Update Gastroenterology & Hepatology September 2022 by GreenX Publishing

LATEST INTERNATIONAL GUIDELINES ON

IBS AND ULCERATIVE COLITIS

IBD

IN PREGNANCY GORD IN INFANTS PEPTIC ULCER DISEASE CLINICAL ARTICLES ON

MONITORING ADHERENCE TO A

VOL 8 ● ISSUE 8 ● 2022

GASTROENTEROLOGY AND HEPATOLOGY

Coverage of the Irish Society of Gastroenterology Summer Meeting, and International Liver Congress 2022 GLUTEN-

FREE DIET

relieve the discomfort

ABBREVIATED PRESCRIBING INFORMATION. Proctosedyl ointment. Each gram of ointment contains 5 mg of hydrocortisone, 5 mg of cinchocaine hydrochloride, 10 mg of aesculin and 10 mg of framycetin sulphate. Presentation: Yellowish white, translucent, homogeneous ointment. Indications: In the local management of pain, pruritus and inflammation associated with internal or external haemorrhoids, and such haemorrhoidal complications as fissures, proctitis, perianal eczema, and post-operative states. Dosage: Application to external surface or by means of the cannula into the rectum, twice daily and after each bowel movement. Treatment should last for a week. Method of administration: Topical, intrarectal and perianal. Contraindications: Use in the presence of untreated infections of viral, bacterial, tuberculous, parasitic or fungal origin. Use in patients hypersensitive to the active ingredient or any of the excipients. Warnings and precautions: Continuous treatment for longer than three weeks should be avoided in patients under the age of three years because of the possibility of adrenocortical suppression and growth retardation. Continuous application without interruption will result in local atrophy of the skin, striae, and superficial vascular dilation. Prolonged use of an anti-infective may result in the development of super-infection due to organisms, including fungi, resistant to that anti-infective. May cause local skin reactions (e.g. contact dermatitis). Before prescribing the product any potential malignancies should be excluded. Pheochromocytoma crisis, which can be fatal, has been reported after administration of corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation. Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Interactions: Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects, in which case patients should be monitored for systemic corticosteroid side effects. Pregnancy and lactation: This product should not be used in pregnancy or lactation unless considered essential by the physician. Driving and operation of machinery: Not applicable. Undesirable effects: Itching, pain or rash. Refer to Summary of Product Characteristics for other undesirable effects. Adverse events should be reported via HPRA Pharmacovigilance, website: www.hpra.ie. Pack size: 30 g. Marketing authorisation holder: Opella Healthcare France SAS T/A Sanofi, 82 Avenue Raspail, 94250 Gentilly, France. Marketing authorisation number: PA23180/002/001. Medicinal product subject to medical prescription. Last revision date: May 2022. Distributed in Ireland by Clonmel Healthcare Ltd, Waterford Road, Clonmel, Co. Tipperary, Ireland. 2022/ADV/PRO/120H

For the local management of pain, pruritus and inflammation associated with internal or external haemorrhoids, and such haemorrhoidal complications as fissures, proctitis, perianal eczema, and post-operative states

Striving to offer the best care

A message from Priscilla Lynch, Editor

As our health services continue to adjust to the new ‘normal’ following the crushing impact of the Covid-19 pandemic, gastroenterology and hepatology 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. While some service improvements have been made, the rollout of Sláintecare’s promised utopia of integrated, fully-staffed services seems as out of reach as ever. Consultant contract talks continue to drag slowly on in a stop-start fashion and it is very clearly time for a radical effort to provide a proper long-term sustainable solution to the capacity deficits in our health services, instead of constant ‘quick fix’ attempts and empty promises.

Despite these challenges, the unwavering desire of our clinicians to offer the most appropriate care to patients continues. This edition features a wide range of specialist clinical articles on the latest treatment approaches across a broad range of disease areas, including a detailed article on medical therapies in inflammatory bowel disease (IBD), a separate update on the management

of IBD in pregnancy, new US and UK guidelines on irritable bowel syndrome (IBS), the latest European guidelines on ulcerative colitis, overviews of the diagnosis and management of peptic ulcer disease, hepatitis E, and gastrooesophageal reflux disease in children, as well as the latest international and local data on hepatitis of unknown origin in children. There is also a special focus on the diagnosis and management of Coeliac disease, including an expert dietitian update on monitoring adherence to a gluten-free diet.

In addition, there is an overview of new World Health Organisation (WHO) clinical guidance on diagnosing and treating hepatitis C virus (HCV), which recommends a radical simplification of the care pathway to overcome barriers in access to testing and treatment; with new recommendations on treatment of adolescents and children and simplified service delivery and diagnostics, to ensure the 2030 global target of HCV elimination is achieved.

Over 6,500 people with HCV have been successfully treated with direct-acting antivirals (DAAs) in Ireland since the HSE’s National Hepatitis C Treatment Programme (NHCTP) was established in 2015. The last couple of years have seen a significant decrease in the numbers of people commencing treatment due to the impact of the coronavirus pandemic, as well as a lack of untreated patients as new case notifications decreased. 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. The NHCTP says it is now working on rolling out new initiatives to help achieve these goals and that clinics are finally returning to normal post-pandemic.

Conference-wise, this edition of Update carries a round-up of the most topical research updates from the 2022 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. There was also exciting phase 3 clinical data on a new curative treatment (bulevirtide) for hepatitis D.

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 rising use of small molecule drugs in IBD, the benefits of smartphone apps for maintaining patient care, and the importance of biopsychosocial care for gastroparesis patients.

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. ■

1 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

Welcome to the latest edition of Update Gastroenterology and Hepatology

Editor Priscilla Lynch priscilla@mindo.ie

Sub-editor

Emer Keogh emer@greenx.ie

Creative Director Laura Kenny laura@greenx.ie

A feel

A feel good result

Entocort®CR Capsules are indicated for the induction of remission in patients with mild-to-moderate Crohn’s disease affecting the ileum and/or the ascending colon, and for the induction of remission in patients with active microscopic colitis.

Entocort® CR 3 mg Gastro-Resistant Hard Capsules. Hard gelatin capsules with an opaque, light grey body and opaque, pink cap, marked CIR 3 mg each containing budesonide 3 mg.

recommended. On discontinuation, reduce dose over 2 to 4 weeks, monitor for withdrawal effects, adjust dose if necessary. Coadministration of CYP3A inhibitors is expected to increase side effects: avoid/monitor (see interactions). With chronic high doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur, very rarely psychiatric/behavioural effects. Children: not recommended. If used monitor child’s growth, evaluate risk-benefit. Long-term studies have not been performed.

INDICATIONS: Crohn’s disease: Induction of remission in mild to moderate Crohn’s disease affecting the ileum and/or the ascending colon. Induction of remission in active microscopic colitis.

DOSAGE AND ADMINISTRATION: Oral use. Swallow whole with water, do not chew.

recommended. On discontinuation, reduce dose over 2 to 4 weeks, monitor for withdrawal effects, adjust dose if necessary. Coadministration of CYP3A inhibitors is expected to increase side effects: avoid/monitor (see interactions). With chronic high doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur, and very rarely psychiatric/behavioural effects. Children: not recommended. If used monitor child’s growth, evaluate risk-benefit. Long-term studies have not been performed.

recommended. On effects, adjust dose increase side effects: glucocorticosteroid and very rarely psychiatric/behavioural monitor child’s growth,

DOSAGE AND ADMINISTRATION: Oral use. Swallow whole with water, do not chew.

Adults: Active Crohn’s disease: 9 mg once daily in the morning, for up to eight weeks. Effect is usually achieved within 2 to 4 weeks. When discontinuing, reduce dose over the last 2 to 4 weeks. Entocort can be used for up to 3 months: 6 mg, once daily in the morning. Long-term use is not recommended. To replace prednisolone in steroiddependent patients, 6 mg once daily in the morning. Prednisolone dose should be tapered. To prevent recurrence after surgery in patients with high disease activity: 6 mg once daily in the morning. No benefit shown in post surgical patients with obstructive fibrostenotic Crohn’s disease.

INTERACTIONS: CYP3A4 inhibitors (e.g. ketoconazole, itraconazole), HIV protease inhibitors and grapefruit juice can increase systemic budesonide, CYP3A4 inducers carbamazepine) may reduce budesonide levels; adjust dose. Colestyramine may reduce Entocort uptake. Raised levels/effects of corticosteroids reported with oestrogens contraceptive steroids. At recommended doses, omeprazole does not affect the pharmacokinetics of oral budesonide whereas cimetidine has a slight but clinically insignificant effect.

Active microscopic colitis: 9 mg once daily in the morning for up to 8 weeks. Reduce dose for last 2 to 4 weeks. Use lowest effective dose.

INTERACTIONS: CYP3A4 inhibitors (e.g. ketoconazole, itraconazole), HIV protease inhibitors and grapefruit juice can increase systemic budesonide, CYP3A4 inducers (e.g. carbamazepine) may reduce budesonide levels; adjust dose. Colestyramine may reduce Entocort uptake. Raised levels/effects of corticosteroids reported with oestrogens and contraceptive steroids. At recommended doses, omeprazole does not affect the pharmacokinetics of oral budesonide whereas cimetidine has a slight but clinically insignificant effect.

INTERACTIONS:

inhibitors and grapefruit (e.g. carbamazepine) reduce Entocort uptake. and contraceptive pharmacokinetics insignificant effect.

USE DURING PREGNANCY AND LACTATION: Pregnancy: Associated with foetal abnormalities in animals; consider risk-benefit. Breast-feeding: Budesonide is excreted in breast milk; at therapeutic doses, exposure to breast-fed infants anticipated to be low.

DURING PREGNANCY AND LACTATION: Pregnancy: Associated with foetal abnormalities in animals; consider risk-benefit. Breast-feeding: Budesonide is excreted in breast milk; at therapeutic doses, exposure to breast-fed infants anticipated to be low.

Active microscopic colitis: 9 mg once daily in the morning for up to 8 weeks. Reduce dose for last 2 to 4 weeks. Use lowest effective dose.

Elderly: As for adults. Experience is limited. Children: Not recommended.

CONTRAINDICATIONS: Hypersensitivity to active or excipients.

PRECAUTIONS AND WARNINGS:

Elderly: As for adults. Experience is limited. Children: Not recommended.

CONTRAINDICATIONS: Hypersensitivity to active or excipients.

PRECAUTIONS AND WARNINGS:

Systemic corticosteroid effects may occur, including glaucoma. Monitor for visual disturbance caused by e.g. cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR).

UNDESIRABLE EFFECTS: Common (≥1/100 to < 1/10): Cushingoid features, hypokalemia, behavioural changes such as nervousness, insomnia, mood swings, and depression, palpitations, dyspepsia, skin reactions (urticaria, exanthema), muscle cramps, menstrual disorders; Uncommon (≥ 1/1,000 to < 1/100): Anxiety, tremor; psychomotor hyperactivity. Rare (≥1/10,000 to <1/1,000): Aggression, blurred vision, glaucoma, cataract, ecchymosis. Very rare (< 1/10,000): Anaphylactic reaction, growth retardation. Systemic corticosteroid effects may occur depending on dose, duration and individual.

Systemic corticosteroid effects may occur, including glaucoma. Monitor for visual disturbance caused by e.g. cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR).

Monitor for infections.

LEGAL CATEGORY: POM. MA No: 2018/003/001.

Systemic corticosteroid effects may occur, including glaucoma. Monitor for visual disturbance caused by e.g. cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR). Monitor for infections.

LEGAL CATEGORY: POM. MA No: 2018/003/001.

USE DURING PREGNANCY abnormalities in animals; breast milk; at therapeutic UNDESIRABLE EFFECTS: hypokalemia, behavioural depression, palpitations, menstrual disorders; hyperactivity. Rare cataract, ecchymosis.

MA HOLDER: TILLOTTS PHARMA GmbH, Warmbacher Strasse 80, 79618 Rheinfelden, Germany.

Systemic corticosteroid

LEGAL CATEGORY: POM. MA No: 2018/003/001.

DATE OF PREPARATION: May 2020.

Caution in: patients with reduced liver function; patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or family history of diabetes or glaucoma or any condition where glucocorticosteroids may have unwanted effects; patients with severe affective disorders (or family history), including depressive or manic-depressive illness and previous steroid psychosis; patients not immune to chicken pox and measles. If exposed, consider immunoglobulin therapy, or antiviral agents. Contains sucrose. Caution when transferring from another glucocorticosteroid to Entocort® CR Capsules, monitor adrenocortical function and unmasked allergies. During surgery or other stress situations, supplementary glucocorticoid treatment is

LEGAL CATEGORY:

HOLDER: TILLOTTS PHARMA GmbH, Warmbacher Strasse 80, 79618 Rheinfelden, Germany.

MA HOLDER: TILLOTTS PHARMA GmbH, Warmbacher Strasse 80, 79618 Rheinfelden, Germany.

DATE OF PREPARATION: May 2020. CODE: 2020/21 Full prescribing information available on request from the Marketing Authorisation holder or from Tillotts Pharma Ltd., 25 Sandyford Office Park, Dublin 18. Tel:(00 353 1) 294 2015. Entocort® is a trademark.

MA HOLDER: TILLOTTS Germany.

CODE: 2020/21 Full prescribing information available on request from the Marketing Authorisation holder or from Tillotts Pharma 25 Sandyford Office Park, Dublin 18. Tel:(00 353 1) 294 2015. Entocort® is a trademark.

DATE OF PREPARATION: available on request Ltd., 25 Sandyford Entocort®

is a trademark.

All-Ireland Gastroenterology, Summer Meeting ( ISG/USG ), Europa Hotel, Belfast, 9-10 June 2022

ALL REPORTS BY NIAMH QUINLAN

Recognising and addressing the causes of drug-induced liver injury

There needs to be greater recognitiation of how “body-building agents” can lead to drug-induced liver injury (DILI), according to Consultant Hepatologist at St Vincent’s University Hospital, Dublin, Dr Omar El-Sherif.

Dr El-Sherif was speaking at the All-Ireland Irish Society of Gastroenterology (ISG)/Ulster Society of Gastroenterology (USG) Summer Meeting, which took place in the Europa Hotel, Belfast on 9-10 June.

He said there are two major groups of body-building agents: Anabolic steroids and herbal or dietary supplements.

Two main phenotypes of liver damage can occur from these agents, according to Dr El-Sherif.

“The common one with anabolic steroids is this bland cholestasis, which can be protracted for many, many months, but thankfully, it’s rarely fatal. And then the

more serious one which is an acute hepatitislike pattern, which we see patients present with liver failure and we’ve transplanted patients for it.”

The recreational drug ketamine is also being seen more recently with regard to liver injury. It can cause cholangiopathy or biliary damage, and prolonged exposure is irreversible, according to Dr El-Sherif.

Other recent trends in relation to DILI include changes to prescribing patterns to reduce risks to patients.

“Anti-epileptic drugs that cause DILI are less used,” according to Dr El-Sherif.

However, he noted that there still is a problem concerning DILIs caused by antibiotic use.

The examples Dr El-Sherif gave were isoniazid, amoxicillin and diclofenac. Using data from the drug-induced liver injury

‘Green endoscopy’ – how to reduce waste in the clinical setting

There is great potential to conduct endoscopy, which is a leading generator of waste in healthcare, in a more environmentally-friendly and sustainable manner, Consultant

Gastroenterologist at King’s College Hospital, London, Dr Bu’ Hayee, told the ISG/USG Summer Meeting audience.

According to a 2017 study in the Waste

network in the USA, he said most of the medication-related DILIs resulted from antibiotic use.

“By and large [these drugs] are given in high doses… and they are also quite old drugs,” according to Dr El-Sherif.

“It’s very uncommon to have severe hepatic injury with some of the newer agents.”

“Drug-induced liver injury is common in hospitalised patients,” Dr El-Sheriff told Update. “You need to recognise it and treat it early, before patients develop significant complications related to it.”

He told the ISG and USG audience that assessing the causality of DILI in hospital patients remains a “diagnosis of exclusion”, as comorbidities, while a major predictor for outcomes, can make it difficult to assess causality. A liver biopsy can help in some cases, he said.

Management and Research journal, endoscopy is the third-highest generator of waste in healthcare.

“[This is] mostly in plastic waste, but also in

4 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

terms of carbon footprint,” said Dr Hayee. He encouraged gastroenterologists to think more about the waste that is generated in clinical settings and how to work towards ‘green endoscopy’.

“The first thing to do is to embed the change in your organisation,” said Dr Hayee. This can be done by creating a team with members from endoscopy user groups and nurses who can be appointed as “green champions” from within endoscopy ranks.

The next step is to start recycling and implement recycling bins for non-patient contact material. “Most hospitals will already have waste management companies or waste management teams that will be able to help

you do this, you just need to ask,” said Dr Hayee. He also encouraged switching to recycled paper, when paper needs to be used, and using digital and electronic systems where possible. While the latter does produce some carbon, it is still less than using “virgin” paper.

He also encouraged healthcare professionals to ensure “everything you do” in terms of procedures, in the context of waste management, is justifiable and appropriate.

“The greatest waste is a procedure that did not need to be performed,” he said.

Gastroenterologists should look at where they can reduce water usage. Decontamination can use huge amounts of water and a “great deal

of effort (carbon)” is used to ensure water quality. “Sterile water is produced in industrial plants; it’s shipped to us in plastic containers and then the plastic containers are thrown in the orange waste,” said Dr Hayee. “We need to work with endoscope manufacturers.”

“Every single time that you meet with an industry rep, lobby them. Ask them what they are doing to be more sustainable.” Dr Hayee reminded the audience that lobbying works, referring to the reduction of plastic straws in the last number of years.

Consultant Gastroenterologist at the Belfast Trust, Dr Philip Hall, who was a Chair for this session of the meeting, told Update that green endoscopy was an area gastroenterologists “need to become much more familiar with”.

Doctors should be able to opt-out of on-call when approaching retirement

Physicians should be allowed to opt-out of being on-call from age 60 onwards, as they approach retirement, the ISG and USG Summer Meeting heard.

The concept of ‘peri-retirement’ was discussed by Consultant Gastroenterologist at the Royal Hampshire County Hospital in the UK, Dr Harriet Gordon, in her talk at the meeting on burnout in gastroenterology.

Peri-retirement would begin when senior doctors and clinical leads reach the age of 55. Then, they would discuss their intentions for the next 10 years to give sufficient time for succession planning. At age 60, they would have the option to opt-out of being on-call.

USG President Dr Tony Tham questioned Dr Gordon on some NHS Trusts being against this concept.

Dr Gordon replied: “Trusts are very lucky to have you working over 60. They certainly have no right to expect you to be on-call, that’s got the full weight of the Academy of Medical

Royal Colleges, the Royal College of Physicians, the BSG, and every other organisation.”

In the final section of her talk, Dr Gordon said: “It’s very, very clear, it’s inappropriate [to be on-call] from the age of 60. And I can help by writing to people and showing the evidence.”

Dr Gordon said implementing such a policy would aid retention and deter health professionals from early retirement. One of the main reasons for burnout is lack of retention,

according to Dr Gordon. Solutions to the issue of burnout are all underpinned by the need for more staff. However, that will take time and the wellbeing and retention of current staff needs to be improved.

“Here and now, we need to relook at how we work, with flexible options and professional initiatives to help retain the workforce,” she also said.

The British Society of Gastroenterologists (BSG) workforce app showed that 37 per cent of total work is now done from home, according to Dr Gordon. While this change of environment can be beneficial, it does mean there is less of a difference between work and home.

“And that in itself can actually create more stress,” Dr Gordon added. “[According to data from the app] 81 per cent of gastroenterologists have no formal break in a working day and the median length of a working day without a break is 10 hours, which is pretty terrible. No wonder we feel stretched and burnt out.”

5 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

Dr Harriet Gordon

Biopsychosocial aspects of gastroparesis covered at ISG/USG meeting

Gastroenterologists should look at the psychological and social aspects in patients with gastroparesis, and not just the biological condition, the ISG/USG Summer Meeting heard in Belfast in June.

Consultant Psychiatrist at the Royal Hospital London, Dr Peter Byrne, covered the biological, psychological, and social influences on patients with gastroparesis, a condition which can cause food to pass through the stomach at a slower than usual rate.

“The challenge... is where people get their information,” Dr Byrne said.

In the 21st Century, these information access points are social media, ‘Doctor Google’, and other subcultures. “And many of these sources of information support and reinforce their symptoms,” he added.

Other social influences can include transgenerational health anxiety and the family narrative of “doctors missing things”. Early childhood experiences of

illness, childhood loss, and childhood abuse can also affect gastro health.

Sleep hygiene is also key, Dr Byrne said: “Get [patients] sleeping better and you will reduce [gastro symptoms].”

Another issue that needs to be “called out” and which is being seen “more and more”, according to Dr Byrne, is patients with eating disorders being seen within gastroenterology rather than psychiatry.

“We have patients denying [anorexia] symptoms. And the ‘pro-ana’ websites are telling them how to deny the symptoms and how to go the gastro route instead of the psychiatry route.” The issue of eating disorders has gotten much worse due to the pandemic, Dr Byrne added.

Doctors are also encouraged to get patients to reduce opioid intake or taking them off the medication for gastric emptying testing. There is also the danger of opioids exacerbating, or causing, gastroparesis.

However, with both sleep hygiene and reduced opioid use, patients can sometimes “argue with it and don’t want to engage with it: You need to call that out.”

He highlighted a study from 2017 in the World Journal of Gastroenterology, which showed 22-23 per cent of patients with gastroparesis experienced depression, while 12.4 per cent experienced severe anxiety. Somatisation was present in 50 per cent of patients.

“I think depression is inevitable, I think it’s missed, but it’s treatable,” Dr Byrne said. “So treat their depression with their consent.” He recommended getting the patient’s GP involved to find a way to access cognitive behavioural therapy, when necessary.

Small-molecule drugs are expanding therapeutic options for IBD patients

Small-molecule drugs are beneficial to patients with inflammatory bowel disease (IBD), however, more data is needed around the treatment, the ISG/USG Summer Meeting heard.

Consultant Gastroenterologist at the University Hospital Leuven in Belgium, Prof Séverine Vermeire, delivered a virtual presentation at the ISG/USG Summer Meeting. After two decades

of using biological drugs (biologics) to treat IBD, small molecule drugs are now entering the therapeutic landscape, according to the Professor.

“For me, they are very welcome additional treatment options that I think are really great assets for our patients with IBD,” she said.

When comparing small molecule drugs with biologics, Prof Vermeire said: “I think

it’s fair to say that all of these agents are in the same efficacy range, [as] our biologics. Are they worse? Certainly not. Are they better? I think we cannot say at the moment.”

According to Prof Vermeire, there is a lack of data comparing small molecules and biologics.

“We do not have head-to-head trials

6 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

‘The issue of eating disorders has gotten much worse due to the pandemic’

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

Long-term prophylaxis in hepatic encephalopathy (HE)2

reported in prescribed necessary, the carefully withdrawal of the necessary anticoagulation.

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

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

max . This sodium (23 ‘sodiumRifaximin is not benefits assessed breastfeeding. Side clinical depression, abdominal ascites, arthralgia and have been urinary cellulitis, rhinitis. Blood thrombocytopenia).

hyperkalaemia and balance

memory

Hypotension, Breathing

Gastrointestinal function test proteinuria.

Prescribers all adverse

€262.41

holder:

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, rifamycin-derivatives 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

Norgine B.V. Antonio Vivaldistraat 150, 1083 HP, Amsterdam, Netherlands Marketing Authorisation number: PA 1336/009/001 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

Norgine B.V. Antonio Vivaldistraat 150, 1083 HP, Amsterdam, Netherlands Marketing Authorisation number: PA 1336/009/001 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:

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.

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 ‘sodiumfree’. 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. 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.

IE-HEP-XIF-2100002

Date of preparation: May 2021.

IRELAND Legal category: Prescription only Cost: €262.41 for 56 tablets Marketing Authorisation holder:

IE-HEP-XIF-2100002

Date of preparation: May 2021.

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

comparing our small molecules with biologics,” she said. “We also lack metaanalyses. We have no, or very few, realworld data.

“I think all of these will be needed in the coming years to help us [in] positioning these agents.”

However, Prof Vermeire highlighted some progress being made towards gaining more information.

For example, a 2022 study in the Clinical

Gastroenterology and Hepatology journal, found tofacitinib, a small molecule drug, was more effective than vedolizumab, a biologic.

“I think it’s a whole combination of realworld data, personal experience, getting comfortable with the medication, and then balancing the benefits and the risks,” Prof Vermeire said. “And you really need to consider the individual patient profile.”

To conclude her presentation, Prof Vermeire gave her personal opinion on what could

be considered the ‘perfect’ ulcerative colitis patient to receive small molecule drugs.

They would be a compliant male or female (who should have no imminent wish for pregnancy); they should also be fit; and preferably under 60 years old. They can be biologic-naive, but can also have taken anti-tumour necrosis factor (anti-TNF) drugs prior.

“I think we should prescribe them [small molecules] as a monotherapy,” the Professor concluded.

IBD care app reduces medical appointments and maintains patient care

An app for patients with irritable bowel diseases (IBD) has been shown to reduce appointments and maintains level of care.

Consultant Gastroenterologist at the London Independent Hospital, Dr Gareth Parkes, live-streamed to the Europa Hotel in Belfast and presented data on the app, My IBD Care, at the ISG/USG Summer Meeting.

Service evaluation showed a 32 per cent decrease in telephone and face-to-face appointments for those using the app.

Also, there were 1.7 fewer appointments per patient per year, according to the statistics.

My IBD Care allows patients to manage medications, set reminder messages, communicate with care teams, view appointments, and track sleep and anxiety, for example.

“This allows us not just to look at patients when we see them maybe once every three months or six months or once a year, but allows us to get a much richer idea of how patients are doing through an entire year,” Dr Parkes said.

He added: “Our primary outcome was to make sure that care did not decrease.”

In a 2021 study by Dr Parkes, patients using My IBD Care were given a follow-up appointment in a year. However, as the

patients were told they would not be seen as they would have been previously, “we wanted to ensure that they didn’t feel that care had decreased because of that,” Dr Parkes told the audience.

Patients were given a short questionnaire about the service, which found that care and IBD control did not drop during their time using the app.

However, Dr Parkes highlighted that not all patients went a whole year without contact to the clinic and some even had “major” flare-ups, due to the complexity of their disease.

“We can use this as a point to say that none of these things should be disadvantaged for patients,” said Dr Parkes. “We come from an area with a very high ethnic mix. And for patients who don’t speak English, these are clearly not tools that you can use for them. It is not for everyone. It is merely for some patients.”

The demographics of patients who used the app at the Royal Hospital London were mostly aged 25-30 years, followed by those aged 31-35.

8 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

Patients were given a short questionnaire about the service, which found that care and IBD control did not drop during their time using the app

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New AGA guidelines outlining drug treatment plans for patients with IBS

AUTHOR: Priscilla Lynch

New treatment guidelines for irritable bowel syndrome (IBS) were recently published (July 2022) by the American Gastroenterological Association (AGA).

The guidelines advise a personalised approach for treating patients with approved drug treatments for IBS with constipation (IBS-C) or IBS with diarrhoea (IBS-D).

The guidelines outline, for the first time, when to use newly-introduced IBS drugs, when to rely on old drugs, and when to use over-the-counter drugs. With more treatments available, physicians can tailor a personalised approach based on the symptoms a patient with IBS is experiencing, pointed out the AGA.

“We have so many treatment options, we can now take a targeted treatment approach to patient symptoms,” said author Dr Shahnaz Sultan. “It’s very important for patients to be open about their IBS symptoms and just as important for gastroenterologists to set realistic expectations for this chronic disease to ensure the best quality-of-life for their IBS patients.”

IBS-C guidelines summary

IBS-C is a subtype of IBS that accounts for more than one-third of IBS cases.

The IBS in America survey, conducted by the AGA, found that individuals with IBS-C are more likely to report feeling self-conscious, avoiding sex, having difficulty concentrating, and not feeling able to reach one’s full potential.

A positive diagnosis of IBS-C can be made on the basis of medical history

and physical examination, evaluation of gastrointestinal symptoms (especially alarm signs), limited diagnostic testing, and use of the symptom-based Rome IV criteria, according to the AGA.

conditional recommendation against the use of selective serotonin reuptake inhibitors (SSRIs) (low certainty).

IBS-D guideline summary

IBS-D is one of the main bowel habit subtypes of IBS, with an estimated 30-to-40 per cent of IBS cases classified as IBS-D.

The panel agreed on eight recommendations for the management of patients with IBS-D. The panel made conditional recommendations for eluxadoline, rifaximin, alosetron, (moderate certainty), loperamide (very low certainty), tricyclic antidepressants, and anstispasmodics (low certainty). The panel made a conditional recommendation against the use of SSRIs (low certainty). 

The presence of alarm features, such as new symptom onset after age 50 years; rectal bleeding not attributable to haemorrhoids or anal fissures; unintentional weight loss; iron deficiency anaemia; nocturnal diarrhoea; and a family history of colon cancer, inflammatory bowel disease, or Coeliac disease, requires more patient-specific investigations.

The panel agreed on nine recommendations for the management of patients with IBS-C. The panel made a strong recommendation for linaclotide (high certainty) and conditional recommendations for tenapanor, plecanatide, tegaserod, and lubiprostone (moderate certainty), polyethylene glycol laxatives, tricyclic antidepressants, and antispasmodics (low certainty). The panel made a

References

1. Lembo A, Sultan S, Chang L, Heidelbaugh JJ, Smalley W, Verne GN. AGA Clinical practice guideline on the pharmacological management of irritable bowel syndrome with diarrhoea. Gastroenterology. 2022 Jul;163(1):137-151. doi: 10.1053/j.gastro.2022.04.017

2. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA Clinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology 2022 Jul;163(1):118-136. doi: 10.1053/j.gastro.2022.04.016

10 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

IBS with diarrhea (IBS-D) is one of the main bowel habit subtypes of IBS, with an estimated 30-to-40 per cent of IBS cases classified as IBS-D

Mucosal healing is the ultimate treatment goal for Ulcerative Colitis (UC) patients.1 Show your mild to moderate patients the way to achieve this with PENTASA once-daily combination therapy.

PENTASA combination therapy is proven to help more of your mild to moderate UC patients achieve mucosal healing and improve quality of life compared to oral therapy alone.2

The PENTASA range offers ﬂexible and convenient treatment options for patients:

· The only time-dependent mesalazine that ensures delivery throughout the entire colon, due to its unique ethyl cellulose coating3-7

· PENTASA once-daily vs. twice-daily dosing achieved comparable mucosal healing scores of 85% and 81%

· Always once-daily administration3-7,9,10

· Range of formulations and dosages to aid patient compliance1,3–7,9,10

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. Sachets andTablets: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. PentasaRectal Suspension10mg/mlis presented in cartons containing 7x100ml bottles. Pentasa Suppository1gis 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: 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: 1. Lamb CA, et al. British Society of Gastroenterology consensus guidelines on the management of inﬂammatory bowel disease in adults. June 2019. Available at: https://www.bsg.org.uk/wp-content/uploads/2019/12/BSG-IBD-Guidelines-2019. pdf. Last accessed July 2022. 2. Probert CSJ, et al. J Crohns Colitis. 2014;8(3):200–207.

Date of preparation: July 2022. IE-PA-2200011.

3. Pentasa Sachet g. SmPC. 4. Pentasa Sachet 2 g. SmPC. 5. Pentasa Sachet 4 g. SmPC. 6. Pentasa Slow Release Tablets 500 mg. SmPC. 7. Pentasa Slow Release Tablets g. SmPC. 8. Pentasa Rectal Suspension g. SmPC. 9. Pentasa Suppositories g. SmPC. 10. Bokemeyer B, etal.JCrohnsColitis.2012;6:476–482.

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ory 1 g, 2 g & 4 g sachets Top ail &

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BSG guidelines for the management of IBS

AUTHOR: British Society of Gastroenterology

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction associated with significant disease burden. It remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care.

In 2021, the British Society of Gastroenterology (BSG) published updated guidelines on the management of IBS. Since publication of the last BSG IBS guidelines in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gutbrain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS.

The primary aim of this guideline is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients.

Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.

Executive summary of recommendations Doctor-patient communication

 Establishing an effective doctor-patient relationship and a shared understanding is key to the management of IBS. Such a

relationship can lead to improved qualityof-life and symptoms, reduce healthcare visits, and enhance adherence to treatment (recommendation: Strong; quality of evidence: Low).

 Patients with IBS would like increased empathy, support and information from clinicians about the nature of the condition, diagnosis and symptom management options (recommendation: Strong; quality of evidence: Low).

exclude inflammatory bowel disease. Local and national guidelines for colorectal and ovarian cancer screening should be followed, where indicated (recommendation: Strong; quality of evidence: Moderate).

 Clinicians should make a positive diagnosis of IBS based on symptoms, in the absence of alarm symptoms or signs, and abnormalities on simple blood and stool tests (recommendation: Strong; quality of evidence: Moderate).

Diagnosis, investigation and education

 The UK’s National Institute for Health and Care Excellence (NICE) guideline definition of IBS (abdominal pain or discomfort, in association with altered bowel habit, for at least six months, in the absence of alarm symptoms or signs) is more pragmatic and may be more applicable to patients with IBS in primary care than diagnostic criteria derived from patients in secondary care, such as the Rome IV criteria (recommendation: Weak; quality of evidence: Low).

 All patients presenting with symptoms of IBS for the first time in primary care should have a full blood count, C reactive protein or erythrocyte sedimentation rate, Coeliac serology and, in patients <45 years of age with diarrhoea, a faecal calprotectin to

 Referral to gastroenterology in secondary care is warranted where there is diagnostic doubt, in patients with symptoms that are severe or refractory to first-line treatments, or where the individual patient requests a specialist opinion (recommendation: Weak; quality of evidence: Low).

 There is no role for colonoscopy in IBS, other than in those with alarm symptoms or signs, or those with symptoms suggestive of IBS with diarrhoea (IBS-D) who have atypical features and/or relevant risk factors that increase the likelihood of them having microscopic colitis (female sex, age ≥50 years, coexistent autoimmune disease, nocturnal or severe, watery, diarrhoea, duration of diarrhoea <12 months, weight loss or use of potential precipitating drugs including non-steroidal anti-inflammatory

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Since publication of the last BSG IBS guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder

drugs (NSAIDs), proton pump inhibitors, etc) (recommendation: Strong; quality of evidence: Moderate).

 In those with symptoms suggestive of IBS-D, but with atypical features such as nocturnal diarrhoea, or a prior cholecystectomy, 23-seleno-25homotaurocholic acid scanning or serum 7α-hydroxy-4-cholesten-3-one, should be considered to exclude bile acid diarrhoea (recommendation: Strong; quality of evidence: Low).

 In patients with IBS and coexisting symptoms suggestive of a defaecatory disorder or faecal incontinence, anorectal physiology tests can be considered, where available, to select those who might benefit from biofeedback (recommendation: Weak; quality of evidence: Low).

 There is no role for testing for exocrine pancreatic insufficiency, or for hydrogen breath testing to rule out small intestinal bacterial overgrowth or carbohydrate intolerance, in patients with typical IBS symptoms (recommendation: Strong; quality of evidence: Weak).

 The diagnosis of IBS, its underlying pathophysiology and the natural history of the condition, including common symptom triggers, should be explained to the patient. This should introduce the concept of IBS as a disorder of gut-brain interaction, together with a simple account of the gut-brain axis and how this is impacted by diet, stress, cognitive behavioural and emotional responses to symptoms, and post-infective changes (recommendation: Strong; quality of evidence: Weak).

First-line treatments

 All patients with IBS should be advised to take regular exercise (recommendation: Strong; quality of evidence: Weak).

 First-line dietary advice should be offered to all patients with IBS (recommendation: Strong; quality of evidence: Weak).

 Food elimination diets based on IgG

antibodies are not recommended in patients with IBS (recommendation: Strong; quality of evidence: Moderate).

 Soluble fibre, such as ispaghula, is an effective treatment for global symptoms and abdominal pain in IBS, but insoluble fibre (eg, wheat bran) should be avoided as it may exacerbate symptoms. Soluble fibre should be commenced at a low dose (3-4g/day) and built up gradually to avoid bloating (recommendation: Strong; quality of evidence: Moderate).

 A diet low in fermentable oligosaccharides, disaccharides and monosaccharides, and polyols (low FODMAP), as a second-line dietary therapy, is an effective treatment for global symptoms and abdominal pain in IBS, but its implementation should be supervised by a trained dietitian and fermentable oligosaccharides, disaccharides and monosaccharides, and polyols should be reintroduced according to tolerance (recommendation: Weak; quality of evidence: Very low).

 A gluten-free diet is not recommended in IBS (recommendation: Weak; quality of evidence: Very low).

 Probiotics, as a group, may be an effective treatment for global symptoms and abdominal pain in IBS, but it is not possible to recommend a specific species or strain. It is reasonable to advise patients wishing to try probiotics to take them for up to 12 weeks, and to discontinue them if there is no improvement in symptoms (recommendation: Weak; quality of evidence: Very low).

 Loperamide may be an effective treatment for diarrhoea in IBS. However, abdominal pain, bloating, nausea, and constipation are common, and may limit tolerability. Titrating the dose carefully may avoid this (recommendation: Strong; quality of evidence: Very low).

 Certain antispasmodics may be an effective treatment for global symptoms and abdominal pain in IBS. Dry mouth,

visual disturbance, and dizziness are common side-effects (recommendation: weak; quality of evidence: Very low).

 Peppermint oil may be an effective treatment for global symptoms and abdominal pain in IBS. Gastrooesophageal reflux is a common sideeffect (recommendation: Weak; quality of evidence: Very low).

 Polyethylene glycol may be an effective treatment for constipation in IBS. Abdominal pain is a common side-effect (recommendation: Weak; quality of evidence: Very low).

Second-line treatments

 Tricyclic antidepressants used as gutbrain neuromodulators are an effective second-line drug for global symptoms and abdominal pain in IBS. 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. 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 (recommendation: Strong; quality of evidence: Moderate).

 Selective serotonin reuptake inhibitors (SSRIs) used as gut-brain neuromodulators may be an effective second-line drug for global symptoms in IBS. 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 (recommendation: Weak; quality of evidence: Low).

 Eluxadoline, a mixed opioid receptor drug, is an efficacious second-line drug for IBS-D in secondary care. It is contraindicated in patients with prior sphincter of Oddi problems or cholecystectomy, alcohol dependence, pancreatitis or severe liver impairment, and lack of availability may limit its use (recommendation: Weak; quality of evidence: Moderate).

13 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

 5-Hydroxytryptamine 3 receptor antagonists are efficacious second-line drugs for IBS-D in secondary care. Alosetron and ramosetron are unavailable in many countries; ondansetron titrated from a dose of 4mg once a day to a maximum of 8mg three times a day is a reasonable alternative. Constipation is the most common side-effect. This drug class is likely the most efficacious for IBS-D (recommendation: Weak; quality of evidence: Moderate to high).

 The non-absorbable antibiotic rifaximin is an efficacious second-line drug for IBS with diarrhoea in secondary care, although its effect on abdominal pain is limited. The drug is licensed for IBS-D in the US, but is not available for this indication in many countries (recommendation: Weak; quality of evidence: Moderate).

 Linaclotide, a guanylate cyclase-C agonist, is an efficacious second-line drug for IBS with constipation (IBS-C) in secondary care. It is likely to be the most efficacious secretagogue available for IBS-C, although diarrhoea is a common side-effect (recommendation: Strong; quality of evidence: High).

 Lubiprostone, a chloride channel activator, is an efficacious second-line drug for IBS-C in secondary care. This secretagogue is less likely to cause diarrhoea than others. However, patients should be warned that nausea is a frequent sideeffect (recommendation: Strong; quality of evidence: Moderate).

 Plecanatide, another guanylate cyclase-C agonist, is an efficacious second-line drug for IBS-C in secondary care. Diarrhoea is a common side-effect and is no less likely than with linaclotide or tenapanor. Although the drug is licensed for IBS-C in the US, it is not yet available for this indication in many countries (recommendation: Strong; quality of evidence: High).

 Tenapanor, a sodium-hydrogen exchange inhibitor, is an efficacious second-line drug for IBS-C in secondary care. Again, diarrhoea is a frequent side-effect. Although the drug

is licensed for IBS-C in the US, it is not yet available for this indication in many countries (recommendation: Strong; quality of evidence: High).

 Tegaserod, a 5-Hydroxytryptamine 4 receptor agonist, is an efficacious secondline drug for IBS-C in secondary care, but is unavailable outside the US. Diarrhoea is a common side-effect (recommendation: Strong; quality of evidence: Moderate).

Psychological therapies

 IBS-specific cognitive behavioural therapy (CBT) may be an efficacious treatment for global symptoms in IBS (recommendation: Strong; quality of evidence: Low).

 Gut-directed hypnotherapy may be an efficacious treatment for global symptoms in IBS (recommendation: Strong; quality of evidence: Low).

 Psychological therapies should be considered when symptoms have not improved after 12 months of drug treatment. Referral can be made at an earlier stage, if accessible locally, and based on patient preference (recommendation: Strong; quality of evidence: Low).

Management of severe or refractory IBS

 Severe or refractory IBS symptoms should prompt a review of the diagnosis, with consideration of further targeted investigation (recommendation: Weak; evidence: Very low).

 Severe or refractory IBS should be managed with an integrated multidisciplinary approach (recommendation: Weak; evidence: Very low).

 Iatrogenic harms due to opioid prescribing, unnecessary surgery and unproven unregulated diagnostic or therapeutic approaches incentivised by financial or reputational gain should be avoided (recommendation: Strong; evidence: Very low).

 Use of combination gut-brain

neuromodulators, termed augmentation, may be considered for more severe symptoms, with vigilance for risks of serotonin syndrome (recommendation: Weak; evidence: Very low).

Other treatments in development

In recent years, there has been considerable interest in the evaluation of faecal microbiota transplantation (FMT) for IBS. Unfortunately, a meta-analysis of five RCTs, containing 267 patients, demonstrated no significant benefit of FMT compared with placebo (RR 0.98; 95 per cent CI 0.58 to 1.66), and in two pooled trials placebo capsules administered orally were superior to capsules containing donor stool (RR 1.96; 95 per cent CI 1.19 to 3.20). Criticisms of the trials, to date, have included small sample sizes, heterogeneity in IBS subtypes recruited, lack of standardisation of donor samples and suboptimal end points used. There is therefore a need for further, large, high-quality trials of FMT for IBS, perhaps targeting subgroups of patients with evidence of dysbiosis, who may be more likely to benefit. At present, therefore, there is insufficient evidence to recommend FMT for IBS outside of a research setting.

Enterosgel, an intestinal adsorbent approved for use in IBS-D and available over-the-counter, is currently the subject of a multicentre RCT in IBS-D.

For IBS-C, there are ongoing trials of an exo-peristalsis device. 

The full guideline is available at: www.bsg. org.uk/clinical-resource/british-society-ofgastroenterology-guidelines-on-the-managementof-irritable-bowel-syndrome/.

Reference

Vasant DH, Paine PA, Black CJ, Houghton LA, Everitt HA, Corsetti M, et al. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut 2021;70:1214-1240

14 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

Updated ECCO guidelines on management of UC in adults

AUTHOR: Priscilla Lynch

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterised by colonic inflammation extending to a variable extent from the rectum. Key updates to the European Crohn’s and Colitis Organisation (ECCO) Guidelines on the Medical and Surgical Treatment of Ulcerative Colitis in Adults have recently been published, which summarise the current evidence.

Changes to medical management

Key areas of importance for the medical treatment of UC include clinical response and remission for maintenance and induction therapies, as well as steroid-free clinical remission. However, a key area of debate is when to escalate treatment. There is less evidence in UC than in Crohn’s disease on the importance of early treatment escalation. At the same time, the experience of recurrent symptom flares can lead to physical and psychological harm, as can repeated exposure to corticosteroids, notes ECCO. “Although the cost of an intervention is a factor reflected in the GRADE (Grading of Recommendations Assessment, Development and Evaluation) process when forming the strength of recommendation, as international guidelines there will be local health economic considerations that this document cannot address. Nevertheless, it is clear that appropriate and timely selection of patients for higher-cost interventions is critical to achieve optimal health economic outcomes,” the new updated guidelines state.

A notable shift from the 2017 ECCO guidelines is the recommendation on considering treatment options based on patient disease severity. Previously, guidelines advised treatment according to the site of the disease and its activity, whereas revised guidelines recommend treatment under sections labelled ‘Medical management of mildly-to-moderately active UC’ and ‘Medical management of moderately-to-severely active UC’.

Another notable change is in regard to new data and treatments. Following the recent MERIT-UC trial conducted by Herfarth et al, which took place in 2018 and concluded that methotrexate was not superior to a placebo in maintaining steroid-free response or remission in UC, it has been removed from the guidelines. New data for vedolizumab, ustekinumab, and tofacitinib have been included in the updated ECCO Therapeutic Guidelines on UC, which have been written in a way that allows for new updates to therapeutics to be included.

The following is a summary of the key recommendations in the 2022 ECCO Guidelines on the Medical Treatment of Ulcerative Colitis in Adults

Medical management of mildly-to-moderately active UC Induction of remission in mildly-to-moderately UC.

Recommendation 1

ECCO recommends 5-aminosalicylates (ASA) at a dose of ≥2g/day (d) to induce remission in patients with mildly-to-moderately active UC [strong recommendation; quality of evidence low].

Recommendation 2

ECCO recommends topical (rectal) 5-ASA at a dose of ≥1g/d for the induction of remission in active distal colitis [strong recommendation, low-quality evidence].

Recommendation 3

ECCO suggests the use of oral 5-ASA (≥2g/d) combined with topical (rectal) 5-ASA over oral 5-ASA monotherapy for induction of remission in adult patients with active UC of at least rectosigmoid extent [weak recommendation; very low-quality evidence].

Recommendation 4

ECCO recommends using topical (rectal) steroids for the induction of remission in

patients with active distal colitis [strong recommendation, very low-quality evidence].

Recommendation 5

ECCO suggests treatment with topical (rectal) 5-ASAs over topical (rectal) steroids for induction of remission in patients with active distal UC [weak recommendation, very low-quality evidence].

Recommendation 6

ECCO suggests the use of colonic-release corticosteroids for induction of remission in patients with active mild-to-moderate UC [weak recommendation, low quality of evidence].

Recommendation 7

ECCO suggests against the use of thiopurines as monotherapy for the induction of remission in patients with active UC [weak recommendation, very low quality of evidence].

Recommendation 8

ECCO recommends the use of oral 5-ASA at a dose ≥2g/d for maintenance of remission in UC patients [strong recommendation; very low quality of evidence].

Recommendation 9

ECCO suggests the use of topical (rectal) 5-ASA for the maintenance of remission in patients with distal UC [weak recommendation, very low-quality evidence].

Recommendation 10

ECCO recommends monotherapy with thiopurines for the maintenance of remission in patients with steroiddependent UC or who are intolerant to 5-ASA [strong recommendation, moderate quality of evidence].

Medical management of moderately-to-severely active UC Induction of remission in moderately-toseverely active UC.

15 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

Recommendation 11

ECCO recommends oral prednisolone for induction of remission in non-hospitalised patients with moderately-to-severely active UC [strong recommendation; very low quality of evidence].

Recommendation 12

ECCO recommends treatment with anti-tumour necrosis factor (TNF) agents [infliximab, adalimumab, and golimumab] to induce remission in patients with moderate-tosevere UC who have inadequate response or intolerance to conventional therapy [strong recommendation, moderate-quality evidence].

Recommendation 13

ECCO recommends treatment with vedolizumab for the induction of remission in patients with moderately-to-severely active UC who have inadequate response or intolerance to conventional therapy [strong recommendation, low quality of evidence].

Recommendation 14

ECCO recommends treatment with tofacitinib to induce remission in patients with moderate-to-severe UC who have inadequate response or intolerance to conventional therapy [strong recommendation, moderate quality of evidence].

Recommendation 15

ECCO recommends treatment with ustekinumab for the induction of remission in patients with moderately-to-severely active UC with inadequate response or intolerance to conventional therapy [strong recommendation, moderate quality of evidence].

Maintenance of remission of moderately-to-severely active UC

Recommendation 16

ECCO recommends anti-TNF agents (infliximab, adalimumab, or golimumab) for the maintenance of remission in patients with UC who responded to induction therapy with the same drug [strong recommendation, high-quality evidence].

Recommendation 17

In UC patients who have lost response to an anti-TNF agent, there is currently insufficient

evidence to recommend for or against the use of therapeutic drug monitoring to improve clinical outcomes.

Recommendation 18

ECCO recommends vedolizumab for maintenance of remission in patients with UC who responded to induction therapy with vedolizumab [strong recommendation, moderate-quality evidence].

Recommendation 19

ECCO suggests the use of vedolizumab rather than adalimumab for the induction and maintenance of remission in patients with moderately-to-severely active UC [weak recommendation, low level of evidence].

Recommendation 20

ECCO recommends tofacitinib for maintaining remission in patients with UC who responded to induction therapy with tofacitinib [strong recommendation, moderate quality of evidence].

Recommendation 21

ECCO recommends ustekinumab for the maintenance of remission in patients with UC who responded to induction therapy with ustekinumab [strong recommendation, moderate quality of evidence].

Changes to surgical management of UC in new guidelines

While UC presents as a mild condition, it often leads to life-threatening and systemic complications that require urgent interventions. Up to 25 per cent of UC patients require a surgical intervention in their lifetime.

Key updates regarding surgery in cases of moderate-to-severe UC in the new ECCO guidelines include that reconstructive ileal pouch-anal anastomosis (IPAA) surgery can be offered to refractory and corticosteroiddependent patients following evidence that this improves patient quality-of-life. The importance of pre-operative optimisation in patients with moderate-to-severe UC is also stressed. Another key update focuses on the use of steroids pre-operatively, which should be avoided or weaned off before restorative

surgery, and where weaning is not possible, surgery should be postponed.

Prophylactic anticoagulation therapy is also advised in adult patients with active UC to reduce the risk of venous thromboembolism, and systemic nutrition is advised despite a lack of evidence.

The updated guidelines state that the modified two-stage colectomy procedure may be associated with fewer complications, as patients are subjected to less surgery, but more evidence is needed to confirm this.

For patients with medically refractory UC, laparoscopic IPAA surgery is the advised choice. This technique is also an ideal option for young females, as it is associated with improved fecundity compared to open surgery. Ileorectal anastomosis (IRA) remains an option for patients with UC who have a minimally affected rectum.

Guideline summary

Acute severe UC (ASUC) and medicallyrefractory UC represent the main indications for surgery in UC patients, the new ECCO guidelines note. ASUC may be the onset feature in up of one-third of UC patients, and is associated with a 30-to-40 per cent risk of colectomy after one or more severe exacerbations, and 10-to-20 per cent of patients with ASUC need a surgical intervention at their first admission.

Patients with ASUC require immediate hospitalisation, and the first-line treatment of ASUC consists of intravenous corticosteroid treatment. However, up to 30 per cent of patients fail to respond to conservative treatments and require a colectomy. In case of failure, after seven days without significant improvements, a surgical intervention is highly recommended to avoid the peri-operative complications usually associated with emergent procedures, ECCO states.

Refractory UC includes steroid dependency and immunomodulator- or biologicrefractory disease, and is often accompanied by a deteriorated patient condition and is a recognised risk factor of poor post-operative

16 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

outcomes; thus a staged procedure is often preferred, to improve patient status and minimise post-operative complications.

Despite the increasing availability of new pharmacological treatments, multiple attempts at conservative management and consequent therapeutic failures may affect the condition of patients with ASUC and refractory UC and considerably influence post-operative outcomes. Accordingly, multidisciplinary management of UC patients is of crucial importance to identify the best therapeutic pathway, says ECCO.

In recent decades, the surgical options for the treatment of refractory UC have evolved.

The ECCO UC surgical guideline recommendations are as follows: Medical management of ASUC

 Statement 1.1.

Intravenous corticosteroids as the initial standard treatment for adult patients with ASUC are recommended, as this treatment induces clinical remission and reduces mortality [EL3].

 Statement 1.2.

Either infliximab or cyclosporine should be used in adult patients with steroid-refractory ASUC. When choosing between these strategies, centre experience and a plan for maintenance therapy after cyclosporine should be considered [EL3].

 Statement 1.3.

There is currently insufficient evidence to determine the optimal regimen of infliximab rescue therapy in patients with ASUC refractory to corticosteroid therapy [EL4].

 Statement 1.4.

Third-line sequential rescue therapies with calcineurin inhibitors (cyclosporine or tacrolimus]) in ASUC refractory to corticosteroid therapy may delay the need for colectomy, but are associated with high rates of adverse events and should only be administered in specialised centres [EL2a].

Medical versus surgical management of refractory moderate-to-severe UC

 Statement 2.1.

Reconstructive surgery may be offered to refractory and corticosteroid-dependent patients and improves quality-of-life despite the risk of early and late complications [EL2b]. Proctocolectomy with end-ileostomy is an alternative for some patients and has lower morbidity and comparable quality-of-life [EL3a].

Pre-operative optimisation of refractory moderate-to-severe UC

 Statement 3.1.

Correction of altered body composition and nutrition imbalances is advised pre-operatively, despite limited evidence [EL5]. There is no evidence to support routine enteral or parenteral nutrition to improve the surgical outcomes of patients with UC [EL5]. Iron supplementation is recommended when iron-deficiency anaemia is present [EL1].

 Statement 3.2.

Patients taking >20mg prednisolone for >six weeks are at increased risk of early complications and pouch-specific complications. Steroids should be weaned before restorative proctectomy or proctocolectomy, and if this is not possible, surgery should be postponed [EL4]. Preoperative thiopurines or cyclosporine do not increase the risk of post-operative complications [EL3]. Patients on biologics might be at increased risk of developing early and late pouch-specific complications; three-stage or two-stage modified approaches with deferred pouch construction could be considered under these circumstances [EL4]. Singlestage restorative proctocolectomy should be avoided in patients receiving biologics [EL5].

 Statement 3.3.

Prophylactic anticoagulation therapy in adult patients with active UC during hospitalisation is recommended, considering the high risk of venous thromboembolism (VTE) during UC flares [EL4].

Surgical strategy of refractory moderate-to-severe UC

 Statement 4.1.

After total proctocolectomy for medicallyrefractory UC, IPAA is the procedure of choice, but permanent end-ileostomy is also a

reasonable option for some patients. A shared decision-making approach should be used to tailor procedure selection to the patient’s preference [EL3].

 Statement 4.2.

IPAA may be performed as a two or three stage procedure. Modified two-stage IPAA may be associated with fewer complications and shorter length of stay than three-stage or two-stage IPAA in patients with medically-refractory UC operated on in expert centres, but more evidence is needed [EL3].

Technical aspects of surgical approaches for refractory moderate-to-severe UC Statement 5.1.

IPAA may be constructed using either a stapled or a handsewn technique, with comparable functional outcomes. Thus, the type of anastomosis should be left to the surgeon’s discretion [EL2].

Statement 5.2.

Laparoscopic surgery is the preferred approach to patients with medically refractory UC, as it is associated with lower intra- and post-operative morbidity, faster recovery, fewer adhesions and incisional hernias, shorter hospital length of stay, improved female fecundity, and better cosmesis [EL2].

Statement 5.3.

Although associated with an increased risk of rectal dysplasia, cancer, and dysplasia or cancer recurrence, patients with UC and a minimally affected rectum can be offered the option of an IRA [EL4]. 

References

1. Raine T, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical treatment. J Crohns Colitis. 2022 Jan 28;16(1):2-17. doi: 10.1093/ecco-jcc/jjab178

2. Spinelli A, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical treatment. J Crohns Colitis. 2022 Feb 23;16(2):179-189. doi: 10.1093/ecco-jcc/jjab177

17 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

WITH RAPID RESPONSES AND PROVEN SEE THE DIFFERENCE XELJANZ® CAN

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 active ankylosing spondylitis (AS) who have responded inadequately to conventional 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 in patients 2 years of age and older, who have responded inadequately to previous therapy with DMARDs. Can be given in combination with 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 orally, with or without food. RA and PsA: The recommended dose is 5 mg 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. AS:

The recommended dose is 5 mg twice daily. Available data suggest that clinical improvement in AS is observed within 16 weeks of initiation of treatment. Continued therapy should be carefully reconsidered in AS patients exhibiting no clinical improvement within this timeframe.

UC: The recommended dose is 10 mg 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 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 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 UC such as tumour necrosis factor 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 oral solution) twice daily, 20 kg - < 40 kg: 4 mg (4 mL oral solution) twice daily, and ≥ 40 kg 5 mg (5 mL oral solution or 5 mg tablet) twice daily. Patients ≥ 40 kg treated with tofacitinib 5 mL oral solution twice daily may be switched to tofacitinib 5 mg tablets twice daily. Available data suggest that clinical improvement is observed in paediatric patients within 18 weeks of initiation. Continued therapy should be carefully reconsidered in a paediatric patient exhibiting no clinical improvement within this timeframe. Dose interruption and adjustment:

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 /L, an absolute neutrophil count (ANC) less than 1x10 /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 /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 prolonged-release 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 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. Paediatric population: 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. Interactions: TTofacitinib total daily dose should be reduced by half in patients receiving potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g. ketoconazole) and in patients receiving 1 or more products that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. fluconazole). Coadministration with potent CYP inducers (e.g. rifampicin) may result in a loss of or reduced clinical response. Coadministration with potent inducers of CYP3A4 is not recommended. 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, ciclosporin 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. In a randomised post authorisation safety

aFrom the start of treatment with XELJANZ in patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. 3

XELJANZ 10 mg BID achieved higher rates of remission (primary endpoint) at week 8 vs placebo in OCTAVE Induction 1 (19% [88/476] vs 8% [10/122]; P=0.007) and OCTAVE Induction 2 (17% [71/429] vs 4% [4/112]; P<0.001)

XELJANZ 10 mg BID achieved higher rates of clinical response at week 8 vs placebo in OCTAVE Induction 1 (60% [285/476] vs 33% [40/122]; P<0.001) and OCTAVE Induction 2 (55% [236/429] vs 29% [32/112]; P<0.001)

In OCTAVE Sustain, for patients showing remission or clinical response following induction, XELJANZ 5 mg BID achieved higher rates of remission at week 52 (primary endpoint) vs placebo (34% [68/198] vs 11% [22/198]; P<0.001).1

Decreases in rectal bleeding and stool frequency Mayo subscores were observed as early as day 3 in patients treated with XELJANZ 10 mg BID2

PROVEN MAINTENANCE OF EFFICACY, CAN MAKE FROM THE START1,2,a

study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose dependent increased risk for VTE was observed with tofacitinib compared to TNF inhibitors. In a post hoc exploratory analysis within this study, in patients with known VTE risk factors, occurrences of subsequent VTEs were observed more frequently in tofacitinib-treated patients that, at 12 months treatment, had D-dimer level greater than or equal to twice the upper limit of normal (2× ULN) versus those with D-dimer level <2×ULN. For patients with RA with known risk factors for VTE, consider testing D-dimer levels after approximately 12 months of treatment. If D-dimer test result is ≥ 2× ULN, confirm that clinical benefits outweigh risks prior to a decision on treatment continuation with tofacitinib. Tofacitinib should be used with caution in patients with known risk factors for VTE, regardless of indication and dose. 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 non-melanoma 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

References:

cancer. In patients over 65 years of age, patients who are current or past smokers, and patients with other malignancy risk factors 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 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 breast-feeding 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 studies 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 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, peripheral oedema, fatigue, increased creatine phosphokinase. 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 medical.information@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.

Last revised: 03/2022.

Ref: XJ 15_0.

1. Sandborn WJ, Su C, Sands BE, et al; for the OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736.

2. Hanauer S et al. Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol 2019;17(1):139-147.

3. XELJANZ Summary of Product Characteristics.

Gastro-oesophageal reflux disease in infants and children

AUTHOR: Eamonn Brady, MPSI

Gastro-oesophageal reflux disease (GORD) is also called ‘gastric reflux disease’ or ‘acid reflux’. It is a condition which develops when the reflux of stomach contents causes troublesome symptoms such as heartburn, or complications such as oesophageal ulcers.

How common is GORD in the general population?

The most common cause of indigestion in Ireland, GORD affects up to one-in-four people. Some 10-to-20 per cent of people in the Western world have at least one bout of GORD per week. This figure is only about 5 per cent in Asia, which gives an indication that our Western diet, which tends to have a higher fat content, is a factor in GORD.

GORD can affect people at any age, including infants and young children. A typical sufferer is twice as likely to be male as female. It is also a common problem for babies and infants, leading to difficulty feeding in more severe cases. It can be controlled by food thickeners, alginates and removing cow’s milk from the infant’s diet if caused by lactose intolerance.

How common is GORD in infants?

The most obvious symptoms of reflux in infants is vomiting or regurgitation. All healthy infants have a tendency for GORD and it is natural for an infant to have a certain amount of regurgitation after feeding. The issue is whether GORD is causing a problem in an infant, rather than whether GORD is occurring at all. Reflux is most common between one-to-four months and approximately 67 per cent of infants have more than one daily episode of regurgitation at four months. Between the ages of six-toseven months, symptoms of reflux decrease from 61 per cent down to 21 per cent. At

12 months of age, only 5 per cent have symptoms. By 12-to-18 months, most cases of GORD will resolve as the sphincter (valve between oesophagus and stomach) matures, the infant adopts an upright posture and begins having a more solid diet.

extremely difficult to burp after feeds; failure to wind them successfully usually means reflux and vomiting are worsening.

 Refusing feeds or frequent feeds for comfort.

 Night-time coughing.

 Sometimes reflux can happen so quickly that it leads to the infant inhaling vomit, leading to respiratory problems such as asthma, bronchitis, and even chest infections.

When to refer?

Symptoms of reflux in infants

Reflux causes frequent or recurring vomiting. This is not the small mouthfuls of vomit seen in all infants, but the vomiting of large amounts. This can happen straight after a feed, or right up until the next feed. When the infant’s oesophagus becomes sore from exposure to the regurgitated acid (the equivalent of heartburn), this leads to irritability, pain, and poor feeding. If GORD is severe, the infant may have difficulty gaining weight.

Other common symptoms of reflux include:

 Sometimes screaming suddenly when asleep. Infants can be inconsolable, especially when laid down flat.

 Poor sleep habits, typically with arching their necks and back during or after feeding.

 Frequent burping or frequent hiccups.

 Swallowing problems.

 Frequent ear infections or sinus congestion.

 Infants are often very windy and

It is very rare for reflux to lead to serious complications. But some infants do have problems and the parent should see a GP if the infant vomits severely or has any of the following symptoms:

 Blood or bile in their vomit;

 Difficulty in swallowing or is choking easily;

 A fever;

 Is irritable, crying and hard to settle;

 Listlessness, dark circles under the eyes, refusal to feed, and dry nappies;

 Breathing problems that could lead to apnoea;

 Is losing weight or not gaining weight as per normal.

Treatment

Avoid overfeeding and try increasing frequency and decreasing volume of feeds. The infant should be supported in an upright position whilst feeding and for at least 45 minutes after feeding to bring up wind. The infant should be handled very gently after feeding and during winding; avoid vigorous patting or rocking.

GORD tends to be worse when lying flat and therefore a gentle raise of the head of an infant’s cot can be useful, so that

20 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

The issue is whether GORD is causing a problem in an infant, rather than whether GORD is occurring at all

the infant’s head is higher than the rest of their body while they sleep. This can be done by putting a pillow or folded blanket under the mattress to create a gentle up-slope. Never attempt to let the infant sleep directly on a pillow, which could be dangerous.

Products to add to an infant’s food

By thickening their food, an infant is less likely to bring it back up. There are products to thicken an infant’s milk, for example, Instant Carobel. There are also ready-thickened feeds such as SMA Staydown.

If breastfeeding and the infant is having problems with bringing up food, Gaviscon Infant sachets may be used instead of the above mentioned products.

Infants are less likely to bring up food if they have sodium alginate (Gaviscon Infant) mixed with their feed or dissolved in water after their meal. Sodium

Medication

Anti-reflux medicines reduce the severity of the reflux by improving the downward movement (ie, motility) of the oesophagus and stomach. They may also reduce acidity so that the reflux is less damaging to the oesophageal lining. They are generally only used if other treatment options like thickeners do not work.

Domperidone helps tighten the valve (called the sphincter) at the end of the oesophagus where it joins the stomach. This will help stop food from flowing back into the oesophagus. It comes in liquid or rectal (suppository) form for infants and children, but is only available with a doctor’s prescription. Directions: By mouth – over one month and body weight up to 35kg, 250-500mcg/ kg three-to-four times a day; body weight 35kg and over, 10-20mg three-to-four times daily, max 80mg daily. By rectum – body weight over 15kg, one 30mg Motilium suppository twice a day, body

correct dose. Directions: Newborn infant under four weeks, 700mcg/kg once-daily, increased if necessary after seven-to-14 days to 1.4mg/kg once daily. Child one month to two years, 700mcg/kg oncedaily, increased if necessary to 3mg/kg, max 20mg once-daily.

Dosage range for omeprazole by weight:

 Child’s body weight 10-20kg: 10mg oncedaily (max 20mg/day).

 Child’s body weight over 20kg: 20mg once-daily (max 40mg/day).

Surgery

Surgery is required in a minority of infants with severe GORD who do not respond to treatment; surgery is not always successful. Sometimes medication needs to be continued after surgery. 

Disclaimer: Brands mentioned in this article are meant as examples only and not meant as preference to other brands.

Bibliography

1. Galmiche JP, Janssens J; The pathophysiology of gastro-oesophageal reflux disease: An overview. Scandinavian Journal of Gastroenterology. 1995, Vol 30, No s211, Pages 7-18

alginate works in three ways: It thickens the milk, making it easier for the infant to cope with; coats the oesophagus all the way down to the stomach; and in the stomach, it forms a raft over the stomach contents, helping to stop the contents of the stomach from escaping back up the oesophagus. Dosage depends on the weight of the infant. Gaviscon Infant sachet(s) can be mixed with cool boiled water, milk feed or expressed breast milk. Gaviscon Infant sachet(s) should not be administered more than six times in 24 hours.

Gaviscon Infant should not be given to premature infants, young children who are ill with a high temperature, diarrhoea, vomiting, or if already using a food thickener.

weight over 35kg, 60mg twice-daily. Some young children taking domperidone may get mild diarrhoea.

H2 blockers reduce the amount of acid in the stomach. Ranitidine, a type of H2 antagonist, was often used for GORD in infants until it was recalled in 2019.

Omeprazole liquid (available as an unlicensed medication in Ireland) and Losec MUPS (omeprazole) are the most used proton pump inhibitors (PPIs) for children. Losec MUPS can be dissolved in water, which is convenient for children’s dosage. A PPI reduces the acidity of the stomach’s contents and is more potent than H2 antagonists. The dose for infants and young children is based on body weight and the doctor will decide the

2. PJ Kahrilas. Gastro-oesophageal reflux disease. New England Journal of Medicine, 2008

3. All PPIs are equivalent for treatment of GORD (POEM). The Pharmaceutical Journal. Vol 275 No 7380 p736. Dec 2005

4. Nickless G, Morgan P. Gastrooesophageal reflux disease and its management. The Pharmaceutical Journal, 1 Dec 2009

5. Patient information from the BMJ Group. GORD in young children. March 21, 2012

6. Stringer D, MS FRCS FRCP. Gastrooesophageal reflux. TOF young children by TOFS (Tracheo-Oesophageal Fistula Support).

7. Clinical practice guidelines. The Royal Young Children’s Hospital Melbourne, GORD in young children, May 2012

8. Liburd J, Hebra A. GORD. eMedicine, May 2009; Paediatric article

21 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

A proton pump inhibitor reduces the acidity of the stomach’s contents and is more potent than H2 antagonists

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: August 2021

CODE: 2021/20

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

Peptic ulcer disease

AUTHOR: Theresa Lowry-Lehnen, RGN, GPN, RNP, BSc, MSc, M Ed, PhD, Clinical Nurse Specialist and Associate Lecturer, South East Technological University (SETU)

Peptic ulcers are ulcerations exceeding 5mm in diameter that develop in the mucosal lining of the stomach or duodenum, resulting from an imbalance between factors promoting mucosal damage (such as gastric acid, pepsin, Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drugs (NSAIDs), and mechanisms promoting gastroduodenal defence, such as prostaglandins, mucus, bicarbonate, and mucosal blood flow. Ulcers smaller than this or without depth are classed as erosions.

While peptic ulcers usually occur in the stomach and proximal duodenum, they may also occur in the lower oesophagus, distal duodenum, or jejunum.

Peptic ulcer disease (PUD) is a significant source of morbidity and mortality worldwide with a lifetime risk of development ranging from 5-to10 per cent. Epidemiological studies, however, have shown a sharp decreasing trend in the past 20-to-30 years in the incidence rates of hospital admissions and mortality associated with the condition, due to improved hygiene, more effective treatments including the widespread use of proton pump inhibitors (PPIs) and judicious use of NSAIDs and aspirin.3

Duodenal ulcers are four times more common than gastric ulcers and are also more common in males than females.1,2 Gastric ulcers are most commonly located on the lesser curvature and duodenal ulcers are most common at the duodenal bulb. Duodenal ulcers occur most frequently in the first portion of the duodenum (over 95 per cent), with approximately 90 per cent located within 3cm of the pylorus and are usually less than or equal to 1cm in diameter.7 Peptic ulcers are round or oval in shape with a smooth base. Acute ulcers have regular borders, while chronic ulcers have elevated borders with inflammation.1,2

The mechanism of PUD results from an imbalance between gastric mucosal protective

Source: https://patient.gastro.org/peptic-ulcer-disease/8

and destructive factors. In PUD there is usually a defect in the mucosa that extends to or beyond the muscularis mucosa. Once the protective superficial mucosal layer is damaged, the inner layers are susceptible to acidity and the ability of the mucosal cells to secrete bicarbonate is compromised. H. pylori can colonise the gastric mucosa and also impair the secretion of bicarbonate, promoting the development of acidity and gastric metaplasia.1,2

Aetiology

Common causes of PUD include H. pylori bacteria, NSAIDs and other medications. Rare causes include Zollinger-Ellison syndrome, malignancy, stress, viral infection, vascular insufficiency, radiation therapy, Crohn’s disease, and chemotherapy.1

H. pylori, a gram-negative bacillus found within the gastric epithelial cells, is responsible for 90 per cent of duodenal ulcers and 70-to-90 per cent of gastric ulcers. H. pylori causes an inflammatory response with neutrophils, lymphocytes, plasma cells, and macrophages within the mucosal layer and causes epithelial

cell degeneration and injury. H. pylori has a wide spectrum of virulence factors allowing it to adhere to and inflame the gastric mucosa. This results in hypochlorhydria or achlorhydria, leading to gastric ulceration.1 All patients found to have peptic ulcers should be tested for H. pylori 7

NSAID use is the second most common cause of PUD and approximately 25 per cent of regular NSAID users will develop PUD. Aspirin users are also twice as likely to develop peptic ulcers as the general population.7 NSAIDs damage the gastroduodenal mucosa through both systemic and local mechanisms, but the systemic inhibition of cyclooxygenase 1 (COX-1) derived prostaglandins is regarded as the main mechanism. The secretion of prostaglandin normally protects the gastric mucosa. NSAIDs block prostaglandin synthesis by inhibiting the COX-1 enzyme, resulting in decreased gastric mucus and bicarbonate production and a decrease in mucosal blood flow.1 Other medications including corticosteroids, bisphosphonates,

23 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

FIGURE 1: Peptic ulcer disease

potassium chloride, and fluorouracil have been implicated in the aetiology of PUD.3

About a fifth of PUD cases are not related to H. pylori, NSAIDs or aspirin, but the accuracy of this value has been challenged due to false negative H. pylori testing or under-reported NSAID use.

Idiopathic PUD may be due to an imbalance between factors that contribute to mucosal integrity and aggressive insults, including a hyper-secretory status.7

Symptoms

Approximately two-thirds of patients with PUD are asymptomatic. In symptomatic patients, the most common presenting symptom of PUD is epigastric pain, which may be associated with dyspepsia, bloating, abdominal fullness, nausea,

invasive and non-invasive medical tests are important for an accurate diagnosis of PUD. A careful history should be obtained and noted for the presence of any complications. Any patient presenting with anaemia, melaena, haematemesis or weight loss should be further investigated for complications, including bleeding, perforation, or cancer. A physical exam may reveal epigastric abdominal tenderness and signs of anaemia.1,3

Endoscopy is the gold standard for diagnosis of PUD. Although invasive, endoscopy allows for biopsy and includes a variety of methods for testing, such as histology, culture, or rapid urease test. Endoscopy can be used to detect H. pylori and can also rule out malignancy.7 Less invasive options include a H. pylori carbon-13 urea breath test or stool antigen test and a full blood count. The urea breath test

gastro-oesophageal reflux disease (GORD), gastric cancer, pancreatitis, biliary colic, and cholecystitis. Life-threatening conditions that can also have similar presentations to PUD include myocardial infarction (MI), mesenteric ischaemia, and mesenteric vasculitis.1

Treatment and management

The treatment plan for peptic ulcers is developed based on the degree of disease noted at diagnosis. Patients who present with complications, including perforation or bleeding, may require surgical intervention. However, the majority of patients are treated with anti-secretory agents to help reduce the amount of acid exposure to the ulcerated region, and in turn, provide symptomatic relief and promote healing. For patients who present with a history of heavy NSAID use, the first step is to advise them to avoid NSAIDs, as this is not only a possible aetiology, but also a cause of worsening symptoms. Smoking and alcohol cessation is also encouraged, as these may exacerbate symptoms.6

Treatment for H. pylori infection

Apart from exclusion of malignant disease, detection of H. pylori infection with histology or rapid urease tests is essential to the subsequent treatment plan.3,4

or early satiety. Other signs include weight loss/gain, haematemesis, and melaena. Signs and symptoms of PUD vary depending upon the age and location of the ulcer. Gastric and duodenal ulcers can be differentiated by the timing of their symptoms in relation to meals. Epigastric pain usually occurs within 15-to-30 minutes following a meal in patients with a gastric ulcer, and two-to-three hours post prandial for patients with a duodenal ulcer. Nocturnal pain is common with duodenal ulcers.1,2 The most common complication of PUD is gastroduodenal bleeding. Perforation is a less frequent, but potentially life-threatening complication. Either of these may be the presenting symptom, particularly in patients taking NSAIDs.5

Investigations and diagnosis

A detailed history including medication use and lifestyle factors, physical examination, and

has high specificity; however, false-negative results can occur in the case of PPI use.6 Other investigations to consider may include fasting serum gastrin level and urine NSAID screen.4

CT scans can identify non-perforated peptic ulcers. However, many patients will need endoscopy or oesophagogastroduodenoscopy (OGD) for further evaluation. Barium endoscopy is an option for patients with contraindications to OGD.

Once the diagnosis of PUD has been made, it is important to establish the aetiology of the disease as this will help develop a treatment plan for the patient, not only acutely, but also a long-term plan to help prevent a recurrence.6

Differential diagnosis is important to rule out conditions which share similar signs or symptoms to PUD, including gastritis,

First-line treatment for H. pylori-induced PUD is a triple regimen comprising two antibiotics and a PPI (See Figure 2). PPIs should be avoided two weeks before testing for H. pylori, as they may increase the risk of a false negative result. Antimicrobials should also be avoided for four weeks before testing.5 Due to increasing antibiotic resistance in H. pylori, treatment has become more difficult, and the efficacy of triple therapy has fallen below 70 per cent in many countries.7

Post eradication testing must be carried out at least eight weeks following completion of therapy. In cases where the first-line regimen to eradicate H. pylori infection has failed, a different treatment regimen should be used as secondline.5 With failure of a second-line regimen the patient should be referred to gastroenterology for endoscopy with culture and antimicrobial susceptibility testing, to tailor therapy and increase the likelihood of eradication success.5

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Gastric and duodenal ulcers can be differentiated by the timing of their symptoms in relation to meals. Epigastric pain usually occurs within 15-to-30 minutes following a meal in patients with a gastric ulcer, and two-to-three hours post prandial for patients with a duodenal ulcer

Anti-secretory drugs used for PUP include H2-receptor antagonists and PPIs. PPIs have largely replaced H2 receptor blockers due to their superior healing and efficacy. PPIs block acid production in the stomach, providing relief of symptoms and promote healing. Treatment may be incorporated with calcium supplements as long-term use of PPIs can increase the risk of bone fractures. The duration of PPI therapy varies for patients depending on the presenting symptoms, level

of compliance, and the risk of recurrence. The majority of patients, however, do not require long-term anti-secretory therapy following H. pylori treatment, upon confirmation of eradication and if they remain asymptomatic.6

NSAID-induced PUD can be treated by stopping the use of NSAIDs or switching to a lower dose. Corticosteroids, bisphosphonates, and anticoagulants should also be discontinued if possible.1

Surgical treatment for PUD is indicated if the patient is non-compliant, unresponsive to medical treatment, or at high risk of complications. A refractory peptic ulcer is defined as one over 5mm in diameter that does not heal despite eight-to-12 weeks of PPI therapy. The common causes are persistent H. pylori infection, continued use of NSAIDs, or significant comorbidities that impair ulcer healing or other conditions like gastrinoma or gastric

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FIGURE 2: Treatment approach for H. pylori (HSE)5 Source: www.hse.ie/eng/services/list/2/gp/antibiotic-prescribing/conditions-and-treatments/gastro/helicobacter-pylori/

LATEST TREATMENT APPROACHES TO H. PYLORI ERADICATION HIGHLIGHTED AT ISG WINTER MEETING

Pat Kelly

The Irish Society of Gastroenterology (ISG) 2021 Winter Meeting, held in early December, heard from Prof Javier Gisbert, Consultant Gastroenterologist at La Princesa University Hospital in Madrid, Spain, who spoke on the topic ‘European registry on H. pylori management: Most relevant results for clinical practice’.

Prof Gisbert provided an overview of eradication therapy and described how this European registry is a large, longterm registry of routine clinical practice by gastroenterologists in Europe, with 30 countries, more than 200 investigators and some 50,000 patients involved.

He gave the attendees a synopsis of a number of studies, one of which showed that prescription of triple-therapies in first-line treatment in Europe has markedly decreased from 50 per cent in 2013, to approximately 30 per cent in 2020.

The prescription of 14-day treatments has significantly increased, while sevenday treatment courses have reduced to practically zero, “which is in line with current guidelines”, said Prof Gisbert.

“All these changes in clinical practice have been associated with an increase in the overall efficacy of eradication therapy of approximately 10 per cent,” said Prof Gisbert.

However, overall, he said “management of H. pylori infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations”.

“Only quadruple therapies lasting for at least 10 days are able to achieve more than 90 per cent eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which has been associated with a corresponding increase in effectiveness.”

Outlining other such studies in which he was involved, Prof Gisbert told the conference that optimised concomitant therapy shows significantly higher cure rates – higher than 90 per cent –compared to triple therapy. “The addition of metronidazole to the standard triple therapy increased eradication rates by 10

per cent, resulting in more mild adverse events, but without impairing compliance with therapy,” he said.

Another study looked at the addition of bismuth to standard triple therapy: “Due to the poor eradication rates of standard triple therapy, the addition of bismuth salts has been proposed for first-line eradication of H. pylori,” said Prof Gisbert.

He also outlined the evolution of antibiotic resistance in H. pylori over recent years and told the meeting that while resistance to clarithromycin remained stable, it has been higher than 15 per cent across these years. “This is the threshold that we generally consider as being indicative of high clarithromycin resistance.” However, metronidazole resistance decreased over this time.

Another study reported by Prof Gisbert looked at the potential to improve overall H. pylori treatment. “Common mistakes include the use of standard triple therapy where it is ineffective, or to prescribe it as eradication therapy for only seven-to-10 days,” said Prof Gisbert.

cancer. Surgical options include vagotomy or partial gastrectomy.1

Patient education is very important for those with PUD. It should include information about the primary causes of PUD, dietary advice, practices to avoid, such as NSAID use, and the risk of any interventions offered including the long-term use of PPIs if it is the therapy of choice for symptomatic management.6

Prognosis

Timely diagnosis and treatment of PUD and its sequelae are crucial to minimise associated morbidity and mortality, as is prevention of PUD among patients at high risk, including those infected with H. pylori and users of NSAIDs.2 Identifying the risk factors and mechanisms that lead to the development of PUD helps to understand the approach behind diagnostic and treatment strategies.7

Prognosis for individuals with PUD is very good if the underlying cause is successfully treated. For most people, treatment that targets the underlying cause is effective at eliminating

PUD. Recurrence of peptic ulcers, however, is common, but recurrence may be prevented or reduced by maintaining good hygiene, avoiding alcohol, smoking and NSAIDs.

References

1. Malik, T. (2021). Peptic ulcer disease. Available at: StatPearls Publications. www. statpearls.com/ArticleLibrary/viewarticle/26913

2. Kavitt R, Lipowska A, Yeboa A, Grainek I. (2019). Diagnosis and treatment of peptic ulcer disease. The American Journal of Medicine Volume 132; Issue 4; pp- 447-456; April 2019

3. Lanas A, Chan, F. (2017). Lancet. Peptic ulcer disease. doi:10.1016/S0140-6736(16)32404-7

4. BMJ Best Practice (2020). Peptic ulcer disease. Available at: https://bestpractice.bmj. com/topics/en-gb/3000205

5. HSE antibiotic prescribing. (2021).

Helicobacter pylori. Available at: www.hse.ie/ eng/services/list/2/gp/antibiotic-prescribing/ conditions-and-treatments/gastro/helicobacterpylori/

6. Woolf A, Haddad, L, Ocasio, G. (2021). Duodenal ulcer (nursing). In StatPearls Publishing. Available at: www.ncbi.nlm.nih.gov/ books/NBK568678/

7. Narayanan M, Reddy K, Marsicano E. (2018). Peptic ulcer disease and Helicobacter pylori infection. Mo Med. 2018 May-Jun; 115(3): 219224. PMCID: PMC6140150

8. Image: https://patient.gastro.org/pepticulcer-disease/

27 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022



Diagnosing and managing IBD

AUTHOR: Donna Cosgrove, MPSI

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract (GIT) that usually start in adolescence and adulthood.1 IBD is split into two categories: Crohn’s disease (CD) and ulcerative colitis (UC). IBD is a debilitating, complex disorder that is caused by multiple factors, including psychological distress, autonomic dysfunction, gut microbiome dysbiosis, genetic predisposition, and immune modulations linked to disease activity.

The aetiology of the disease is not fully understood, although as with most diseases, there is both an environmental and genetic component. In general, there is an immune response in the mucosa that is too easily triggered, and lasts longer than usual.

Genetic studies have shown that there is a 30-fold higher risk of developing IBD if a sibling has it, compared to the general population. Genome-wide association studies (GWAS) have helped identify hundreds of genetic variants that are present in CD and UC.1 Many of these are associated with genes involved in immune stimulation, or mucosal barrier function. Evidence suggests inverse associations between risk of IBD and determinants for more diverse gut microbiomes in early life, ie, early exposure, pets, larger family size, greater number of siblings, and breastfeeding. There is altered gut microbiota in IBD, but it is still uncertain as to whether this is a cause or a consequence of the disease.

Microfilms formed by bacteria in healthy guts give protection to the intestinal lining: This is often not present to the same extent in IBD. There is also

a strong association between diet and disease. Smoking is linked with more severe disease in CD, yet with UC, smoking cessation commonly causes disease relapse. Stress and its effect on the immune system are of relevance to IBD, as in other chronic and complex inflammatory disorders.

In IBD, there is an increased production of pro-inflammatory cytokines (such as TNF alpha, IL-6, IFN -Ɣ). Epithelial barrier damage from this inflammation can lead to increased intestinal

These psychiatric comorbidities are more pronounced during active disease, however, there is also evidence to suggest that they can contribute to relapse even in times of remission.

UC occurs when chronic inflammation occurs in the large intestine (the innermost layer of the colon and rectum) with abnormal immune system activation,1,2 UC can develop at any age, but the peak incidence is between 15 and 25 years of age with a second, smaller peak between 55 and 65 years. 3

permeability and the influx of intestinal lumen microbes and antigens into the underlying layer, worsening symptoms. Common IBD symptoms caused by intestinal damage that results from the exaggerated inflammatory response include:1 Diarrhoea, rectal bleeding, intermittent nausea and vomiting, and abdominal pain and tenderness. Complications such as anaemia, malnutrition, obstruction, fistulae, infection, and increased colon cancer risk are associated with IBD. The disease can also have extra-intestinal manifestations, such as joint problems, skin conditions, chronic liver disease, and eye conditions (ie, uveitis).

Any chronic disease, including IBD, is associated with a greater burden of psychological distress, depression, anxiety, and altered quality-of-life.

CD has a variable age of onset and disease location, affecting any part of the GIT from the mouth to the anus, and across all layers of the bowel wall. The lower small intestine (ileum) and colon are most commonly affected.1,2

Diagnosis and management

There is no treatment for the cause of IBD: Clinical management focuses on treating symptoms – keeping patients in remission, primarily aiming to reduce inflammation levels if symptoms reoccur, and also aiming to prolong the time spent in remission and mucosal healing periods.1 As many as 85 per cent of patients with IBD do not ingest/ absorb adequate nutrition. IBD patients should be encouraged to eat a varied diet that meets their energy, macro and micronutrient requirements. Supplementation with enteral or

28 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

Genetic studies have shown that there is a 30-fold higher risk of developing IBD if a sibling has it, compared to the general population

parenteral nutrition may be required to achieve this.

Other modifiable factors should be considered, like sleep pattern, sideeffects from medication, anaemia, iron deficiency, electrolyte disturbance, thyroid dysfunction, vitamin D and B12 deficiency, and psychological symptoms. 2 IBD patients with disabling fatigue should be investigated for subclinical disease activity. Non-pharmacological therapies, such as supportive psychotherapy, stress management or graded exercise, may be useful. Patients with functional bowel symptoms, ie, in remission or with mildly active disease, only might find dietary advice, as for irritable bowel syndrome (IBS) useful (ie, low FODMAP diet).

In 2021, the British Society of Gastroenterology (BSG) Clinical Services and Standards Committee (CSSC) published updated guidelines for the management of IBD in adults. Pharmacological treatment recommendations here are taken both from this 2 and the UK’s National Institute for Health and Care Excellence (NICE) guidelines, which were most recently updated in 2019.

3,7

For mild-to-moderate UC, 2,3 management with oral mesalamine/5-aminosalicylic acid (5-ASA), 2-3g daily is recommended. In flare-ups, dose escalation of 4-4, 8g daily orally and the use of 5-ASA enemas can improve symptoms. All UC patients should be offered a combination of oral and enema 5-ASA, as oral and topical therapy of 5-ASA can be superior to oral alone; however, there may be practical difficulty for the patient in administering and retaining the enema. 2 In mild-to-moderate UC where 5-ASA induction therapy fails, oral prednisolone should be used. This is superior to 5-ASA for induction of remission, but due to significant sideeffects, should not be recommended as the first-line. When a course of corticosteroids is used to treat the

disease in any case, a time-limited course of four-to-eight weeks (depending on the steroid) is advised. Topically-acting oral steroids like budesonide multi-matrix formulations, ie, Cortiment, which releases budesonide at a controlled rate throughout the colon, can be used if systemic corticosteroids are not acceptable. Budesonide has a lower rate of systemic adverse effects than conventional corticosteroids (33 per cent vs 55 per cent), and is not associated with adrenal suppression or a significant reduction in bone mineral density.

oral 5-ASA, once-daily administration should be sufficient, as studies showed no difference in efficacy between a 1g suppository once-daily compared to a 500mg one-to-three times daily. Using a suppository at bedtime is probably the most practical approach, and it allows the suppository to be retained for the longest possible time.

For patients who respond well to 5-ASA suppositories, maintenance treatment is not required. For patients who do require maintenance proctitis treatment, using a suppository every two or three nights does not seem to significantly reduce the maintenance of remission. UC patients who do not respond or are intolerant to 5-ASA suppositories and oral 5-ASA may be switched to corticosteroid suppositories. 2 Any UC patients on 5-ASA who need multiple corticosteroid courses per year require treatment escalation with a thiopurine (ie, azathioprine, mercaptopurine).

For severe UC, treatment with prednisolone 40mg daily is recommended, weaning over six-to-eight weeks. 2 The optimal dose regimen is still unclear, but 40mg is more effective than 20mg daily, and there is no evidence to show benefit with doses higher than 40-to-60mg daily.

Single daily dosing is just as effective as split dosing. About half of patients experience short-term adverse drug reactions (ADRs) such as acne, oedema, sleep, and mood disturbance, glucose intolerance, and dyspepsia. 2 If there is no response within two weeks, escalation to biologics for treatment, or hospital admission, may be necessary.

In proctitis specifically, topical 5-ASA first-line is recommended, ie, a 1g 5-ASA suppository, with the addition of an oral 5-ASA if necessary. 2,3 The suppository, which delivers the drug to the rectum directly, is more effective in this case than a topical steroid. As with

The main way in which the NICE and BSG guidelines differ for UC treatment is about when it is appropriate to start treatment with biological agents in IBD. NICE 4 recommends the anti-TNF drugs infliximab, adalimumab or golimumab for treatment of moderate-to-severe UC only where disease has not responded to conventional treatment, or where these are unsuitable.

Vedolizumab is recommended for treating moderately-to-severely active UC. 5

Tofacitinib is recommended as an option when conventional therapy or a biological agent cannot be tolerated, but is also an option for when response to treatment has been lost. 6 It is a small molecule, taken orally, which gives it the advantage of less immunogenicity and loss of response over time compared with biological agents.

Whereas NICE guidelines advise use of biologics mainly after conventional treatment is unsuitable, BNG guidelines

29 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

UC can develop at any age, but the peak incidence is between 15 and 25 years of age with a second, smaller peak between 55 and 65 years

say that due to the increasing range of biologics with less toxicity than thiopurines, there is strong justification for moving directly to these agents. 2 Network meta-analyses comparing efficacy of anti-TNF drugs show similar levels of efficacy.

The choice of immunosuppressive therapy depends on a few factors:

 Route of administration.

 Speed of response to induction therapy (need for bridging therapy).

 Potential immunogenicity/need for combination therapy.

 Side-effects.

 Availability of infusion facilities and therapeutic drug monitoring.

Methotrexate is not suitable for maintaining remission in UC: A Cochrane review found it to be no better than placebo.

Colectomy is a treatment option if symptoms are inadequately controlled or if the patient has a poor quality-of-life on conventional therapy.3

Crohn’s disease therapies

Mild-to-moderate ileocaecal CD can be treated with ileal-release budesonide 9mg once daily for eight weeks to induce remission. 2 One 9mg dose is as effective as 3mg three times daily. This has been found to be as effective as oral prednisolone (40mg daily tapering to 5mg at eight weeks) with fewer side-effects.

Moderate-to-severely active uncomplicated CD should be treated initially with systemic corticosteroids, with patients showing extensive disease being considered for biological therapy.

Active Crohn’s colitis can be treated with an eight-week course of systemic corticosteroids, first-line, to induce remission.

For patients with moderate-to-severe CD responding to prednisolone, BSG guidelines advise early introduction of maintenance therapy with thiopurines or methotrexate to minimise risk of

flare as prednisolone is withdrawn, which is common. 2 Once prednisolone is stopped, azathioprine or mercaptopurine are suitable for monotherapy in the maintenance of remission. Methotrexate may also be used for the maintenance of remission of CD. The BSG recommended dose is at least 15mg weekly.

Subcutaneous administration has better bioavailability than oral, particularly at doses above 15mg weekly. Methotrexate should be given with folic acid to reduce gastrointestinal and liver toxicity, 5mg weekly (traditionally one-to-two days after the methotrexate dose).

For patients first presenting or with a single exacerbation of CD in one year, NICE guidance7 advises monotherapy with a glucocorticosteroid to induce remission. Budesonide can be used if this is not suitable, but it may be less effective, even though it has fewer side-effects. ASA treatment is a third option, but is not as effective as the steroidal options. If there are two or more exacerbations per year, NICE recommends azathioprine or mercaptopurine as an add-on treatment to steroid options to induce remission.

Patients refractory to conventional therapy should be considered for biological therapy. 2 Infliximab and adalimumab are options for adults with severe active CD who haven’t responded to immunosuppressive/corticosteroid treatments.7 NICE guidelines advise informing the person that there is uncertainty around the efficacy and long-term ADRs of monotherapy with infliximab/adalimumab vs combination therapy with an immunosuppressant. However, the more recent BSG guidelines state that combination therapy of infliximab with a thiopurine should be used in preference to infliximab monotherapy, because this has been shown to be more effective than monotherapy infliximab in CD. 2 Immunomodulator use also reduces the risk of immunogenicity. Although there is evidence that there are clinical benefits of combination therapy

with an immunomodulator in the case of adalimumab, the importance of this is not as strong in studies of adalimumab as it is for infliximab.

Ustekinumab is an option for treating moderately-to-severely active CD for adults who have not responded, or lost response to, a TNF alpha inhibitor.8 Vedolizumab is an option for treating moderately-toseverely active CD if a TNF alpha inhibitor has failed or cannot be tolerated.9

Mild oesophageal or gastroduodenal CD may be treated with PPIs. For moderate or severe disease, treatment with corticosteroids may also be required, and other immunosuppressive or biological therapies, as for CD elsewhere in the gut.

Surgery for the majority of patients with CD is not curative, with high rates of disease recurrence by one year. People with CD who do not wish to be on maintenance treatment should be advised of the importance of not smoking, and to plan a followup promptly if they experience any exacerbations of symptoms. People who do opt for maintenance treatment can be offered azathioprine or mercaptopurine.

In patient surveys, it has been established that adherence can be an issue; therefore, once-daily dosing to simplify the dosing regimen should be considered where possible for each patient.

Colorectal cancer risk is related to inflammation, therefore mucosal healing should be the primary goal of colorectal cancer prevention, regardless of the treatment used. 5-ASA is a safe and effective long-term treatment, and while there is no clear evidence that continuing 5-ASA in particular reduces colorectal cancer risk, if subsequent assessment after stopping 5-ASA shows mucosal inflammation, 5-ASA should be restarted.

Monitoring on pharmacotherapy

Any IBD patients commencing immunomodulators or biologics

30 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

AMGEVITA® AND ME HOW AND WHEN IS IT GIVEN?

CITRATE FREE

AMGEVITA® AND ME

® awarded best value biosimilar medicine in a citrate free formulation of adalimumab by the Medicines Management Programme

AMGEVITA® is injected under the skin (a subcutaneous injection) a specially designed pen called SureClick® or using a pre-filled

AND WHEN IS IT GIVEN?

is injected under the skin (a subcutaneous injection) with designed pen called SureClick® or using a pre-filled syringe.

AMGEVITA® 40mg SureClick® Pre-filled pen

You should inject in the tummy, or the tops of your legs (thighs), see diagram below. The medicine travels into your bloodstream to work on the areas that are inflamed and causing your symptoms.

AMGEVITA® 20mg Pre-filled syringe

inject in the tummy, or the tops of your legs (thighs), below.

medicine travels into your bloodstream to work on the areas inflamed and causing your symptoms.

Your doctor, pharmacist or nurse will show you or your parent/carer how to give the injection. It’s important the injection is given correctly for it to work.

pharmacist or nurse will show parent/carer how to give the important the injection is given it to work.

Further information is available on request or in the Summary of Product Characteristics (SmPC) at www.medicines.ie.

You may have the injection in hospital or doctor may change this to best suit what works for you.

IE-AMB-0122-00002. Date of preparation: January 2022.

Legal Category: POM. Marketing Authorisation Numbers:

EU/1/16/1164/001

have the injection in hospital or You can give it to yourself or your can do this for you. Usually, the given every 2 weeks, but your change this to best suit what you. follow the advice of your team and ask to speak to them not feeling well.

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.

References:

Adult

• Rheumatoid arthritis

• Ankylosing spondylitis (AS)

• Axial spondyloarthritis without radiographic evidence of AS

• Psoriatic arthritis

Paediatric

You need to follow the advice of your healthcare team and ask to speak to them if you are not feeling well.

• Polyarticular juvenile idiopathic arthritis (JIA) (from 2 years of age)

• Enthesitis-related arthritis (from 6 years of age)

Further information is available on request or in the Summary of Product Characteristics (SmPC) at www.medicines.ie.

• Crohn’s disease

• Crohn’s disease (from 6 years of age)

Adverse reactions /events should using the available methods via Amgen Limited

• Ulcerative colitis

• Psoriasis

• Ulcerative Colitis (from 6 years of age)

For full and detailed instructions on how to administer your AMGEVITA®, please read the instructions provided in the product carton.

• Hidradenitis suppurativa

• Uveitis

• Plaque psoriasis (from 4 years of age)

Further information is available on at www.medicines.ie.

References:

1. BVBM Amgevita Product Information Sheet. https://www.hse.ie/eng/about/who/cspd/ncps/ medicines-management/best-value-medicines/best-value-biological-medicines/bvb-medicineamgevita-product-information-sheet.pdf. Accessed January 2022.

1. BVBM Amgevita Product Information medicines-management/best-value-medicines/best-value-biological-medicines/bvb-medicine-

2. Medicines Management Programme Best-Value Biological Medicines: Adalimumab 20 mg solution for injection. https://www.hse.ie/eng/about/who/cspd/ncps/medicines-management/best-valuemedicines/best-value-biological-medicines/mmp-report-bvb-medicine-adalimumab-20mgmarch-2021.pdf. January 2022.

detailed instructions on how to

• Adolescent hidradenitis suppurativa (acne inversa) (from 12 years of age)

• Uveitis (from 2 years of age)

– 1 pack: AMGEVITA 20 mg solution for injection in pre-filled syringe EU/1/16/1164/003 – 2 pack: AMGEVITA 40 mg solution for injection in pre-filled syringe EU/1/16/1164/007 – 2 pack: AMGEVITA 40 mg solution for injection in pre-filled pen Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands.

your AMGEVITA®, please read the A B C

RIGHT A B C

Amgevita® Awarded best value biologic medicine in a citrate free formulation of adalimumab and is the only BVBM awarded for 20mg adalimumab. NOW BVBM FOR 20MG ADALIMUMAB

AWA R DED AWA R DED

BVBM

amgevita-product-information-sheet.pdf. 2. Medicines Management Programme for injection. https://www.hse.ie/eng/about/who/cspd/ncps/medicines-management/best-valuemedicines/best-value-biological-medicines/mmp-report-bvb-medicine-adalimumab-20mgmarch-2021.pdf. January 2022. ©2022 Amgen Inc. All rights reserved. IE-AMB-0122-00002. Date of preparation: Legal Category: POM. Marketing Authorisation EU/1/16/1164/001 – 1 pack: AMGEVITA EU/1/16/1164/003 – 2 pack: AMGEVITA EU/1/16/1164/007 – 2 pack: AMGEVITA Marketing Authorisation Holder: Amgen Further information AMGEVITA® AND WHEN IS IT GIVEN? injected under the designed pen called in the tummy, below. travels into your and causing your pharmacist or nurse parent/carer how to important the injection work. the injection in hospital give it to yourself do this for you. every 2 weeks, change this to best follow the advice of and ask to speak feeling well. detailed instructions AMGEVITA®, please Amgevita® Awarded best value biologic in a citrate free formulation adalimumab and is the only awarded for 20mg adalimumab. NOW BVBM FOR 20MG ADALIMUMAB awarded best value biosimilar in a citrate free formulation of adalimumab by the Medicines Management Programme BVBM AWA R DED AWA R DED www.medicines.ie. subcutaneous using a pre-filled your legs work on RIGHT B juvenile idiopathic age) arthritis age) age) age) age) hidradenitis inversa) age) years of age)

treatment should undergo screening for hepatitis B (HBV), hepatitis C (HCV), and HIV (and varicella-zoster, VZV, if no history of chickenpox, shingles or varicella vaccination). 2 Live vaccines are contraindicated if the patient is on immunosuppression. These include BCG, oral influenza vaccine, MMR, polio, rotavirus, oral typhoid, VZV, and yellow fever. Annual influenza vaccination (injection) is recommended for all immunosuppressed patients.

5-ASA

Patients treated with 5-ASA should have renal function monitored at baseline, after two-to-three months, and then annually. Renal disease is not only linked with 5-ASA therapy, but can also be a complication of the disease itself. 2

Corticosteroids

Patients receiving prolonged courses of corticosteroids should have a tapering course when stopping to avoid adrenal suppression. They should be warned about possible steroid withdrawal syndrome, which can present as weakness, fatigue, loss of appetite, weight loss, nausea and vomiting, diarrhoea and abdominal pain, and so can mimic the underlying disease. It is estimated to occur in about half of patients tested immediately after withdrawal of medium-/high-dose prednisolone used for long periods. 2

Prolonged corticosteroid use should be minimised: They are effective to induce remission, but have no role in preventing relapse. All patients on corticosteroids for a disease flare should also take 800-to-1,000mg/day calcium and 800IU/day vitamin D. Factors that have a negative impact on bone mineral density should be addressed, ie, smoking, alcohol intake and the positive impact of muscle-building/weight-bearing exercise. Patients starting corticosteroids should be assessed for risk of osteoporosis. Those at high-risk should be started on bisphosphonate therapy. 2,8 Patients on prolonged courses should have blood

pressure, glycaemic control, and serum potassium monitored. 2

Thiopurines

BSG guidelines recommend that azathioprine and mercaptopurine should be started at the full dose, because there is no evidence that starting at low doses and then gradually increasing up to target improves safety or tolerance, and low-dose initiation may delay achieving the correct target dose.

IBD patients in prolonged remission on thiopurines, and who have mucosal healing, may stop the drug after discussion of risks and benefits and considering patient preference. Reintroduction if relapse occurs is usually successful. 2

Before starting, the following are recommended:

 Baseline FBC, urea and electrolytes (U&E), and LFT measurement.

 If available, test NUDT15 genotype, as some genetic variants in NUDT15 are associated with thiopurine-related myelosuppression.

 Screen for HCV, HBV, HIV, refer if positive, consider HBV vaccination.

 Check VZV immunity and vaccinate if low.

 Vaccinate for influenza and pneumococcal vaccine.

 Check cervical screening is up-to-date (studies have found an increased risk of cervical dysplasia among women with IBD).

 Check thiopurine methyltransferase (TPMT, the enzyme that metabolises thiopurines) and start at target dose once the result is available. If very low: Avoid thiopurine.

 Monitoring: FBC, U&E, and LFT at least at weeks two, four, eight, and 12, and then at least three-monthly.

Methotrexate

Methotrexate has comparable safety to thiopurines. IBD patients initiating methotrexate therapy should have baseline FBC, U&E, and LFT measurement, with monitoring of these bloods at least at weeks two, four, eight,

and 12, and then at least three-monthly, with monitoring for side-effects. 2 Risk of cirrhosis is much lower than previously thought. Due to teratogenic and embryotoxic effects of methotrexate, prior to conception, women should discontinue methotrexate for six months.

Immunomodulators or biologics

IBD patients receiving immunomodulators or biologics should have an annual review of treatment, including consideration of response and treatment continuation, optimisation or cessation. Pre-treatment screening and blood monitoring of therapy on vedolizumab and ustekinumab should at present follow recommendations for anti-TNF drugs due to insufficient long-term safety data at this time to recommend an alternative algorithm.

Treatment options for failure of initial anti-TNF therapy include increasing dose, shortening dosage interval, switching to alternative anti-TNF, or switching to a different drug class. Secondary loss of response to anti-TNF therapy can occur as a consequence of immune-mediated neutralising antibodies to the drug (although there are likely to be other mechanisms, including non-neutralising, drug-clearing antibodies or non-immunemediated mechanisms). 2

Treatments: Mechanism of action

5-ASA

5-ASA medicines interfere with the metabolism of arachidonic acid to prostaglandins and leukotrienes, scavenge reactive oxygen species, and effect leukocyte function and production of cytokines.10 Recent research has also shown that 5-ASA medicines may act by activating a class of nuclear receptors involved in the control of inflammation, cell proliferation, apoptosis, and metabolic function, the gamma form of peroxisome proliferator-activated receptors.11 These receptors are expressed at high levels in colon epithelial cells, and regulated at least in part stimulated by gut bacteria.

32 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

Thiopurines

Azathioprine is a product of 6-mercaptopurine that is metabolised in the liver and gut. Both drugs are slow acting, which is why they are not suitable choices for induction of remission. The mode of action of these drugs includes inhibition of several pathways in nucleic acid biosynthesis. This prevents proliferation of cells involved in the determination and amplification of the immune response,12 ie, damaging DNA 0is through the incorporation of thiopurine analogues.

Methotrexate

Methotrexate is a competitive antagonist of folic acid, which has a cytotoxic and antiproliferative effect due to inhibition of dihydrofolate reductase. This blocks DNA and RNA synthesis.13

Corticosteroids

Prednisolone decreases inflammation by suppressing leukocyte migration and reversing increased capillary permeability. After attachment to cellular glucocorticoid receptors, prednisolone enters the nucleus, binds, and activates specific nuclear receptors, resulting in altered gene expression and inhibition of pro-inflammatory cytokine production.14

TNF alpha inhibitors

Adalimumab, golimumab, and infliximab are monoclonal antibodies that inhibit the pro-inflammatory cytokine, TNF alpha. 4

Integrin receptor antagonists

Vedolizumab is a humanised monoclonal antibody. It targets α 4 β 7 integrin, which is expressed in certain white blood

cells that are found in the gut. 5 α 4 β 7 integrin is responsible for recruiting these inflammatory cells to inflamed bowel tissue. Vedolizumab, therefore, specifically targets the gut.

Janus kinase inhibitors

Tofacitinib is a selective and specific inhibitor of pro-inflammatory receptor signalling: It inhibits the process of intracellular signalling from the receptor to the cellular nucleus and inhibits the inflammation process via a new pathway, inhibition of the Janus kinases (JAK). 6

Cytokine inhibitors

Ustekinumab is a human monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin-12 (IL-12) and interleukin-23 (IL-23), which activate certain T-cells in the inflammatory cascade.8 

References

1. Tavakoli P, Vollmer-Conna U, HadziPavlovic D, Grimm MC. 2021 A review of inflammatory bowel disease: A model of microbial, immune and neuropsychological integration. Public Health Reviews, 42, 1603990

2. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. 2019. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, 68(Suppl 3), s1-s106

3. National Institute for Health and Clinical Excellence (2019). Ulcerative colitis: Management [NG130]. Available at: www.nice.org.uk/guidance/ng130/ resources/ulcerative-colitis-managementpdf-66141712632517

4. National Institute for Health and Care Excellence (2021). Infliximab, adalimumab and golimumab for treating moderatelyto-severely active ulcerative colitis after the failure of conventional therapy. Available at: www.nice.org.uk/guidance/ta329/resources/ infliximab-adalimumab-and-golimumabfor-treating-moderately-to-severely-activeulcerative-colitis-after-the-failure-ofconventional-therapy-pdf-82602495307717

5. National Institute for Health and Care Excellence (2021). Vedolizumab for treating moderately-to-severely active ulcerative colitis. Available at: www. nice.org.uk/guidance/ta342/resources/ vedolizumab-for-treating-moderatelyto-severely-active-ulcerative-colitispdf-82602604482757

6. National Institute for Health and Care Excellence (2018). Tofacitinib for treating moderately-to-severely active ulcerative colitis. Available at: www.nice.org.uk/ guidance/ta547/resources/tofacitinib-formoderately-to-severely-active-ulcerativecolitis-pdf-8260696644550 9

7. National Institute for Health and Care Excellence (2019). Crohn’s disease: Management [NG129]. Available at: www.nice.org.uk/guidance/ng129/ resources/crohns-disease-managementpdf-66141667282885

8. National Institute for Health and Care Excellence (2017). Ustekinmab for treating moderately-to-severely active Crohn’s disease after previous treatment. Available at: www.nice.org.uk/guidance/ta456/ resources/ustekinumab-for-moderatelyto-severely-active-crohns-disease-afterprevious-treatment-pdf-82604848449733

9. National Institute for Health and Care Excellence (2015). Vedolizumab for treating moderately-to-severely active Crohn’s disease after prior therapy. Available at: www.nice.org.uk/guidance/ta352/resources/ vedolizumab-for-treating-moderately-toseverely-active-crohns-disease-after-priortherapy-pdf-82602664948933

10. Punchard NA, Greenfield SM, Thompson RPH. 1992. Mechanism of action of 5-aminosalicylic acid. Mediators of inflammation, 1(3), 151-165

11. Desreumaux P, Ghosh S. 2006. Mode of action and delivery of 5-aminosalicylic acid – new evidence. Alimentary Pharmacology & Therapeutics, 24, 2-9

12. Nielsen OH, Vainer B, Rask-Madsen J. 2001. The treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Alimentary Pharmacology & Therapeutics, 15(11), 1699-1708

13. Djurić Z, Šaranac L, Budić I, Pavlović V, Djordjević J. 2018. Therapeutic role of methotrexate in pediatric Crohn’s disease. Bosnian Journal of Basic Medical Sciences, 18(3), 211

14. Puckett Y, Gabbar A, Bokhari A (2022). Prednisone. StatPearls. Available at: www. ncbi.nlm.nih.gov/books/NBK534809

33 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

Inflammatory bowel disease in pregnancy

AUTHOR: Dr Niamh Keating, Academic Clinical Fellow, UCD Perinatal Research Centre, School of Medicine, University College Dublin, and National Maternity Hospital, Dublin

Inflammatory bowel disease (IBD), ie, Crohn’s disease and ulcerative colitis (UC), is commonly diagnosed between the age of 15-to-35 years, and therefore is often encountered in women of reproductive age.1

Crohn’s disease can affect any part of the gastrointestinal tract from the mouth to anus and is characterised by transmural inflammation and skip lesions.

UC is characterised by mucosal inflammation of the colon.

Risk factors for IBD include genetic factors, alterations in the gut microbiome, nonsteroidal anti-inflammatory drug (NSAID) use, smoking in Crohn’s disease, and stress.

IBD is increasingly commonly encountered in pregnancy, however, patients with Crohn’s disease experience higher rates of voluntary childlessness. 2 This may be explained by misinformation, and subsequent fear of the effect their disease and medications will have on pregnancy.3,4 Poorly controlled disease is associated with sub-fertility.5 Active disease is associated with increased pregnancy risks including rates of pre-term delivery, Caesarean section, and low birth weight.6 Effective treatment enables the majority of women with IBD to have healthy pregnancies, however.

IBD pregnancies can be complex and require multidisciplinary team input involving gastroenterologists, IBD nurses, obstetricians, midwives, and colorectal surgeons where necessary. Well-controlled disease in women of reproductive age allows them to consider and plan for pregnancy. Optimal disease control before and during pregnancy is imperative.

A meta-analysis of disease activity in pregnancy found that women with active disease at conception had twice the risk of ongoing active disease during pregnancy, compared to those in remission at conception.7 Active disease may impair fertility, 5 and in pregnancy it is associated with an increased risk of low birthweight and pre-term labour.6

This article outlines the impact of pregnancy on the disease, the impact of the disease on the pregnancy including considerations for delivery, and the role of pre conception counselling.

The impact of pregnancy on IBD

While evidence is conflicting, in general pregnancy does not increase the risk of a disease flare in women with IBD provided the disease is well controlled at conception.1 Women with active disease at conception are at a higher risk of a disease flare during pregnancy.7 In women with a history of surgical management for IBD, the growth of the uterus in the second and third trimester can lead to surgical complications, such as adhesional bowel obstruction or volvulus. The indications for emergency surgery in pregnancy are the same as for those outside of pregnancy.

34 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

IBD is increasingly commonly encountered in pregnancy, however, patients with Crohn’s disease experience higher rates of voluntary childlessness

FIGURE 1: Ulcerative colitis versus Crohn‘s disease

Ultrasound or MRI are preferred over CT for evaluation of an acute abdomen in pregnancy to avoid foetal radiation exposure. Surgical complications although rare are associated with a risk of pre-term delivery and foetal loss. 8

All women with IBD in pregnancy should be linked with a dietitian and should be screened for nutritional deficiencies. Adequate weight gain in pregnancy is important for foetal growth and women with active disease in pregnancy or evidence of malabsorption should have ultrasound assessment of foetal growth in the third trimester to screen for growth restriction.

The impact of IBD on pregnancy

It has been suggested that women with IBD have lower fertility rates although this may be explained by an increase in voluntary childlessness. Pelvic adhesions, pelvic abscesses, and subsequent tubal disease are associated with subfertility. Women may choose not to become pregnant due to concerns about the effect of their disease on pregnancy, safety of medication or mode of delivery. Obstetric outcomes in women with quiescent disease are similar to pregnant women without IBD. Higher rates of miscarriage, low birth weight, and pre-term birth are noted in women with active disease at conception.

Caesarean birth is generally recommended for obstetric indications only and the majority of women with IBD have no contraindication to vaginal birth, although a high rate of Caesarean section is seen in this cohort.9 Elective Caesarean birth is recommended in women with active perianal disease due to the implications for healing in the event of perineal trauma during vaginal delivery. The presence of an ileoanal pouch or ileoanal anastomosis is a relative indication for Caesarean delivery, but the decision must be individualised, taking into account the patient’s preference and history.10

Induction of labour is usually only indicated for obstetric reasons, but may be considered at term in women with active

BREASTFEEDING AND IBD PATIENTS

Breastfeeding is beneficial for babies, as breastmilk has greater immunological and nutritional benefits than formula feeds. Evidence of the effect on infants of drugs that mothers may be taking during breastfeeding is limited. Often, the amount of drug transferred into breastmilk is low and insufficient to produce a discernible effect. When making recommendations about continued drug use and breastfeeding, consideration must be given to the amount of active metabolite or drug derived to the infant according to the drug pharmacokinetics, efficiency of absorption through the gut, and subsequent distribution elimination in the mother.

Aminosalicylates are excreted in low concentrations in breastmilk. Infants of mothers taking these drugs might develop diarrhoea, in which case the aminosalicylates should be stopped. Steroid usage during breastfeeding is deemed safe, as the

concentrations that enter breastmilk are low. Thiopurines are detectable in breastmilk, but at very low levels compared to those in plasma as early as four hours after ingestion. Their metabolites are almost undetectable in breastfed infants, and no increased risks of infection have been demonstrated. Ciclosporin is safe in breastfeeding, but the potential risk of immunosuppression of the baby should be discussed with the mother before initiation.

Methotrexate should not be used during breastfeeding. It is present in breastmilk and has been associated with immunosuppression and neutropaenia in the infant.

Source: British Society of Gastroenterology. 2021. Available at: www.bsg.org.uk/web-educationarticles-list/management-of-thepregnant-patient-with-inflammatorybowel-disease/

disease where optimal medical treatment is not possible due to pregnancy.

Pre-conception counselling

All women of childbearing age with IBD should have a discussion about pregnancy intentions and contraception in order to prevent an unplanned pregnancy. Women wishing to become pregnant should be advised to avoid conception at a time when their disease is active as this is associated with poorer pregnancy outcomes. Preconception advice should take into account medication, and ideally women should be stable on medication that is safe to continue in pregnancy prior to pregnancy.

The biologic agents used in IBD (most commonly anti-TNF alpha antibodies) are largely safe to continue during pregnancy. Infliximab and adalimumab are transferred across the placenta with the highest rate of transfer occurring in

the third trimester.11 For this reason, these medications are often discontinued at approximately 30 weeks’ gestation.

Certolizumab does not cross the placenta so readily and can be safely used throughout pregnancy. The biologic agent ustekinumab is recommended for refractory disease and there is limited data on its use in pregnancy. What data is available shows no evidence of harm and an evaluation of the risks and benefits should be undertaken with the patient.12 Consideration may be given to continuing biologic agents throughout pregnancy in women at a high risk of flare.13

It is advisable to avoid live vaccination for the first six months of life in any infant exposed in utero to biologic agents in the third trimester.14 Biologic agents can be used in breastfeeding, as while present in small amounts in breastmilk they are

35 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

broken down in the infant’s GI tract.15

The aminosalicylates sulfasalazine and mesalazine are commonly used to treat UC and are generally considered safe in pregnancy and breastfeeding.16

Azathioprine is commonly used as a steroidsparing agent in IBD and is not associated with any increased risk of congenital malformation, miscarriage, low birth weight or pre-term birth.17

Steroid use is generally not recommended at higher doses in the first trimester due to an association with cleft lip and palate although this has been disputed.18 Steroid use in later pregnancy is associated with hypertension and gestational diabetes,

however, their benefit usually outweighs these risks if they are required to maintain disease remission. Women exposed to prolonged steroid use in pregnancy require additional steroid cover intrapartum/at the time of elective Caesarean to reduce the risk of an adrenal crisis.

Mycophenolate mofetil and methotrexate are contraindicated in pregnancy due to teratogenic effects and women of reproductive age using these agents should be advised to use effective contraception.

Women with IBD should be reassured that many medications are safe to continue in pregnancy and the majority of women will have healthy pregnancies with good outcomes.

Women should be encouraged to stop smoking prior to pregnancy, both for the benefit to the pregnancy and because of its association with increased disease activity in Crohn’s disease.19

Conclusion

With improved medical treatment the majority of women with IBD can expect favourable pregnancy outcomes. Pre-conception planning and multidisciplinary input from obstetrics and gastroenterology are paramount. Safety data for biologic agents is improving and the majority of treatments can be continued to the third trimester. Conception should be planned for a time when disease is in remission to reduce the risk of obstetric complications. 

References

1. Beaulieu DB, Kane S. Inflammatory bowel disease in pregnancy. World J Gastroenterol 2011;17(22):2696-701

2. Marri SR, Ahn C, Buchman AL. Voluntary childlessness is increased in women with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13(5):591-9

3. Selinger CP, Ghorayeb J, Madill A. What factors might drive voluntary childlessness (VC) in women with IBD? Does IBD-specific pregnancy-related knowledge matter? J Crohns Colitis. 2016;10(10):1151-8

4. Mountifield R, Bampton P, Prosser R, Muller K, Andrews JM. Fear and fertility in inflammatory bowel disease: A mismatch of perception and reality affects family planning decisions. Inflamm Bowel Dis. 2009;15(5):720-5

5. Ban L, Tata LJ, Humes DJ, Fiaschi L, Card T. Decreased fertility rates in 9,639 women diagnosed with inflammatory bowel disease: A United Kingdom populationbased cohort study. Aliment Pharmacol Ther 2015;42(7):855-66

6. Lee HH, Bae JM, Lee BI, Lee KM, Wie JH, Kim JS, et al. Pregnancy outcomes in women with inflammatory bowel disease: A 10-year nationwide population-based cohort study. Aliment Pharmacol Ther. 2020;51(9):861-9

7. Abhyankar A, Ham M, Moss AC. Metaanalysis: The impact of disease activity at conception on disease activity during

pregnancy in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;38(5):460-6

8. Hill Chm J, Clark A, Scott N. Surgical treatment of acute manifestations of Crohn’s disease during pregnancy. Journal of the Royal Society of Medicine. 1997;90(2):64-6

9. Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut. 2007;56(6):830-7

10. Van der Woude C, Ardizzone S, Bengtson M, Fiorino G, Fraser G, Katsanos K, et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. Journal of Crohn’s and Colitis. 2015;9(2):107-24

11. Gisbert JP, Chaparro M. Safety of anti-TNF agents during pregnancy and breastfeeding in women with inflammatory bowel disease. Am J Gastroenterol. 2013;108(9):1426-38

12. Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 2016;75(5):795-810

13. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. British Society of Gastroenterology consensus guidelines on the management of

inflammatory bowel disease in adults. Gut. 2019;68(Suppl 3):s1-s106

14. Mahadevan U, Robinson C, Bernasko N, Boland B, Chambers C, Dubinsky M, et al. Inflammatory bowel disease in pregnancy clinical care pathway: A report from the American Gastroenterological Association IBD Parenthood Project Working Group. Am J Obstet Gynecol. 2019;220(4):308-23

15. Picardo S, Seow CH. A pharmacological approach to managing inflammatory bowel disease during conception, pregnancy, and breastfeeding: Biologic and oral small molecule therapy. Drugs. 2019;79(10):1053-63

16. Gaidos JK, Kane SV. Managing IBD therapies in pregnancy. Current treatment options in gastroenterology. 2017;15(1):71-83

17. Mahadevan U, Long MD, Kane SV, Roy A, Dubinsky MC, Sands BE, et al. Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease. Gastroenterology. 2021;160(4):1131-9

18. Skuladottir H, Wilcox AJ, Ma C, Lammer EJ, Rasmussen SA, Werler MM, et al. Corticosteroid use and risk of orofacial clefts. Birth Defects Res A Clin Mol Teratol 2014;100(6):499-506

19. Sutherland LR, Ramcharan S, Bryant H, Fick G. Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology. 1990;98(5):1123-8

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Monitoring adherence to a gluten-free diet

AUTHOR: Elaine Neary, RD, Clinical Specialist Dietitian in Gastroenterology

“I want you to consider that everything we’re doing is wrong.” This was the opening statement made by a Professor of Gastroenterology presenting at a UK symposium last year. The topic of discussion was how we monitor Coeliac disease after initial diagnosis. With adherence rates reported to be between 42-and-92 per cent, it is true that many Coeliacs are at risk of developing complications such as lymphoma, ulcerative jejunitis, osteoporosis, infertility, and nutritional deficiencies. In children signs of non-adherence include faltering growth and delayed puberty. To reduce the incidence of comorbidity we must have the right tools to detect gluten exposure. There are a variety of methods used in practice to assess adherence to a gluten-free diet –validated scores, questionnaires, ask the patient, request a dietitian review, and serology. Biomarker and score results give us quick reassurance; until they don’t.

Long-term follow-up in Coeliac disease remains controversial. Currently, there are no effective non-invasive markers of gluten-free diet adherence, with point-of-care testing, dietary adherence questionnaires, and serology all having poor sensitivity for the detection of villous atrophy (VA). Despite this information being disseminated in the literature and at conferences, serological response continues to be used as a surrogate for histological recovery. A recent survey reported 65 per cent of gastroenterologists in Canada used bloods including serology as a monitoring tool. The details suggest serology was performed less frequently in adults than children, in favour of routine intestinal biopsy, showing a trend towards the use of the gold standard assessment.

There are inherent difficulties in using Coeliac serology as a monitoring tool. In order to obtain clinically meaningful endpoints, it is essential that patients are eating a certain amount of gluten prior to testing. Guidelines vary on the amounts and duration with one institution saying gluten in more than one meal daily for six weeks, and another recommending one-tothree slices of bread daily for one-to-three months before testing. Once you can be sure the patient is adequately prepared for a test there are a few other serological anomalies to consider. It is reported that 1.7-to-5 per cent of Coeliacs are affected by seronegative Coeliac disease (SNCD). This is a rare and still poorly defined

like flipping a coin. There is a 50 per cent chance of persistent villous atrophy with a negative IgA tTg result.

If you decide to pursue biopsy as a method of monitoring and find persistent villous atrophy, there are caveats here too. There are many mimics of villous atrophy including use of non-steroidal anti-inflammatory drugs (NSAIDs) or olmesartan, helicobacter pylori gastritis, giardiasis, collagenous or microcytic colitis to name but a few. The timing of a biopsy must also be selected carefully. Villous atrophy improves on a strict gluten-free diet, but this may take two-to-three years so be careful not to repeat the biopsy too early. It

form of Coeliac disease, presenting with negative serology, villous atrophy, genetic compatibility, with or without symptoms of malabsorption and who demonstrate clinical and histological response to a gluten free diet. A further 2 per cent of Coeliacs have IgA deficiency. This is a separate entity to seronegativity. In this case, if not done automatically by the lab, you need to order IgG antibodies as an alternative to IgA antibodies. According to a recent meta-analysis, sensitivity of the anti-tissue transglutaminase (tTg) antibody for ongoing villous atrophy was only 43.6 per cent. So even if well considered and accurately prepared there appears to be a limit to how much serological testing can tell us about mucosal healing. It is

has been suggested that immune tolerance is possible over time. A recent study showed that neither occasional nor voluntary dietary gluten intake was associated with the onset of clinical, serological, histologic, or endoscopic changes in a group of Coeliac patients. Interestingly, no association was found between histological alterations and the amount of gluten intake following diagnosis. This means the traditional advice of a strict gluten-free diet for all warrants further investigation and review. The tolerable amount of gluten is still contended, and this casts a shadow over current dietary advice. Perhaps there is a subset of patients where a more relaxed approach can be considered, but we need the monitoring tools to allow that to happen in a safe way.

37 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

Perhaps there is a subset of patients where a more relaxed approach can be considered, but we need the monitoring tools to allow that to happen in a safe way

Dietetic assessment of adherence also has limitations. Targeted dietetic intervention through removal of identified gluten sources or avoidance of trace amounts of gluten led to resolution of persistent villous atrophy in only 50 per cent of patients studied.

Coeliac serology appears to be a poor surrogate marker for mucosal recovery and dietary assessment may fail to uncover a potential gluten source in some patients with ongoing villous atrophy. This could be explained by non-disclosure or under reporting of dietary intake, but warrants further investigation. Although current clinical guidelines do not recommend routine repeat biopsy, it appears to be the surest way to monitor mucosal healing and response. Although such a change in clinical practice would have financial implications, the cost of non-adherence has a clear impact on the health of individuals. Equally, an overly strict gluten-free diet can affect quality-of-life. In the meantime, we need more accurate non-invasive markers of mucosal damage in children and adults with Coeliac disease who are following a gluten-free diet. Perhaps novel biomarkers such as gluten immunogenic peptide (GIP) might have the ability to increase detection rates of non-adherence. This convenient urine test checks for gluten exposure. There has been criticism of false negatives, but researchers say testing over several days is a pragmatic approach. According to one study, three negative urine tests from three different days revealed a 97 per cent possibility of no villous atrophy. New biomarkers are promising and will add to our understanding of gluten metabolism and, with additional studies, could be used as a supplemental tool in the future management of our patients.

The spectrum of gluten-related disorders (GRDs) includes dermatitis herpetiformis, gluten ataxia, wheat intolerance and nonCoeliac gluten sensitivity. Greater awareness of testing guidelines is important to both diagnose and effectively manage GRDs lifelong. UK National Institute for Clinical Care and Excellence (NICE) guidelines recommend that serological testing for

Coeliac disease should be considered in people with unexplained neurological symptoms, particularly peripheral neuropathy or ataxia, specifically anti gliadin antibodies (AGA). According to the gluten sensitivity neurology service at Sheffield University, UK, these disorders account for 26 per cent of all neuropathies. A new cut-off point for AGA has been set to diagnose neurological dysfunction such as gluten ataxia (GA). GA is the second highest cause of ataxia in the UK; 40 per cent of these have villous atrophy. The significance of abnormal AGA outside of enteropathy in untreated GA, however, is the prevention of cerebellum atrophy. A gluten-free diet normalises AGA if detected early. It also improves spectroscopy imaging. In the case of late diagnosis, the diet can only stabilise GA. Unfortunately, this tends to be the case in the absence of gastrointestinal symptoms and average time to diagnosis is 10 years resulting in permanent neurological damage. Ask a patient to stand on one foot and walk heel to toe to assess gait. To further increase detection rates, healthcare practitioners should be alert to reports of intractable headaches and balance problems. Patients usually do not report these to their gastroenterologist because they are focused on bowel issues, but these may have been reported to a GP or other

healthcare professional. Coeliac disease also increases the risk of vascular dementia.

In conclusion, the impact of non-adherence to a gluten-free diet can have wide-ranging effects on our patients from chronic micronutrient deficiencies to infertility. Current monitoring methods fall short in detecting rates of non-adherence in Coeliac disease, leading to comorbidities that are largely preventable. Long-term monitoring is not as straightforward as we once thought and requires more thorough consultation. Do not rely on serology alone. Serology, dietary adherence, and mucosal remission do not have a perfect relationship. The only way to know for sure if your patient is responding to diet therapy is to repeat biopsy. GRDs are lifelong chronic conditions. Patients require a long-term monitoring plan at time of diagnosis with access to appropriate services and healthcare professionals including a registered dietitian. Despite the high prevalence of Coeliac disease in Ireland, there are currently no dedicated community or primary care services to co-ordinate the necessary follow-up. Care is managed by gastroenterology outpatient departments and GPs around the country. To reiterate the opening statement, please consider everything we are doing is wrong.

References

1. Schiepatti A, Savioli J, Vernero M, Borrelli de Andreis F, Perfetti L, Meriggi A, Biagi F. Pitfalls in the diagnosis of Coeliac disease and gluten-related disorders. Nutrients. 2020 Jun 7;12(6):1711. doi: 10.3390/nu12061711

2. Rej A, Aziz I, Sanders DS. Coeliac disease and non Coeliac wheat or gluten sensitivity. J Intern Med 2020;288:537-4

3. Sharkey LM, Corbett G, Currie E, Lee J, Sweeney N, Woodward JM. Optimising delivery of care in Coeliac disease –comparison of the benefits of repeat biopsy and serological follow-up. Aliment Pharmacol Ther. 2013 Nov;38(10):1278-91. doi: 10.1111/apt.12510

4. Silvester JA, Rashid M. Long-

term management of patients with celiac disease: Current practices of gastroenterologists in Canada. Can J Gastroenterol. 2010 Aug;24(8):499-509. doi: 10.1155/2010/140289

5. Elli L, Bascuñán K, di Lernia L, Bardella MT, Doneda L, Soldati L, et al. Safety of occasional ingestion of gluten in patients with Coeliac disease: A real-life study. BMC Med. 2020 Mar 16;18(1):42. doi: 10.1186/ s12916-020-1511-6

6. Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, MM, et al. British Society of Gastroenterology. Diagnosis and management of adult Coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014 Aug;63(8):121028. doi: 10.1136/gutjnl-2013-306578

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

Coeliac disease in focus

AUTHOR: Theresa Lowry-Lehnen, RGN, GPN, RNP, BSc, MSc, MEd, PhD, Clinical Nurse Specialist and Associate Lecturer, South East Technological University

Coeliac disease is an autoimmune disorder triggered by gluten ingestion in geneticallypredisposed individuals, resulting in mucosal inflammation and villous atrophy in the small intestine leading to malabsorption. It is a chronic disease and is not an allergy or food intolerance. Coeliac disease is one of the most common autoimmune conditions, with a prevalence of 0.5-to-1 per cent of the general population, with a female-to-male ratio ranging from 2:1 to 3:1.1,2 Prevalence estimates based on serologic screens indicate the disorder may be present in 1/150 in Europe, and 1/250 in some parts of the US. Current prevalence estimates in some regions including Ireland are as high as 1/100.4 There are an estimated 50,000 people in Ireland living with Coeliac disease, and a further 400,000 who are gluten intolerant. Many cases of Coeliac disease go undiagnosed.5,13

Onset of Coeliac disease can occur at any age, although symptoms are most likely to develop in early childhood after weaning with gluten, and the introduction of cereals into the diet in the first year of life. Coeliac disease can also occur in later adulthood, and is often diagnosed in people aged 40-to-60 years. Coeliac disease is higher in first-degree Coeliac disease relatives (10to-20 per cent) and in other at-risk groups, particularly patients with Down syndrome, type 1 diabetes, or IgA deficiency.1,2 The condition is more common in people with type 1 diabetes and autoimmune thyroid disease. Between 4-and-9 per cent of people with type 1 diabetes also have Coeliac disease, compared with 1 per cent in the general population. People with autoimmune thyroid disease are at a higher risk (1-to-4 per cent) of having Coeliac disease compared with 1 per cent in the general population.12 Coeliac disease is a chronic condition, and, currently, the only treatment consists of permanent exclusion of gluten from the diet.3

Aetiology and pathophysiology

Coeliac disease is a hereditary disorder caused by sensitivity to the gliadin fraction of gluten, a protein found in wheat. Similar proteins are present in rye and barley. In a genetically-susceptible person, gluten-sensitive T-cells are activated when gluten-derived peptide epitopes are presented. The inflammatory response causes characteristic mucosal villous atrophy in the small intestine. This destruction, in turn, leads to the decreased functionality of the intestinal surface and malabsorption. The lack of

intermittent diarrhoea is sometimes the presenting symptom and steatorrhoea ranging from mild to severe. Some patients have weight loss, although rarely enough to become underweight. Anaemia, glossitis, angular stomatitis, and aphthous ulcers are often seen in these patients. Manifestations of vitamin D and calcium deficiencies such as osteomalacia, osteopaenia, and osteoporosis are common. Both males and females may have reduced fertility and women may have amonorrhoea. 3,4

nutrient absorption impacts directly on the digestive system, but also indirectly on all the systems of the body. This results in generally poor health, and is why Coeliac disease can have signs and symptoms arising from almost any body system, and not just the gastrointestinal system.4

Presentation

Coeliac disease is more commonly detected in infants and children younger than three years of age, and is characterised by diarrhoea, anorexia, pallor, abdominal distention, muscle wasting, and failure to thrive. Stools are often soft, bulky, clay-coloured, and offensive. Older children may present with anaemia, weight loss or failure to grow normally. Adults may present with diarrhoea, bloating, constipation, and abdominal pain. 3 Lassitude, weakness, and anorexia are common. Mild and

About 10 per cent of patients with Coeliac disease develop dermatitis herpetiformis (DH), a skin condition caused by gluten intolerance. DH is an intensely pruritic papulovesicular rash that is distributed symmetrically over the extensor areas of the elbows, knees, buttocks, shoulders, and scalp. It usually responds to the exclusion of gluten from the diet, but can take a long time for a gluten-free diet to clear the rash. For individuals with DH, a skin biopsy is usually sufficient for diagnosis of both DH and Coeliac disease. It is not necessary to perform an endoscopic biopsy, as the skin biopsy is definitive.14 Dapsone, a sulfone, is an oral antibacterial medication prescribed for DH, which is taken twice daily. Dapsone can cause side-effects such as headache and depression and may need to be prescribed for up to two years. The lowest effective dose should be prescribed. 3,4,13

Untreated Coeliac disease leads to chronic ill health and complications. Complications which may or may not be present at diagnosis include osteoporosis, ulcerative jejunitis, malignancy-intestinal lymphoma, functional hyposplenism, vitamin D deficiency, and iron deficiency.11

Serological testing for Coeliac disease should be offered to people with persistent unexplained abdominal or

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Untreated Coeliac disease leads to chronic ill health and complications

gastrointestinal symptoms; faltering growth; prolonged fatigue; unexpected weight loss; severe or persistent mouth ulcers; unexplained iron, vitamin B12 or folate deficiency; type 1 diabetes at diagnosis; autoimmune thyroid disease at diagnosis; irritable bowel syndrome in adults; and first-degree relatives of people with Coeliac disease.11

Diagnosis

A diagnosis of Coeliac disease is suspected clinically, based on history and laboratory abnormalities suggestive of malabsorption. Family incidence is an indicator and Coeliac disease should also be strongly considered in patients with iron deficiency without obvious gastrointestinal bleeding. A confirmed diagnosis depends on serologic markers and a small-bowel biopsy. Anti-tissue transglutaminase antibody (tTG) and anti-endomysial antibody (EMA) have sensitivity and specificity of 90 per cent. These antibodies decrease in titre in patients on a glutenfree diet and are useful in monitoring dietary adherence.4 Diagnostic serologic testing is done with patients following a gluten-containing diet. To obtain a reliable result the patient must have been consuming gluten for more than one meal a day for six weeks. It is important to advise the patient not to start a glutenfree diet until diagnosis is confirmed

by a specialist, even if the results of a serological test are positive.11

Coeliac disease is strongly associated with variations of the human leukocyte antigen (HLA) DQ gene. Research has shown that the HLA DQ2 and HLA DQ8 variants are almost always present in people with Coeliac disease of white, Northern European background. Although less clear, these variants probably play a similar role in other ethnic groups. Testing for the HLA DQ2 and HLA DQ8 variants alone cannot be used to diagnose Coeliac disease, as these genes are present in a large proportion of the population, including people who do not have Coeliac disease. In the UK, the National Institute for Health and Care Excellence (NICE) recommends to only consider using HLA DQ2 (DQ2.2 and DQ2.5) and HLA DQ8 testing in diagnosis of Coeliac disease in specialist settings; eg, children who are not having a biopsy or people who have already limited gluten from the diet and choose not to have a gluten challenge.6,11

Serological tests to investigate suspected Coeliac disease in young people and adults should test for total immunoglobulin A (IgA) and IgA tissue transglutaminase (tTG) as the first choice; IgA endomysial antibodies (EMA) if IgA tTG is weakly positive and consider using

IgG EMA, IgG deamidated gliadin peptide (DGP) or IgG tTG if IgA is deficient. Serological tests to investigate suspected Coeliac disease in children should test for total IgA and IgA tTG as the first choice, and consider using IgG EMA, IgG DGP or IgG tTG if IgA is deficient.11

If either serological test is negative, Coeliac disease is unlikely. However, it is possible to have a negative test and still have Coeliac disease; for example, patients already on a gluten-free diet and therefore the antibodies are negative. A minority of Coeliac patients may have IgA deficiency and the screening test results can be misleading, so the total serum IgA should be checked to detect IgA deficiency. 3,8

If either serological test is positive, the patient should have a diagnostic smallbowel biopsy. The gold standard for the diagnosis of Coeliac disease is a duodenal mucosal biopsy which shows villous atrophy.4 Biopsy remains essential for the diagnosis of adult Coeliac disease and cannot be replaced by serology alone. Exceptions are patients with coagulation disorders and pregnant women, in whom biopsy may not be feasible or should be postponed until postpartum. 8

In Coeliac disease, the damage to the lining of the intestine is classified according to the

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TABLE 1: Classification of histologic findings in Coeliac disease. Available at: https://celiac.org/about-celiac-disease/screening -and-diagnosis/diagnosis/

Marsh classification scale:7

 Marsh 0: lining of the intestine is normal and unlikely that the person has Coeliac disease.

 Marsh 1: Increased number of lymphocytes seen, but there are normal villi.

 Marsh 2: Increased number of lymphocytes, the depressions in the lining of the intestine are deeper than normal, but normal villi length.

 Marsh 3: The villi are becoming flattened.

 Marsh 4: The villi are completely flattened.

Originally the Marsh scale ranged from 0-to-4, with type 3 indicating Coeliac disease. The scale has since been simplified to allow for more consistency and reproducibility between pathologists.14

There are situations when the diagnosis is not clear. Some patients experience symptoms despite no identified changes on the small bowel biopsy. There is also seronegative Coeliac disease where despite typical symptoms and significant villous atrophy of the duodenal biopsy, there is no serological evidence of the disease. 3

Treatment and management

The main treatment of Coeliac disease is a lifelong, strict, gluten-free diet. These include wheat protein, gliadin, rye protein, secalin, and barley protein, hordein. The goal of treatment is to relieve symptoms, achieve mucosal healing, avoid complications of Coeliac disease, and have a good quality-of-life with a nutritionallycomplete gluten-free diet. This is best achieved when patients are motivated, receive expert information and are involved in their own care and treatment. Follow-up and annual review are necessary to ensure adequate response to treatment, prevention of complications, and maintenance of motivation to remain gluten free.8

As a gluten-free diet is the primary treatment option for people with Coeliac disease, it is important that a dietitian or healthcare professional with a specialist interest in Coeliac disease plays a significant role in the patient’s care and

follow-up. Many of the common problems associated with the long-term management of Coeliac disease happen because of nonadherence to a gluten-free diet.11 Patient education is important and a healthcare professional with a specialist knowledge of Coeliac disease should explain to the patient, and their family members or carers the importance of a gluten-free diet, and provide detailed information to help the patient follow it. This should include: Information on which types of food contain gluten and suitable alternatives, including gluten-free substitutes, explanations of food labelling information sources about gluten-free diets, recipe ideas and cookbooks, how to manage social situations, eating out and travelling

Coeliac disease can safely eat avenin. Before including oats in the diet, the Coeliac disease patient should talk to a dietician or clinician, and check the oats are pure with no possibility of contamination from other grains. Coeliac-friendly versions of oats are widely available. Oats should be avoided until the gluten-free diet is working well. They can be re-introduced into the diet, when the patient is symptom free, but should be stopped if symptoms re-occur.13 Symptoms usually improve over the course of several weeks once a glutenfree diet is initiated. Patients who do not respond need further review, and also an assessment of compliance with the gluten-free diet. Serology testing can assess compliance. Non-compliance can be unintentional, and an individual may be still ingesting gluten without realising it. 3

away from home, including travel abroad, avoiding cross-contamination with gluten in the home, minimising the risk of accidental gluten intake when eating out, and the role of national and local Coeliac support groups.11

Many everyday foods are gluten free including meat, vegetables, cheese, potatoes, and rice. Foods containing gluten include bread, pasta, cereals, biscuits, crackers, cakes, pastries, pies, gravies, and sauces. However, gluten-free varieties of these and other products exist. It is important to check the labels on food, as many products, particularly processed food, contain gluten additives. Gluten may also be found in non-food products, such as some medications, postage stamps, and lipstick.13

Oats contain a protein called avenin which is like gluten, but most people with

Treatment and management involve assessing the impact of malabsorption on the body. Nutritional deficiencies are common in Coeliac disease and should be identified and treated. Full blood count, iron stores, folate, ferritin, vitamin B12, levels of vitamin D, and other fat-soluble vitamins, and bone mineral density should be monitored.3 A DEXA scan may be required for those with bone thinning or osteoporosis. A gluten-free diet itself can also be associated with lower levels of certain micronutrients. Fibre, iron, calcium, vitamin D, vitamin B6, vitamin B12, and folate deficiencies have all been noted in people following a gluten-free diet. Gluten-free foods themselves have been shown to be lower in thiamine, riboflavin, niacin, folate, iron, and dietary fibre. This may primarily be because gluten-free foods tend not to be fortified, and be refined.

Coeliac patients should be encouraged to consume foods high in iron and folate to combat these deficiencies, and supplements should be considered if recommended intakes cannot be achieved through diet alone. Calcium and vitamin D deficiencies may also be present and supplements are necessary if intake is insufficient. Other nutritional deficiencies may include

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A gluten-free diet itself can also be associated with lower levels of certain micronutrients

magnesium, zinc, niacin, and riboflavin. Most nutritional deficiencies will resolve due to mucosal healing and increased absorption, once a gluten-free diet is established.9

The key elements of managing Coeliac disease through diet are to choose and eat foods that are gluten-free; consume a well-balanced diet; including good sources of calcium, iron, vitamin D, and B vitamins; eat foods that are rich in fibre; always check foods and fluids in the coeliac society list of gluten-free foods, and check food labels. The emphasis of dietary management in Coeliac disease should focus on the nutritional quality of the diet, and not just simply ‘foods allowed’ or ‘foods to avoid’.9

Prognosis, outlook, and support

Prognosis for individuals diagnosed early and who remain compliant with a glutenfree diet is good, however, a lifelong diet completely free of gluten can be costly and challenging. Strict compliance with a gluten-free diet is difficult, and relapses are common. Many patients continue to experience symptoms, often due to imperfect adherence to a gluten-free diet.

People with Coeliac disease face a lifelong condition that can be emotionally and physically debilitating, and which left untreated can lead to a significant reduction in quality-of-life. While a large selection of gluten-free products are available in major supermarkets and food outlets with more supports available now than in the past, increased awareness of Coeliac disease as a worldwide health problem is necessary, to help patients cope with the illness and its treatment. Patient support and information is an integral part of the management of Coeliac disease. Clinicians play a lead role by providing ongoing assessment, management, support, and education.

Future drug therapies are currently in development with the hope of reducing the burden of living with Coeliac disease, and improving long-term health outcomes. Clinical trials are in progress, but only a few have reached later clinical trial phases. Other scientific challenges include obtaining a better understanding of phenotypes and seronegative Coeliac disease. There is ongoing work on developing possible nondietary therapies that would enable people with Coeliac disease to tolerate gluten.

One of the main focuses of the research in this area is immune modulators. Ongoing research and therapeutic strategies aimed at developing a vaccine and desensitising those with Coeliac disease to gliadin peptides could provide a preventative and definitive cure for Coeliac disease. Identification of future cure and/or alternative treatments to a gluten-free diet brings hope for Coeliac disease patients, who are unavoidably burdened by dietary restrictions.

The Coeliac Society of Ireland, https:// coeliac.ie/, is a registered charity that provides information and support to people diagnosed with Coeliac disease throughout Ireland. The Society is part of the European Association of Coeliac Societies (AOECS) involved in setting standards for gluten-free foods both within the European Union and internationally. The society empowers the Coeliac and gluten-intolerant community by providing them with information, food lists, advice, and practical solutions as they navigate a gluten-free lifestyle. They represent patient interests by advocating to government health agencies for improved resources and services, so that patients and their families can access the care they need. 

References

1. Caio G, Volta U, Sapone A, Leffler DA, De Giorgio R, Catassi C, Fasano A. 2019. Coeliac disease: A comprehensive current review. BMC medicine, 17(1), 142. doi: 10.1186/s12916-019-1380-z

2. Fasano A, Catassi C. Coeliac disease. N Engl J Med. 2012; 367:2419–2426. doi: 10.1056/NEJMcp1113994

3. Posner E, Haseeb M. 2022. Coeliac disease. Stat Pearls Publishing. Available from: www. ncbi.nlm.nih.gov/books/NBK441900/

4. Ruiz A. 2021. Coeliac disease. MSD Manual Professional Version. Available at: www.msdmanuals.com/ professional/gastrointestinal-disorders/ malabsorption-syndromes/celiac-disease

5. Coeliac Society of Ireland. 2021. Getting diagnosed. Available at: https:// coeliac.ie/getting-diagnosed/

6. Coeliac UK. 2022. Advice before testing and recommended tests. Available at: www.coeliac.org.uk/ healthcare-professionals/diagnosis/ recommended-tests/#:~:text=Testing%20 for%20the%20HLA%20DQ2,consider%20 using%20HLA%20DQ2%20(DQ2

7. Coeliac UK (2022). Classification of biopsy results. Available at: www.coeliac.org.uk/ information-and-support/coeliac-disease/ getting-diagnosed/blood-tests-and-biospy/

8. Ludvigsson J, Bai J, Biagi F, et al. Diagnosis and management of adult coeliac disease: Guidelines from the British Society of Gastroenterology. Gut. 2014; 63: 1210-1228

9. Coeliac Society of Ireland. 2021. Nutritional Deficiencies. Available at: https://coeliac.ie/healthcareprofessionals/nutritional-deficiencies/

10. Coeliac Society of Ireland. 2021.

Healthcare professionals. Available at: https://coeliac.ie/healthcare-professionals/

11. NICE. 2015. Coeliac disease: recognition, assessment and management. NICE guideline. National Institute for Health and Care Excellence. Available at: https:// coeliac.ie/wp-content/uploads/2020/06/ coeliac-disease-recognition-assessmentand-management-1837325178565.pdf

12. Coeliac UK. 2022. Conditions linked to coeliac disease. Available at: www.coeliac. org.uk/information-and-support/coeliacdisease/conditions-linked-to-coeliac-disease/

13. HSE. 2021. Coeliac disease. Treatment. Health Service Executive. Available at: www2. hse.ie/conditions/coeliac-disease/treatment/

14. Coeliac Disease Foundation. 2021. Coeliac disease diagnosis. Available at: https://celiac.org/about-celiac-disease/ screening-and-diagnosis/diagnosis/

42 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

Hep C: New WHO treatment guidance

AUTHOR: Priscilla Lynch

The World Health Organisation (WHO) has published newly-updated guidance on hepatitis C virus (HCV) infection – with new recommendations on treatment of adolescents and children, simplified service delivery, and diagnostics.

The updated guidance was released during a joint WHO-EASL-CDC symposium at the EASL International Liver Congress 2022 in London. These guidelines recommend a radical simplification of the care pathway to overcome barriers in access to HCV testing and treatment.

According to 2019 data, 58 million people live with chronic hepatitis C infection, which results in about 400,000 deaths each year. In 2016, WHO set out ambitious goals to eliminate viral hepatitis B and C as a public health threat by 2030. While good progress has been made in several champion countries, there remains a major testing and treatment gap. In 2019, still only 21 per cent of the 58 million with chronic hepatitis C infection had been diagnosed overall and 13 per cent treated.

The WHO’s new global health sector strategy sets new actions and targets to eliminate viral hepatitis by 2030, by driving new infections and deaths down to half a million each, globally – a reduction of 90 per cent and 65 per cent, respectively.

The three key new WHO recommendations include:

 Simplified service delivery and task sharing: WHO is recommending a shift to delivering testing and treatment in primary care, at harm reduction sites and in prisons, and to care delivered by GPs and nurses, rather than specialists.

 More efficient and simplified hepatitis diagnostics: The use of point-of-care (POC) HCV ribonucleic acid (RNA) assays is now recommended as an additional approach

alongside laboratory-based RNA assays to diagnose the infection. This is especially applicable to marginalised populations, such as persons who inject drugs, and hard-to-reach communities with limited access to healthcare and high rates of loss to follow-up.

 Harmonised and simplified hepatitis treatment for children and adolescents: Treatment is now recommended for the first time for all adolescents and children down to age three years. These guidelines align existing recommended directacting antiviral (DAA) regimens for adults (sofosbuvir/daclatasvir (SOF/DCV), sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (G/P)) for use in adolescents and children. This is expected to simplify procurement, promote access to treatment among children in low- and middle-income countries (LMICs), and contribute to global efforts to eliminate the disease. Until recently there had been less attention to addressing HCV in children and adolescents, and there were no DAA regimens approved for use in children. In 2018 there were an estimated 3.26 million children and adolescents, aged 18 years and younger, living with chronic HCV infection. Early diagnosis and treatment in adolescents and children are key to preventing long-term morbidity related to chronic hepatitis C infection.

The 2022 WHO guidelines also include other updates such as inclusion of new manufacturers’ protocols on use of dried blood spots for HCV serology and RNA viral load testing, and new data to inform limit of detection for HCV RNA viral load assays as a test of cure.

HCV in Ireland

There are an estimated 20,000 people in Ireland living with chronic hepatitis C infection in Ireland; of these cases, many

are undiagnosed. New disease notifications have declined in recent years; there were 326 notifications of hepatitis C in 2020, compared with a 2015 baseline of 670 – a reduction of over 50 per cent. The number of hepatitis C-related deaths in Ireland has been estimated at 168 (163-204) for 2019, slightly above the estimated 166 figure for the 2015 baseline, however.

The HSE’s National Hepatitis C Treatment Programme (NHCTP) was established in 2015, and over 6,500 people with HCV have been successfully treated with DAAs through the programme to date. The Covid-19 pandemic, however, had a significant impact on the amount of patients treated in the last few years; 1,196 were treated with DAAs in 2019 compared to 532 in 2020, and 529 in 2021.

While the NHCTP remains hopeful that it can reach the HCV elimination target by 2030, local campaigners such as the Hepatitis C Partnership have warned that Ireland remains two decades off elimination targets. They say this is largely due to limited availability of communitybased testing and treatment.

However, the NHCTP told Update that services are returning to normal following the impact of the Covid-19 pandemic, and it is focusing on identifying undiagnosed cases. In this regard, a contract for community online hepatitis C testing has been awarded to SH24. The programme is currently working with SH24 to develop a testing platform and plans to pilot it in a number of locations later in the year.

In addition, the expansion of the community programme is ongoing. In this regard, the NHCTP has purchased a number of GeneXpert/Fibroscan machines for various sites to progress the treatment of hepatitis C in the community. 

43 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

Putting hepatitis E on the radar

AUTHORS: Priscilla Lynch and Pat Kelly

Hepatitis E infection is a disease of the liver caused by hepatitis E virus (HEV), a virus which can infect both animals and humans (zoonosis).

Symptoms of hepatitis E are similar to those of other types of acute viral hepatitis and include:

 Yellowing of the skin and eyes (jaundice);

 Darkening of the urine;

 Pale stools;

 Tiredness;

 Fever;

 Nausea;

 Vomiting;

 Abdominal pain;

 Loss of appetite.

Hepatitis E infection often has no symptoms or causes mild disease; therefore many cases are not diagnosed. In general, people who are infected with hepatitis E fully recover within four-to-six weeks without any treatment.

Rarely, chronic infection may develop in people with suppressed immune systems, for example after a solid organ transplant. More severe disease can also occur in a small number of cases, and HEV infection may result in liver failure in those who already have liver disease and some people with hepatitis E may develop neurological symptoms.

Pregnant women infected with genotype 1 or 2 hepatitis E infections are also at risk of severe liver disease. However, these genotypes are associated with travel to developing countries and are not indigenous to Ireland.

Hepatitis E infection occurs worldwide, but the risk of infection is higher in countries or in situations where the levels of sanitation and hygiene are poor.

In developed countries, hepatitis E was traditionally considered to be an infection associated with travel to areas with poor sanitation. However, HEV infection is increasingly recognised as a cause of liver dysfunction in developed countries,

according to the Health Protection Surveillance Centre (HPSC).

Hepatitis E became a notifiable disease in Ireland in December 2015 and the Irish Blood Transfusion Service (IBTS) introduced hepatitis E screening for all blood donations on 4 January 2016. Notifications include cases of hepatitis E that are detected through IBTS blood donor screening and cases of hepatitis E that are diagnosed because they present to a GP or hospital with clinical symptoms of viral hepatitis. Case numbers had been on the rise in recent years in Ireland (See Figure 1) (73 in 2019, 77 in 2020), but dropped significantly last year (58), with 24 cases by the end of week 33 this year.

However, HEV is not a notifiable disease in many countries, so the real incidence of the disease is unclear, but health professionals here should be aware of the risk of autochthonous HEV infection and should consider it in the differential diagnosis of non-travel-associated hepatitis, regardless of the age and the sex of the patient.

How is hepatitis E spread?

In developed countries, the virus may spread from animals to humans through the consumption of undercooked or raw pig and game meat, processed pork, and shellfish. It has also been shown to spread directly by handling animals, particularly pigs.

In regions of the world where sanitation may be poor (Asia, Africa, and Central America), the virus spreads by drinking contaminated water.

Direct spread of hepatitis E from one person to another is very rare, though the virus has passed between people through blood transfusion.

The incubation period for hepatitis E is 15-to 60-days, the average being 40 days.

Can hepatitis E be treated/prevented?

There remains no vaccine for HEV (except in China) or specific treatment and the infection usually resolves on its own spontaneously. Therapy should be supportive and is aimed at maintaining comfort, hydration, and adequate nutrition. Hospitalisation is sometimes required in severe cases and should be considered for pregnant women.

HEV infection avoidance

 Cook meat and meat products thoroughly;

 Avoid raw or undercooked meat and shellfish;

 Good personal hygiene, with special emphasis on careful hand-washing after using the toilet and before preparing and eating food.

When travelling to countries with poor sanitation:

 Avoid drinking unpurified water;

 Boil all drinking water, including water for brushing teeth;

 Avoid raw or undercooked meat and shellfish;

 Good personal hygiene, with special emphasis on careful hand-washing after using the toilet and before preparing and eating food.

A challenging disease

A world-renowned authority on viral hepatitis, Prof Heiner Wedermeyer, Professor of Gastroenterology at University Hospital Essen and Hannover Medical School in Germany, gave an update on ‘Hepatitis E and other viruses’ at last year’s Irish Society of Gastroenterology 2021 Winter Meeting. He described HEV as a challenging diagnosis and difficult to treat.

“HEV is very frequent and completely underestimated and it’s really something that we in the fields of gastroenterology and hepatology have to think about,” said Prof Wedermeyer. “For example, if you have a

44 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

patient with acute hepatitis, in Germany we do lab screenings for A, B, and C, and then they stop. The most frequent cause of acute hepatitis in Germany is hepatitis E, and this is something we should keep in mind.”

HEV can infect not only humans, but also pigs and cows, and this inter-species transmission is most predominant when pigs and cows are co-housed, explained Prof Wedermeyer. Recent research has shown that it can also be found in sheep, rabbits, cats, goats, camels, and even dogs. HEV genotype 3 infects humans and is found mainly in pigs; however, a hepatitis E-like virus is also found in rats and can also infect humans, said Prof Wedermeyer, and some such cases have been identified in China.

“HEV may cause permanent hepatitis in pregnant women, but it is very important to note that it only infects HEV genotype 1, which is found in India. So if pregnant women in Europe eat meat [infected with HEV], for example, they are not at risk of developing permanent hepatitis,” he told the conference.

He briefly discussed liver-related complications and said on ward rounds, his main concerns

are acute and chronic liver failure, particularly in chronic disease courses in the immunocompromised. “The huge field of extrahepatic complications is largely underestimated,” he said, commenting that in diagnostics, one should consult with a virologist and the laboratory to establish which assay and algorithm they are using.

Prof Wedermeyer summarised: “For the future of hepatitis E research, I think we need to better define the animal and environment reservoir,” he said. “This holds true for many European countries, [to define] how big the threat is. In Germany, HEV has even been detected in drinking water…. I think it is probably impossible to ‘escape’ from hepatitis E. Most of us have been somehow exposed, even if not infected, to HEV, along with probably almost every other person in Europe, and the disease burden needs to be determined.

“A practical question is, should we really treat all blood products for HEV RNA and we should ask is this pooling sufficient, or is there a remaining risk for HEV infections,” he continued. “We need more research

to explain why some patients have severe acute [disease] courses, or mild acute courses, and why others have progressive chronic liver disease. Also, the role of immunosuppressants in pregnancy requires further investigation, as do extrahepatic manifestations, because these are very frequent and we do not have very good treatment algorithms for these situations.

“This leads me to think that we need more basic research in virology and immunology in the field of hepatitis E. Probably most importantly, ribavirin is a step forward, but we need alternative antiviral drugs. I think that’s very clear and for all hepatitis E patients, the message holds true that coffee is good for the liver; coffee reduces the risk of developing liver cirrhosis and hepatocellular carcinoma.”

Reference

1. Health Protection Surveillance Centre. Hepatitis E: Factsheet. 2022. Available at: www.hpsc.ie/a-z/hepatitis/ hepatitise/factsheet/

45 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022



Figure 1: Number of hepatitis E notifications in Ireland by year and quarter, 2016 to 2020 Source: HPSC. Last updated 5 March 2021

Acute hepatitis of unknown cause in children: Latest updates

AUTHOR: Priscilla Lynch

An increase in severe acute hepatitis cases of unknown aetiology among previously healthy children was first reported by the UK to the World Health Organisation’s (WHO’s) International Health Regulations (IHR) notification system on 5 April 2022 (testing had excluded viral hepatitis types A, B, C, D, and E and other known causes of acute hepatitis).

Following this alert, the US, Ireland, and several other European Union, European Economic Area (EU/EEA), and other countries, have reported suspected cases.

As of 25 August 2022, 513 cases of acute hepatitis of unknown aetiology in children had been reported by 21 countries in the European region: (Austria (six), Belgium (14), Bulgaria (one), Cyprus (two), Denmark (eight), France (nine), Greece (12), Ireland (26), Israel (five), Italy (36), Latvia (one), Luxembourg (one), the Netherlands (15), Norway (six), Poland (18), Portugal (20), Republic of Moldova (one), Serbia (one), Spain (46), Sweden (12), and the UK (273)).

According to the latest situation update from the European Centre for Disease Prevention and Control (ECDC), the aetiology and pathogenetic mechanisms of disease are still under investigation. A possible association with current adenovirus infection has been identified, but other hypotheses and possible co-factors, such as another infection (including Covid-19) or something in the environment, are also being investigated Most cases continue to be reported as sporadic, unrelated cases. It is not yet clear whether all cases identified following the original alert are part of a true increase compared to the baseline rate of hepatitis of unknown aetiology in children, the ECDC noted recently.

Ireland

As of 31 August, 28 probable cases of children with hepatitis of unknown cause have been identified in Ireland and a small number of children are under investigation, according to the Health Protection Surveillance Centre (HPSC). This is more than would usually be expected over this period of time. The Irish cases have no links to the UK cases.

To date, no single virus has been identified in all Irish cases. Investigations are currently ongoing to identify the cause of these illnesses. Data is provisional and based on information available at the time of reporting and are subject to change.

The common viruses that cause hepatitis (hepatitis viruses A, B, C, and E) have not been detected in any of the cases. In Ireland, as in other countries, investigations are underway to determine if current or prior Covid-19 infection may increase the risk of this disease in some children. None of the Irish cases who were tested on admission to hospital had evidence of Covid-19 infection at that time. The majority of the cases had not received Covid-19 vaccination. Ireland is liaising closely with ECDC, UK, and WHO colleagues in efforts to identify the cause of this illness.

All probable cases of hepatitis of unknown origin to date in Ireland are in children between the ages of 0 and 12 years of age; 27 of the 28 cases were hospitalised. Two children have received a liver transplant and there has been one death associated with this disease.

GPs and paediatric consultants are aware of the recent increase in cases of hepatitis amongst children and will be alert to identify any further cases that may develop.

Advice for parents on symptoms of hepatitis

Parents are advised to go to their GP if their child develops symptoms of hepatitis. Symptoms of hepatitis can include:

 Pale, grey-coloured poo (stools);

 Dark urine;

 Yellowing of the eyes and skin (jaundice).

If their child has any of these three symptoms, parents should contact their GP without delay. The GP will assess the child and refer on for further assessment as indicated.

Other symptoms include:

 Muscle and joint pain;

 A high temperature;

 Feeling and being sick;

 Feeling unusually tired all the time;

 A general sense of feeling unwell;

 Loss of appetite;

 Tummy pain;

 Itchy skin.

Parents are advised to go to their GP if their child develops symptoms of hepatitis. The GP will assess the child and refer on for further assessment as indicated.

If a child is unwell with respiratory or diarrhoeal or hepatitis symptoms, parents should keep their child at home and do not send them to créche/preschool/school until they are better.

Good respiratory and hand hygiene, including supervising hand washing in young children, can help to prevent adenovirus and other infections that can cause hepatitis. 

See www.hpsc.ie for more information and guidance leaflets.

46 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

International Liver Congress 2022

Significant treatment breakthroughs for NAFLD unveiled at ILC 2022

Results from two trials have given researchers hope that significant progress can be made against the rise in nonalcoholic fatty liver disease (NAFLD), now the world’s fastest growing disease, which affects one-in-four people around the globe.

The results were presented at the International Liver Congress 2022 (ILC 2022) in London, which took place from 22-26 June and was convened by the European Association for the Study of the Liver (EASL).

A first in-human trial of the drug Pemvidutide, a novel GLP-1/glucagon dual receptor agonist, has shown that it is remarkably effective at reducing a person’s weight, but what sets its aside from weight-loss drugs is that it simultaneously reduces liver fat. This placebo-controlled, double-blind, first-in-human trial aimed to assess the safety and pharmacokinetics of Pemvidutide, and to evaluate its effects on weight loss and liver fat content (LFC).

Scott Harris, of biopharmaceutical company Altimmune in the US, noted that by week 12, the 36 subjects receiving Pemvidutide achieved mean weight losses of 4.9 per cent, 10.3 per cent, and 9.0 per cent at the 1.2mg, 1.8mg, and 2.4mg doses, respectively, vs 1.6 per cent for subjects receiving placebo. Weight loss occurred rapidly and consistently across study weeks. Subject plots at 1.8mg suggested sustained effects over time. MRI-PDFF

analyses following six weeks of treatment revealed all five subjects with fatty liver (≥5 per cent) at baseline, including some as high as 19.5 per cent, receiving 1.8mg or 2.4mg Pemvidutide had reductions in LFC to undetectable levels (limit of detection 1.5 per cent), a >90 per cent mean reduction.

“The global burden of NAFLD is so high that we’re going to need all the prevention and treatment tools at our disposal to make any real inroads over the coming years,” said Prof Aleksander Krag, Vice SecretaryGeneral of EASL, and Professor and Senior Consultant of Hepatology and Director of the Odense Liver Research Centre at the University of Southern Denmark and Odense University Hospital in Denmark.

“Prevention through diet is a no-brainer policy: It’s something most people can do of their own accord and it costs governments very little. For the sake of our younger generations, we have to take the issue of good diet seriously.

“Banning advertising of junk food, for instance, would be a good start.

Harris concluded that the rapid and potent reductions in body weight and LFC, including double-digit weight-loss in 12 weeks and decreases in LFC to levels below the limit of detection, without the need for dose titration, suggest Pemvidutide could be a promising new agent for treatment of non-alcohol related steatohepatitis (NASH) and its co-morbidities.

In a separate randomised trial comparing two types of weight reducing diets, presented at ILC 2022, researchers concluded that a low-carbohydrate high-fat diet is much more effective at reducing liver fat in people living with type 2 diabetes than a high-carbohydrate low-fat diet.

“But educating young people and their families is going to be the key to unlocking this looming public health disaster. People need reassuring about why a good diet is so important in the long-term, which ensures they live more healthily and longer,” concluded Prof Krag.

NAFLD is already the fastest growing cause of hepatocellular carcinoma (HCC), and NASH is the second, more serious stage of NAFLD. If left unchecked, the annual predicted cost of NAFLD in Europe is estimated to be greater than €35 billion in direct costs to the health system, and a further €200 billion by way of wider costs to society.

47 Gastroenterology and Hepatology | Volume 8 | Issue 8 | 2022

People need reassuring about why a good diet is so important in the long-term, which ensures they live more healthily and longer

Priscilla Lynch presents a round-up of the most topical research presented at this year’s International Liver Congress 2022

New effective treatment and cure for hepatitis D

Results from a phase 3 trial presented at ILC 2022 have confirmed that the drug bulevirtide (BLV) can successfully treat and cure hepatitis D virus (HDV).

A stand-alone cure for hepatitis D has so far eluded scientists. Found in 2-to-3 per cent of people living with hepatitis B (HBV), chronic hepatitis D (CHD) is the most acute of the hepatitis family and extremely hard to treat. Now for the first time, using bulevirtide, an inhibitor of HBV and HDV entry into liver cells, it is possible to successfully treat it.

In this study 150 patients with CHD were randomised to three treatment groups and stratified based on the absence or presence of compensated cirrhosis: Arm A (control): No active anti-HDV treatment for 48 weeks followed by BLV 10mg/d for 96 weeks (n=51), and arms B or C: Immediate treatment with BLV at 2mg/d (n=49) or 10mg/d (n=50), respectively, each for 144 weeks, after which all arms enter treatment-free follow-up for an additional 96 weeks. The primary endpoint of combined response was defined

as undetectable HDV RNA or decrease by ≥2log10 IU/mL from baseline and ALT normalisation at week 48; other endpoints included viral response (undetectable HDV RNA or decrease by ≥2log10 IU/mL from baseline), ALT normalisation, change in HDV RNA levels, and change in liver stiffness measured by elastography.

Heiner Wedemeyer of the Medizinische Hochschule in Hannover, Germany reported that at week 48, similar combined responses were seen in the two BLV arms, which were significantly greater than in the control arm. Viral and biochemical responses were also similar in the BLV arms and significantly greater than control (p<.0001). BLV was safe and well-tolerated during the 48-week treatment period. Asymptomatic elevations in total serum bile salts and injection site reactions occurred at a greater frequency at the higher BLV dose level. There were no participants having an adverse event (AE) leading to discontinuation of BLV and no serious AEs attributed to BLV treatment. Wedemeyer concluded that the study

demonstrates that treatment with BLV resulted in a significantly greater combined response compared to control. Monotherapy with BLV was also safe and well-tolerated.

Other announcements during ILC 2022 included phase 3 trial results of a new drug to treat acute hepatic porphyria, promising steps towards the long-sought cure for hepatitis B, and results of the largest human trial of pre-emptive drugs administered before transplantation of a hepatitis C compromised organ that fully protects patients from post-operative infection.

“We may well be entering into a new golden age of hepatology science,” said Prof Thomas Berg, Secretary-General of EASL and Head of the Division of Hepatology at Leipzig University Medical Centre in Germany.

“There is respite coming for those people living with hepatitis D and we are making progress towards finding a cure for hepatitis B, which affects millions people around the world. The science is inching us towards a potential public health revolution.”

Results of a high intensity test and treat (HITT) programme for Hep C in English prisons

The results of a high intensity test and treat (HITT) programme pilot for hepatitis C in English prisons were presented at ILC 2022.

The UK’s NHS is committed to eliminating viral hepatitis C (HCV) by 2025, and elimination in the prison population is key to achieving that goal. The Hepatitis C Trust has introduced a HITT programme to assess and treat people in prisons in England. The initiative is aiding prisons achieve micro-elimination and has also generated useful data about the prevalence of hepatitis C in prisons and how it varies between establishments.

Between June 2019 and September 2021, 34 HITT initiatives were successfully completed

across England: Seven in female prisons and 27 in male prisons. Of the 23,388 prison population, 19,049 inmates agreed to be tested. Of those 1,234 people tested positive for presence of HCV antibodies, of whom 175 tested positive for presence of HCV RNA. All 175 prisoners found to have a current infection commenced treatment.

At ILC 2022, Beatrice Emmanouil, of the NHS, reported that a team comprising of NHS staff, nurses and peers with lived experience of HCV and incarceration were sent into the prisons and offered HCV testing to the whole prison population using prison-wing-based testing with point of care antibody tests, followed up by using either blood draws or dried blood

spot testing for confirmation of viraemia in antibody-positive people. All infected people were offered therapy with direct acting antivirals (DAAs) within two weeks, and often on the same day using point of care HCV RNA testing and pan-genotypic medication.

Emmanouil concluded that there was great variation between establishments, with remand prisons having significantly higher prevalence than re-settlement prisons. Prevalence was also higher in women’s prisons compared to men’s prisons.

For more information on ILC 2022 go to https://easl.eu/event/international-livercongress-2022.

48 Volume 8 | Issue 8 | 2022 | Gastroenterology and Hepatology

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For all that matters in medicine

Choose a different path for your

Ulcerative Colitis patients’ future.

SIMPONI is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.1

Simponi 50 mg, 100 mg Solution for Injection in pre-filled pen Simponi 50 mg Solution for Injection in pre-filled syringe (golimumab)

ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing PRESENTATION Simponi 50 mg solution for injection in pre-filled pen Simponi 50 mg solution for injection in pre-filled syringe Simponi 100 mg solution for injection in pre-filled pen INDICATIONS Rheumatoid Arthritis (RA): Simponi, in combination with methotrexate (MTX), is indicated for: the treatment of moderate to severe, active rheumatoid arthritis in adults when the response to disease-modifying anti-rheumatic drug (DMARD) therapy including MTX has been inadequate; the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with MTX. Simponi, in combination with MTX, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function; Psoriatic Arthritis (PsA): Simponi, alone or in combination with MTX, is indicated for the treatment of active and progressive PsA in adults when the response to DMARD therapy has been inadequate. Simponi has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease and to improve physical function. Ankylosing Spondylitis (AS): Simponi is indicated for the treatment of severe, active AS in adults who have responded inadequately to conventional therapy. Non-radiographic axial spondyloarthritis (nr-Axial SpA): Simponi is indicated for the treatment of severe, active nr-Axial SpA who have had an inadequate response to or are intolerant to NSAIDs Ulcerative colitis (UC): Simponi is indicated for treatment of moderately to severely active UC in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies. Polyarticular juvenile idiopathic arthritis (pJIA): Simponi 50mg in combination with MTX is indicated for the treatment of polyarticular juvenile idiopathic arthritis in children with a body weight of at least 40 kg, who have responded inadequately to previous therapy with MTX. DOSAGE AND ADMINISTRATION Simponi should be injected subcutaneously. Treatment should be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of RA, PsA, AS, nr-Axial SpA, UC or pJIA. After proper training in subcutaneous injection technique, patients may self-inject, if their physician deems it appropriate. RA: Simponi 50 mg given once a month, on the same date each month, concomitantly with MTX. PsA: Simponi 50 mg given once a month, on the same date each month, alone or in combination with MTX. AS and nr-Axial SpA: Simponi 50 mg given once a month, on the same date each month. Clinical response is usually achieved within 12-14 weeks of treatment (3 or 4 doses). Continued therapy should be reconsidered in patients who show no evidence of therapeutic benefit within this time period. In patients weighing more than 100 kg who do not achieve an adequate clinical response after 3 or 4 doses, increasing the dose of golimumab to 100 mg once a month may be considered, taking into account the increased risk of certain serious adverse reactions with the 100 mg dose compared with the 50 mg dose. UC: Patients weighing < 80 kg: Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2. Patients who have an adequate response should receive 50 mg at week 6 and every 4 weeks thereafter. Patients who have an inadequate response may benefit from continuing with 100 mg at week 6 and every 4 weeks thereafter. Patients weighing ≥ 80 kg: Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 100 mg every 4 weeks. During maintenance treatment, corticosteroids may be tapered, following clinical practice guidelines. Clinical response is usually achieved within 12-14 weeks of treatment (after 4 doses). pJIA: Simponi 50 mg administered once a month, on the same date each month, for children with a body weight of at least 40 kg. Clinical response is usually achieved within 12 to 14 weeks of treatment (after 3-4 doses). Missed dose: If a patient forgets to inject Simponi on the planned date, the forgotten dose should be injected as soon as the patient remembers. The patient should be instructed not to inject a double dose. Older patients (≥ 65 years): no dose adjustment required. Paediatric patients (<18 years): For indications other than pJIA, Simponi is not recommended. Patients with renal and hepatic impairment: Simponi is not recommended. CONTRAINDICATIONS Patients with a hypersensitivity to golimumab or any of the excipients; Patients with active tuberculosis (TB) or other severe infection such as sepsis and opportunistic infections; patients with moderate or severe heart failure (NYHA class III/IV). PRECAUTIONS AND WARNINGS Infections: Patients must be monitored closely for infection before, during and for 5 months after cessation of treatment. Exercise caution when considering golimumab in patients with chronic infection or a history of recurrent infection including use of concomitant immunosuppressive therapy. Golimumab should not be given to patients with clinically important active infection. Patients should be advised of the potential risk factors. Bacterial infections (including sepsis and pneumonia), mycobacterial (including TB), invasive fungal and opportunistic infections, including fatalities, have been reported. The invasive fungal infection should be suspected if they develop a serious systemic illness. There was a greater incidence of serious infections, including opportunistic infections and TB, in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. Serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infection. There have been reports of active TB in patients receiving golimumab, including patients previously treated for latent TB. Patients should be evaluated for active or latent TB before golimumab treatment. All such tests should be recorded on the Patient Reminder Card provided with the product. If active TB is diagnosed, treatment with golimumab should not be initiated. If latent TB is diagnosed, treatment with anti-TB therapy must be initiated before initiation of golimumab. Patients on golimumab should be monitored closely for signs and symptoms of active TB and advised to seek medical advice if signs and/or symptoms of TB appear. Hepatitis B (HBV) reactivation: Reactivation of HBV occurred in patients receiving golimumab who were chronic carriers. Some cases had a fatal outcome. Patients should be tested for HBV infection before initiating treatment with golimumab Malignancies and lymphoproliferative disorders: Caution is advised when considering golimumab treatment in patients with history of malignancy or continuing treatment in patients who develop a malignancy, additional caution should be exercised in patients with increased risk for malignancy due to heavy smoking. A risk for the development of malignancies in children and adolescents cannot be excluded. Rare cases, usually fatal, of hepatosplenic T-cell lymphoma (HSTCL) have been reported, the majority of cases occurred in adolescent and young males nearly all on concomitant treatment with azathioprine (AZA) or 6-mercaptopurine (6–MP). The potential risk with the combination of AZA or 6-MP and golimumab should be carefully considered. A risk for the development for HSTCL in patients treated with TNF-blockers cannot be excluded. Colon dysplasia/carcinoma - Screen for dysplasia in all patients with UC who are at increased risk or had a prior history for dysplasia or colon carcinoma. In newly diagnosed dysplasia patients the risks and benefits of continued golimumab use should

be carefully assessed. Melanoma and Merkel cell carcinoma (all TNF-blocking agents including golimumab) have been reported, periodic skin examination is recommended, particularly for patients with risk factors for skin cancer. Heart Failure: Golimumab should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and golimumab must be discontinued in patients who develop new or worsening symptoms of heart failure. Some cases had a fatal outcome. Neurological events: Use of anti-TNF therapy, including golimumab, has been associated with cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and peripheral demyelinating disorders. Discontinuation of golimumab should be considered if these disorders develop. Carefully consider the benefits and risks before initiation of therapy in patients with a history of demyelinating disorders. Surgery: Patients requiring surgery whilst on golimumab therapy should be closely monitored for infections. Autoimmune processes: If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with golimumab and is positive for antibodies against double-stranded DNA, treatment should be discontinued. Haematological reactions: There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anaemia, and thrombocytopaenia in patients receiving TNF-blockers, including golimumab. Patients should be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias. Discontinuation should be considered in patients with significant haematologic abnormalities. Vaccinations/therapeutic infectious agents: It is recommended that live vaccines or any therapeutic infectious agents should not be given concurrently. Allergic reactions: If an anaphylactic reaction or other serious allergic reaction occurs, administration of golimumab should be discontinued immediately, and suitable treatment initiated. The needle cover of the pre-filled pen contains latex and may cause allergic reactions in those sensitive to latex. Special populations: Older patients (≥ 65 years): Adverse events, serious adverse events and serious infections in patients aged ≥65 were comparable to those observed in younger patients. However, caution should be exercised when treating the elderly, particular attention should be paid to infections. There were no patients age 45 and over in the nr-Axial SpA study. Paediatric patients (<18 years): Vaccinations: it is recommended that prior to initiating golimumab therapy, paediatric patients be brought up to date with all immunisations in agreement with current immunisation guidelines. Excipients: Simponi contains sorbitol (E420). In patients with rare hereditary problems of fructose intolerance, the additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. INTERACTIONS Combination of golimumab and other biological therapeutics used to treat the same conditions as golimumab, including anakinra and abatacept is not recommended. PREGNANCY AND LACTATION Administration of golimumab is not recommended during pregnancy or breast-feeding. Women of childbearing potential should use adequate contraception and continue its use for at least 6 months after the last golimumab treatment. SIDE EFFECTS Refer to SmPC for complete information on side effects Very Common (≥ 1/10): upper respiratory tract infection; Common (≥1/100): bacterial infections, lower respiratory tract infections, viral infections, bronchitis, sinusitis, superficial fungal infections, abscess, leukopenia (including neutropenia), anaemia, allergic reactions, autoantibody positive, depression, insomnia, dizziness, headache, paraesthesia, hypertension, asthma and related symptoms, dyspepsia, gastrointestinal and abdominal pain, nausea, gastrointestinal inflammatory disorders, stomatitis, alanine aminotransferase increased, aspartate aminotransferase increased, pruritus, rash, alopecia, dermatitis, pyrexia, asthenia, injection site reaction, chest discomfort, bone fractures were reported. Serious, including fatal adverse events have been reported including septic shock, lymphoma, leukaemia, melanoma, Merkel cell carcinoma, hepatosplenic T-cell lymphoma*, leukopenia, thrombocytopaenia, pancytopaenia, aplastic anaemia, agranulocytosis, serious systemic hypersensitivity reactions (including anaphylactic reaction), skin exfoliation, vasculitis (systemic), sarcoidosis, demyelinating disorders, congestive heart failure, arrhythmia, ischaemic coronary artery disease, thrombosis, interstitial lung disease and lupus-like syndrome. * Observed with other TNF-blocking agents. Paediatric population: pJIA: The safety of golimumab has been studied in a phase III study of 173 pJIA patients from 2 to 17 years of age. The average follow-up was approximately two years. In this study, the type and frequency of adverse events reported were generally similar to those seen in adult RA studies. PACKAGE QUANTITIES 1 x 50 mg pre-filled pen containing 50 mg of golimumab in 0.5 ml solution for injection 1 x 50 mg pre-filled syringe containing 50 mg of golimumab in 0.5 ml solution for injection 1 x 100 mg pre-filled pen containing 100 mg of golimumab in 1 ml solution for injection Legal Category: Prescription Only Medicine. Marketing

Authorisation Number 50 mg Pre-filled Pen EU/1/09/546/001 50 mg Pre-filled Syringe EU/1/09/546/003 100 mg

Pre-filled Pen EU/1/09/546/005

Marketing Authorisation Holder Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, The Netherlands Date of Revision of Text: February 2019 © Merck Sharp & Dohme Ireland (Human Health) Limited 2019. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. X-083G-Feb2019. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie Adverse events should also be reported to MSD (Tel: 01-299 8700)

References:

1. Simponi (Golimumab) Summary of Product Characteristics (SmPC). Last updated November 2020. Available at www.medicines.ie

2. Reinisch W et al. Long-term Benefit of Golimumab for Patients with Moderately-to-Severely Active Ulcerative Colitis: Results from the PURSUIT-Maintenance Extension. J Crohns Colitis. 2018;12(9):1053-1066

Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 Ireland

SIMPONI delivers long-term disease control, maintaining efficacy and safety profile over 4 years.2

Image by permission of Sussex Wildlife Trust

IE-GOL-00203 Date of Preparation:

August 2022