. Caution should be used with administration to frail or debilitated patients, in patients with impaired gag reflex, with the possibility of regurgitation or aspiration, or with diminished levels of consciousness, severe renal impairment, cardiac failure (grade III or IV of NYHA), those at risk of arrhythmia, dehydration or severe acute inflammatory bowel disease.

In debilitated fragile patients, patients with poor health, those with clinically significant renal impairment, arrhythmia and those at risk of electrolyte imbalance, the physician should consider performing a baseline and post-treatment electrolyte, renal function test and ECG as appropriate. Any suspected dehydration should be corrected for before use of Plenvu. There have been rare reports of serious arrhythmias including atrial fibrillation associated with the use of ionic osmotic laxatives for bowel preparation, predominantly in patients with underlying cardiac risk factors and electrolyte disturbance.

If patients develop any symptoms indicating arrhythmia or shifts of fluid/ electrolytes during or after treatment, plasma electrolytes should be measured, ECG monitored and any abnormality treated appropriately. If patients experience severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until the symptoms subside.

Post-marketing cases of ischaemic colitis, including serious, have been reported in patients treated with macrogol for bowel preparation. Macrogol should be used with caution in patients with known risk factors for ischaemic colitis or in case of concomitant use of stimulant laxatives (such as bisacodyl or sodium picosulfate). Patients presenting with sudden abdominal pain, rectal bleeding or other symptoms of ischaemic colitis should be evaluated promptly.

The sodium content, 458.5mmol (10.5g), should be taken into consideration for patients on a controlled sodium diet. The potassium content, 29.4mmol (1.1g), should be taken into consideration by patients with reduced kidney function or those on a controlled potassium diet. Interactions: Medicinal products taken orally within one hour of starting colonic lavage with Plenvu may be flushed from the gastrointestinal tract unabsorbed. The therapeutic effect of drugs with a narrow therapeutic index or short half-life may be particularly affected.

Plenvu may result in a potential interactive effect if used with starchbased food thickeners. Macrogol ingredient counteracts the thickening effect of starch, effectively liquefying preparations that need to remain thick for people with swallowing problems.

Fertility, pregnancy and lactation: There are no data on the effects of Plenvu on fertility in humans. There were no effects on fertility in studies in male and female rats.

It is preferable to avoid the use of Plenvu during pregnancy.

It is unknown whether Plenvu active ingredients/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from Plenvu therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Effects on ability to drive and use machines: Plenvu has no influence on the ability to drive and use machines.

Undesirable effects: Diarrhoea is an expected outcome. Common: vomiting, nausea, dehydration. Uncommon: abdominal distension, anorectal discomfort, abdominal pain, drug hypersensitivity, headache, migraine, somnolence, thirst, fatigue, asthenia, chills, pains, aches, palpitation, sinus tachycardia, transient increase in blood pressure, hot flush, transient increase in liver enzymes, hypernatraemia, hypercalcaemia, hypophosphataemia, hypokalaemia, decreased bicarbonate, anion gap increased/ decreased, hyperosmolar state. Refer to the SmPC for a full list and frequency of adverse events. Legal category: Product subject to medical prescription which may be renewed

MA Number: PA 1336/005/001

MA Holder: Norgine B.V., Antonio Vivaldistraat 150, 1083HP Amsterdam, The Netherlands

Additional information is available on request or in the SmPC. For further information contact: Norgine Pharmaceuticals Limited, Norgine House, Moorhall Road, Harefield, Middlesex, United Kingdom UB9 6NS. Telephone: +44(0)1895 826606. Email: medinfo@norgine.com

Date of preparation: March 2021

Company reference: IE-GE-PLV-2100006

Healthcare professionals are asked to report any suspected adverse reactions via the HPRA Pharmacovigilance Website: www.hpra.ie. Adverse events should also be reported to Norgine Pharmaceuticals Ltd on: Tel: +44 (0)1895 826 606 Email: medinfo@norgine.com

and Moviprep Orange (Macrogol 3350, sodium sulfate anhydrous, ascorbic acid, sodium ascorbate, sodium chloride and potassium chloride) PLEASE

IE PRESCRIBING INFORMATION: Moviprep and Moviprep Orange (Macrogol 3350, sodium sulfate anhydrous, ascorbic acid, sodium ascorbate, sodium chloride and potassium chloride) PLEASE REFER TO THE FULL SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) BEFORE PRESCRIBING. Presentation: Powder for oral solution contained in two separate sachets, A and B. Sachet A contains macrogol 3350 100g; sodium sulfate anhydrous 7.5g; sodium chloride 2.691g and potassium chloride 1.015g. Sachet B contains ascorbic acid 4.7g and sodium ascorbate 5.9g. Uses: Bowel cleansing prior to any clinical procedure requiring a clean bowel. Dosage and administration: For oral use. AdultsandOlderPeople:A course of treatment consists of two litres of Moviprep / Moviprep Orange. A litre consists of one sachet A and one sachet B dissolved together in water to make one litre of solution. The reconstituted solution should be drunk over a period of one to two hours. This process should be repeated with a second litre to complete the course. A further litre of clear fluid is recommended during the course of treatment. This course of treatment can be taken either as divided or as single doses and timing is dependent on whether the clinical procedure is conducted with or without general anaesthesia as specified below: For procedures conducted under general anaesthesia:

CHARACTERISTICS (SmPC) BEFORE PRESCRIBING. Presentation: Powder for oral solution contained in two separate sachets, A and B. Sachet A contains macrogol 3350 100g; sodium sulfate anhydrous 7.5g; sodium chloride 2.691g and potassium chloride 1.015g. Sachet B contains ascorbic acid 4.7g and sodium ascorbate 5.9g. Uses: Bowel cleansing prior to any clinical procedure requiring a clean bowel. Dosage and administration: For oral use. AdultsandOlderPeople:A course of treatment consists of two litres of Moviprep / Moviprep Orange. A litre consists of one sachet A and one sachet B dissolved together in water to make one litre of solution. The reconstituted solution should be drunk over a period of one to two hours. This process should be repeated with a second litre to complete the course. A further litre of clear fluid is recommended during the course of treatment. This course of treatment can be taken either as divided or as single doses and timing is dependent on whether the clinical procedure is conducted with or without general anaesthesia as specified below: For procedures conducted under general anaesthesia: 1. Divided doses: one litre in the evening before and one litre in the early morning of the day of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange as well as any other clear fluids has finished at least two hours before the start of the clinical procedure.

1. Divided doses: one litre in the evening before and one litre in the early morning of the day of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange as well as any other clear fluids has finished at least two hours before the start of the clinical procedure. 2. Single dose: two litres in the evening before the clinical procedure or two litres in the morning of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange as well as any other clear fluids has finished at least two hours before the start of the clinical procedure. For procedures conducted without general anaesthesia: 1. Divided doses: one litre in the evening before and one litre in the early morning of the day of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange as well as any other clear fluids has finished at least one hour before the start of the clinical procedure. 2. Single dose: two litres in the evening before the clinical procedure or two litres in the morning of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange has finished at least two hours before the start of the clinical procedure. Ensure consumption of any clear fluids has finished at least one hour before the clinical procedure. Patients should be advised to allow for appropriate time to travel to the colonoscopy unit. No solid food should be taken from the start of the course of treatment until after the clinical procedure. Children: Not recommended below 18 years of age. Contraindications: Known or suspected hypersensitivity to any of the ingredients, gastrointestinal obstruction or perforation, disorders of gastric emptying, ileus, phenylketonuria, glucose-6-phosphate dehydrogenase deficiency, toxic megacolon which complicates very severe inflammatory conditions of the intestinal tract including Crohn’s disease and ulcerative colitis. Do not use in unconscious patients. Warnings and precautions: Diarrhoea is an expected effect. Administer with caution to fragile patients in poor health or patients with serious clinical impairment such as impaired gag reflex, or with a tendency to aspiration or regurgitation, impaired consciousness, severe renal insufficiency (creatinine clearance <30 mL/min), cardiac impairment (NYHA grade III or IV), those at risk of arrhythmia (e.g. those on treatment for cardiovascular disease or who have thyroid disease), dehydration, severe acute inflammatory bowel disease. Dehydration, if present, should be corrected before using Moviprep / Moviprep Orange. The reconstituted Moviprep / Moviprep Orange does not replace regular fluid intake and adequate fluid intake must be maintained. Semi-conscious patients or patients prone to aspiration or regurgitation should be closely monitored during administration, particularly if this is via a nasogastric route. If symptoms indicating arrhythmia or shifts of fluid or electrolytes occur, plasma electrolytes should be measured, ECG monitored and any abnormality treated appropriately. In debilitated fragile patients, patients with poor health, those with clinically significant renal impairment, arrhythmia and those at risk of electrolyte imbalance, the physician should consider performing a baseline and post-treatment electrolyte, renal function test and ECG as appropriate. The possibility of serious arrhythmias, predominantly in those with underlying cardiac risk factors and electrolyte disturbance cannot be ruled out. If patients experience symptoms which make it difficult to continue the preparation, they may slow down or temporarily stop consuming the solution and should consult their doctor. Moviprep Orange is not recommended for patients with glucose-galactose malabsorption. Post-marketing cases of ischaemic colitis, including serious, have been reported in patients treated with macrogol for bowel preparation. Macrogol should be used with caution in patients with known risk factors for ischaemic colitis or in case of concomitant use of stimulant laxatives (such as bisacodyl or sodium picosulfate).

2. Single dose: two litres in the evening before the clinical procedure or two litres in the morning of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange as well as any other clear fluids has finished at least two hours before the start of the clinical procedure. For procedures conducted without general anaesthesia: 1. Divided doses: one litre in the evening before and one litre in the early morning of the day of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange as well as any other clear fluids has finished at least one hour before the start of the clinical procedure. 2. Single dose: two litres in the evening before the clinical procedure or two litres in the morning of the clinical procedure. Ensure consumption of Moviprep / Moviprep Orange has finished at least two hours before the start of the clinical procedure. Ensure consumption of any clear fluids has finished at least one hour before the clinical procedure. Patients should be advised to allow for appropriate time to travel to the colonoscopy unit. No solid food should be taken from the start of the course of treatment until after the clinical procedure. Children: Not recommended below 18 years of age.

Contraindications: Known or suspected hypersensitivity to any of the ingredients, gastrointestinal obstruction or perforation, disorders of gastric emptying, ileus, phenylketonuria, glucose-6-phosphate dehydrogenase deficiency, toxic megacolon which complicates very severe inflammatory conditions of the intestinal tract including Crohn’s disease and ulcerative colitis. Do not use in unconscious patients. Warnings and precautions: Diarrhoea is an expected effect. Administer with caution to fragile patients in poor health or patients with serious clinical impairment such as impaired gag reflex, or with a tendency to aspiration or regurgitation, impaired consciousness, severe renal insufficiency (creatinine clearance <30 mL/min), cardiac impairment (NYHA grade III or IV), those at risk of arrhythmia (e.g. those on treatment for cardiovascular disease or who have thyroid disease), dehydration, severe acute inflammatory bowel disease. Dehydration, if present, should be corrected before using Moviprep / Moviprep Orange. The reconstituted Moviprep / Moviprep Orange does not replace regular fluid intake and adequate fluid intake must be maintained. Semi-conscious patients or patients prone to aspiration or regurgitation should be closely monitored during administration, particularly if this is via a nasogastric route. If symptoms indicating arrhythmia or shifts of fluid or electrolytes occur, plasma electrolytes should be measured, ECG monitored and any abnormality treated appropriately. In debilitated fragile patients, patients with poor health, those with clinically significant renal impairment, arrhythmia and those at risk of electrolyte imbalance, the physician should consider performing a baseline and post-treatment electrolyte, renal function test and ECG as appropriate. The possibility of serious arrhythmias, predominantly in those with underlying cardiac risk factors and electrolyte disturbance cannot be ruled out. If patients experience symptoms which make it difficult to continue the preparation, they may slow down or temporarily stop consuming the solution and should consult their doctor. Moviprep Orange is not recommended for patients with glucose-galactose malabsorption. Post-marketing cases of ischaemic colitis, including serious, have been reported in patients treated with macrogol for bowel preparation. Macrogol should be used with caution in patients with known risk factors for ischaemic colitis or in case of concomitant use of stimulant laxatives (such as bisacodyl or sodium picosulfate).

Patients presenting with sudden abdominal pain, rectal bleeding or other symptoms of ischaemic colitis should be evaluated promptly. Moviprep/Moviprep Orange contains 363.2 mmol (8.4g) of sodium per course of treatment (two litres) equivalent to 420% of the WHO recommended maximum daily intake of 2g of sodium for an adult. To be taken into consideration by patients on a controlled sodium diet. Only a proportion (up to 112.4 mmol (2.6g) per course of treatment) of sodium is absorbed. It also contains 28.4 mmol (1.1g) of potassium per two litres. To be taken into consideration in patients with reduced kidney function or patients on a controlled potassium diet. Interactions: Oral medication should not be taken within one hour of administration as it may be flushed from the GI tract and not absorbed. Moviprep / Moviprep Orange may result in a potential interactive effect if used with starch-based food thickeners. Macrogol ingredient counteracts the thickening effect of starch, effectively liquefying preparations that need to remain thick for people with swallowing problems. Fertility, pregnancy and lactation: There are no data on the effects on fertility. There are no data on the use in pregnancy or lactation so it should only be used if judged essential by the physician. Effects on ability to drive and use machines: No influence on the ability to drive and use machines Side Effects: Very common: abdominal pain, nausea, abdominal distension, anal discomfort, malaise and pyrexia. Common: sleep disorder, dizziness, headache, vomiting, dyspepsia, rigors, thirst and hunger. Uncommon: dysphagia, abnormal liver function tests and discomfort. Not known: allergic reaction including anaphylactic reaction, dyspnoea and allergic skin reactions including angioedema, urticaria, pruritus, rash, erythema; electrolyte disturbances including blood bicarbonate decreased, hyper and hypocalcaemia, hypophosphataemia, hypokalaemia and hyponatremia and changes in the blood chloride levels; dehydration; convulsions associated with severe hyponatraemia; transient increase in blood pressure; arrhythmia, palpitations; flatulence and retching. Refer to the SmPC for a full list and frequency of adverse events. IRELAND Pack sizes: Lemon- or orange-flavoured powder in sachets, 1 treatment pack (2 x sachet A + 2 x sachet B). Legal category: Product subject to medical prescription which may be renewed. MA Number: PA 1336/001/001 (Moviprep); PA 1336/001/002 (Moviprep Orange). MA Holder: Norgine BV, Antonio Vivaldistraat 150, 1083 HP Amsterdam, The Netherlands. Additional information is available on request or in the SmPC. For further information contact: Norgine Pharmaceuticals Limited, Norgine House, Moorhall Road, Harefield, Middlesex, UB9 6NS, UK. Tel: +44(0)1895 826606. Email: medinfo@norgine.com Date of preparation: April 2021 Company reference: IE-GE-MPR-2100001

Patients presenting with sudden abdominal pain, rectal bleeding or other symptoms of ischaemic colitis should be evaluated promptly. Moviprep/Moviprep Orange contains 363.2 mmol (8.4g) of sodium per course of treatment (two litres) equivalent to 420% of the WHO recommended maximum daily intake of 2g of sodium for an adult. To be taken into consideration by patients on a controlled sodium diet. Only a proportion (up to 112.4 mmol (2.6g) per course of treatment) of sodium is absorbed. It also contains 28.4 mmol (1.1g) of potassium per two litres. To be taken into consideration in patients with reduced kidney function or patients on a controlled potassium diet. Interactions:

Oral medication should not be taken within one hour of administration as it may be flushed from the GI tract and not absorbed. Moviprep / Moviprep Orange may result in a potential interactive effect if used with starch-based food thickeners. Macrogol ingredient counteracts the thickening effect of starch, effectively liquefying preparations that need to remain thick for people with swallowing problems. Fertility, pregnancy and lactation: There are no data on the effects on fertility. There are no data on the use in pregnancy or lactation so it should only be used if judged essential by the physician. Effects on ability to drive and use machines: No influence on the ability to drive and use machines Side Effects: Very common: abdominal pain, nausea, abdominal distension, anal discomfort, malaise and pyrexia. Common: sleep disorder, dizziness, headache, vomiting, dyspepsia, rigors, thirst and hunger. Uncommon: dysphagia, abnormal liver function tests and discomfort. Not known: allergic reaction including anaphylactic reaction, dyspnoea and allergic skin reactions including angioedema, urticaria, pruritus, rash, erythema; electrolyte disturbances including blood bicarbonate decreased, hyper and hypocalcaemia, hypophosphataemia, hypokalaemia and hyponatremia and changes in the blood chloride levels; dehydration; convulsions associated with severe hyponatraemia; transient increase in blood pressure; arrhythmia, palpitations; flatulence and retching. Refer to the SmPC for a full list and frequency of adverse events. IRELAND Pack sizes: Lemon- or orange-flavoured powder in sachets, 1 treatment pack (2 x sachet A + 2 x sachet B). Legal category: Product subject to medical prescription which may be renewed. MA Number: PA 1336/001/001 (Moviprep); PA 1336/001/002 (Moviprep Orange). MA Holder: Norgine BV, Antonio Vivaldistraat 150, 1083 HP Amsterdam, The Netherlands. Additional information is available on request or in the SmPC. For further information contact: Norgine Pharmaceuticals Limited, Norgine House, Moorhall Road, Harefield, Middlesex, UB9 6NS, UK.

clinical significance in moving the period by 10 working days, and as previously indicated, international data suggests that a screening colonoscopy could be offered at a longer interval, without adverse patient impact.

Critical metric

A critical metric in the quality assurance system is the adenoma detection rate (ADR). This is measured in terms of both the individual colonoscopist and screening unit. The minimum ADR standard is 45 per cent of colonoscopies and the achievable standard is greater than or equal to 50 per cent.

The majority of units and colonoscopists are meeting the minimum target and many have more than 50 per cent yields, stated Prof MacMathuna. An overall ADR of 56.7 per cent was recorded in BowelScreen data for the second screening round.

Does the programme often identify outliers from the ADR standard? “Not often, but we do,” answered Prof MacMathuna.

“If there is an outlier, we assess the performance of the individual… we look at the total numbers, the clinical lead looks at the total numbers of that individual and their past record. So it is noted centrally and it is the clinical lead’s responsibility to highlight that with the individual.

“We are kept informed of KPIs of all the clinicians, and this includes the surgeons who operate on the patients found to have cancer, the radiologists who examine the CT colons for us and the pathologists likewise….”

On occasions where a private company has been used by some BowelScreen units, Prof MacMathuna maintained that “we have visibility and confirmation of their KPIs in terms of caecal intubation, ADRs, etc”.

At present, BowelScreen has no plans to request publication of quality assurance screening data per identifiable unit.

Hospital identifiable data has now been included in the national data reports of the National GI Endoscopy Quality Improvement Programme.

Future screening practice

Like most areas of medical practice, the delivery of bowel screening is likely to evolve over the coming years in line with evidence.

Within a decade, it is possible the FIT test may be replaced by a blood test that would more accurately select people requiring colonoscopy.

“The ‘holy grail’ of a screening programme ideally would be a blood test that would identify an individual who has polyps and then we would only target the individuals with a positive blood test for colonoscopy and it would significantly reduce the need for doing a large number of colonoscopies in individuals who turn out don’t need it,” commented Prof MacMathuna.

“There is a lot of work going on and we are potentially getting involved in a large study with collaborators in the States and Europe about this type of study, which I think, hopefully, in five-to-10 years, would replace the FIT test and be much more selective and accurate.”

For now, the FIT test remains an important primary screening tool for colorectal cancer. Indeed, it could be increasingly used for some symptomatic patients (who are not describing blood among their symptoms) to help identify those likely to benefit from colonoscopy. Some centres in Ireland and other countries are investigating use of the FIT and the calprotectin stool test in certain (lower risk) symptomatic cohorts to select for colonoscopy.

Tel: +44(0)1895 826606. Email: medinfo@norgine.com

Date of preparation: April 2021 Company reference: IE-GE-MPR-2100001

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Adverse events should also be reported to Norgine Pharmaceuticals Ltd on: Tel: +44 (0)1895 826 606. Email: medinfo@norgine.com

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Adverse events should also be reported to Norgine Pharmaceuticals Ltd on: Tel: +44 (0)1895 826 606. Email: medinfo@norgine.com

PLENVU, MOVIPREP, NORGINE and the sail logo are registered trademarks of the Norgine group of companies.

“There haven’t been any quality issues of concern. We are keeping an open mind about using any of that type of outsourcing in future. We are trying to increase the capacity by bringing more units on board and perhaps doing some weekend work in different units.”

The idea would be to prioritise for colonoscopy those individuals likely to have polyps, cancer, or inflammatory bowel disease.

PRESCRIBING INFORMATION: Moviprep

FIT testing in symptomatic patients is being coordinated through the hospitals rather than primary care. “But I think there will be more and more discussion of non-invasive tests in the community, both within the bowel screen programme as it stands and in the symptomatic clinical load.”

Internationally, research is also examining use of artificial intelligence (AI) as a means of enhancing detection of adenomas during colonoscopy. Prof MacMathuna noted that the need for enhanced detection is particularly relevant in regard to flat lesions on the right side of the colon.

These flat lesions can be subtle and missed “even by the most experienced colonoscopists”.

“There have been some other techniques where you put in a dye in the colon as you are coming back from the caecum. And that shows changes that you would have missed by ordinary white light,” he explained. =“The idea behind AI is to be able to pick these things up and flag it for you at the time. Because you want a system whereby you can detect something that was otherwise undetectable and take it out, as opposed to do a study and have to put the patient through another colonoscopy.”

AI is controversial as it can lead to picking up “incidental tiny hyperplastic polyps that have no consequence” resulting in over-treatment.

Prof MacMathuna added that Dr Conor Lahiff, Consultant Gastroenterologist at the Mater Misericordiae University Hospital in Dublin, is doing a study using dye-based colonoscopy with BowelScreen support.

It is important to find ways to enhance detection of flat lesions as they are shown to have cancer potential and may develop more rapidly than other precancerous growths –potentially developing into cancer within five years, whereas bowel cancer generally develops over a period of 10 years. These lesions could account for a significant proportion of postcolonoscopy interval cancers (ie, diagnosed within three years of normal colonoscopy), which are described as uncommon in the screening programme.

Post-CervicalCheck crisis

On foot of the Scally report into CervicalCheck, the HSE commissioned expert reviews of all interval cancer management processes for the three national cancer screening programmes.

The report on BowelScreen noted that, in keeping with most international screening programmes, it had not considered interval cancers as unintended or unanticipated incidents as they were “an accepted, unavoidable occurrence in population screening programmes”.

As such, a universal disclosure policy had not been implemented for interval cancers by BowelScreen except where harm had been attributed to programme failings.

“This was most notable following a patient safety incident in one of the programme’s endoscopy units in 2014. The management of that incident and the quality assurance measures in place within the BowelScreen programme were reviewed by an external expert following the incident. The BowelScreen programme was found to have implemented open disclosure in an appropriate manner…,” stated the report.

The expert report, published in October 2020, made a number of recommendations for BowelScreen including strengthening informational materials on the benefits and limitations of screening and including explicit information on the occurrence of interval cancers and on the opportunity to discuss their case should a patient develop a post-colonoscopy colorectal cancer (PCCRC). It also recommended improving communications with the NCRI to enable timelier validation of interval cancers and the calculation of the interval cancers rate in the BowelScreen programme.

In accordance with the BowelScreen memorandum of understanding with local screening units, the unit “will continue to openly discuss the diagnosis, treatment plan and review of the screening colonoscopy with the patient following diagnosis of a PCCRC”, advised the report.

Anyone diagnosed with bowel cancer can request a review of their screening history and BowelScreen is putting in place a new review process currently.

Prof MacMathuna said the programme has been working with the NCRI to develop an IT link to enhance BowelScreen’s capture of information on all interval cancers.

In due course, “it will give us a much more accurate reflection of our postcolonoscopy cancer rate, which is the international benchmark”.

No legal cases have been issued against BowelScreen in regard to interval cancers.

“BowelScreen to date hasn’t gotten into that space. The presumption with my colleagues, however, is that it is only a matter of time.” By its nature, the material available for review in bowel screening differs from that in breast and cervical screening programmes.

“The colonoscopy situation is that the colonoscopy report is a narrative in writing, with specific photographs of areas of the caecum and rectum and whatever lesions are detected. There is never a cancer that you are seeing on a photograph that the colonoscopist somehow says wasn’t there, it doesn’t work like that.”

Medico-legal concerns have not yet been a deterrent to recruitment. “Most of the units are happy to engage with BowelScreen as they see it as a positive initiative in terms of their specialty. As well, there is a financial incentive because they get additional nursing expertise, they get help towards equipment and resources and some places will get additional medical staff. So it is positive.”

But if the situation becomes “more medicolegally contentious”, as with BreastCheck and CervicalCheck, GI doctors may decide to stick to the symptomatic clinical service. “It will compromise, if not discontinue, the screening programmes if the medico-legal situation remains the same unfortunately.…”

“Hopefully it won’t come to that.” ■

Irritable bowel syndrome in focus

Irritable bowel syndrome (IBS) is a common, chronic gastrointestinal (GI) disorder characterised by symptoms of abdominal pain and disturbances in bowel habits in the absence of known organic pathology. The condition affects between 5 and 10 per cent of healthy individuals at any one time and in most people runs a relapsing and remitting course. IBS is recognised as a multifactorial disorder, with GI dysmotility, inflammation, visceral hypersensitivity and altered intestinal microbiota contributing to symptomatology.1

Symptoms of IBS include loose, frequent stools, constipation, bloating, and abdominal pain and cramps. Patients may notice symptoms following the intake of specific foods or that symptoms, such as stool consistency or pain location, change over time. Patients may also present with headache, lethargy, nausea, bladder symptoms or faecal incontinence.1,2,9

The condition typically occurs before the age of 45 years and is more common in people aged 20-to-30 years.5 IBS appears to become less common with age and does not affect life expectancy or lead to other serious diseases. IBS affects both men and women, but the condition occurs more frequently in women. Women tend to have more frequent and severe IBS symptoms during menses and menopausal women have fewer symptoms than women who are still menstruating.10 Women more commonly report symptoms of abdominal pain and constipation, while men more commonly report diarrhoea. Men, however, are much less likely than women to report signs of IBS.2,4

The causes and pathophysiology of IBS are complex and remain poorly understood. Theories include combinations of gut-brain axis problems, gut motility disorders, pain sensitivity, infections including small intestinal bacterial overgrowth, neurotransmitters, genetic factors, and food sensitivity. Onset may be triggered by an intestinal infection or stressful life event. It is thought that a number of factors

may contribute to development of the disorder. Genetic predisposition and environmental interactions, such as familial susceptibility and psychosocial stressors, have been implicated in the multifactorial pathogenesis of IBS.1 Diet and stress have been proposed as contributing factors to this heterogeneous disorder. Because stress has been identified as a mechanism in the development of IBS, the major components of the stress response system, the autonomic nervous system (ANS), and the hypothalamicpituitary-adrenal (HPA) axis have been the subject of numerous investigations of IBS.1

IBS is commonly associated with other functional, somatoform and mental disorders. In over 20 per cent of cases, there is an overlap of IBS with functional GI disorders of the upper GI system, particularly functional dyspepsia and gastro-oesophageal reflux disease (GORD), and of the lower GI system, such as diarrhoea, incontinence, pelvic floor dyssynergia, and constipation. Psychiatric comorbidities are present in approximately 50 per cent of IBS patients and include depressive symptoms, anxiety and eating disorders.10

A strong association between GI infections and the development of IBS has been established. Around one in nine patients exposed to infectious enteritis may develop IBS, at a rate four times higher than non-exposed individuals. The greatest risk is associated with protozoal and bacterial infections, with viral infections having a lower risk of development of IBS. The severity of acute gastroenteritis increases the risk of developing IBS, but symptoms usually decrease over time.10 In IBS, the epithelial barrier, gut microbiota, food antigens, and bile acids give rise to abnormal responses in the main regulators of sensorial and motor functions, such as the hypothalamus-pituitaryadrenal axis, the immune system, the brain-gut axis and the enteric nervous system.10

Classification criteria and diagnosis IBS has been categorised as a functional

bowel disorder, ie, it is not associated with any structural or biochemical abnormalities in the GI tract. No specific laboratory or imaging tests can diagnose IBS. The Rome criteria (See Table 1) are used to diagnose IBS when the presence of organic disease such as inflammatory bowel disease (IBD), colon cancer, and Coeliac disease have been excluded.1,2

The Rome III classification diagnostic criteria served as the symptom-based, diagnostic criteria for IBS since their release in 2006 and subtyped IBS patients based on predominant stool pattern: Constipation (IBS-C), diarrhoea (IBS-D), mixed (IBS-M) or unsubtyped (IBS-U). Rome III classified the disorder by symptom onset greater than six months and recurrence of at least three days per month during the last three months. Diagnostic criteria required abdominal discomfort or pain to be associated with two or more of the following: Improvement with defecation, onset associated with change in the form of stool, or onset associated with a change in the frequency of stool.

In early 2016 the Rome Foundation released Rome IV, an updated classification system for conceptualising and diagnosing functional GI disorders.1 The Rome IV definition of IBS maintains symptom chronicity greater than six months and current activity present within the prior three months, however, symptom frequency has been changed to at least one day per week from at least three days per month. Pain related to bowel movements is required, rather than just improving with bowel movements, because, in some cases, pain can worsen after bowel movements. The ‘onset’ of abdominal pain has been eliminated from the association of pain with changes in stool. Rome IV also updated the subtyping of IBS patients (IBS-C, IBS-D, IBS-M and IBS-U), in that stool type is based on days with abnormal bowel movements, as opposed to bowel movements on all days. The term ‘discomfort’ was eliminated from the criteria because it is non-

specific and has different meanings in different languages. Rome IV retains the Bristol Stool Form Scale as a useful tool to categorise bowel habit.1,10 The Rome IV process also redefined IBS as a disorder of gut-brain interaction, in recognition of the complex interplay of biological, psychological, and social factors underpinning the condition.11

In the absence of any biomarker being available for IBS, the condition is diagnosed using a positive approach, based on the clinical history. To make an accurate diagnosis of IBS, it is generally recommended to incorporate Rome IV criteria along with the patient history including dietary questions, physical examination including abdominal and anorectal examination, laboratory tests such as full blood count, C-reactive protein or erythrocyte sedimentation rate (ESR), possible Coeliac disease serology, and when indicated a colonoscopy and/or upper GI endoscopy and other tests. An abdominal x-ray can be considered to rule out faecal loading

if constipation is the predominant symptom. When Rome IV criteria are present and alarm features are absent, only a limited number of laboratory tests are recommended without the need to perform invasive investigations.10 Patients may have IBS-type symptoms for many years without presenting to medical care, often self-managing their symptoms without medical input, and some may never consult. Nevertheless, lower GI symptoms frequently prompt people to present to primary care, accounting for approximately one-in-12 of all consultations.11 Functional GI disorders, such as IBS, are by far the most common diagnosis, but symptoms can be difficult to assess and the possibility of colorectal cancer or IBD may create diagnostic uncertainty for clinicians, and anxiety for patients.11

GPs are usually the first point of contact and provide the diagnosis and medical care for most people with IBS. Management guidelines encourage GPs to make a positive diagnosis of IBS, based on symptoms, in the absence of

Rome III Rome IV

Diagnostic timeframe Symptom onset greater than six months

Symptom activity during the last six months

Symptom frequency at least three days per month

Symptom onset greater than six months

Symptom activity during the last three months

Symptom frequency at least one day per week

Symptom description Abdominal discomfort or pain Abdominal pain

Symptom association (two or more)

Improvement with defecation

Improvement with defecation in the form of stool

Onset associated with a change in the frequency of stool

Predominant stool pattern of IBS

subtype: IBS-C, IBS-D, IBS-M, IBS-U

Tool to categorise bowel habit

alarm symptoms or signs that warrant referral to exclude colorectal cancer or abnormalities on simple investigations. However, persistent abdominal bloating or distension in female patients should prompt consideration of CA125 and pelvic ultrasound to exclude ovarian cancer.11 It is important to question patients about dietary and medication changes, life stressors and support networks, as part of the diagnostic assessment. Alternative diagnoses that should be considered when patients present with IBS symptomatology include Coeliac disease, microscopic colitis (MC), IBD including Crohn’s disease and ulcerative colitis, bile acid malabsorption, colorectal cancer, and dyssynergic defecation.3

Once a diagnosis of IBS has been made, the GP should endeavour to follow-up with the patient within the next two months to ensure symptoms are not getting progressively worse, which may be indicative of a more sinister underlying disease process.11

BSG guidelines on the management of IBS (July 2021)

Related to defecation

Associated with a change in the form of stool

Associated with a change in the frequency of stool

Stool type based on bowel movements on all days Stool type based on days with abnormal bowel movements

Bristol Stool Form Scale

Bristol Stool Form Scale

The newly published (July, 2021) British Society of Gastroenterology (BSG) guidelines on the management of IBS (available at https://gut. bmj.com/content/70/7/1214) state: “This more restrictive nature of the Rome IV criteria calls into question whether they should be used to diagnose IBS in clinical practice, and a more pragmatic definition of the symptoms that constitute IBS may be preferred. The National Institute for Health and Care Excellence (NICE) guideline for the management of IBS in primary care recommends a broader, more pragmatic, definition of IBS, focusing on abdominal pain or discomfort associated with altered stool frequency or stool form for at least six months, in the absence of alarm symptoms or signs, and acknowledging that coexistent bloating, lethargy, nausea, backache or bladder symptoms are common.”11

Furthermore, the 2021 BSG guidelines with regard to the diagnosis of IBS in primary care state: “The Rome diagnostic criteria are based on specific symptoms of a defined duration and frequency, which have been derived predominantly from secondary care patients and are rarely used in primary care. Their

applicability to clinical practice has been challenged as unnecessarily restrictive and only a minority of people diagnosed with IBS in primary care fullfill them.

“This restrictive diagnostic approach to IBS may be unhelpful and overly complicated in this setting, where fundamentals of clinical management are common across all these functional gastrointestinal disorders. Applying rigid criteria potentially leaves many patients with troublesome impactful symptoms without a clear diagnosis, increasing uncertainty and leading to issues with providing appropriate advice and management options. The NICE guideline definition of IBS is therefore preferable.”11

The new BSG 2021 guidelines also point out: “The fall in prevalence in IBS that results from the changes made in moving from the Rome III to Rome IV criteria is noteworthy, reflecting the more restrictive nature of the latter. This has important clinical implications because, although as intended, the criteria are now more specific for diagnosing IBS, up to 50 per cent of patients who believe they have IBS will no longer meet criteria for the condition. Instead, they will be diagnosed as having another functional bowel disorder, such as functional diarrhoea, functional constipation or functional abdominal bloating or distension.

“Moreover, there may be an impact on treatment trials in IBS, and the interpretation of results, because patient populations recruited using the Rome IV criteria will differ from those recruited using Rome III, and may have more severe symptoms and higher degrees of psychological comorbidity Moving from Rome III to Rome IV IBS may therefore reduce the likelihood of novel pharmacological therapies demonstrating efficacy in future randomised controlled trials (RCTs), due to the spectrum of symptom severity, or may mean that trials need to be considerably larger, and therefore more expensive to conduct, to show a beneficial effect.”

Treatment

There is no known permanent ‘cure’ for IBS. Treatment is focused on symptom control, in order to improve quality-of-life. There is no

definitive treatment for the management of the condition and a combination of lifestyle and dietary advice and use of pharmacological therapies is often required. Pharmacological management, including laxatives, antidiarrhoeals and certain antispasmodics, is centred on treatments that alleviate symptoms of IBS, but which are not specifically authorised for IBS itself. Education and reassurance is an important aspect of patient care and treatment, explaining the natural history of the disease and providing reassurance that it is a benign condition. It is important to build up a good rapport with the patient, including them in the decision-making process and ensuring their voice and concerns are heard as well as validating their symptoms. Management of IBS involves an integrated approach and treatment options include establishment of an effective patient-provider relationship, education,

reassurance, nutritional interventions, and pharmacological and psychological therapy.2,5,9,10 Key skills, in relation to chronic disorders such as IBS in general practice, are for the GP/ clinician to make a positive diagnosis, provide a simple explanation of the pathophysiology underlying the symptoms, clarify the patient’s main concerns and manage current symptoms in the wider context of the patient’s life. The clinician-patient relationship, continuity of care, empathy, including acknowledgement of the impact of symptoms on daily life, a shared understanding of IBS and shared decisionmaking can assist in providing appropriate education, signposting to reputable online information or peer support, reassurance, advice and management options. There should be a realistic discussion concerning the limitations of all available treatments for IBS to manage expectations. It is important

to stress that cure is unlikely, but substantial improvement in symptoms, social functioning and quality-of-life is achievable.11

Pharmacological therapy

The choice of pharmacological therapy depends on the nature and severity of IBS symptoms. Many drug treatment options for IBS are available over-the-counter (OTC). Antispasmodics are among the most frequently used OTC treatments for IBS and can be broadly divided into antimuscarinics and smooth muscle relaxants. Antimuscarinics, including dicycloverine, propantheline, otilonium bromide and hyoscine butylbromide, reduce intestinal motility, whereas alverine and mebeverine are direct-acting intestinal smooth muscle relaxants.11 Butylscopolamine, due to its ability to antagonise the binding of acetylcholine to the muscarinic receptor at the neuromuscular junction, leads to smooth muscle relaxation, however, due to antimuscarinic adverse effects such as constipation, it should not be used in patients with IBS-C.10 Mebeverine, a spasmolytic without atropine-like side-effects, has high efficacy for abdominal pain and reduction in daily defecation frequency, as well as an improvement in well-being, with good tolerability with minor complications. Peppermint oil inhibits smooth muscle contraction through calcium channel blockade and has been proven to reduce IBS symptoms, being a safe and effective treatment. Antispasmodics are thought to improve symptoms of abdominal pain and have been shown to provide short-term relief of symptoms.5,10

Osmotic laxatives such as polyethylene glycol are often recommended to improve constipation for those with IBS-C, however, they have not been shown to improve abdominal pain or bloating. Stimulant laxatives may also be used. Lactulose is not recommended, as it increases gas production, causes bloating and can exacerbate symptoms.2 Patients who have not responded to laxatives from the different classes and who have constipation for at least 12 months can be treated with linaclotide, however, caution must be taken due to its predisposition to fluid and electrolyte imbalance. Linaclotide

is contraindicated in GI obstruction inflammatory disease.5

Loperamide hydrochloride is the first-line choice of anti-motility drug for relief of diarrhoea due to its action on opioid receptors in the GI tract, and because it does not readily cross the blood brain barrier. It inhibits peristalsis, prolongs gut transit and reduces faecal volume. As constipation is an adverse effect, it should be used with caution for patients with IBS-M. Patients with IBS should be advised how to adjust their dose of laxative or anti-motility drug according to stool consistency with the aim of achieving a soft, well-formed stool.2,5

symptoms, but unfortunately these are not always readily accessible.5,11

Diet and lifestyle changes are important for effective self-management of IBS. First-line dietary advice should be offered to all patients with IBS. Patients should be encouraged to increase physical activity, with recommended guidelines of 30 minutes at least five days a week and advised to eat regularly without missing or leaving long gaps between meals. Dietary advice should also include limiting fresh fruit consumption to no more than three portions per day. The fibre intake of patients with IBS should be reviewed. If an increase in dietary fibre is required, soluble fibre, such as ispaghula husk, or foods high in soluble fibre, such as oats, are recommended. Intake of insoluble fibre such as bran and resistant starch should be discouraged as they may exacerbate symptoms. Fluid intake, mainly water, should be increased to at least eight cups per day and the consumption of caffeine, alcohol and carbonated drinks reduced/ avoided. Artificial sweetener sorbitol should be avoided in patients with diarrhoea. Where probiotics are being used, continue for at least four weeks while monitoring the effect.5,9,11

A low-dose tricyclic antidepressant (TCA), such as amitriptyline hydrochloride (unlicensed indication), can be used for abdominal pain or discomfort as a second-line option in patients who have not responded to antispasmodics, anti-motility medications or laxatives. They should be commenced at a low dose, eg, 10mg amitriptyline once a day and titrated slowly to a maximum of 30-50mg once a day.11 An SSRI may be considered in those who do not respond to a tricyclic antidepressant. As with tricyclic antidepressants, they can be initiated in primary or secondary care, but careful explanation as to the rationale for their use is required, and patients should be counselled about their side-effect profile.5,9,11

Non-pharmacological treatment

Psychological interventions can be offered to patients who have no relief of IBS symptoms after 12 months of drug treatments. There is good evidence that psychological treatments directed against IBS symptoms, especially cognitive behavioural therapy (CBT) and hypnotherapy, are helpful for many patients’

A growing focus of clinical research has been to improve IBS symptomatology through dietary modifications.6 Over 80 per cent of individuals with IBS report foodrelated symptoms, especially to fermentable carbohydrates and fats.11 Food ingestion can contribute to the generation of symptoms through stimulation of chemoreceptors, mechanoreceptors, by osmotic actions, altered secretion, activation of motor reflexes, and colonic fermentation. Dietary intolerance in IBS patients has been attributed to gluten, wheat, lactose, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) as well as fructose malabsorption. FODMAPs are short chain carbohydrates found in a variety of fruits, vegetables, dairy products, artificial sweeteners, and wheat that are poorly absorbed in the small intestine and subsequently fermented by bacteria in the distal small and proximal large intestine.11 This is a normal phenomenon, common to everyone. The resultant production of gas potentially results in bloating and flatulence.

IBS has been categorised as a functional bowel disorder, ie, it is not associated with any structural or biochemical abnormalities in the GI tract

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Contains a unique combination of two clinically researched synergetic strains.

Calcium: Contributes to the normal function of digestive enzymes.

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Calcium: Contributes to the normal function of digestive enzymes.

Pantothenic Acid, Vitamin B6: Contribute to the reduction of tiredness and fatigue.

Pantothenic Acid, Vitamin B6: Contribute to the reduction of tiredness and fatigue.

VITAMIN D SUPPLEMENTS INEFFECTIVE TREATMENT FOR PAINFUL IBS SYMPTOMS Priscilla Lynch

Vitamin D supplements are not an effective treatment for easing painful symptoms of IBS, a new study from the University of Sheffield reveals.

Scientists from the University’s Department of Oncology and Metabolism – in conjunction with health supplement company, BetterYou – carried out trials on participants who suffer with the chronic condition to assess whether vitamin D reduced the severity of their symptoms, and whether it could improve their quality-of-life.

Results of the study – published in the European Journal of Nutrition –found that despite an improvement in vitamin D status in the participants in response to a vitamin D3 oral spray supplementation over a 12 week trial, there was no difference to their IBS symptom severity over this period, nor a reported change in the participants’ quality-of-life.

Carried out in collaboration with Sheffield Teaching Hospitals NHS Foundation Trust, the study also identified that although vitamin D supplements do not ease symptoms of IBS, a vitamin D deficiency is widespread amongst the IBS population, potentially leading to an increased risk of suffering from fractures and osteoporosis in the long-term.

Co-author of the study Dr Liz Williams, a Senior Lecturer in Human Nutrition at the University of Sheffield,

Although FODMAPs can produce certain digestive discomfort in some people, they do not cause intestinal inflammation and can also help avoid it, because they produce beneficial alterations in the intestinal flora that contribute to maintaining the good

said: “There has been interest from researchers and from patient groups in the potential of high dose vitamin D to alleviate symptoms of IBS, but there haven’t been many properly controlled trials in this area. What our research shows is that supplementing vitamin D at a safe dose did not reduce the severity of IBS symptoms.

“It is worth noting, however, that the vitamin D supplementation did correct deficiencies in those people who were found to have poor vitamin D status, and this is important for other aspects, such as bone and muscle health.”

Lead-author Professor of Human Nutrition and Health at Newcastle University and Honorary Fellow at the University of Sheffield, Bernard Corfe, said: “For some people living with severe IBS, low vitamin D levels may be attributable to changes in diet and lifestyle. Some may feel due to the severity of their symptoms that they limit their outdoor activities due to the anxiety their symptoms can cause, or alter their diet to avoid certain foods triggering their symptoms.

“Unfortunately all of these coping mechanisms can be detrimental to overall health and wellbeing and reduce exposure to valuable sources of vitamin D.

“Given that vitamin D is essential for overall health and wellbeing, it is still important people with IBS get

tested and treated and seek dietary advice so it does not impact on their long-term health.”

The research team at Sheffield were the first to suggest a possible link between people living with IBS and low vitamin D levels in 2012, and have since followed the issue closely. This new study is the largest, and most definitive study to date showing clearly that vitamin D supplementation does not ease severe IBS symptoms.

Although little is known about why and how the debilitating condition develops, and there is currently no cure for IBS, further research is trying to identify better ways to support and manage people living with the chronic condition.

Prof Corfe added: “There is a range of management strategies that people living with IBS can seek help with from their GP, but because of the heterogeneity of the syndrome, managing IBS can be trial and error for each individual patient.

“As it is estimated that between 5 and 15 per cent of the population could be living with IBS – some undiagnosed due to the anxiety and embarrassment their symptoms can cause – it is vitally important we continue with research to find new ways to diagnose, treat, and understand the impact of IBS on the population.”

health of the colon. FODMAPs are not the cause of IBS nor other functional GI disorders, but rather a person develops symptoms when the underlying bowel response is exaggerated or abnormal.7 A low FODMAP diet is recommended as a second-line diet for IBS,

under the guidance of a trained dietitian.11 Exclusion diets have been used in patients with IBS, for instance with wheat and dairy, although conflicting results have been reported.1 Food elimination diets based on IgG antibodies are not recommended in patients with IBS.11

Parallel to the focus on dietary modifications are efforts to alter the intestinal microbiota. Undigested food is used by intestinal microbes (GI microbiota) upon entering the intestine, and microbiota play a major role in GI processes and overall health.8 The faecal microbiome of patients with IBS may differ significantly from that of healthy individuals. The theory that this might, in part, be involved in pathophysiology has led to interest in whether probiotics can be used to alter the microbiome.11 Numerous studies have investigated the utility of probiotics in IBS, in efforts to manipulate the intestinal microbiota and improve symptomatology.8 Although there are some inconsistencies in different studies, there is sufficient evidence to suggest their efficacy in reducing IBS symptoms, such as bloating, abdominal pain and flatulence.10

New therapies

Novel drugs that have been tested successfully in chronic idiopathic constipation, including elobixibat and mizagliflozin, a sodiumglucose cotransporter-1 inhibitor, are likely to undergo testing in IBS-C.11 Plecanatide, a peptide guanylate cyclase C receptor agonist is a promising therapeutic option and an efficacious second-line drug for IBS-C in secondary care. In a phase 3 clinical trial it led to a significant reduction of IBS symptoms, however, diarrhoea is a common side-effect. Although the drug is licensed for IBS with constipation in the US, it is not yet available for this indication in many countries.10,11 Tenapanor, an inhibitor of the GI sodium/ hydrogen exchanger NHE3 and an efficacious second-line drug for IBS with constipation in secondary care, is another novel agent. It increases intestinal fluid volume and transit, leading to an improvement of constipation, bloating and pain. Again, diarrhoea is a frequent side-effect and although the drug is licensed for IBS with constipation in the US, it is also not yet available for this indication in many countries.10,11 Tegaserod, a 5-Hydroxytryptamine 4 receptor agonist, is also an efficacious second-line drug for IBS with constipation in secondary care, but is unavailable outside the US and diarrhoea is a common side-effect.11 Colesevelam, a bile acid sequestrant, has been evaluated in patients with IBS-D. Clinical trials demonstrated that

colesevelam increases the delivery of bile acids to stools, improving stool consistency, and increases hepatic bile acid synthesis, avoiding steatorrhoea in IBS-D patients.10 The highly selective 5-HT4 agonist minesapride has been studied in two phase 2 dose-ranging RCTs in patients with IBS-C. A dose of 40mg once a day was superior to placebo, in terms of improvements in number of bowel movements per week, abdominal pain and global symptoms. The drug was well-tolerated, with diarrhoea the most common side-effect, and there were no cardiovascular adverse events.11

Other novel approaches include drugs that act on cannabinoid receptors, which are expressed in the GI tract and may also modulate pain expression.11

References

1. Weaver K, Melkus G, Henderson A. (2017). Irritable bowel syndrome: A review. American Journal of Nursing: June 2017Volume 117 - Issue 6 - p 48-55 doi: 10.1097/01. NAJ.0000520253.57459.01. www.ncbi. nlm.nih.gov/pmc/articles/PMC5453305/

2. Callachand N. (2020). Irritable bowel syndrome in focus. Medical Independent Published August 6 2020. Available at: www.medicalindependent.ie/irritablebowel-syndrome-ibs-in-focus/

3. Lacy B, Mearin F, Chang L, Chey W, Lembo A, Simren M, Spiller R. (2016). Bowel disorders. Gastroenterology. 2016; 150:1393–1407. doi: 10.1053/j.gastro.2016.02.031

4. Healthline (2021). Everything you want to know about IBS. Available at: www.healthline. com/health/irritable-bowel-syndrome

5. BNF British National Formulary (2020). Edition 80. September 2020 – March 2021. British Medical Association/Royal Pharmaceutical Society, London

6. Chey W. (2016). Food: The main course to wellness and illness in patients with irritable bowel syndrome.

Although faecal microbiota transplantation (FMT) was thought to be a potential therapeutic option, current evidence suggests there is no improvement in global IBS symptoms after FMT.10

Efforts in identifying the different pathophysiological mechanisms involved in symptom generation have allowed the development of new symptom-based and targeted therapies. New insights and ongoing research into trials of novel treatments, including pharmacological, dietary and behavioural therapies, device-based treatments and FMT will hopefully bring a better quality-of-life to patients with IBS, as they contribute to a new understanding of this common syndrome. ■

American Journal of Gastroenterology 2016;111:366-371. doi: 10.1038/ajg.2016.12

7. Mullin G, Shepherd S, Chander R, Ireton-Jones C, Matarese L. (2014). Irritable bowel syndrome: Contemporary nutrition management strategies. Journal of Parenteral and Enteral Nutrition. 2014;38:781–799. doi: 10.1177/0148607114545329

8. Barbara G, Feinle-Bisset C, Ghoshal U, Santos J, Vanner S, Vergnolle N, Quigley E. (2016). The intestinal microenvironment and functional gastrointestinal disorders. Gastroenterology. 2016;150:1305–1318. doi: 10.1053/j.gastro.2016.02.028

9. NHS (2021). Irritable Bowel Syndrome. National Health Service, UK. Available at: www. nhs.uk/conditions/irritable-bowel-syndrome-ibs/

10. Ferreira A, Garrido M, Castro-Poças F. (2020). Irritable bowel syndrome: News from an old disorder. GE Port J Gastroenterol 2020; 27:255–268

11. BSG (2021). British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. British Medical Journal Volume 70, Issue 7. Available at: https:// gut.bmj.com/content/70/7/1214

NOW BVBM FOR 20MG ADALIMUMAB

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AMGEVITA®▼ (adalimumab) Brief Prescribing Information

Please refer to the Summary of Product Characteristics (SmPC) before prescribing Pharmaceutical Form: Single dose pre-filled syringe contains 20mg adalimumab in 0.4mL (50 mg/mL) solution, 40mg adalimumab in 0.8mL (50 mg/mL) solution or single dose pre-filled pen (SureClick®) contains 40mg adalimumab in 0.8mL (50 mg/ mL) solution. Indications and Dosage: please refer to SmPC for full information. For subcutaneous injection. Treatment should be initiated and supervised by specialist physicians experienced in conditions for which AMGEVITA® is indicated. Ophthalmologists should consult with an appropriate specialist before starting treatment. Give patients a Patient Reminder Card. After training in injection technique, patients may self-inject with medical follow-up as necessary. Optimise other concomitant therapies (e.g. corticosteroids and or/immunomodulatory agents). Rheumatoid arthritis (RA), adults: In combination with methotrexate (MTX) for: 1. Moderate to severe, active RA with inadequate response to disease-modifying antirheumatic drugs (DMARDs) including MTX ; 2.Severe, active and progressive RA not previously treated with MTX. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Dosage: 40 mg every other week (EOW). Continue concomitant MTX. In monotherapy, patients may require 40 mg every week or 80 mg EOW if there is a decrease in clinical response. Reconsider treatment beyond 12 weeks if no clinical response. Consider need for dose interruption, e.g. before surgery or if serious infection occurs. Polyarticular juvenile idiopathic arthritis (pJIA), paediatrics ≥ 2 years: In combination with MTX for active pJIA with inadequate response to one or more DMARDs. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate.

Dosage: 10 kg to < 30 kg: 20 mg EOW. ≥ 30 kg: 40 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Enthesitis-related arthritis (ERA), paediatrics ≥ 6 years: Active ERA with inadequate response to or intolerance to conventional therapy. Dosage: 15 kg to < 30 kg: 20 mg EOW. ≥ 30 kg: 40 mg EOW.

Ankylosing spondylitis (AS), adults: Severe active AS with inadequate response to conventional therapy. Axial spondyloarthritis without radiographic evidence of AS (nr-axSpA), adults: Severe nr-axSpA with objective signs of inflammation (elevated CRP and/or MRI), and an inadequate response to or intolerance to nonsteroidal anti-inflammatory drugs. Psoriatic arthritis (PsA), adults: Active and progressive PsA with inadequate response to DMARDs. Dosage (AS, nr-axSpA, PsA): 40 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Psoriasis, adults: Moderate to severe chronic plaque psoriasis in candidates for systemic therapy.

Dosage: 80 mg at Week 0, followed by 40 mg EOW from Week 1. Reconsider treatment beyond 16 weeks if no clinical response. Refer to SmPC. Paediatric

BRAND NAME

Plaque Psoriasis, ≥ 4 years: Severe chronic plaque psoriasis with inadequate response to or if topical therapy and phototherapies are inappropriate. Dosage: 15 kg to < 30 kg: 20 mg followed by 20 mg EOW starting one week after initial dose. ≥ 30 kg: 40 mg then 40 mg EOW starting one week after initial dose. Reconsider treatment beyond 16 weeks if no clinical response. Safety has been assessed in paediatric patients with plaque psoriasis for a mean of 13 months. Hidradenitis suppurativa (HS), adults and adolescents ≥ 12 years: Active moderate to severe HS (acne inversa) with inadequate response to conventional systemic therapy. Dosage, adult: 160 mg at Day 1, followed by 80 mg at Day 15. At day 29 continue with 40 mg every week or 80 mg EOW. Reintroduction after treatment interruption: 40mg every week or 80mg EOW. Dosage: adolescent (≥ 30 kg): 80 mg at week 0 then 40 mg EOW starting at week 1. If response is inadequate, consider increasing to 40 mg every week or 80 mg EOW. Dosage, adult and adolescent: Antibiotics may be continued if necessary. Use concomitant topical antiseptic wash on a daily basis. Reconsider treatment beyond 12 weeks if no improvement. Periodically evaluate the benefit and risk of continued treatment. Crohn’s disease (CD), adults: Moderately to severely active CD with no response despite a full and adequate course of, intolerance to or contraindication for a corticosteroid and/or an immunosuppressant therapy. Dosage: Induction: 80 mg at Week 0, then 40 mg at Week 2. For a more rapid response: 160 mg at Week 0, then 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose EOW. Corticosteroids may be tapered in accordance with clinical guidelines. If decrease in clinical response, can increase to 40 mg every week or 80 mg EOW. If no response by Week 4 there may be benefit from continued therapy to Week 12. Reconsider treatment beyond 12 weeks if no clinical response. Paediatric CD ≥ 6 years: Moderately to severely active CD with inadequate response to, intolerance to or contraindication to conventional therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator. Dosage: < 40 kg: Induction: 40 mg at Week 0 then 20 mg at Week 2. For a more rapid response: 80 mg at Week 0 then 40 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance starting at week 4: 20 mg dose EOW. If insufficient response, consider 20 mg every week. Dosage: ≥ 40 kg: Induction: 80 mg at Week 0 then 40 mg at Week 2. For a more rapid response: 160 mg at Week 0, then 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance starting at week 4: 40 mg dose EOW. If insufficient response, consider 40 mg every week or 80 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Ulcerative colitis (UC), adults: Moderately to severely active UC with inadequate response to, intolerance to or contraindication for conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA). Dosage: Induction: 160 mg at Week 0 and 80 mg at Week 2. Maintenance:

40 mg EOW. Corticosteroids may be tapered in accordance with clinical guidelines. If insufficient response, consider increasing to 40 mg every week or 80 mg EOW. Do not continue treatment beyond 8 weeks if no clinical response. Paediatric UC, ≥6 years: Moderately to severely active UC with an inadequate response to conventional therapy including corticosteroids and/or 6-MP or AZA, or who are intolerant to or have contraindications. Dosage: < 40 kg: Induction: 80 mg at Week 0 and 40 mg at Week 2. Maintenance starting at week 4: 40mg EOW. Dosage: ≥ 40 kg: Induction: 160 mg Week 0 and 80 mg Week 2. Maintenance starting at week 4: 80mg EOW. Patients reaching 18 years should continue their prescribed maintenance dose. Reconsider treatment beyond 8 weeks if no clinical response. No relevant use in children <6 years. Uveitis, adults: Non-infectious intermediate, posterior and panuveitis with inadequate response to corticosteroids, in patients in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate. Dosage: 80 mg at Week 0 and 40 mg EOW from Week 1. There is limited experience in initiation of treatment with adalimumab alone. Treatment can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered starting two weeks after initiating treatment with AMGEVITA®. Evaluate on a yearly basis the benefit and risk of continued treatment. Paediatric uveitis, ≥ 2years: Chronic non-infectious anterior uveitis with inadequate response or intolerance to conventional therapy, or in whom conventional therapy is inappropriate. In paediatric uveitis, there is no experience in the treatment with AMGEVITA® without concomitant treatment with methotrexate.

Dosage: < 30 kg: 20 mg EOW in combination with MTX. Dosage: ≥ 30 kg: 40 mg EOW in combination with MTX. A loading dose of 40 mg (< 30 kg) or 80 mg (≥ 30 kg) may be administered 1 week in advance of maintenance therapy. No clinical data on use of loading dose in patients < 6 years. Evaluate benefit and risk of continued treatment on a yearly basis. Contraindications: Hypersensitivity to the active substance or to any excipients; Active tuberculosis (TB) or other severe infections such as sepsis and opportunistic infections; Moderate to severe heart failure (NYHA class III/IV). Warnings and Precautions: Clearly record the name and batch number. Infections: Patients taking TNF-antagonists are more susceptible to serious infections, especially if impaired lung function. Monitor for infections, before, during and for 4 months after treatment. Do not initiate treatment during an active infection, until infection is controlled. Consider risk/benefit prior to treatment in patients exposed to TB or who have travelled in areas of high risk of TB or endemic mycoses. Evaluate new infections and monitor closely. Stop treatment if new serious infection or sepsis and treat. Exercise caution in patients with a history of recurring infections or who are predisposed to infections, including the use of concomitant immunosuppressive medications. Serious Infections: Consult SmPC for details.

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AMGEVITA® 40mg SureClick® Pre-fi lled pen

AMGEVITA® 20mg Pre-fi lled syringe

AMGEVITA® 40mg Pre-fi lled syringe

Information for Healthcare Professionals

The Medicine Management Programme recommends AMGEVITA® as a citrate-free formulation of adalimumab.

Serious infections, including those associated with hospitalisation or death, were reported in patients receiving treatment. TB: Reactivation and new onset TB, both pulmonary and extra-pulmonary (disseminated). Screen all patients before therapy initiation for active or inactive (latent) TB. Perform detailed medical assessment and appropriate screening tests for TB in all patients and results recorded on patient reminder card. If latent TB is suspected, consult physician with appropriate expertise Despite prophylaxis, TB reactivation has occurred on adalimumab. If active TB is diagnosed, do not initiate AMGEVITA® treatment. Other opportunistic infections: Opportunistic infections were observed in patients receiving adalimumab. Stop AMGEVITA® in patients with signs and symptoms of such infections. Consult with physician with appropriate expertise for diagnosis and administration of empiric antifungal therapy. Hepatitis B reactivation: Reactivation of HBV has occurred in chronic carriers; some cases were fatal. Test patients for HBV infection before initiating treatment. HBV carriers should consult a specialist physician and be closely monitored for reactivation of HBV infection throughout therapy and for several months after treatment. If reactivation occurs, stop treatment and initiate appropriate antiviral and supportive treatment. Neurological events: Caution in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. Consider discontinuation if any of these develop. Perform neurologic evaluation in patients with non-infectious intermediate uveitis prior to initiation of treatment and regularly during treatment. Allergic reactions: Reports of serious allergic reactions including anaphylaxis. For serious allergic or anaphylactic reaction, stop AMGEVITA® immediately and initiate appropriate therapy. Dry natural rubber: The needle cover of the pen (SureClick®) is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. Malignancies and lymphoproliferative disorders: A possible risk of malignancy, some fatal, including lymphomas and leukaemia, cannot be excluded (see SmPC). Examine all patients, especially those with a medical history of extensive immuno-suppressant therapy or psoriasis patients with a history of PUVA treatment, for non-melanoma skin cancer prior to and during treatment. Melanoma and Merkel cell carcinoma have also been reported. Caution in COPD patients, and in patients with increased risk for malignancy due to heavy smoking. Consider the potential risk with the combination of AZA or 6-MP and AMGEVITA® (hepatosplenic T-cell lymphoma has occurred). Caution in patients with a history of malignancy. Risk of developing dysplasia or colon cancer unknown. Screen patients with UC, history of dysplasia or colon carcinoma, for dysplasia before and during treatment. Haematologic reactions: Adverse events of the haematologic system, including medically significant cytopenia, have been reported. Advise patients to seek immediate medical attention if signs and symptoms of blood dyscrasias develop. Vaccinations: Patients may

receive concurrent vaccinations, except for live vaccines. Bring paediatric patients up to date with all immunisations prior to initiating treatment. Congestive heart failure: See contraindications. Caution in mild heart failure (NYHA class I/II). Discontinue treatment if new or worsening symptoms of congestive heart failure. Autoimmune processes: Autoimmune antibodies may form. Stop treatment if development of a lupus-like syndrome with positive antibodies against doublestranded DNA. Surgery: Consider the long half-life of AMGEVITA® for planned surgical procedures. Monitor closely for infections. There is limited safety experience in patients undergoing arthroplasty or surgical procedures. Elderly patients: Serious infections were higher in patients over 65, some of which were fatal. Consider risk of infections in these patients. Interactions: Antibody formation was lower when AMGEVITA® was given together with MTX rather than as monotherapy. Combination of AMGEVITA® with other biologic DMARDs (e.g. anakinra and abatacept) or other TNF-antagonists is not recommended. Fertility, pregnancy and lactation Only use during pregnancy if clearly needed. Women of childbearing age to consider use of adequate contraception during and for at least 5 months after the last treatment.

Administration of live vaccines (e.g. BCG) to infants exposed to AMGEVITA® in utero is not recommended for 5 months following the mother’s last injection during pregnancy. AMGEVITA® can be used during breastfeeding. Effects on ability to drive and use machines: AMGEVITA® may have a minor influence on the ability to drive and use machines. Adverse Reactions: Very common ≥ 1/10: Respiratory tract infections, leukopenia), anaemia, lipids increased, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash ), musculoskeletal pain, injection site reaction Common ≥ 1/100 to < 1/10: Systemic infections, intestinal infections, skin and soft tissue infections, ear infections, oral infections , reproductive tract infections , urinary tract infections, fungal infections, joint infections, skin cancer excluding melanoma, benign neoplasm, leucocytosis, thrombocytopenia, hypersensitivity, allergies, hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphatemia, dehydration, mood alterations , anxiety, insomnia, paraesthesias, migraine, nerve root compression, visual impairment, conjunctivitis, blepharitis, eye swelling, vertigo, tachycardia, hypertension, flushing, haematoma, asthma, dyspnoea, cough, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, Sicca syndrome, worsening or new onset of psoriasis , urticaria, bruising , dermatitis, onychoclasis, hyperhidrosis, alopecia, pruritus, muscle spasms , renal impairment, haematuria, chest pain, oedema, pyrexia, coagulation and bleeding disorders, autoantibody test positive , blood lactate dehydrogenase increased, impaired healing. Serious, including fatal, adverse reactions have been reported including infections/sepsis, TB, opportunistic infections, allergic reactions, HBV reactivation and malignancies.

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome. Other less common and rarely reported adverse reactions are listed in the SmPC. Pharmaceutical Precautions: Store in a refrigerator (2°C – 8°C). Do not freeze. Keep in the outer carton in order to protect from light. Out of the refrigerator, may be stored up to 25°C for up to 14 days. Legal Category: POM. Presentation and Marketing Authorisation Number. AMGEVITA® 20 mg solution for injection in pre-filled syringe: EU/1/16/1164/001 – 1 pack: cost AMGEVITA® 40 mg solution for injection in pre-filled syringe: EU/1/16/1164/003 – 2 pack AMGEVITA® 40 mg solution for injection in pre-filled pen: EU/1/16/1164/007 – 2 pack. Marketing Authorisation Holder: Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin D09 TX31. AMGEVITA® is a registered trademark of Amgen Inc. Date of PI preparation: July 2021 (Ref: IE-AMB-0721-00001)

This medicinal product is subject to additional monitoring. Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen Limited on +44 (0) 1223 436441 or Freephone 1800 535 160.

1. BVBM Amgevita Product Information Sheet. https://www.hse.ie/ eng/about/who/cspd/ncps/medicines-management/best-valuebiologicalmedicines/bvb-medicine-amgevita-product-information-sheet. pdf. Accessed August 2021.

2. Oireachtas.ie, Debates, December 2020, Written Answer by Minister for Health. https://www.oireachtas.ie/en/debates/question/2020-12-10/373/. Accessed August 2021.

3. Medicines Management Programme Best-Value Biological Medicines: Adalimumab 20 mg solution for injection. https://www.hse.ie/eng/about/ who/cspd/ncps/medicines-management/bestvalue-medicines/bestvalue-biological-medicines/mmp-report-bvbmedicine-adalimumab-20mgmarch-2021.pdf. Accessed Aug 2021.

4. AMGEVITA® (adalimumab) summary of product characteristics.

IE-AMB-0821-00004

Date of preparation: September 2021

Prescribing AMGEVITA® has lead to significant savings for the health service, in the order of millions of euros1,2,3

Diverticular disease and diverticulitis – an overview

Diverticular disease and diverticulitis are two closely-related digestive conditions that affect the large intestine. Small bulges occur on the lining of the intestines; these pouches or bulges can become inflamed or infected, which leads to symptoms. Symptoms of diverticular disease include lower abdominal pain and bloating. Diverticulitis is more serious than diverticular disease and symptoms include more severe abdominal pain and a high temperature of 38°C or above.

Men and women are equally affected by diverticular disease and diverticulitis, although the condition is more likely to appear at a younger age (under 50) in men. Diverticular disease rates are high in Western countries, including Europe and North America, and low in African and Asian countries. Diet is thought to be the reason for this, explained by the fact that people in Western countries tend to eat less fibre in their diet compared to the diet of people in less developed countries.

Diverticula

Diverticula (plural) is the medical term used to describe the small pouches that stick out of the side of the large intestine (colon). Diverticula are quite common and are associated with ageing. The pressure of hard stools passing through the large intestine that has become weakened with age causes the pouches to form. Approximately 50 per cent of the population suffers from diverticula by the time they are 50 years old, and 70 per cent have diverticula by the time they are 80 years old. Most people with diverticula do not have any symptoms; this is known as diverticulosis.

Diverticular disease

One-in-four people who develop diverticula will experience symptoms such as abdominal pain. Having symptoms associated with diverticula is known as diverticular disease.

Diverticulitis

Diverticulitis describes infection that occurs when bacteria becomes trapped inside one of the pouches, leading to inflammation and triggering more severe symptoms. Diverticulitis can lead to serious complications, such as an abscess inside the intestine.

Symptoms

Diverticular disease

The most common symptom of diverticular disease is intermittent pain in the lower abdomen, mainly in the lower left-hand side. The pain is often worse when eating, or shortly afterwards. Passing stools and passing wind (flatulence) may relieve the pain. Other symptoms of diverticular disease include a change in normal bowel habits, such as constipation or diarrhoea (or episodes of constipation followed shortly by diarrhoea), bloating and rectal bleeding.

Diverticulitis

The main symptom of diverticulitis is a constant and severe pain. The pain usually starts below the navel before moving to the lower left-hand side of the abdomen. For genetic reasons, people of Asian background tend to develop diverticula in a different part of their colon, meaning the pain may occur in the lower right-hand side of the abdomen in Asian people. Apart from severe stomach pain, other symptoms of diverticulitis include a high temperature of 38°C or above; nausea; vomiting; a frequent need to urinate; pain when urinating; constipation; and bleeding from the rectum.

It is important to get diverticulitis treated quickly. The sooner diverticulitis is treated with antibiotics, the lower the risk of complications developing. If a person has the symptoms of diverticular disease and the condition has previously been diagnosed, they do not usually need to

contact their GP because the symptoms can be treated at home. If a person has not been diagnosed with the condition, they should contact their GP to rule out other conditions that have similar symptoms, such as irritable bowel syndrome (IBS) or ulcerative colitis.

Causes

Diverticular disease

It is not known why only one-in-four people with diverticula develop symptoms of diverticular disease. Several factors have been identified that appear to increase the risk of developing diverticular disease including:

 Smoking.

 Being overweight or obese.

 Having a history of constipation.

 Physical inactivity.

 Use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or diclofenac.

Diverticulitis

Diverticulitis is caused by an infection of one or more of the diverticula. It is thought that an infection develops when a hard piece of stool gets trapped in one of the pouches. This gives bacteria in the stool the chance to multiply and spread, triggering an infection.

Diagnosis

Diverticular disease can be difficult to diagnose from the symptoms alone because there are many other conditions that cause similar symptoms, such as IBS. As a first step, blood tests can rule out other conditions such as Coeliac disease.

To confirm diverticula, the inside of the large intestine needs to be examined using a colonoscopy. Another technique for confirming the presence of diverticula is a barium enema x-ray. When a person has a previous history of diverticular disease, the GP

will usually be able to diagnose diverticulitis from symptoms and a physical examination. A blood test may be taken because a high number of white blood cells indicate infection. Further tests will be needed if there is no previous history of diverticular disease to rule out other possible conditions, such as gallstones or a hernia. A barium enema x-ray may be used, as well as a CT scan.

Treatment

Diverticular disease

Eating a high-fibre diet can help control symptoms. Some people will notice an improvement after a few days, although it can take around a month to fully feel the benefits. Most cases of diverticular disease can be treated at home. Paracetamol is recommended to help relieve symptoms. NSAIDs such as aspirin and ibuprofen are not recommended because they irritate the lining of the stomach and can upset the stomach and increase the risk of internal bleeding.

Heavy or constant rectal bleeding occurs in about one-in-three cases of diverticular disease. This can happen if the blood vessels in the large intestine are weakened by the diverticula, making them vulnerable to damage. The bleeding is usually painless, but losing too much blood can be potentially serious and warrants immediate attention as patients may need a blood transfusion.

Warning signs of heavy bleeding include:

 Feeling very dizzy.

 Mental confusion.

 Pale, clammy skin.

 Shortness of breath.

Fibre

Not eating enough fibre is thought to be a key reason why diverticula develop. Fibre makes stools softer and larger so that less pressure is needed by the large intestine to push stools out of the body. Eating low-fibre food produces small, hard stools. These are more difficult for the muscles of the large intestine to move and will cause the person to strain. The pressure of moving the hard, small pieces of stools through the large intestine creates weak spots in the outside layer of muscle. This allows the inner layer to squeeze through these

weak spots, creating the diverticula.

If fibre intake is low, it is recommended to gradually increase fibre intake over the course of a few weeks. This will help to prevent the sideeffects associated with a high-fibre diet, such as bloating and flatulence. If these symptoms occur initially after increasing fibre intake, they will reduce after a few weeks as the intestines get used to increased fibre. Drinking plenty of fluids will help to prevent side-effects. Fibre supplements, usually in the form of sachets of powder that are mixed with water, are available from pharmacies.

People with diverticular disease are recommended to eat between 18g-to-30g of fibre daily. However, a more specific target may be required, depending on individual height and weight.

Sources of fibre include:

 Fresh fruit, such as peaches, oranges, pears, bananas, and apples.

 Vegetables, such as baked beans, kidney beans, peas, broccoli, and cabbage.

 Dried fruit, such as apricots and prunes.

 Nuts, such as almonds, peanuts, and sunflower seeds.

 Breakfast cereals, such as bran flakes.

 Brown versions of bread, rice, and pasta

Portions of food highest in fibre and the amount of fibre found in typical portions are as follows:

Fresh fruit

 Pear (with skin): A medium-size pear contains 4g of fibre.

 Orange: A medium-size orange contains 3g of fibre.

 Apple (with skin): A medium-size apple contains 2g of fibre.

 Raspberries: Two handfuls of raspberries (80g) contain 2g of fibre.

 Banana: A medium-size banana contains 2g of fibre.

 Tomato juice: One small glass of tomato juice (200ml) contains 1.5g of fibre.

Dried fruit

 Apricots: Three whole apricots contain 5g of fibre.

 Prunes: Three whole prunes contain 5g of fibre.

Vegetables

 Baked beans (in tomato sauce): A half can of baked beans (200g) contains 7g of fibre.

 Red kidney beans (boiled): Three tablespoons of red kidney beans contain 5g of fibre.

 Peas (boiled): Three heaped tablespoons of peas contain 4g of fibre.

 Brussels sprouts (boiled): Eight Brussels sprouts contains 3g of fibre.

 Potatoes (old, boiled): One medium-size potato contains 2.5g of fibre.

 Spring greens (boiled): Four heaped tablespoons of spring greens contain 2g of fibre.

 Carrots (boiled, sliced): Three heaped tablespoons of carrots contain 2g of fibre.

Breakfast cereals

 Weetabix: Two pieces of Weetabix c ontain 4g of fibre.

 Porridge (milk or water): One medium-size bowel of porridge contains 2.3g of fibre.

 All-Bran: A medium-size bowel of AllBran contains 10g of fibre.

 Bran Flakes: One medium-size bowel of Bran Flakes contains 4g of fibre.

 Muesli (no added sugar): One mediumsize bowel of muesli contains 3g of fibre.

Bread, rice, and pasta

 Pitta bread (wholemeal): One piece of pitta bread (75g) contains 4g of fibre.

 Pasta (plain, fresh cooked): One medium portion of pasta (200g) contains 4g of fibre.

 Wholemeal bread: Two slices of wholemeal bread contains 3.5g of fibre.

 Brown bread: Two slices of brown bread contain 2.5g of fibre.

 Brown rice (boiled): One medium portion of brown rice (200g) contains 2g of fibre.

Nuts

 Almonds: Twenty almonds contain 2.5g of fibre.

 Peanuts (plain): A tablespoon of peanuts contains 1.5g of fibre.

 Brazil nuts: Ten Brazil nuts contain 1.5g of fibre.

Diverticulitis treatment

Mild diverticulitis can be treated by a GP with antibiotics and analgesics. Sticking to a fluid-only diet for a few days may be recommended until symptoms improve. Solid foods can then be gradually reintroduced over a two- or three-day period.

Treatment at hospital

For severe diverticulitis, hospital treatment may be needed. Hospital treatment is recommended if:

 Unable to drink enough fluids to stay hydrated.

 Unable to take antibiotics by mouth.

 The pain cannot be controlled using paracetamol.

 General state of health is poor.

 Weakened immune system.

 GP suspects complications.

 Symptoms fail to improve after two days of treatment at home.

IV antibiotics are generally used as well as an IV drip for hydration and nutrition for those admitted to hospital with diverticulitis. Most people start to improve within two-to-three days.

Surgery

In the past, surgery was recommended as a preventative measure for people who had two episodes of diverticulitis as a precaution to prevent complications. This is no longer the case, as studies have found that in most cases, the risks of serious complications of surgery (estimated to be around one-in-100) usually outweigh the benefits. However, there are exceptions to this, such as:

 A history of serious complications arising from diverticulitis.

 Symptoms of diverticular disease from a young age (it is thought that the longer a person lives with diverticular disease, the greater the chances of having a serious complication).

 A weakened immune system.

Colectomy

Surgery for diverticulitis involves removing the affected section of the large intestine, ie, colectomy. There are two ways that a colectomy can be performed:

 An open colectomy, where the surgeon makes a large incision in the abdomen and removes a section of the large intestine.

 Laparoscopic colectomy – a type of keyhole surgery where the surgeon makes a few small incisions in the abdomen and is guided by a camera to remove a section of large intestine.

Open colectomies and laparoscopic colectomies are thought to be equally effective in treating diverticulitis and have a similar risk of complications. Laparoscopic colectomies have the advantage of having a faster recovery time, and they cause less post-operative pain.

Stoma surgery

In some cases, the surgeon may decide that the large intestine needs to heal before it can be reattached, or that too much of the large intestine has been removed to make reattachment possible. In such cases, stoma surgery may be necessary. There are two ways that stoma surgery can be carried out:

 An ileostomy, where a stoma is made in the right-hand side of the abdomen. The small intestine is separated from the large intestine and connected to the stoma, and the rest of the large intestine is sealed. The person wears a pouch connected to the stoma to collect waste material.

 A colostomy, where a stoma is made in the lower abdomen and a section of the large intestine is removed and connected to the stoma. As with an ileostomy, the person wears a pouch to collect waste material.

In most cases, the stoma will be temporary and can be removed once the large intestine has recovered from the effects of the surgery. This will usually take at least nine weeks. If a large section of the large intestine is affected by diverticulitis and needs to be removed, the person may need to have a permanent ileostomy or colostomy.

In general terms, surgery is usually successful, although it does not achieve a complete cure in all cases. Following

surgery, an estimated one-in-12 of people will have a recurrence of the symptoms of diverticular disease and diverticulitis.

Complications

Complications of diverticulitis affect onein-five people with the condition. Those most at risk of developing complications are younger people (under 50 years of age).

An abscess inside the large intestine is the most common complication of diverticulitis. Abscesses are usually treated with percutaneous abscess drainage (PAD) where a radiologist uses an ultrasound or CT scanner to locate the site of the abscess.

A fistula is another common complication of diverticulitis. Fistulas can be potentially serious, as they can allow bacteria in the large intestine to travel to other parts of the body, triggering infections, such as an infection of the bladder (cystitis). Fistulas are usually treated with surgery to remove a small section of the colon that contains the fistula.

In rare cases, an infected diverticula splits, spreading the infection into the lining of the abdomen, ie peritonitis. Peritonitis can be life-threatening and requires immediate treatment with antibiotics. Surgery may also be required to repair any damage and to drain any pus that has built up.

If the infection has badly scarred the large intestine, it may become partially or totally blocked. A totally blocked large intestine is a medical emergency because the tissue of the large intestine will start to decay and eventually split, leading to peritonitis.

A partially-blocked large intestine is not as urgent, but treatment is still needed. If left untreated, it will affect the ability to digest food. It will also cause considerable pain. In some cases, the blocked part of the large intestine can be removed during surgery. However, if the scarring and blockage is more extensive, a temporary or permanent colostomy may be needed. ■

References on request

An overview of Coeliac disease

Coeliac disease is an autoimmune condition where the body’s immune system attacks its own tissue when gluten is consumed. This reaction then causes chronic inflammation and damage to the lining of the small intestine, which can then prevent vital nutrients in food from being absorbed. The deficiencies caused as a result of this aggressive process can lead to a range of symptoms, ranging from mild discomfort to, if left undiagnosed, serious health problems, specifically in the digestive system as well as the rest of the body.

Whilst common, Coeliac disease is not an allergy or a food intolerance; it is a serious, chronic condition. Indeed, many people living with the condition feel that is some ways, the seriousness of Coeliac disease is somewhat trivialised these days as they become (wrongly) grouped with many people who make the modern lifestyle choice to go ‘gluten-free’.

Whilst there is no ‘cure’ for Coeliac disease as such, the key to the long-term successful management of living a full and active life with Coeliac disease is strict adherence to a gluten-free diet; a necessity, not a choice.

As is the case with many chronic conditions, early diagnosis, acceptance, and strict dietary change are vital to minimising the impact of Coeliac disease, both to a person’s health and daily living.

In terms of prevalence, it is estimated that perhaps at least one-in-100 people in Ireland are affected by Coeliac disease. Expert opinion indicates, however, that this figure may be underestimated by up to 30 per cent, as people with milder symptoms go undiagnosed or in many cases, are misdiagnosed with another condition which presents symptoms similar to those in Coeliac disease.

Coeliac disease typically has an incidence ratio of 3:1 female-to-male, so it is more common in women. Those with particular conditions, ie, type 1 diabetes, Down syndrome, Turner’s syndrome and autoimmune thyroid disease, carry an increased risk of developing Coeliac disease.

Whilst Coeliac disease can develop at any time of life, symptoms are most likely to appear either in:

 Early infancy – between eight-to-12 months old, although it may take some considerable time to achieve a correct diagnosis;

 Or more commonly, later in life, in the 40-to-60 years-old range.

There is strong evidence of a genetic link to developing Coeliac disease, so first-degree relatives of an individual with Coeliac disease also carry a higher risk, perhaps 10 per cent, of developing it.

Causes

Why people develop Coeliac disease is as yet unknown. It is essentially caused by an adverse immune system reaction to the dietary protein gluten, which is found in three types of cereal:

 Barley.

 Rye.

 Wheat.

For those with Coeliac disease, gluten plays a role in preventing absorption of vital nutrients such as vitamin D and calcium. In normal function, the immune system produces antibodies to help the body fight harmful threats such as bacteria and viruses; however, with Coeliac disease, the immune system mistakes one of the constituent substances of gluten (gliadin) as a threat to the body, producing antibodies to attack it. As a result of this erroneous attack, the surface of the intestine becomes inflamed (red and distended).

In a normal intestine, the surface is covered by millions of villi, their function being to increase the overall surface area of the intestine to aid more effective food digestion. With Coeliac disease, the damage and inflammation to the intestinal lining because of the adverse immune reaction flattens the villi, significantly reducing their ability to function as a digestive aid. As a consequence, the gut is unable to digest the nutrients from food, thereby triggering a variety of symptoms of Coeliac disease.

In severe cases of Coeliac disease, where the digestive system has broken down considerably, malnutrition caused by a critical lack of vital nutrients is a potential danger. Malnutrition can result in loss of function in other parts of the body and diminishes the body’s ability to recover from wounds or infection. Other severe symptoms may include muscle wastage, mental confusion, and an inability to stay warm.

Symptoms

Whether diagnosed or undiagnosed and untreated, symptoms of Coeliac disease can vary widely from person-to-person.

For some, symptoms may only be mild and perhaps occasional, whilst for others, they may be persistent and severe; the reason for this variance is not known. In some cases, particularly with family groups, Coeliac disease may be latent, not having been triggered.

With Coeliac disease, because the body is unable to absorb nutrients fully (malabsorption), the most common symptom is diarrhoea that is often severe and foul-smelling.

This symptom is often misdiagnosed or presumed by the sufferer to be irritable bowel syndrome (IBS).

Other common symptoms may include:

 Constipation.

 Excessive wind/flatulence.

 Persistent or unexplained gastrointestinal symptoms, such as nausea and vomiting.

 Recurring stomach pain, cramping or bloating.

 Extreme tiredness:

● Iron, vitamin B12 or folic acid deficiency.

● Anaemia.

 Sudden or unexpected weight loss (but not in all cases).

 Mouth ulcers.

 Itchy skin rash (dermatitis herpetiformis, see below).

 Neurological (nerve) problems such as ataxia (loss of co-ordination, poor balance) and peripheral neuropathy (numbness and tingling in the hands and feet).

Dermatitis herpetiformis

Whilst not a direct symptom of Coeliac disease, but also gluten-related, up to 20 per cent of people with Coeliac disease may also develop an itchy skin rash – dermatitis herpetiformis. The rash presents as red raised patches with blisters that burst when scratched.

Most commonly affecting the elbows, shoulders, knees, buttocks, and face, it can however, appear anywhere on the body. It can appear at any age, but is most common in those in their 50s and 60s. For most, it should clear-up once a gluten-free regimen is established. For those where the rash is more belligerent, diaminodiphenyl sulfone can be prescribed and has proved successful in helping to clear the condition.

Diagnosis

With many of the symptoms of Coeliac disease being common to other conditions, people may not necessarily think of it as the cause, often attributing their symptoms to stress or age or just a consequence of modern living. People may go for considerable periods of time treating conditions such as constipation, indigestion, bloating, etc, as stand-alone issues, perhaps using readily available over-the-counter (OTC) medications.

As stressed earlier, given the vital role early successful diagnosis of Coeliac disease can have on the long-term healthy prognosis for a patient, it is important that Coeliac disease is considered as a potential cause for these issues.

Ky to diagnosis is a blood test in the first instance to test for antibodies (IgA tissue transglutaminase). The patient should be advised that prior to the test, they maintain their current regular diet, which should include gluten, to ensure the accuracy of the result. This should continue until/if a diagnosis of Coeliac disease is confirmed.

If Coeliac disease antibodies are present in the blood sample, referral to a gastroenterologist for an endoscopy and biopsy of the intestines is the next step to confirm and rule out other conditions. In some cases, where no antibodies are present in the blood sample, but symptoms continue, the GP might still refer for biopsy.

If a diagnosis of Coeliac disease is confirmed, further tests are usually advised to help assess the extent to which it has affected the patient, as in some cases it may have been undiagnosed for years. These include checking iron and vitamin levels in the blood, specifically checking for anaemia that may be present due to deficient digestion.

A DEXA scan may also be ordered if the GP has concerns that the Coeliac disease may have already started to thin the bones or almost certainly for those with existing osteoporosis prior to diagnosis.

Treatment

From a medical perspective, the GP may require the patient to attend an annual check-up. This may not be much more than a discussion on progress, together with perhaps height and weight check. This relates to full absorption of calories and also any height loss related to potential osteoporosis concerns.

Depending on the situation, the GP may also recommend supplements such as

calcium and vitamin D, particularly in the months following diagnosis.

The simplest and most effective treatment for Coeliac disease is excluding foods that contain gluten for life. With the immediate removal of gluten from the diet, the gut will begin to heal quickly, and the patient will see an improvement in health within a short period of time. Depending on the extent of the damage prior to diagnosis, it may take months or even years for the intestine to heal fully.

On the face of it, excluding gluten may sound relatively simple; however, for many, it is a daunting task. The new regimen of checking everything they eat, food labels, menus, etc, can prove extremely challenging. Even the smallest amount of gluten can result in the return of previous debilitating symptoms.

In the early stages, it is vital that the newlydiagnosed patient consults with a dietitian. They will be an invaluable source of help and support in the early days, helping the patient establish a healthy, balanced, gluten-free diet.

Unlike the austere and extremely limited gluten-free world of 20 or 30 years ago, there is a huge selection of gluten-free products now available in all the major supermarkets and food outlets. In addition, there are many local and online supports available. Some of the major organisations, ie, the Coeliac Society of Ireland (www.coeliac. ie), produce and maintain extensive lists of gluten-free products, which are updated regularly. These will become an integral part of the patient’s dietary management.

Outlook

There is now a much higher level of awareness of Coeliac disease throughout society and access to support channels and gluten-free foods has never been greater.

With early diagnosis and adherence to a gluten-free diet, Coeliac disease can be managed effectively, with virtually no limitations to enjoying a healthy lifestyle for the vast majority of those living with the condition. ■

How dietitians are helping to reduce gastroenterology waiting lists in Ireland

Like other healthcare professionals, dietitians choose a specialty during their career. Following three years at basic grade level, dietitians are eligible to apply for senior roles in their area of interest. It takes at least five years of further practice to be eligible for a clinical specialist role. The expertise at this level not only complements, but enhances the care of patients.

Years of working alongside our medical colleagues has given dietitians an understanding of pinch points within specialties. This opens doors of opportunity for collaboration and development. Dietitians, like other health and social care providers (HSCPs) are innovating in the management of chronic diseases such as diabetes, obesity, kidney disease and home nutritional support leading to reduced hospital admissions and use of scarce hospital resources. Dietitians working in areas of advanced practice are pushing the boundaries to assist and support the Sláintecare strategy.

Naturally gastroenterology is an area dietitians are familiar with because diet and the gastrointestinal (GI) tract are intrinsically linked. All five nutrition processes – ingestion, digestion, absorption, assimilation, egestion –depend on the viability of the gut. These processes are greatly impacted by GI disorders such as inflammatory bowel disease (IBD), Coeliac disease, and irritable bowel syndrome (IBS), and therefore patients with these conditions are at high risk of malnutrition and

require dietetic input from the outset.

Dietitians assess nutritional status, diagnose malnutrition and set nutritional care plans that mitigate against poor GI function. We recently shared that 74 per cent of patients with IBS attending Tallaght University Hospital (TUH) believed their symptoms were due to what they were eating. The majority, 75 per cent, of this cohort wanted to see a dietitian, but only 4 per cent got access to our services. Disappointingly, 65 per cent claimed they received no information from any HSCP about diet or their condition at diagnosis.

To quote a survey carried out by the Irish Society of Colitis and Crohn’s (ISCC), 61 per cent of patients with IBD believed their IBD specialists disregarded the importance of nutrition. However, a study of 1,562 gastroenterologists published in 2018 revealed that 90 per cent of GI doctors felt diet was as effective, if not more effective, than medications for IBS. Yet only 21 per cent of them routinely referred their patients to a registered dietitian. If nutrition is an integral part of GI care and expected by our patients, how can we deliver this in an era of lengthy waiting lists and inequitable access to services?

As outlined earlier, many GI conditions are chronic and relapsing in nature requiring routine monitoring by doctors to avoid serious morbidity and/ or mortality. Crippling demand for hospital gastroenterology services have led to lengthy waiting lists, poor clinical

outcomes, and patient dissatisfaction, particularly in relation to patients with functional GI disorders (FGIDs).

FGIDs are disorders of gut–brain interaction. It is a group of disorders classified by GI symptoms related to any combination of the following: Motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system (CNS) processing. Symptoms sometimes overlap with other GI disorders, such as non‑ulcer dyspepsia or Coeliac disease. They are one of 33 adult and 14 paediatric conditions including IBS, functional dyspepsia, sphincter of Oddi dysfunction, belching disorders, and chronic constipation. Often these conditions coexist with others equally complex in nature. According to the World Gastroenterology Organisation (WGO), more than 25 per cent of patients with IBS D (IBS with diarrhoea) have bile acid malabsorption and 20 to 50 per cent report fibromyalgia. Just over half, 51 per cent (n=93), of patients surveyed at the TUH FGID clinic had a GI comorbidity, such as IBD, Coeliac disease or diverticular disease.

IBS

IBS is the most common chronic debilitating FGID seen in health services. Aetiology is unknown, but many dynamics are involved, including gut hypersensitivity, gut brain axis, low grade mucosal inflammation, disturbed colonic motility, and previous GI infection. Environmental factors like stress and anxiety can exacerbate symptoms.

Various subgroups have been defined –constipation predominant, diarrhoea predominant, mixed and unclassified. Symptoms include abdominal pain, bloating, and disordered bowel habits. Extra GI manifestations such as urological or gynaecological symptoms are also common. Diagnosis is clinically based using the ROME IV or NICE criteria.

Unfortunately the time taken to get a diagnosis of IBS can be up to seven years. In that time patients suffer undue anxiety and depression. Often these patients are told what it is not, rather than what it is. Patients need a positive and direct diagnosis, not a diagnosis of exclusion, because quality-of-life is low with a high prevalence of suicidal ideation. Anxiety and depression increase with severity and length of disease. In my experience the earlier these patients are seen, the better the chance of some resolution. Deep-seated anxiety and depression are barriers to progress. TUH has reported that high HADS-D (Hospital Anxiety and Depression Score for Depression) scores are a predictor of poor therapeutic outcomes following dietitian-led diet and lifestyle intervention. Patients with FGIDs require time, a commodity in short supply at a busy medical clinic. With a high placebo response of 15-to-72 per cent reported in literature, reassurance is a powerful tool.

The exact incidence of IBS in Ireland is unknown, but estimates indicate between 9-to-23 per cent of the global adult population are affected. A populationbased study in Europe found an overall prevalence of 11.5 per cent. Females are twice as likely to be affected as males with a preponderance in younger patients. Recent trends indicate a significant prevalence in the older population. In some cases symptoms date back to childhood or a previous trauma, such as abuse or bereavement.

Global burden of FGIDs

FGIDs are a significant burden to healthcare providers globally. IBS has

been associated with increased healthcare costs, with some studies suggesting annual direct and indirect costs of up to $30 billion. In 2003 the NHS spent £45.6 million or 0.1 per cent of the total annual expenditure on IBS, which in current times would equate to £115 million. We know patients with IBS visit the doctor more frequently, use more diagnostic tests, consume more medications, miss more work-days, have lower work productivity, are hospitalised more frequently, and consume more overall direct costs than those without IBS.

and consultants alike. Repeated clinic appointments and medical or surgical procedures alongside polypharmacy are well documented issues encountered on the bumpy patient journey. Due to unresolved symptoms patients display healthcare-seeking behaviour and often attend multiple hospital services including pain, neurology, and gynaecology. Despite this barometer of how poorly we are performing for this cohort, current clinical pathways are either inefficient or, in most cases, absent. So where should health services target and invest resources to tackle this elephant in the consultation room?

Resource utilisation is highest in patients with severe symptoms and poor healthrelated quality-of-life (HRQOL). IBS is the second highest cause of work absenteeism and presenteeism after the common cold. FGIDs in their various forms comprise 25-to-50 per cent of all referrals to gastroenterologists. A recent webinar noted that IBS accounts for one-in-30 patients attending primary care in the UK. Compare that to one-in-100 with Coeliac disease and one-in-250 with IBD and the size of the problem becomes apparent.

Unfortunately medical and pharmacological management has been largely unsuccessful in managing global symptoms to date. Novel drug treatments are coming on stream, but are expensive and patients have difficulty affording them and seek funding from hardship schemes. Poor clinical outcomes lead to a revolving door experience for patients

Dietetic services have been highlighted in a UK NICE clinical guideline cost report as a potential cost-saving resource. Diet and lifestyle change is recognised as an effective primary management strategy for FGIDs. Access to correct and timely dietary advice is important as it encourages disease acceptance, but this is a challenge given what we know about dietetic staffing. Counselling should include information on general lifestyle, physical activity, symptom-targeted medication, and encourage a self-help approach. Clinical practice guidelines suggest a step-up approach, because standard lifestyle advice reduces symptoms by 49 per cent. TUH reported similar results of 46 per cent in a group setting.

FODMAP diet

Second-line advice, such as a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet should only be considered where symptoms persist. FODMAPs are osmotically active carbohydrates known to induce GI symptoms in those with FGID. It has been shown that approximately 75 per cent of patients who are prescribed the diet report a sustained symptom response. A recent evaluation has shown that the FODMAP diet is only highly effective when implemented by specifically trained dietitians, despite a growing trend for non-dietetic education.

If nutrition is an integral part of GI care and expected by our patients, how can we deliver this in an era of lengthy waiting lists and inequitable access to services?

A new model of care

Traditionally patients with FGIDs referred to tertiary dietetic services are transferred to community dietetic services, which remain grossly under-resourced with lengthy caseloads of higher-risk patients. Even if community dietetic departments were adequately resourced, a lack of specialised training required to manage FGID means services would require investment. The nutrition subcommittee of the National Clinical Programme (NCP) for Gastroenterology and Hepatology (NCPG&H) are advocating for increased staffing in dietetics to facilitate alternative models of care. Dietitians as the first point of contact can assess and manage these patients under the clinical governance of a consultant gastroenterologist. The dietitian-led FGID clinic at TUH is an example of the Sláintecare 'right care, right place, right time' model of care, which aims to triage patients to the most appropriate HSCP for their need and improve the overall patient experience.

At TUH we found patients referred from primary care with IBS-like symptoms were waiting on average three-to-five years to be seen by a consultant gastroenterologist. Approximately 20 per cent of patients attending gastroenterology clinics had a documented history of FGID. Using a quality initiative framework, a new pathway was devised whereby referrals from GPs were triaged by a consultant gastroenterologist. Patients with negative screens were diverted to a dietitian-led education programme involving faceto-face group education or individual appointments. The programme has since transitioned online due to the pandemic. Patients are reviewed by phone or via the HSE’s Attend Anywhere video call platform.

Pilot results avoided 77 new gastroenterology appointments and 68 new scope referrals (savings €47,138), with 331 patients being removed from the return waiting list for gastroenterology avoiding an estimated 110 scopes (savings €103,090). There was a 42 per cent reduction in gut hormone profiling

for these patients (savings €12,210) and the return gastroenterology waiting list reduced by 10 per cent. Clinically, 46 per cent of patients have had a significant improvement in their symptoms following first-line dietary advice, with 73 per cent reporting significant improvement after low FODMAP dietary advice. Every one, 100 per cent, of the patients attending the service would recommend it to friends and family with 97 per cent gaining useful and practical information. We also found there was a statistically significant reduction in use of medication after 12 weeks on the programme. We noted a reduction in the prevalence of anxiety from 63-to54.3 per cent and in depression from 33.3-to-22.2 per cent in those who gained symptomatic relief.

a dietitian-first gastroenterology clinic in Queensland Australia in 2016 showed that 78 per cent of category 2 and 3 patients referred to a gastroenterologist could be managed exclusively in the dietitian-led clinic. Category 2 was being defined as having a condition that could potentially require more complex care if treatment is delayed, while category 3 was having a condition that is unlikely to deteriorate quickly or require more complex care if treatment is delayed. These included suspected/confirmed Coeliac disease or IBD, undiagnosed low haemoglobin, gastroesophageal reflux disease (GORD) or malnutrition. The dietitian was given authority to request pathology tests and triage appropriate patients to colonoscopies and scans and provided nutritional advice where appropriate. Patients who could not be managed exclusively by the dietitian progressed to a consultation with the gastroenterologist.

Conclusion

Tallaght was the first post of its kind in the Republic of Ireland. Due to its success there have been an additional three posts sanctioned at clinical specialist level in both Dublin and regional hospitals.

This is not a novel idea. The strategy of extending the scope of HSCP practice to address issues within the health system has been adopted by the UK, US, and Australia. Benefits of extended scope practitioners (ESPs) include shorter waiting times, faster diagnoses, better clinical outcomes, and increased patient satisfaction. Examples of GI dietitian-led value for money services in the UK include dietitian-led Coeliac clinics, dietitian-first gastro clinics, and primary care IBS services. Evaluation of

We all know the phrase – If you change nothing, nothing will change. Disrupting the status quo is inevitable. In workforce submissions we need to consider skill mix for our patients going forward. Which professional does the patient need to see for optimal outcomes? The patient journey is no longer linear and does not always need to start with a doctor. We need to consider patients’ expectations and rethink the practice that all patients need to see a doctor. We need more GI specialised HSCPs, including registered dietitians, clinical nurse specialists (CNSs), GI physiologists, and GI psychologists to manage the complexities of these patients. In the meantime, a sensible approach to managing your patients with FGIDs in the short-term would be to get other HSCPs at your practice to deliver firstline lifestyle advice to patients as per UK NICE guidelines and reserve onward dietetic referral and expertise for secondary interventions such as the low FODMAP diet. ■

References on request

Benefits of extended scope practitioners (ESPs) include shorter waiting times, faster diagnoses, better clinical outcomes, and increased patient satisfaction

Latest European guidelines for microscopic colitis

Microscopic colitis (MC) is an increasingly recognised inflammatory bowel disease (IBD) associated with significant symptom burden and an impaired health-related quality-of-life.

It is characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, non-bloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, collagenous colitis (CC), lymphocytic colitis (LC) and incomplete microscopic colitis (MCi).

With persistent uncertainties and new developments in the clinical management of MC, the United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) identified the need to develop updated clinical practical guidelines in order to increase awareness for MC and support clinicians to improve clinical care of MC patients in daily routine practice. New European guidelines on MC by the UEG and EMCG were published in late 2020. These EMCG/UEG guidelines provide evidenced-based statements and recommendations for essential aspects of the clinical management of MC. They provide information on epidemiology and risk factors of MC, as well as evidencebased statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics.

Several unmet needs have been identified, including a better understanding of the natural course and pathophysiological mechanisms of disease, reliable non-invasive biomarkers, validated instruments for assessment of disease activity and new treatment modalities.

The main objective and potential of these guidelines is to increase awareness for a

presumably under-recognised medical condition and to improve medical care and patient outcomes.

Presentation and incidence

The pathogenesis of MC is complex and multifactorial, potentially including luminal factors, immune dysregulation, and genetic predisposition.

The clinical course of MC is variable, with chronic or recurrent mild to severe symptoms persisting for months to years, having a significant negative impact on quality-of-life.

of 50.1 per 100,000 person-year for CC and 61.7 per 100,000 persons for LC.

The pooled frequency of MC in patients with unexplained chronic watery diarrhoea is 12.8 per cent (95% CI: 10-16), with significant heterogeneity (I2 = 93.6%).

In relation to risk factors, former but especially current smoking is associated with an increased risk for both CC and LC.

The risk of developing CC or LC is higher in women than in men.

Chronic or frequent use of proton pump inhibitors (PPIs), non-steroidal antiinflammatory drugs (NSAIDs) or selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of MC. However, this does not imply a causal relationship. The guidelines suggest considering withdrawing any drugs that are suspected of having a chronologic relationship between introduction of the agent(s) and the diarrhoeal onset.

The diagnosis of MC relies on the histological examination of colonic biopsies and requires dedicated gastroenterologists, endoscopists, and histopathologists.

According to the guidelines, the pooled overall incidence rate of MC is estimated to be 11.4 (95% CI: 9.2-13.6) cases per 100,000 person-years. The incidence of CC and LC ranges from 0.6 to 16.4 cases per 100,000 person-years and from 0.6 to 16.0 cases per 100,000 person-years, respectively.

The pooled overall prevalence of MC is estimated to be 119 (95% CI: 73-166) per 100,000 persons, with an overall prevalence

MC does not raise the risk of colorectal cancer or adenoma; thus a special surveillance colonoscopy programme is not recommended.

MC diagnosis should be ruled out in patients fulfilling the criteria for functional bowel disease, especially in the presence of MC risk factors and/or in the absence of irritable bowel syndrome (IBS)-therapy response.

Diagnosis

Endoscopic findings are recognised with increased frequency in patients with MC; however, they are non-specific, the guidelines note.

The histopathologic criteria of CC are a thickened subepithelial collagenous

The main objective and potential of these guidelines is to increase awareness for a presumably under-recognised medical condition and to improve medical care and patient outcomes

band ≥10µm combined with an increased inflammatory infiltrate in the lamina propria. The criteria apply to haematoxylin and eosin (HE)-stained slides.

The histopathologic criteria of LC are an increased number of IELs ≥20 per 100 surface epithelial cells combined with an increased inflammatory infiltrate in the lamina propria and a not significantly thickened collagenous band (<10µm). The criteria apply to HE-stained slides.

For histological diagnosis of MCi, the guidelines note that MCi comprises incomplete CC (CCi; defined by a thickened subepithelial collagenous band >5µm but <10µm) and incomplete LC (LCi; defined by >10IELs but <20IELs and a normal collagenous band). Both types show a mild inflammatory infiltrate in the lamina propria. The criteria apply to HEstained slides.

In borderline cases, it is recommended to use a supplementary special stain or an immunohistochemical staining procedure in addition to HE stains.

In patients with suspected MC, the guidelines recommend ileocolonoscopy with biopsies from at least the right and left side of the colon. They recommend against histological monitoring in patients with MC and state that faecal calprotectin is not useful to exclude or monitor MC.

The guidelines also recommend screening for Coeliac disease in patients with MC. Testing for bile acid diarrhoea is not part of routine diagnostic work-up in patients with MC, but can be considered in patients who experience non-response to budesonide treatment.

Treatment

In relation to treatment, based upon the available evidence and expert opinion, a therapeutic algorithm for MC is included in the guidelines (Figure 1). This algorithm is supported by a high level of agreement among the guideline group (strongly agree 64.3 per cent, agree 35.7 per cent).

For patients with active MC the guidelines

Active Microscopic Colitis

Induction: Budesonide 9 mg daily, 6 to 8 weeks

Clinical remission

Clinical non-response

Avoid risk factors*

Intolerance, patient‘s preference

Loperamide, Cholestyramine

Clinical relapse

Induction: Budesonide 9 mg/d

Maintenance: Budesonide low-dose (3-6 mg/d) +/- loperamide

Chronic active disease despite budesonide ≥6 mg/d, intolerance

* smoking, NSAID, PPI ** i.e. bile acid diarrhoea, coeliac disease

state that oral budesonide, which is currently the only licensed drug for treatment of MC, should be the medical therapy of choice. The use of prednisolone or other corticosteroids than budesonide for the treatment of MC is recommended against.

Other causes for diarrhea identified by new clinical work-up**

Treat accordingly

consider alternatives: Loperamide, cholestyramine (or in combination), adalimumab, infliximab, azathioprine/6-MP, vedolizumab, surgery

treatment with thiopurines, anti-TNF drugs or vedolizumab in these patients.

Induction: Budesonide 9 mg daily, 6 to 8 weeks

Avoid risk factors*

Intolerance, patient‘s preference

Clinical non-response

Loperamide, Cholestyramine

The guidelines recommend against the use of methotrexate, probiotics, and mesalazine for treatment of MC, and say there is not enough evidence for the use of loperamide, antibiotics, or bismuth subsalicylate.

Induction: Budesonide 9 mg/d

Chronic active disease

Maintenance: Budesonide low-dose (3-6 mg/d) +/- loperamide

Other causes for diarrhea identified by new clinical work-up**

Surgery can be considered in selected patients as a last option if all medical therapy fails.

Chronic active disease despite budesonide ≥6 mg/d, intolerance

* smoking, NSAID, PPI ** i.e. bile acid diarrhoea, coeliac disease

In the case of chronic active disease, longterm treatment with oral budesonide with the lowest possible dose for as long as needed is advised. The question of budesonide withdrawal should be discussed with the patient and decided on an individual basis. In the case of long-term budesonide treatment, supplementation with calcium/vitamin D and monitoring of bone mineral density may be considered on an individual basis, especially in patients with additional risk factors for osteoporosis.

In patients with MC and bile acid diarrhoea the guidelines suggest treatment with bile acid binders. Loperamide may be used on demand if needed.

In budesonide-refractory patients and in patients requiring budesonide more than 6mg per day to maintain clinical remission, alternative medical therapies including immunomodulators or biologics should be considered. The guidelines recommend

Treat accordingly

consider alternatives: Loperamide, cholestyramine (or in combination), adalimumab, infliximab, azathioprine/6-MP, vedolizumab, surgery

In the absence of a formally validated metric of disease activity, disease activity and clinical remission in MC should be assessed by the Hjortswang criteria (clinical remission: mean of <3 stools per day and a mean <1 water stool per day during a oneweek registration). ■

Reference

1. Miehlke S, Guagnozzi D, Zabana Y, Tontini GE, Kanstrup Fiehn AM, Wildt S, et al. European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations. United European Gastroenterol J. 2021 Feb 22;9(1):13–37. doi: 10.1177/2050640620951905.

[Epub ahead of print 2020 Aug]. PMID: 33619914

Treatment targets in inflammatory bowel disease

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders affecting the gastrointestinal tract (GIT). Different disease behaviours have been described based on the extent, depth and severity of mucosal injury. Cumulative injury due to unchecked inflammation results in complications including toxic dilatation, perforation, stricture formation and penetrating complications, leading to abscess and fistula development. These complications often require surgical resection of diseased segments of intestine. The aetiology of inflammatory bowel disease (IBD) is unclear but involves a complex interplay of host genetic, microbiome and environmental factors. As no curative therapy is currently available, the aim of treatment in IBD is focused on inducing and maintaining disease remission to reduce progressive bowel damage.

Increasingly potent anti-inflammatory and immunosuppressant therapies have been employed to control disease and prevent progression. Several different inflammatory cytokine pathways have been implicated resulting in targeted biological therapies. Treatment targets in IBD have evolved with the development of these increasingly successful and complex therapeutic modalities (Table 1). The traditional targets of symptom control and normalisation of inflammatory markers are no longer acceptable targets as these have not been shown to prevent disease progression. With the development of targeted biological therapies, therapeutic goals and end-points have shifted towards achieving resolution of mucosal inflammation and ulceration, thereby minimising the development of disease complication, reducing hospitalisation and need for surgical intervention. A ‘treat-to-target’ approach has been increasingly supported, with the target

moving beyond clinical response or remission to focus sharply on endoscopic response. There is an increasing body of evidence to suggest a more profound disease remission and normalisation of intestinal function when mucosal healing is achieved. Nonetheless, accurate assessment of intestinal healing beyond direct endoscopic visualisation remains a challenge and some remain sceptical that the risk of treatment toxicity and costs involved in achieving such targets outweigh the benefits and do not necessarily alter the natural history of the disease.

This article will review the components of disease monitoring in IBD including clinical,

disease course prevention of complications, or rates of surgical intervention. Clinical disease activity indices including the Harvey Bradshaw index (HBI), and the Crohn’s disease activity index (CDAI) for CD as well as the (partial) Mayo score for UC, which focus mainly on clinical signs and symptoms, provide simple assessment tools for the clinical setting. While symptom relief is important for patients and correlates with improved quality-of-life as measured by patient reported outcomes (PRO), it is an insufficient treatment target in isolation. Clinical symptoms alone correlate poorly with the extent of mucosal inflammation in CD and may indeed over-estimate the

biochemical, and endoscopic assessment, and discuss the evidence for mucosal healing as the optimal treatment target to prevent cumulative bowel damage and subsequent surgical resection.

Clinical remission

The initial treatment of CD and UC involved non-selective systemic immunosuppression with treatment success monitored largely by clinical symptoms (and simple blood markers of inflammation in some cases). It became evident however that by achieving clinical remission alone, there was no impact on

extent of disease activity. Furthermore, the CALM study demonstrated that treatment escalation guided by symptoms alone does not result in corresponding endoscopic healing. Indeed, a significant number of patients who achieve clinical remission will have persistent endoscopic activity on assessment. On the other hand, persistent symptoms may not necessarily reflect ongoing clinical activity, but may suggest an element of an irritable bowel, bile acid malabsorption or bacterial overgrowth. Therefore, the resolution of symptoms alone as a treatment goal is no longer an acceptable target, as this may lead to

This evolving ‘treat to target’ therapeutic strategy in IBD has been greatly influenced by the management of other chronic inflammatory conditions such as the inflammatory arthropathies, where the concept of early appropriate treatment to prevent higher disease burden and subsequent disability or loss of function is well established

under treatment or indeed over treatment.

Non-invasive assessment of mucosal healing

Non-invasive biomarkers of inflammation including C-reactive protein (CRP) and faecal calprotectin (FCP) have been employed to detect disease activity in IBD with varying success across studies. The addition of these objective biomarkers of inflammation to clinical symptoms to create a composite assessment tool improves the sensitivity in detecting endoscopic disease activity. CRP correlates well with severe endoscopic activity and treatment response to biologic therapy, however, it is less sensitive for mild to moderate disease activity. While there is an association between low CRP values and reduced risk of clinical relapse, a normal CRP does not exclude endoscopic activity as approximately 20-to-30 per cent of patients do not mount a CRP response. Therefore, it cannot be used as a reliable measure of mucosal healing.

Indeed, there is no consensus regarding the optimal CRP cut-off to determine disease remission with values of <5 and <10 used as targets in various studies. Moreover, as CRP production may itself be inhibited by potent inhibitors of pro-inflammatory cytokines, a CRP decrease may not in fact correlate with healing of the mucosa. FCP has the advantage of increased sensitivity for intestinal inflammation however it is not IBD-specific. FCP correlates poorly with clinical disease indices but performs better as a measure of endoscopic disease activity correlating closely with endoscopic severity indices, with a sensitivity of 82 per cent in detecting endoscopic disease activity. Reductions in FCP following treatment initiation have been associated with improved longer-term outcomes, with a persistently elevated FCP following treatment induction increasing the likelihood of subsequent relapse. It is unclear however what threshold of FCP should be targeted, with one study demonstrating an accuracy of 87 per cent in detecting endoscopically active disease using a threshold of >70ug/g, while others found that cut-off values of 82-168ug/g at week 12-to-14 following anti-TNF therapy initiation was

predictive of clinical remission. Moreover, the authors of the recent STRIDE-II update consider the range of 100-250ug/g a grey zone given the low reliability of FCP. The value of FCP as a marker of disease activity applies mainly to colonic and ileocolonic disease with its ability to detect ileal disease significantly reduced, limiting its use in CD. Given the ambiguity regarding effective thresholds and its limited reliability beyond the colon, FCP alone cannot be supported as a reliable measure of mucosal healing in IBD.

Endoscopic healing

Disruption to the intestinal barrier function and the subsequent host immune response is a key component of the pathogenesis in IBD. Targeting mucosal healing and restoring the normal intestinal mucosal function is therefore more likely to result in better longer-term outcomes. The presence of persistent inflammation, whether associated with clinical symptoms or not, is associated with a higher risk of hospitalisation, with frequency of disease exacerbation (many of which require corticosteroid use), and with long-term disease-related complications (Table 2). The resolution of intestinal inflammation and ulceration is therefore an integral component in the success of medical therapies in CD. Ileo-colonoscopy remains the gold standard by which to assess mucosal

healing and allows direct visualisation.

Several endoscopic scoring systems are used to stratify disease severity including the Crohn’s Disease Endoscopic Index of Severity (CDEIS), the Simple Endoscopic Score for Crohn’s Disease (SES-CD), and the Rutgeerts’ Score for post-operative recurrence for CD, as well as the Mayo score and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for UC. These scoring systems grade the severity of mucosal disease activity based on the presence of erythema, oedema, superficial or deep ulceration, and the extent of mucosal surface involvement either in the native or postoperative bowel.

Direct visualisation also allows for the detection of complications such as stricture formation and possible therapeutic intervention such as stricture dilatation. However, as an invasive test its repeated use for serial and dynamic assessment is limited both by patient and capacity factors. Video capsule endoscopy is more acceptable to patients and provides a visual assessment of small bowel mucosa, however, it is limited by the risk of retention due to stricture formation and is not universally available.

The identification of valid biomarkers of disease activity would therefore represent an

Reduction in SES-CD ≥50%

Yzet et al (2019) CDEIS = 0

CDEIS 1-4

TABLE 1: Treatment targets in Crohn’s disease

48)

Partial mucosal healing

attractive and acceptable method of disease monitoring. Nonetheless, the currently available non-invasive serum and faecal biomarkers, while demonstrating modest sensitivity at detecting mucosal inflammation, do not detect the presence of disease complications such as deep ulcers, strictures, or fistulae with any reproducible accuracy. Their use may better lie in identifying patients with persistent sub-clinical disease activity that would benefit from further, more invasive, disease assessment.

Defining mucosal healing

Clinical trials of newer biological agents have focused on mucosal healing as a treatment target which, when achieved, has been associated with sustained steroid-free remission, reduced hospitalisation and need for surgery, as well as improved quality-oflife. Despite the shared treatment target, there is no validated definition of mucosal healing in patients with IBD, or indeed a consensus regarding how best it should be assessed. Various definitions or descriptions have been employed and used almost interchangeably across studies ranging from partial response, mucosal improvement, and endoscopic remission. There is no consensus regarding the extent of healing necessary to alter the disease course. Whether this entails complete endoscopic resolution of mucosal inflammation and ulceration or rather an

improvement from baseline has been debated. Initial clinical trials involving biologic agents assessed drug efficacy in terms of clinical remission, specifically targeting a CDAI <150 measured at time points ranging from four to 52 weeks, but did not identify mucosal healing as a specific target. The SONIC trial was the first to propose mucosal healing as a treatment target, qualified by the resolution of ulceration from baseline to week 26 and demonstrated higher rates of mucosal healing with combination infliximab and azathioprine therapy compared with either as monotherapy. This was the first study to establish the concept of using a combination of immunosuppressive agents in IBD to achieve corticosteroid-free remission and mucosal healing. Following this, the CALM study assessed biologic-naïve patients with active endoscopic CD (CDEIS >6) with treatment escalation with adalimumab based on symptoms alone compared with symptoms and biomarkers combined. The treatment target in the study was mucosal healing defined by a CDEIS score of <4 with the absence of deep ulcers at 48 weeks. This study demonstrated higher rates of mucosal healing in those with timely treatment escalation based on clinical symptoms combined with biomarkers.

This evolving ‘treat to target’ therapeutic strategy in IBD has been greatly influenced by the management of other chronic

inflammatory conditions such as the inflammatory arthropathies, where the concept of early appropriate treatment to prevent higher disease burden and subsequent disability or loss of function is well established. Increasingly, more ambitious therapeutic goals have been targeted involving the resolution of mucosal inflammation and ulceration with the aim of preventing irreversible bowel damage. Most recently the STARDUST trial, which assessed the efficacy of maintenance ustekinumab in CD using endoscopic response as its primary outcome, defined response by a reduction in SES-CD of ≥50 per cent at week 48 from baseline. Interestingly, it found similar rates of endoscopic response in patients treated with ustekinumab maintenance using either a treat-to-target or standard of care approach.

While there remains uncertainty regarding the optimum target or extent of mucosal healing, treatment strategies in both clinical trials and clinical practice are evolving and supporting the early introduction and escalation of biologic agents aimed at the more comprehensive target of improvement of mucosal injury. One small recent retrospective study with a median follow up of 4.8 years demonstrated lower rates of treatment failure, less requirements for surgery, and fewer hospitalisations in patients achieving complete mucosal healing (CDEIS=0) compared with partial healing (CDEIS 1-4).

We now recognise that IBD is characterised by progressive bowel damage. There are risks of silent disease progression involving stricturing and penetrating complications and risk of disease flare if treatment is based solely on treating symptoms. Biomarkers such as CRP and FCP are useful but lack sensitivity and are therefore best employed as suggested by STRIDE II, as intermediate treatment targets. Ultimately, consensus now favours endoscopic monitoring and the optimisation of treatment when feasible to achieve endoscopic mucosal healing. The benefits of achieving this target include reductions in the frequency of disease exacerbations, less corticosteroid use, lower risk of hospitalisation

Food, (and not so) glorious food

Food is important in so many aspects of life and health. It can bring joy, love, comfort, cultural expression, and good health. But like many will know there is a dark side to food, in particular when it is inadequate, in excess, contaminated, or of poor quality. Food is powerful. Food and food choices can carry and increase the risk of diseases, result in malnutrition, contribute to climate destabilisation and even cause death. Trying to address these health issues can sometimes feel as helpless as facing an asteroid hurtling towards Earth. The impact of food-related disease

Food and infectious disease (i) H. pylori

The bacteria helicobacter pylori (H. pylori) can infect the stomach and cause a spectrum of symptoms and disease. It not only affects the infected individual, but also has wider healthcare implications. H. pylori is thought to be transmitted through contaminated food and water, as well as person-to-person spread. It can be carried asymptomatically, cause gastritis, ulcer formation, gastric adenocarcinoma and MALT lymphoma, as well as contribute to the burden of

are infected with H. pylori, and up to 80 per cent of populations in developing countries. Of these, 10 per cent will develop a duodenal or gastric ulcer, and up to 3 per cent may develop gastric cancer and MALT lymphoma. H. pylori is therefore an important health problem, and a significant contributor to the global burden of disease.

A ‘test and treat’ strategy has been shown to be effective in eradicating H. pylori. It also significantly reduces the need for endoscopy by approximately twothirds of cases. This contributes to an overall reduction in healthcare costs. The annual national cost of elective day case upper gastrointestinal (GI) endoscopy performed in Ireland is an estimated €29.9 million per year.

can have a significant impact on an individual’s health, but also cause a chainreaction that is felt across healthcare and society for many years to come. This article will review the public health consideration of food and nutrition, and the important interventions that physicians can integrate into their daily practice, benefitting patients and the wider population.

Food and disease

Communicable and non-communicable disease can arise from food and malnutrition. This is something that physicians encounter on a daily basis, through their management of people with obesity, cardiovascular disease, infectious colitis or gastroenteritis, and many more conditions.

dyspepsia in the population. It has been estimated that approximately 40 per cent of the population will at some time in their lives experience dyspepsia, and 2 per cent will lose time from work because of it. Approximately 20-to-50 per cent of populations in Western countries

To maximise health and healthcare benefits, H. pylori should be eradicated. This in turn should be confirmed with follow-up investigations to ensure eradication has been successful. Eradication of H. pylori is the most effective way in preventing the recurrence of duodenal ulcer, and contributes to the reduction of the burden of dyspepsia and other negative outcomes of H. pylori infection (see Table 1). Population screening for H. pylori bacteria in the Irish context has previously been

Approximately 20-to-50 per cent of populations in Western countries are infected with H. pylori, and up to 80 per cent of populations in developing countries. Of these, 10 per cent will develop a duodenal or gastric ulcer, and up to 3 per cent may develop gastric cancer and MALT lymphoma

discussed. There are potential positives of screening, however, there are additional considerations such as antimicrobial stewardship, and demand on services. This is a particular consideration with increasing antimicrobial resistance as well as the pandemic having given rise to a backlog of healthcare delivery. An effective local implementation of a ‘test and treat’ strategy, with followup for eradication, has the potential to significantly decrease the burden of disease in our populations, decrease the use of long-term medications, and reduce the burden on endoscopy departments.

(ii) Food poisoning

Another common communicable disease encountered in gastroenterology is ‘food poisoning’; gastroenteritis and infectious colitis. Verocytotoxigenic E. Coli (VTEC) is a particular issue in Ireland (see Figure 1), and a significant public health burden. VTEC can be spread from person-to-person, through contact with farm animals or through contaminated food and water. Ireland has the highest incidence of VTEC in Europe at a rate of 18.6/100,000. Once again, its impact is not only a risk to the infected individual, but additionally causes major challenges to close contacts and the healthcare setting.

There is a risk of developing haemolytic uraemic syndrome (HUS) in 5-to-12.5 per cent of people with VTEC, in particular in paediatrics and the elderly, which can be fatal in 3-to-5 per cent of people. Approximately 12 per cent can have long-term sequelae from HUS. VTEC can be suspected not only on clinical grounds based on symptoms, but also on epidemiological grounds, such as contact with farm animals or using drinking water from an untreated private well. It has a low infectious dose, can be carried asymptomatically, and have prolonged shedding of the virus in stool.

In a healthcare setting, there are a number of vulnerable persons at higher risk of acquiring and spreading the infection. Healthcare workers play

an important role in reducing that risk through good hand washing and food handling practices. A healthcare worker who contracts VTEC will also be required to submit two negative stool samples in order to return to work (ie, microbiological clearance). In adults, VTEC can take on average seven days due to viral shedding, and in children it could take several weeks following the resolution of diarrhoea. Antibiotics are ineffective in treating VTEC. Prevention is better than cure, and therefore handwashing is better than repeated stool samples.

Food and nutrition

There are also many non-communicable diseases associated with food and nutrition that have a wider public health impact. The healthcare system in Ireland faces the double burden of malnutrition that includes undernutrition as well as obesity.

(i) Undernutrition

Malnutrition is a significant health issue in Irish hospitals. One-in-three people admitted to hospital is malnourished. Undernutrition can increase a person’s risk of infection, pressure sores, falls, readmission, and death. There is also an associated increased healthcare cost and prolonged hospital stays in those who are malnourished. Overall it results in poorer outcomes for patients, with many of these potentially avoidable. Disease-related

malnutrition annual cost is estimated to be €1.42 billion, representing more than 10 per cent of the total health and social care budget. Screening at-risk patients with a validated screening tool will result in early detection and management of those at risk. Widespread implementation of screening for malnutrition such as the Malnutrition Universal Screening Tool (MUST) at admission will result in more effective interventions, improve patient outcomes and reduce healthcare costs. Trainees can avail of nutrition study days, a core part of higher specialist training (HST), to support their education and deepen their understanding of their role in the prevention of malnutrition-related health outcomes.

(ii) Obesity

On the other end of the spectrum is obesity. Ireland has one of the highest levels of obesity in Europe with 60 per cent of adults and more than 20 per cent of children living with overweight and obesity. Obesity increases the risk of developing a number of GI health issues, including but not limited to Barrett’s oesophagus, gastroesophageal reflux disease (GORD), inflammatory bowel disease (IBD), colonic polyps, and some GI cancers such as oesophageal, gastric, colorectal, hepatocellular, and pancreatic cancer. The endoscopic investigation and management of these conditions is further complicated by obesity. Some studies have

shown that people with obesity may require more aggressive bowel prep, and there is speculation that there may be increased difficulty achieving caecal intubation, potentially prolonging the procedure, increasing the risk to the patient, and the risk of an incomplete procedure. Gastroenterology clinics and endoscopy are seeing a rise in patients living with obesity.

Screening and brief health interventions for obesity can be effective in supporting weight loss. In clinical practice, it is rare to make these opportunistic interventions on weight. Healthcare workers are among the most trusted in society as an information source, and screening opportunistically and advising on weight loss can help support your patients to improve health. This can be further enhanced by supporting them through referral to an available community weight-loss programme. This may cost the health service initially, but one study in the UK showed that a community weight-loss programme is cost-effective from the third year and cost-saving from the ninth year onwards over an entire 20-year period, as it reduces the number of obesityrelated health conditions. Ireland currently has some community weightloss programmes on offer that may be available in your catchment area.

(iii) Adequate nutrition

Adequate nutrition is one of the most effective (and least costly) ways to decrease the global burden of disease. Screening for malnutrition and early involvement of dietetics are important tools at a physician’s disposal. Moreover, to further support adequate nutrition, the HSE has a ‘Healthy Food for Life’ campaign with many readily available online resources. They have healthy eating guidelines for all people over the age of five years, including for older and pregnant or breastfeeding people. The 101 Square Meals recipe book is a freely available starting point for those people that are open to improving their nutrition.

Understanding and supporting nutrition is an important part of the national Gastroenterology and Hepatology Higher Specialist Training (HST) curriculum:

“To understand energy homeostasis, under nutrition and be capable of determining nutritional status, applying that knowledge and appropriate skills to providing additional nutritional support….”

Despite the importance of nutrition as a leading cause of morbidity and mortality, nutrition being a recognised learning outcome in HST, and patients placing their trust in doctors as their information source on nutrition, many physicians are not confident in their nutrition-related counselling skills. This represents a gap in the needs of our patients and the delivery of care. To mitigate against the rising tide of nutrition-related illness, doctors should be skilled in meeting the needs of the people they serve and empower people to achieve better health outcomes. The Irish Society for Clinical Nutrition and Metabolism (IrSPEN) has a number of educational and professional resources, including the Life Long Learning (LLL) Programme for medical professionals.

Food and climate

Healthcare is a major contributor to climate destabilisation, and therefore paradoxically a contributor to the burden of disease in our patients. Food, including hospital food, has an important role in its intersectional and pivotal place in climate destabilisation. Globally, Ireland is considered a ‘major emitter’ of greenhouse gases which contribute to climate breakdown, and is considered one of the worst in the European Union. An estimated 71 per cent of emissions from healthcare are derived from the healthcare supply chain; the goods and services an organisation avails of. These are known as scope 3 emissions. They are as of a result of the activities of healthcare but are not owned or controlled by the institution itself, eg, pharmaceuticals, medical devices, personal protective equipment (PPE).

Of these, 9 per cent are associated with the provision of food and agricultural products. It is estimated that up to 49 per cent of the food provided to patients in Irish hospitals is not eaten. Uneaten food is wasted food, is not contributing to nutrition, but directly contributing to increased costs and increased emissions. Early consultation with dietetics to tailor the food to the nutritional needs of the patient can reduce food waste, reduce the climate impact, and support your patients’ health.

Conclusion

This year, NASA and the European Space Agency (ESA) plan to test a new launch that would aim to nudge an asteroid off course and away from Earth. The asteroid causing concern is 11 million light years from Earth, and is not an immediate threat, but they are preparing now. Much like an asteroid, being conscious of the role food and nutrition plays in the health of our patients and implementing strategies to redirect their course toward better health outcomes is preventative. Food and nutrition play a powerful and complex role in health and healthcare in Ireland, and healthcare workers are an important driver in the direction of their patients’ health. Incorporating preventive practices on a daily basis for the future health of patients, wider society and the planet, can feel like nudging an asteroid that is impossibly far away. It takes awareness, extra time, uncertainty if it will work every time, and the results will take years to see. Unlike deflecting an asteroid, we have clear evidence that adequate nutrition is an effective and low cost way to reduce the global burden of disease. Taking the time in daily practice to screen for food-related infectious diseases, to screen for malnutrition on admission, to screen people living with obesity who may be ready and accepting of change, and to further our education in nutrition counselling may just nudge the trajectory of your patients’ health out of the path of disease. ■

References on request

The European obesity crisis

The European obesity epidemic is one of the most significant and greatest public health challenges that we face today. Over the past few decades, we have seen a stark increase in obesity and now over half of the EU’s population are considered either overweight or obese. This brings a huge burden with suffering and loss of life and it is vital that we unite and act now to reverse this trend and protect future generations.

There are a multitude of digestive and liver diseases that are associated with overweight and obesity. For example, almost 75 per cent of obese individuals have a fatty liver, increasing the prevalence of non-alcoholic fatty liver disease (NAFLD). Additionally, obesity is fast becoming a health risk that is overtaking tobacco as the leading preventable cause of cancer, with evidence showing increased colorectal, pancreatic, oesophageal, gastric and liver cancer rates in obese people. Combined, these five cancers are responsible for over 365,000 deaths per year in the EU, representing almost one-inthree cancer-related deaths.

As well as affecting the health and wellbeing of individuals, obesity places a substantial strain on public healthcare systems, with both direct and indirect costs having an evident effect on society. Estimated to cost the EU over €70 billion annually through healthcare costs, obesity is a driver of lost workplace productivity and stretched healthcare services.

Equally alarming is that there is little expectation that obesity figures will decrease, or even plateau, in the near future. Recent studies have reported that one-in-three children in Europe between the ages of six and nine are either overweight or obese. Childhood weight problems continue throughout later life

too, with evidence showing that four-infive obese adolescents continue to have weight problems as adults.

Like in adults, paediatric fatty liver disease is emerging as one of the most significant complications of childhood obesity. Studies in Germany, for example, have shown a 30 per cent prevalence of NAFLD in overweight and obese children and adolescents.

must do more to increase the availability of quality healthy foods, at a lesser price, to influence consumer choices. The taxation of unhealthy food, like sugar-sweetened beverages (SSBs), has been shown effective in reducing the consumption in Portugal, and could be a measure to be further implemented. On the opposite side there is a need of state economic support for the production and sale of fruit and vegetables. Also, campaigns to increase the availability and reduce the cost of water, such as the 'Drink Up' campaign, can be very significant in reducing obesity.

Promoting a change in eating culture, from ‘on-the-go’ food consumption to nutritious cooked meals, can be achieved through adopting policies that restrict the marketing of unhealthy foods and encourage the reformulation of products to reduce fat and sugar content. Policies that restrict the marketing of unhealthy foods, especially to children, and public health educational programmes can also be enhanced to inform what constitutes a healthy diet.

So, what can be done? Promoting the adoption of healthy lifestyle choices is key in tackling rising adult and childhood obesity rates, especially in tackling high consumption of processed and ultraprocessed foods, which are often high in salt, sugar, and fats. Consumption of ultra-processed foods has dramatically risen in recent decades, with consumers opting for ‘fast food’ items including soft drinks, confectionary, and frozen ready meals instead of home-cooked meals, that are usually healthier.

To limit the consumption of these unhealthy foods, the European Commission and national governments

There is an immediate requirement across our continent for a drastic change in attitudes, approaches, and behaviours towards food consumption. Due to the level of change required, it can only be shifted if there are coherent EU and Member State plans. Through this, we can achieve a new environment for members of the public to be encouraged to, and want to, make healthier and more informed choices related to food consumption.

If we do not change our approach now, the burden of obesity on chronic digestive diseases is only going to become greater, with higher disease prevalence, death rates and economic costs as a result. ■

Obesity is fast becoming a health risk that is overtaking tobacco as the leading preventable cause of cancer, with evidence showing increased colorectal, pancreatic, oesophageal, gastric and liver cancer rates in obese people

The role of bariatric surgery in alleviating the impact of obesity on chronic digestive diseases

The number of patients with obesity and their proportion of the population has been rising worldwide. The World Health Organisation (WHO) claim that globally 1.3 billion people are overweight and 600 million people have obesity. Obesity rates have more than doubled in the last 40 years and are now in excess of 10 per cent for both males and females.

Obesity is associated with an increased incidence of gastrointestinal cancer and the number of obese patients has been increasing in the field of gastroenterological surgery. Many of the leading causes of death and morbidity are chronic disorders, such as colorectal and pancreatic cancer, for which obesity can often be a key contributing factor. Therefore, we can confidently say that obesity is one of the most significant health challenges we face. Bariatric surgery can play an important role in the treatment of obesity and needs to be considered alongside conventional approaches.

The influence of obesity on gastroenterological surgery has been widely studied but few reports have focused on individual organs or surgical procedures. The evidence suggests that faster, sustained and long-term results for patients with obesity can be achieved via surgery. Bariatric surgery is the only treatment modality that produces continuous weight loss in patients with severe obesity. This has the potential to reduce all-cause mortality compared to obese patients not undergoing surgery and weight reduction, despite a relevant mental burden on patients with bariatric surgery that needs to be adequately addressed during follow-up.

More specifically, sustained weight loss via bariatric surgery has been shown to reduce the risk of cancer of any type by 78 per cent.

Weight loss is associated with a reduced risk of a number of metabolic comorbidities, including type 2 diabetes, increased blood pressure and non-alcoholic fatty liver diseases (NAFLD). Studies have also demonstrated that bariatric surgery leads to greater weight loss after the event, when compared with conventional therapy. Amongst the different types of surgical interventions, malabsorptive procedures have typically enhanced weight loss further in comparison with purely restrictive procedures.

Obesity can cause complications and technical challenges in colorectal, pancreatic and liver cancer surgical procedures, particularly in prolonging operative time. Obesity will prolong hepatic resection operative time by approximately 50 minutes, with indications that resection time, blood loss, and rate of pulmonary complications all rise in patients with a BMI above 30. Performing bariatric surgery can help reduce these issues.

In relation to colorectal surgery specifically, while studies have suggested that obesity does not have a negative impact on mortality, various studies have shown that obesity is a significant risk factor for complications and morbidity after surgery. This clearly supports the idea of reducing obesity wherever possible before colorectal surgery through bariatric surgery.

A reduction in obesity-related digestive

diseases from bariatric surgery has broader benefits that need to be considered. If less patients are being diagnosed with conditions like colorectal, pancreatic and oesophageal cancer, it means less visits to their physicians and the hospital.

This in turn helps reduce healthcare costs and the burden placed on healthcare systems, which is particularly important right now during the SARSCoV-2 pandemic. One study has shown that the cost per 1kg of weight loss following bariatric surgery is around 30 per cent of the same weight loss through conventional means.

The obesity crisis in Europe is one of the most serious issues we currently face. There is a clear need for preventive and therapeutic measures and strategies at individual and public health level. Patients with severe obesity can particularly benefit from surgery as their first-line treatment, but this needs to be supported with structured behavioural therapies, dietary programmes and lifestyle changes to reduce calorie intake and increase exercise.

Prof Markus Peck, Chair of the UEG Public Affairs Committee, comments: “Obesity is placing an increasingly significant burden on healthcare systems across Europe and each day the mission to overcome this challenge grows greater. It is essential that we develop and deliver optimal prevention, treatment and care solutions to help tackle obesity and ensure European citizens can live healthy and enjoyable lives with increasing chances of active and healthy ageing.” ■

Hep C : Latest treatment guideline updates

Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide, with approximately 71 million people chronically infected worldwide, leading to 400,000 deaths annually due to cirrhosis complications and liver cancer (hepatocellular carcinoma).

In Ireland, the Health Protection and Surveillance Centre (HPSC) estimates that between 20,000 and 30,000 people are infected with hepatitis C, and of those, approximately 10,000 have been diagnosed, though this figure is disputed by some of the hepatology clinical community.

In 2016, the World Health Organisation (WHO) adopted the first Global Health Sector Strategy on Viral Hepatitis, calling for its elimination as a public health threat. The strategy presented a target for 2030 of reducing new HCV infections by 80 per cent and mortality by 65 per cent. All WHO Member States, including Ireland, have approved this strategy.

One of the major difficulties in eradicating HCV is that significant numbers of patients are unaware of their infection and remain undiagnosed.

Thus key to the eradication goal is actively seeking out undiagnosed HCV cases – healthcare providers should screen individuals with risk factors –and providing free, widely available access to direct acting antivirals (DAAs), which can cure more than 95 per cent of cases and dramatically reduce long-term complications, like liver

failure and hepatocellular carcinoma, with minimal side-effects.

In June 2019, the European Association for the Study of the Liver (EASL) published the EASL Policy Statement on Hepatitis Elimination , and called on all European countries to implement a six-step action plan based on the WHO’s 2030 elimination targets.

and treatments, including accurate rapid HCV antibody screening and confirmatory viral load testing that can be accomplished in a single clinical visit and pan-genotypic DAAs that are available in fixed dose combinations.

In 2018, EASL first published comprehensive clinical practice guidelines, EASL Recommendations: Treatment of Hepatitis C , to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process, by describing the current optimal management of patients with acute and chronic HCV infections.

These recommendations were updated in September 2020 (final update of the series), and can be summarised as follows:

At the end of 2019, EASL and three other health associations also joined forces in a call-to-action initiative: The call-toaction document outlines four clinical strategies that liver disease associations and their constituents can use in their continuing HCV elimination efforts, including simplifying diagnostic and treatment algorithms, integrating HCV treatment with primary care and other disease programmes, decentralising HCV services to local level care, and tasksharing care with primary care clinicians and other healthcare practitioners.

The call-to-action also highlights the efficacy of existing screening

What is new in this final version of the EASL recommendations?

First of all, there are clear recommendations for the diagnosis of the infection, as well as for screening in order to link-to-care as many infected subjects as possible.

Classically, the diagnosis of the HCV infection is based on the detection of anti-HCV antibodies followed by confirmation of the presence of the virus by a molecular, generally polymerase chain reaction (PCR)-based, technique. HCV core antigen testing can be used as an alternative to RNA testing by PCR. For screening, the classical serum or plasma ELISA can be replaced by a

One of the major difficulties in eradicating HCV is that significant numbers of patients are unaware of their infection and remain undiagnosed

whole-blood ELISA on dried blood spots, or by a rapid diagnostic test performed on serum, plasma, whole blood, or even saliva. Reflex testing for confirmation of replication is recommended to simplify and shorten access to treatment.

Once the diagnosis has been made, all subjects with recently acquired or chronic hepatitis C who are naïve to treatment or treatment-experienced (interferon, ribavirin and/or sofosbuvir) should be treated without delay.

Pangenotypic combinations of two directacting antivirals (sofosbuvir/velpatasvir or glecaprevir/pibrentasvir) should be preferred in the therapeutic indication.

Today, the majority of patients should have access to a simplified treatment, without prior determination of the HCV genotype and subtype.

What is required to start antiviral therapy of hepatitis C?

Only three pieces of information are necessary for treatment initiation, according to the revised guidelines: proof of viral replication (presence of RNA or core antigen), determination of the presence or absence of cirrhosis by a non-invasive test (possibly APRI or FIB4, which are easily accessible), and the study of possible drug-drug interactions.

In this case, patients may be treated with sofosbuvir/velpatasvir for 12 weeks, or with glecaprevir/pibrentasvir for eight weeks if they have no cirrhosis or if they have cirrhosis and are treatment-naïve, and 12 weeks if they have cirrhosis and a history of treatment failure. “This simplified approach results in very high sustained virological response rates and, above all, easy access to treatment for a very large number of patients. It is a key option for achieving the WHO elimination targets,” said EASL.

In specialised departments, it remains advisable to perform HCV genotype and subtype determination in order

to offer cirrhotic subjects infected with HCV genotype 3 an enhanced treatment to optimise their response rates, the revised guidelines note. HCV genotype and subtype determination is also very important in regions where HCV subtypes inherently resistant to NS5A inhibitors are frequently found in infected subjects, or in industrialised countries in subjects originating from these regions. However, such determination should be based on sequence analysis (because hybridisation-based assays cannot discriminate these subtypes), which is not available in many places. In the absence of reliable data with the most recent ‘pangenotypic’ dual therapies for most of these subtypes,

plus glecaprevir/pibrentasvir provides a better barrier to resistance to NS5A inhibitors. Treatment can also be reinforced by adding ribavirin and/or extending its duration to 16 or 24 weeks in the most problematic subjects.

What do the updated recommendations mean for the treatment of particular patient groups?

The treatment of many particular HCV-infected groups has been updated in this final version of the recommendations. An important novelty concerns paediatric treatments for which clear indications are given, pending the approval of the corresponding drug formulations.

it is recommended to treat them with the triple combination sofosbuvir/ velpatasvir/voxilaprevir as first-line therapy (subtypes 1l, 4r, 3b, 3g, 6u, 6v or any other subtype that naturally harbours polymorphisms conferring reduced susceptibility to NS5A inhibitors).

What is new on treatment of patients who failed previous antiviral therapy?

Retreatment of patients who failed to achieve viral eradication after an NS5A or protease inhibitor-containing regimen is based on a triple combination of sofosbuvir, velpatasvir and voxilaprevir. In the most difficult-to-cure patients (advanced cirrhosis, multiple treatment failures, presence of complex resistanceassociated substitution profiles), the use of the combination of sofosbuvir

The treatment of adolescents is identical to that for adults. The treatment of HCV during pregnancy is also discussed (but not recommended in the current state of knowledge). Other special groups that are discussed include patients with decompensated cirrhosis, those with hepatocellular carcinoma, solid organ (including liver) transplant recipients, patients who inject drugs and subjects under opioid substitution, and incarcerated subjects. The specific problem of certain co-morbidities (manifestations of HCV related to the formation of immune complexes, patients with renal impairment, co-infection with the hepatitis B virus, hemoglobinopathies and coagulation disorders) is also covered.

Source: https://easl.eu/publication/ easl-recommendations-on-treatment-ofhepatitis-c-2020/

Today, the majority of patients should have access to a simplified treatment, without prior determination of the HCV genotype and subtype

Ireland: National Hepatitis C Treatment Programme

The HSE’s National Hepatitis C Treatment Programme (NHCTP) was established in 2015, and is supported by a Clinical Advisory Group (CAG) and a Programme Advisory Group (PAG). All prescribing clinicians are entitled to membership of the CAG, which concurs with international guidelines and adopts the recommendations as best-practice in the Irish setting. Almost 6,000 people with HCV have been successfully treated with DAAs through the programme to date.

Offered through designated hospital clinics initially, in 2017 DAA treatment was successfully expanded to the drug treatment service with onsite dispensing. In 2019 a community prescribing and dispensing pilot programme (GPs and pharmacists) was initiated, with new guidelines published by the ICGP, and updated in July 2020.

Although the preferred treatment route remains through one of the eight hospital-based treatment centres, community treatment may be preferred if patients find it difficult to attend the hospital-based services for logistical, social or psychological reasons, the guidelines note. For the present, community treatment is restricted to low-risk patients. Patients with cirrhosis, organ transplantation, HIV and recurrent HCV infection should be referred to a hospital treatment centre. It is expected that these criteria may change over time.

Speaking in 2020, Clinical Director of the Programme, Prof Aiden McCormick, Consultant Hepatologist, St Vincent’s University Hospital, Dublin, said Ireland had achieved the interim WHO elimination targets for 2020, and appeared “to be on target to achieve the 2030 elimination targets. More robust metrics will be required to confirm we are achieving this. The targets will only be achieved

if we can identify the majority of infected patients in the country, which requires buy-in from all healthcare providers. Eradication will also require intensification of public health preventative measures, including needle exchange, etc, to prevent new infections and re-infections. It is a goal which can and should be achieved in Ireland.”

Any GPs wishing to become involved in HCV DAA treatment should contact the NHCTP at nhctp@hse.ie.

Dublin and University College Dublin.

“In 2020, we treated approximately 550 people and less than 100 of those in the wider community setting. We have to re-think how we can reach our target of treating 1,500 people per year to eliminate hepatitis C by 2030.

“People on methadone are being identified all the time, but people who may previously have been drug users, but are no longer engaged in care, may be part of the silent epidemic of those lost to follow up.

“We now have a lost cohort of hepatitis C sufferers. Everyone should have a hep C test once in their lifetime, probably during their 40s, as is the case in the US,” Dr Lambert said.

Other groups, he said, must now be targeted for screening, including those who developed HCV from sexual contact, tattoos and non-intravenous drug use.

Behind targets

However, on July 28 this year, to mark World Hepatitis Day, campaigners warned that with around 600-700 new HCV diagnoses annually, Ireland is two decades off elimination targets.

They said this is due to limited availability of treatment for those outside specialist addiction services.

The number being treated by DAAs fell significantly during the Covid-19 pandemicm – from 354 in the first three months of 2019 to just 110 in the first quarter of this year.

The NHCTP treated a total of 1,196 HCV patients with DAAs in 2019 compared to a total of 532 in 2020.

“At the moment, we have probably had as many, if not more, new infections in the past five years as we have treated,” said Prof Jack Lambert, Consultant in Infectious Diseases and Genitourinary Medicine, Mater Misericordiae Hospital,

The infection of large numbers of people from Eastern Europe with tainted blood products following the fall of the Soviet Union – and now living here – is also a contributing factor to rising HCV cases, Dr Lambert noted.

“The scandal is that our neighbours in the UK can have someone tested and beginning treatment within an hour. We are nowhere near that in the community and there are only a handful of GPs prescribing here,” said Ms Kristy Hayes, Head of Advocacy with the Hep C Partnership.

“We are not among the 11 countries worldwide on track to meet elimination targets by 2030.”

In addition, increased alcohol consumption during the Covid-19 pandemic-related lockdown among those unaware they have the infection has also led to more patients presenting with advanced liver disease, advocates point out. ■

The NHCTP treated a total of 1,196 HCV patients with DAAs in 2019 compared to a total of 532 in 2020

TREATMENT-NAÏVE HEPATITIS C PATIENTS*

HELP YOUR PATIENTS START THE JOURNEY TO BEING FREE FROM HEPATITIS

Start 8-week once-daily MAVIRET® in October and your patients can finish Hepatitis C treatment in time for the New Year1*§

9 98% cure† (n=1218/1248) with 8-week MAVIRET® in treatment naive patients with genotype (GT) 1-6 Hepatitis C without cirrhosis or with compensated cirrhosis2

9 The most common adverse reactions (≥10% prevalence) were headache and fatigue2

9 0.2% discontinuation rate due to adverse reactions2

† Cure = sustained virologic response (SVR12), defined as HCV RNA less than the lower limit of quantification at 12 weeks after the end of treatment and was the primary endpoint in all the clinical studies.1

* Refers to GT 1–6, excluding decompensated cirrhotic patients and liver or kidney transplant recipients. MAVIRET® is not indicated in decompensated cirrhosis. The recommended duration of MAVIRET® is 12 weeks in liver or kidney transplant recipients, with or without cirrhosis.1

§ Tablets should be swallowed whole, taken at the same time with food and not chewed, crushed, or broken.1

MAVIRET® is contraindicated in patients with severe hepatic impairment (Child-Pugh C) and not recommended in patients with moderate hepatic impairment (Child-Pugh B).1

Maviret®▼ 100mg/40mg film-coated tablets PRESCRIBING INFORMATION. PRESENTATION: Each film-coated tablet contains 100 mg glecaprevir and 40 mg pibrentasvir. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. INDICATION: For treatment of Chronic Hepatitis C Virus (HCV) in adults and children aged 3 years and older. DOSAGE AND ADMINISTRATION: Oral. Treatment to be initiated and monitored by physician experienced in the management of patients with HCV infection. See SmPC for full posology. Dosage: Adults, adolescents aged 12 years and older, or children weighing at least 45 kg: The recommended dose of Maviret is 300 mg/120 mg (three 100 mg/40 mg tablets), taken orally, once daily at the same time with food. Treatment Duration: Patients without prior HCV therapy (GT 1, 2, 3, 4, 5, 6): No cirrhosis: 8 weeks. Cirrhosis: 8 weeks. Patients who failed prior therapy with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin: GT 1, 2, 4-6: No cirrhosis: 8 weeks. Cirrhosis: 12 weeks. GT 3: No cirrhosis: 16 weeks. Cirrhosis: 16 weeks. Special Populations: HIV-1 Co-infection: Follow the dosing recommendations as above. For dosing recommendations with HIV antiviral agents, refer to SmPC for additional information. Elderly: No dose adjustment required. Renal impairment: No dose adjustment required. Hepatic impairment: No dose adjustment recommended in patients with mild hepatic impairment (Child-Pugh A). Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C). Liver or kidney transplant patients: 12 weeks in liver or kidney transplant recipients with or without cirrhosis, with 16 week treatment duration to be considered for GT 3infected patients who are treatment experienced with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin. Paediatric Population: safety and efficacy of Maviret in children less than 3 years or under 12 kg have not been established and no data are available. Coated granule formulation available for children aged 3 years to 12 years and weighing 12 kg to 45 kg. Refer to SPC for dosing based on body weight. As Tablets and Coated granules

are not interchangeable full course of treatment with same formulation required. Diabetic Patients: Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medicines modified when necessary. CONTRAINDICATIONS: Hypersensitivity to the active substances or to any of the excipients. Patients with severe hepatic impairment (Child-Pugh C). Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate, ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone). SPECIAL WARNINGS AND PRECAUTIONS: Hepatitis B Virus reactivation: HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should, therefore, be monitored and managed according to current clinical guidelines. Hepatic impairment: Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C). Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor: GT 1-infected (and a very limited number of GT 4-infected) patients with prior failure on regimens that may confer resistance to glecaprevir/pibrentasvir were studied in the MAGELLAN-1 study. The risk of failure was, as expected, highest for those exposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistance has not been established. Accumulating double class resistance was a general finding for patients who failed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1. No re-treatment data is available for patients infected with GT 2, 3, 5 or 6. Maviret is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/ or NS5A-inhibitors. Lactose: Maviret contains lactose. Patients with rare hereditary

problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. INTERACTIONS: See SmPC for full details. Contraindicated: Dabigatran etexilate, carbamazepine, phenytoin, phenobarbital, primidone, rifampicin, ethinyloestradiolcontaining products, St. John’s wort, atazanavir, atorvastatin, simvastatin. Not Recommended: darunavir, efavirenz, lopinavir/ritonavir, lovastatin, ciclosporin doses > 100 mg per day. Use Caution: digoxin, pravastatin, rosuvastatin, fluvastatin, pitavastatin, tacrolimus. Monitor Levels: Digoxin, Monitor INR with all vitamin K antagonists. No dose adjustment: Losartan, valsartan, sofosbuvir, raltegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, levonorgestrel, norethidrone or norgestimate as contraceptive progestogen. FERTILITY, PREGNANCY AND LACTATION: Maviret is not recommended in pregnancy. It is not known whether Maviret and its metabolites are excreted in breast milk. No human data on the effect of glecaprevir and/or pibrentasvir on fertility are available. SIDE EFFECTS: See SmPC for full details. Very common side effects (≥1/10): headache, fatigue. Common side effects (≥1/100 to <1/10): diarrhoea, nausea, asthenia. Frequency not known (cannot be estimated from the available data): pruritus.

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900

LEGAL CATEGORY: POM(S1A) MARKETING AUTHORISATION NUMBER/PRESENTATIONS: EU/1/17/1213/001 – blister packs containing 84 (4 cartons x 21 tablets) film-coated tablets. MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany. Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. DATE OF REVISION: June 2021 PI/1213/009

International Liver Congress 2021 meeting report

Priscilla Lynch presents a round-up of the most topical research from this year’s International Liver Congress, which took place in June and was convened by the European Association for the Study of the Liver (EASL)

ILC 2021 opens with focus on impact of Covid-19 on global liver disease

Leading liver disease researchers announced important new developments on the impact of the Covid-19 pandemic on people living with liver disease at the 2021 International liver Congress (ILC 2021) convened by the European Association for the Study of the Liver (EASL). This includes new data indicating that people with advanced liver disease are extremely vulnerable to the novel coronavirus and results of a study that indicates that the Pfizer–BioNTech Covid-19 vaccine confers low immunity on people with advanced liver disease thus a third booster shot is being recommended.

Other announcements included new insights into the impact of the Covid-19 pandemic on the incidence of alcohol related liver disease and mortality rates of people with non-alcoholic fatty liver disease (NAFLD) and some encouraging data on tenofovir in preventing serious Covid-19 illness amongst people living with chronic hepatitis B.

Chronic liver disease increases the odds of Covid-19 death by 80 per cent

A study presented at ILC 2021 found that chronic liver disease increased the odds of Covid-19 death by 80 per cent.

The researchers used the French National Hospital Discharge database to select patients (N=187,283; mean age 66 years; 25 per cent men) aged 18 years and older who

were discharged in the year 2020 with a diagnosis code for Covid-19. They captured standardised discharge summaries, including demographics (sex, age at entry, and postal code of residency); primary and associated discharge diagnosis codes according to the WHO International Classification of Diseases, tenth revision (ICD-10); medical procedures received; length of stay; and discharge modes (including in-hospital death).

and alcohol-use disorders reduced the odds of mechanical ventilation, and therapeutic effort limitation may have contributed to Covid-19 deaths of patients with chronic liver disease.

Meanwhile, a separate study presented at the meeting showed that people living with metabolic associated fatty liver disease (MAFLD) are at higher risk of dying from Covid-19.

Overall, 16,338 (8.7 per cent) patients diagnosed with chronic liver disease were admitted for Covid-19 in France in 2020 and 3,943 (24.1 per cent) of them died, including 2,518 (63.9 per cent) after a liverrelated complication.

Having chronic liver disease increased the odds of Covid-19 death by 80 per cent, while liver-related complications

In this study a total of 348 patients admitted in a tertiary referral hospital located in México city with a positive SARSCoV-2 PCR test from 4 April to 24 June 2020 were analysed. Three groups were formed: Control group (n=80), isolated hypertransaminasemia (IH) group (n=185) and MAFLD group (n=83). Additionally, other variables associated with severity in Covid-19 were obtained, including gender, age, and comorbidities (T2D, hypertension and obesity). A Binary Logistic Regression adjusted to the variables associated with severity in Covid-19 was made to obtain OR of death between the groups.

The researchers reported that the adjusted odds ratio for death with respect to the control group were people living with MAFLD were five times likelier to die during hospitalisation with Covid-19 than people without these factors.

... people living with MAFLD were five times likelier to die during hospitalisation with Covid-19 than people without these factors

New research reveals that tenofovir can reduce the severity of Covid-19 infection in chronic hepatitis B patients

New research presented at ILC 2021 reveals that tenofovir can reduce the severity of Covid-19 infection in chronic hepatitis B patients.

The study aim was to analyse the incidence and severity of Covid-19 in patients with chronic hepatitis B on the antiviral drug treatment tenofovir or entecavir. A database search of 4,736 chronic hepatitis B patients from 28 Spanish hospitals was undertaken.

Beatriz Mateos Muñoz of the Hospital Universitario Ramón y Cajal in Spain reported that 117 patients with Covid-19 were identified, 67 of whom were taking tenofovir and 50 on entecavir.

Just over a third (41, 35 per cent) out of the 117 patients with Covid-19 were hospitalised, and five (4.3 per cent) and six (5.1 per cent) admitted to ICU or died, respectively.

Compared with patients on tenofovir, those on entecavir had significantly (p<0.05) greater rates of obesity (22 vs 9 per cent), diabetes (32 vs 12 per cent), ischaemic cardiopathy (14 vs 3 per cent) and arterial hypertension (44 vs 18 per cent). There was a trend for greater severity of advanced (F3-F4) fibrosis in the entecavir groups (35 vs 18 per cent, P= 0.06).

The incidence of Covid-19 in patients

on tenofovir or entecavir was similar but compared with those on tenofovir, patients on entecavir more often had severe Covid-19, required ICU, ventilatory support, had longer hospitalisation or died. In multivariate logistic regression adjusted by age, sex, obesity, comorbidities and fibrosis stage, tenofovir reduced by six-fold the risk of severe Covid-19.

Patients with chronic hepatitis B on tenofovir have a lower risk of severe Covid-19 infection than those on entecavir, and tenofovir seems to exert a protective effect in patients with chronic hepatitis B infected by Covid-19, the study concluded.

Impact of Covid-19 restrictions on patients with

There was a significant rise in hospital admissions of alcoholic hepatitis patients during the Covid-19 pandemic in a studied region of Canada, according to new data presented at ILC 2021.

The large population-based study evaluated the impact of Covid-19 restrictions on patients with alcoholic and non-alcoholic cirrhosis as well as alcoholic hepatitis who were hospitalised in Alberta, Canada.

The researchers identified 2,916 hospitalisations for non-alcoholic cirrhosis, 2,318 hospitalisations for alcoholic cirrhosis, and 1,408 alcoholic hepatitis hospitalisations between 2018 and 2020.

Abdel-Aziz Shaheen, of the University of Calgary in Canada, reported that alcoholic hepatitis patients had a significant increase in average monthly admissions (69.5 vs 39.6, P<0.001) with April 2020 being the

inflection point. Although alcoholic hepatitis patients admitted post Covid-19 restrictions were younger (median age 43 vs 47, P=0.02), there were no significant differences in admission outcomes preand post-Covid-19 among the alcoholic hepatitis cohort.

Monthly admission rates were stable for non-alcoholic and alcoholic cirrhosis, however, there was a significant 9 per cent increase in alcoholic hepatitis admissions per month between March and September and the average rate of alcoholic hepatitis hospitalisations compared to overall hospitalisations doubled from 11.6/10,000 general hospitalisations to 22.1/10,000 general hospitalisations for the same period.

alcoholic and non-alcoholic cirrhosis as well as alcoholic hepatitis

Monthly admission rates were stable for nonalcoholic and alcoholic cirrhosis, however, there was a significant 9 per cent increase in alcoholic hepatitis admissions

Advanced liver disease a risk factor for lower immune response to Covid-19 vaccine

Older age, and advanced fibrosis with decreased steatosis are risk factors for a lower Covid-19 vaccine response, and these patients may need an additional booster shot, according to the findings of an Israeli study presented at ILC 2021.

Researchers undertook an analysis of 88 patients living with hepatic fibrosis who had received both doses of the Pfizer-BioNTech Covid-19 vaccine to assess their immune response.

Histologic NAS grading and CRN fibrosis scoring showed significant changes. Mean NAS scoring found in the excellent responders as compared with 2.9±1.2 in the good responders (p=0.045), that is mainly derived from significant steatosis changes of 1.6±0.9 vs. 1.2±0.7, repeatedly (p=0.02). Hepatocyte ballooning and lobular inflammation were similar. Importantly, advanced fibrosis corelated with weaker vaccine responses. Mean fibrosis scoring was 1.7±1.1 vs. 2.2±1.5, percentage of advanced fibrosis (F3-F4) were 23 per

cent vs 48 per cent of each group, respectively (p=0.05). Findings were also confirmed by significant changes in blood tests.

Rifaat Safadi of the Hadassah-Hebrew University Hospital in Israel explained that older age, and advanced fibrosis with decreased steatosis are risk factors for lower vaccine response, and added that a third dose vaccine booster in these high-risk factor populations should be evaluated in future trials.

RNAi therapeutic antiviral drug shows promise in chronic hepatitis B infection

The RNAi therapeutic antiviral drug VIR2218 shows promise in participants with chronic hepatitis B infection, new trial data presented at ILC 2021 showed.

VIR-2218 is an investigational GalNAcconjugated small interfering ribonucleic acid (siRNA) therapeutic in development

to silence all major hepatitis B virus transcripts, from both cccDNA and integrated DNA, across all 10 hepatitis B virus genotypes as a single siRNA.

At the conference, Ed Gane of the University of Auckland in New Zealand reported that two doses of VIR-2218 at

Substantial reductions in HBsAg were observed in both HBeAg- and HBeAg+ participants across all dose levels, suggesting that VIR-2218 may silence transcripts from both cccDNA and integrated DNA

for functional cure of chronic hepatitis B virus infection (CHB). VIR-2218 was created using Enhanced Stabilisation Chemistry Plus, which retains in vivo potency while reducing off-target effects. VIR-2218 targets a conserved region of the X gene and is designed

20-200mg given four weeks apart were well tolerated in chronic hepatitis B participants. Substantial reductions in HBsAg were observed in both HBeAgand HBeAg+ participants across all dose levels, suggesting that VIR-2218 may silence transcripts from both cccDNA and

integrated DNA. The antiviral activity of VIR-2218 demonstrated in this study supports continued development as part of combination regimens targeting functional cure.

“Scientists and advocates have long argued that if we are realistically going to eliminate hepatitis B, then we will need a functional cure,” said Prof Philip Newsome, Secretary General of EASL and Professor of Experimental Hepatology and Director of the Centre for Liver Research at the University of Birmingham in the UK. “The results from the trial of RNAi therapeutic drug VIR-2218 are an encouraging example that a cure is possible sooner than later with potential real-world implications for the 300 million people living with the disease.”

Each year 30 million people become newly infected with hepatitis B and an estimated 884,000 people die each year from the disease and related complications such as liver cancer.

Phase 3 trial data on antiviral drug bulevirtide monotherapy in chronic hepatitis D

Encouraging interim data from a phase 3 trial of antiviral drug bulevirtide monotherapy in patients with chronic hepatitis delta was presented at ILC 2021.

Bulevirtide is a first-in-class entry inhibitor for the treatment of chronic hepatitis D virus (HDV) infection. Bulevirtide has shown pronounced virological and biochemical responses (HDV RNA and ALT declines) in two phase 2 trials (MYR202/MYR203).

This latest study showed encouraging data from a predefined 24 weeks interim analysis of the MYR301 phase 3 study in hepatitis B and D virus co-infected patients receiving 2mg/qd or 10mg/qd dose bulevirtide monotherapy in comparison to observation with no antiviral treatment (a total of 150 patients).

Heiner Wedemeyer of the Hannover Medical Hospital in

Germany noted that after 24 weeks of study, this phase 3 trial confirms that monotherapy with bulevirtide is safeand well tolerated in patients with compensated hepatitis delta.

The 24 weeks of treatment with bulevirtide was associated with significant HDV RNA declines and improvements in biochemical disease activity. He concluded that these findings further support the conditional approval of bulevirtide.

chemotherapy combined with sintilimab may help cure early HCC

Hepatic arterial infusion chemotherapy in combination with the PD-1 inhibitor sintilimab may be the best curative option for early stage hepatocellular carcinoma (HCC), according to new phase 2 data presented at ILC 2021.

This study aimed to explore the efficacy and safety of hepatic arterial infusion chemotherapy in combination with sintilimab in locally advanced, potentially resectable HCC. A total of 30 patients were enrolled with a median age of 50.5 years (range 34-70), 93.3 per cent male, and 96.7 per cent HBV-infected. The median treatment cycle was two years.

Tumour evaluation was performed every six-to-eight weeks. Patients with tumour reduction and eligible for R0 resection were referred for hepatectomy, then continued with sintilimab monotherapy to at most 16 courses. Primary endpoint was progression-free survival (PFS) per RECIST 1.1 defined as time from the first day of treatment to disease progression

or postoperative relapse or death.

Li Xu of the Sun Yat-sen University Cancer Centre in China explained that as of April 2021, 29 patients had been evaluated regularly with median follow-up time of 17.1 months (range: 6.5-25.6). Median PFS

Hepatic arterial infusion chemotherapy in combination with this PD-1 inhibitor showed a high conversion rate and good safety profile

and overall survival (OS) were not reached, and 12 months PFS and OS rates were 57.6 per cent (95% CI 41.9-79.2) and 82.3 per cent (95% CI 69.4-97.1), respectively.

The overall response rate and disease

control rate were 44.8 per cent (13/29) and 75.9 per cent (22/29), respectively. A total of 19 (65.5 per cent) patients received hepatectomy with three pathologic complete responses (pCR). Another two patients with deep response received radical ablation, and one was confirmed pCR by needle biopsy.

To date 14 patients remain tumour free. Most treatment-related adverse events were grade 1-2, the most common being pyrexia (10 per cent), rash (10 per cent) and pruritus (10 per cent). Only one patient experienced reversible immunerelated liver dysfunction of grade 4. No other grade 3-5 treatment related adverse events were observed.

Hepatic arterial infusion chemotherapy in combination with this PD-1 inhibitor showed a high conversion rate and good safety profile. The combined strategy may be considered as an optimal treatment choice to provide a chance of cure in locally advanced and potentially resectable HCC the study concluded.

Infusion

Novel liver dialysis device shows encouraging preliminary results in chronic liver failure

A novel liver dialysis device that rids the body of dysfunctional albumin and replaces it with fresh albumin significantly improved survival rates among patients with acute-on-chronic liver failure (ACLF), according to data presented at ILC 2021.

Treatment of ACLF is an unmet need. Currently, standard of care involves treating infections with antibiotics and supporting individual organs, dialysis for kidney failure and vasopressors for low blood pressure. There are very few disease-modifying options at present; steroids may have a role in some liver condition, but a large proportion of patients are non-responders to steroids, and steroids come with the inherent risk of new infections. Liver transplant is an option but is not available in the UK for many of these patients.

This randomised study tested the hypothesis that Dialive, a novel liver dialysis device, could significantly improve the prognosis of ACLF patients. The primary end point was safety; device performance; clinical and pathophysiologic effects. Dialive

principally replaces dysfunctional albumin and removes pathogen and damage associated molecular patterns.

A total 32-ACLF patients with alcoholic cirrhosis were randomised either to Dialive or standard of care. A minimum of three Dialive sessions (max five) were needed for the patient to be evaluable. The trial was conducted in

other important organs such as kidneys, brain and lungs.

Dr Banwari Agarwal, Consultant in Critical Care Medicine, Royal Free Hospital, London, UK, noted that while the number of the patients studied is relatively small, the data so far is very encouraging, suggesting that the patients treated with Dialive were significantly more likely to recover from this acute flare and return to the pre-illness levels of liver and other organ function. Dialive was found to be safe and significantly increased the proportion of patients resolving ACLF whilst reducing time to resolution. The data thus justifies the start of late-phase clinical trials, he said.

patients who presented in ICUs with an acute flare of their chronic liver disease, which rapidly progressed to a severe additional worsening of the liver function and failure of a combination of

Dr Agarwal added that the main advantages of Dialive were two-fold: a) it is relatively simple to assemble and takes advantage of equipment already in use in ICUs, and b) it targets two important pathobiological mechanisms known to trigger acute decline in liver function and associated with other organs failure, namely the patient’s own damaged albumin and development of an intense systemic inflammatory response.

Treatment advances for NAFLD announced at ILC 2021

Leading hepatology researchers announced a number of important new developments in the treatment of non-alcoholic fatty liver disease (NAFLD) at ILC 2021. These included new data on trials involving RNAi

therapeutics, antivirals and structurally engineered fatty acids to treat NAFLD, which is now one of the fastest growing diseases globally.

Linked to growing rates of obesity and

diabetes, NAFLD has emerged as the most prominent cause of chronic liver disease worldwide and occurs in about onequarter of the global population. Experts predict that over the next decade, NAFLD will become the leading cause of end-stage

This randomised study tested the hypothesis that Dialive, a novel liver dialysis device, could significantly improve the prognosis of ACLF patients

liver disease and liver transplantation.

In the UK liver disease is the biggest cause of death in those aged between 35-49 years old. NAFLD is already the fastest growing cause of hepatocellular carcinoma (HCC), the commonest form of liver cancer in the US, France and the UK. Non-alcohol related steatohepatitis (NASH) is the second, more serious stage of NAFLD.

One study presented at the conference linked food insecurity to death of adults with NAFLD and advanced fibrosis.

This study followed 34,134 eligible participants followed for a median 7.2 years. Of these, 4,816 had NAFLD (mean age 51, 58 per cent male, 14 per cent below the poverty line; mean age 69, 55 per cent male, 15 per cent below the poverty line) with food insecurity present in 28 per cent and 21 per cent, respectively.

(HR=1.37; 95 per cent CI:1.01-1.86).

Dr Ani Kardashian, Assistant Professor for Clinical Medicine, University of Southern California, US, reported a significant interaction between food insecurity and poverty-income ratio among those with advanced fibrosis (P=0.015). Food insecurity was associated with greater mortality in adults with advanced fibrosis and poverty (HR=2.27, 95% CI:1.41-3.66), but not among those without poverty (HR=1.09, 95% CI:0.66-1.59).

She recommended that interventions that address food insecurity among adults with liver disease should be prioritised to improve health outcomes in this population.

In relation to new treatments for NASH, a positive study was presented on the use of HSD17B13, a member of the hydroxysteroid dehydrogenase

in healthy volunteers and patients with NASH or suspected NASH.

ARO-HSD was administered by subcutaneous injection to male and female healthy volunteers (19-52 years old) in a single-dose escalation design at doses of 25, 50, 100 and 200mg (four active, four placebo per dose level) and followed to day 113. Five patients (40-50 years old) with suspected NASH (based on MRI-PDFF liver fat >8 per cent and ALT>ULN) administered 100mg AROHSD have completed the day 71 biopsy.

Safety was assessed in all subjects including laboratory measures of liver function. A liver biopsy was collected at baseline and day 71 in patients and change from baseline in hepatic HSD17B13 mRNA expression and protein levels were measured. Additional multi-dose patient cohorts will be analysed following availability of the day 71 liver biopsies.

Rohit Loomba of the University of California, US, noted that ARO-HSD was well-tolerated in both healthy volunteers and patients, with no ARO-HSD related serious adverse events reported, no related drug discontinuations, and no ARO-HSD associated grade 3 or 4 laboratory abnormalities (NCI-CTCAE v5.0).

All-cause age-adjusted mortality was 12 per 1,000 person-years among NAFLD participants (11 if food secure, 15 if food insecure) and 32 per 1,000 person-years among advanced fibrosis participants (28 if food secure, 50 if food insecure). In multivariate models adjusted for age, race/ethnicity, poverty-income ratio, education level, insurance status, haemoglobin A1c, body mass index, and smoking, food insecurity was independently associated with higher all-cause mortality among those with NAFLD (HR=1.46, 95 per cent CI:1.081.97) and those with advanced fibrosis

family involved in the metabolism of hormones, fatty acids, and bile acids. Human genetic data indicate that a loss-of-function mutation in HSD17B13 provides strong protection against alcoholic and non-alcoholic steatohepatitis. ARO-HSD is an investigational GalNAc-conjugated RNAi therapeutic designed to replicate this observed protective loss-offunction effect by knocking down HSD17B13 expression in hepatocytes.

This study reports initial results from the ongoing first in human clinical study, AROHSD1001 (NCT04202354),

In all five patients, hepatic HSD17B13 mRNA decreased by a mean of 84 per cent (range: 62-96 per cent) from baseline. Two patients had a protein decrease of 92 per cent and 97 per cent, while the other three patients' day 71 measurements were below the assay’s level of quantitation. Patients had a mean decrease from baseline in ALT of 46 per cent (26-to-53 per cent) at day 85. There were no significant changes in weight or lipid parameters.

The study concluded that ARO-HSD is the first investigational RNAi therapeutic to demonstrate robust

Human genetic data indicate that a loss-of-function mutation in HSD17B13 provides strong protection against alcoholic and non-alcoholic steatohepatitis

inhibition of HSD17B13 mRNA and protein expression with associated reductions in AT and recommended the continued development of ARO-HSD in patients with alcoholic and nonalcoholic steatohepatitis.

Separately, interim analysis of a phase 2 study presented at ILC 2021 conference showed that a novel structurally engineered fatty acid significantly reduced relevant markers of NASH and fibrosis in four months.

key atherogenic lipoproteins. There was no change in weight or BMI suggesting a treatment effect independent of weight loss. Both LFC and cT1 were unchanged which is consistent with ICO’s mechanism of action. Treatment was well tolerated with no evidence of hepatoxicity, cardiovascular events or other safety concerns.

Prof Arun Sanyal of the Virginia Commonwealth University, Richmond, US, noted that treatment of NASH

University of Oxford, UK, reported that non-invasively identified NASH patients treated with 100mg per day of resmetirom for up to 52 weeks demonstrated rapid and sustained reduction in hepatic fat, fibrosis stage as assessed by biomarkers, MRE and FibroScan, LDL and atherogenic lipids, liver enzymes and inflammatory biomarkers

A total of 169 patients were enrolled in the open label arm; all completed 16 weeks, and 64 had completed 52 weeks. Demographics included mean age 55.7 (11.5 (SD)), 69 per cent female, BMI 35.8 (6.0), diabetes 43 per cent, hypertension 62 per cent, dyslipidaemia >70 per cent, mean ASCVD score 11.5 per cent. Fibroscan (kPa 7.7 (3.6)) and mean MRI-PDFF 18 per cent (7 per cent) are consistent with F2 stage NASH.

Icosabutate (ICO) is a novel, oral, once-daily, liver-targeted, engineered eicosapentaenoic acid derivative with potent anti-inflammatory and antifibrotic effects acting primarily through the G-coupled protein receptor (GPR120) and the arachidonic acid signalling pathways related signalling pathways. The ICONA trial is an ongoing 52-week, multicentre, placebo-controlled, phase 2b study enrolling 264 subjects with biopsy confirmed NASH.

Rapid, sustained, and significant dose-dependent decreases were seen with both doses in ALT, AST, GGT, and ALP at levels predictive of histologic improvement. The 600mg dose showed significant reductions in PRO-C3 and ELF score (both total score and individual components) supporting an effect on fibrogenesis. Participants hsCRP significantly decreased by 52 per cent with 600mg in conjunction with improvements in glycaemic control and

patients with ICO for 16 weeks had a dose-dependent improvement in multiple relevant biologic pathways, with broad and potent effects on markers of liver injury, inflammation and fibrogenesis along with improvements in glycaemic control and atherogenic lipids. Prof Sanyal concluded that these data, combined with a favourable safety profile to date, support a potential for impacting liver histology at 52 weeks as well as improving common comorbid conditions seen in NASH patients.

In another presentation, the liverdirected, orally active, selective thyroid hormone receptor- β agonist resmetirom was shown to reduce fibrosis. The study reported results from a 52-week phase 3 registrational double blind placebocontrolled NASH clinical trial to study the effect of resmetirom.

Statistically significant (p<0.0001) MRI-PDFF reduction of 53 per cent (3.3 per cent) overall, and a 62 per cent reduction in a SHBG responder group were observed at week 52. MRE was statistically significantly reduced at weeks 16 and 52. At week 52 Fibroscan CAP and kpa were reduced relative to baseline. LDL-C (-23 per cent (2.3 per cent (SE)), apolipoprotein-B (-22 per cent (2.3 per cent)), triglycerides (med, -32(7.8) mg/dL), and lipoprotein(a) (-39 per cent (4.6 per cent)) were statistically significantly reduced compared to baseline. Decreases from baseline: ALT - 22 IU, AST -12 IU, GGT -25 IU(P<0.0001). Statistically significant reductions in inflammatory and fibrosis biomarkers hsCRP, reverse T3, ELF and M30 were observed. No safety flags were identified.

Prof Harrison concluded that the results supported the use of non-invasive tests to monitor individual NASH patient response to resmetirom treatment. ■

The study reported results from a 52-week phase 3 registrational double blind placebo-controlled NASH clinical trial to study the effect of resmetirom

doctorCPD.ie

The

spectrum of treatment for inflammatory bowel disease

A comprehensive overview of the pathology, epidemiology and diagnosis of inflammatory bowel disease (IBD), and the latest treatment and management strategies.

Authors: Dr Jayne Doherty, SpR in Gastroenterology, and Dr Garret Cullen, Consultant Gastroenterologist, Centre for Colorectal Disease, St Vincent’s University Hospital, Dublin

Other effects that have been reported include:

Clostridial infections, urinary tract infections, candidiasis, pneumonia cellulitis, upper respiratory tract infection and rhinitis. Blood disorders (e.g. anaemia, thrombocytopenia). Anaphylactic reactions, angioedemas, hypersensitivity. Anorexia, hyperkalaemia and dehydration. Confusion, sleep disorders, balance disorders, convulsions, hypoesthesia, memory impairment and attention disorders. Hypotension, hypertension and fainting. Hot flushes. Breathing difficulty, pleural effusion, COPD. Gastrointestinal disorders and skin reactions. Liver function test abnormalities. Dysuria, pollakiuria and proteinuria. Oedema. Pyrexia. INR abnormalities.

Prescribers should consult the SmPC in relation to all adverse reactions.

IRELAND

Legal category: Prescription only

Cost: €262.41 for 56 tablets

Marketing Authorisation holder: Norgine B.V. Antonio

Vivaldistraat 150, 1083 HP, Amsterdam, Netherlands

Marketing Authorisation number: PA 1336/009/001

Long-term prophylaxis in hepatic encephalopathy (HE)2

For further information contact: Norgine Pharmaceuticals Limited Norgine House Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, UK Telephone: +44 (0)1895 826 606

E-mail: Medinfo@norgine.com

Ref: IE-HEP-XIF-2100010

Date of preparation: April 2021

Ireland

References:

1. National Institute for Health and Care Excellence. Rifaximin for preventing episodes of overt hepatic encephalopathy: appraisal guidance TA337 for rifaximin.

Available from: http://www.nice.org.uk/guidance/ta337

2. TARGAXAN® 550 Summary of Product Characteristics. Available for Ireland from: www.medicines.ie

Successful completion of this module will earn you 2 CPD credits C

Product under licence from Alfasigma S.p.A. TARGAXAN is a registered trademark of the Alfasigma group of companies, licensed to the Norgine group of companies. NORGINE and the sail logo are registered trademarks of the Norgine group of companies.

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IE-HEP-XIF-2100007

Date of preparation: May 2021.

The only licensed treatment for the reduction in recurrence of episodes of overt hepatic encephalopathy ≥ 18 years1

XELJANZ®• (tofacitinib) Prescribing Information:

Please refer to the Summary of Product Characteristics (SmPC) before prescribing XELJANZ 5 mg or 10 mg film-coated tablets, XELJANZ 11 mg prolonged release tablets or XELJANZ 1 mg/mL oral solution..

Presentation: Film-coated tablet containing tofacitinib citrate, equivalent to 5 mg or 10 mg tofacitinib. Prolonged-release tablets containing tofacitinib citrate, equivalent to 11 mg tofacitinib. Oral solution containing tofacitinib citrate, equivalent to 1 mg/mL tofacitinib.

Indications: Please note not all presentations are licensed for all indications, please see dosage section for details: In combination with methotrexate (MTX) for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. Can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate. In combination with MTX for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease modifying antirheumatic drug (DMARD) therapy. For the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. For the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive [RF+] or negative [RF-] polyarthritis, and extended oligoarthritis), and juvenile psoriatic arthritis (PsA) in patients 2 years of age and older, who have responded inadequately to previous therapy with DMARDs. Can be given in combination with methotrexate (MTX) or as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Dosage: Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of the condition for which tofacitinib is indicated. Tofacitinib is given with or without food. RA and PsA: The recommended dose is 5 mg orally twice daily or 11 mg once daily which should not be exceeded. Treatment with tofacitinib 5 mg film coated tablets twice daily and tofacitinib 11 mg prolonged release tablet once daily may be switched between each other on the day following the last dose of either tablet. UC: The recommended dose is 10 mg given orally twice daily for induction for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16. The recommended dose for maintenance treatment is tofacitinib 5 mg given orally twice daily. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known venous thromboembolism (VTE) risk factors, unless there is no suitable alternative treatment available. For patients with UC who are not at increased risk for VTE, tofacitinib 10 mg orally twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice daily and failed to respond to alternative treatment options for ulcerative colitis such as tumour necrosis factor inhibitor (TNF inhibitor) treatment. Tofacitinib 10 mg twice daily for maintenance treatment should be used for the shortest duration possible. The lowest effective dose needed to maintain response should be used. Polyarticular JIA and juvenile PsA: The recommended dose in patients 2 years of age and older: 10 kg - < 20 kg: 3.2 mg (3.2 mL of oral solution) twice daily, 20 kg - < 40 kg: 4 mg (4 mL of oral solution) twice daily, and ≥ 40 kg 5 mg (5 mL of oral solution or 5 mg film-coated tablet) twice daily. Patients ≥ 40 kg treated with tofacitinib 5 mL oral solution twice daily may be switched to tofacitinib 5 mg film-coated tablets twice daily. Patients < 40 kg cannot be switched from tofacitinib oral solution. Dose interruption in adults and paediatric patients: Tofacitinib treatment should be interrupted if a patient develops a serious infection until the infection is controlled. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 0.75 x 10 9/L, an absolute neutrophil count (ANC) less than 1x10 9 /L or with haemoglobin less than 9 g/dL. It is recommended not to initiate dosing in paediatric patients with an absolute neutrophil count (ANC) less than 1.2 x 10 9/L or with haemoglobin less than 10 g/dL. Renal impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Patients with severe renal impairment the dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal renal function is 5 mg twice daily or 11 mg prolongedrelease tablet once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal renal function is 10 mg twice daily. Patients with severe renal impairment should remain on a reduced dose even after haemodialysis. Hepatic impairment: No dose

Characteristics.

RAPID

EFFICACY

AN ORAL JAK INHIBITOR FOR THE TREATMENT OF RA, PsA AND

adjustment is required in patients with mild hepatic impairment. Patients with moderate hepatic impairment dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal hepatic function is 5 mg twice daily or 11 mg prolonged-release tablet once daily.

Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal hepatic function is 10 mg twice daily. Tofacitinib should not be used in patients with severe hepatic impairment. Elderly: No dose adjustment is required in patients aged 65 years and older. Use with caution as increased risk and severity of adverse events. See also Warnings & Precautions for use in patients over 65 years of age.

Interactions: Tofacitinib total daily dose should be reduced by half in adult and paediatric patients receiving potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g. ketoconazole) and in patients receiving 1 or more concomitant medicinal products that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g. fluconazole).

Coadministration of tofacitinib with potent CYP inducers (e.g. rifampicin) may result in a loss of or reduced clinical response. Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Only in paediatric patients: available data suggest that clinical improvement is observed within 18 weeks of initiation of treatment with tofacitinib.

Continued therapy should be carefully reconsidered in a patient exhibiting no clinical improvement within this timeframe. The safety and efficacy of tofacitinib in children less than 2 years of age with polyarticular JIA and juvenile PsA has not been established. The safety and efficacy of tofacitinib in children less than 18 years of age with other indications (e.g. ulcerative colitis) has not been established. The safety and efficacy of tofacitinib prolonged-release formulation in children aged less than 18 years have not been established. Contraindications:

Hypersensitivity to any of the ingredients, active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections, severe hepatic impairment, pregnancy and lactation. Warnings and Precautions: Patients treated with tofacitinib should be given a patient alert card. Use in patients over 65 years of age: Considering the increased risk of serious infections, myocardial infarction, and malignancies with tofacitinib in patients over 65 years of age, tofacitinib should only be used in patients over 65 years of age if no suitable treatment alternatives are available. Combination with other therapies: There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies. Tofacitinib should be avoided in combination with biologics and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporine and tacrolimus. Venous thromboembolism (VTE): Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib. Tofacitinib should be used with caution in patients with known risk factors for VTE, regardless of indication and dosage. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known VTE risk factors, unless there is no suitable alternative treatment available. Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with suspected VTE, regardless of dose or indication. Infections: Serious and sometimes fatal infections have been reported in patients administered tofacitinib. Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection. Patients should be closely monitored for infections, with prompt diagnosis and treatment. Treatment should be interrupted if a serious infection develops. As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. Tuberculosis: Patients should be evaluated for both active and latent TB prior to being treated with tofacitinib. Patients who test positive for latent TB should be treated with standard antimycobacterial therapy before administering tofacitinib. Viral Reactivation: In clinical studies viral reactivation and cases of herpes zoster have been observed. Screening for viral hepatitis should be performed in accordance with clinical guidelines prior to starting therapy with tofacitinib. The impact on chronic viral hepatitis is not known. Major adverse cardiovascular events (MACE): MACE have been observed in patients taking tofacitinib. In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of myocardial infarctions was observed with tofacitinib compared to TNF inhibitors. In patients over 65 years of age, patients who are current or past smokers, and patients with other cardiovascular risk factors, tofacitinib should only be used if no suitable treatment alternatives are available. Vaccinations: Prior to initiating tofacitinib, it is recommended that all patients, particularly pJIA and jPsA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines. Live vaccines should not be given concurrently with tofacitinib. Malignancy and lymphoproliferative

disorder: Tofacitinib may affect host defences against malignancies. In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of malignancies excluding nonmelanoma skin cancer (NMSC), particularly lung cancer and lymphoma, was observed with tofacitinib compared to TNF inhibitors. Lung cancers and lymphoma in patients treated with tofacitinib have also been observed in other clinical studies and in the post marketing setting. Other malignancies in patients treated with tofacitinib were observed in clinical studies and the post marketing setting, including, but not limited to, breast cancer, melanoma, prostate cancer, and pancreatic cancer. In patients over 65 years of age, patients who are current or past smokers, and patients with other malignancy risk factors (e.g. current malignancy or history of malignancy other than a successfully treated non-melanoma skin cancer) tofacitinib should only be used if no suitable treatment alternatives are available. NMSCs have been reported in patients treated with tofacitinib; the risk of NMSC may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended in patients at increased risk for skin cancer. Interstitial lung disease: Caution is recommended in patients with a history of chronic lung disease as they may be more prone to infection. Asian patients are known to be at higher risk of ILD, caution should be exercised with these patients. Gastrointestinal perforations: Tofacitinib should be used with caution in patients who may be at increased risk, e.g. history of diverticulitis or concomitant use of corticosteroids or NSAIDs. Hypersensitivity: Cases of drug hypersensitivity associated with tofacitinib administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately. Laboratory Parameters: Increased incidence of lymphopenia and neutropenia have been reported, and decreases in haemoglobin, which should be monitored in accordance with the SmPC. Monitor ANC and haemoglobin at baseline, 4-8 weeks and 3 monthly, ALC at baseline and 3 monthly. Tofacitinib has been associated with increases in lipid parameters, maximal effects were observed within 6 weeks. Monitoring should be performed 8 weeks after initiation and managed according to hyperlipidaemia guidelines. Increases in liver enzymes greater than 3x ULN were uncommonly reported; use caution when initiating with potential hepatotoxic medicinal products. Gastrointestinal obstruction with a non-deformable prolonged-release formulation: Caution should be used when administering tofacitinib 11 mg prolonged release tablets to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). Pregnancy & Lactation: Use of tofacitinib during pregnancy and breastfeeding is contraindicated. Side Effects: RA: The most common serious adverse reactions were serious infections; pneumonia, cellulitis, herpes zoster, UTIs, diverticulitis, appendicitis and opportunistic infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials were headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension. UC: The most commonly reported adverse reactions in patients receiving tofacitinib 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia. Commonly reported adverse reactions (>1/100 to <1/10) across all indications were pneumonia, influenza, herpes zoster, urinary tract infection, sinusitis, bronchitis, viral upper respiratory tract infection, pharyngitis, anaemia, headache, hypertension, cough, abdominal pain, vomiting, diarrhoea, nausea, gastritis, dyspepsia, rash, arthralgia, pyrexia, oedema peripheral, fatigue, blood creatine phosphokinase increased. Refer to section 4.8 of the SmPC for further information on side effects, including description of selected adverse reactions. Legal Category: S1A. Marketing Authorisation Number: EU/1/17/1178/003 – 5 mg (56 film-coated tablets); EU/1/17/1178/007 – 10 mg (56 film-coated tablets); EU/1/17/1178/012 – 11 mg (28 prolonged-release tablets); EU/1/17/1178/015 1mg/mL oral solution. Marketing Authorisation

Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer. com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24, + 353 1 467 6500.

˱ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions.

Last revised: 08/2021.

Ref: XJ 12_0.

of preparation: September 2021