Update Journal – Rheumatology & Pain by GreenX Publishing

COMPLETE

DEMONSTRABLE JOINT EFFICACY

PROVEN DURABILITY*

Most patients who started on TREMFYA® stayed on TREMFYA® long-term1,2

Durability*, also known as patient retention or drug survival is a combination of efficacy, safety, tolerability and patient satisfaction or preference. DISCOVER-2 was a Phase 3, double-blind, multi-centre, placebo-controlled study that evaluated the efficacy and safety of TREMFYA® in bio-naïve patients with active PsA.1

Tremfya▼ 100 mg solution for injection in pre-filled pen PRESCRIBING INFORMATION.

ACTIVE INGREDIENT(S): Guselkumab. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Treatment of active psoriatic arthritis in adult patients, alone or in combination with methotrexate, who have had an inadequate response or have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy. DOSAGE & ADMINISTRATION: For use under guidance/supervision of physician experienced in diagnosis and treatment of conditions for which Tremfya is indicated. Subcutaneous injection. Avoid areas showing psoriasis. Adults: For both indications, 100 mg at weeks 0 and 4, followed by maintenance dose every 8 weeks. In the case of psoriatic arthritis, for patients at high risk for joint damage according to clinical judgement, consider a dose of 100 mg every 4 weeks. Consider discontinuation if no response after 16 weeks of treatment for plaque psoriasis and 24 weeks for psoriatic arthritis. Children: No data available in children/adolescents <18 years. Elderly: No dose adjustment required, limited information in subjects aged ≥ 65 years, very limited information > 75 years. Renal & Hepatic impairment: Not studied. CONTRAINDICATIONS: Serious hypersensitivity to active substance or excipients; clinically important, active infection. SPECIAL WARNINGS & PRECAUTIONS: Infections: Potential to increase risk. If signs/symptoms of clinically important chronic/ acute infection occur, monitor closely and discontinue Tremfya until resolved. Tuberculosis: Evaluate patients for TB pre-treatment; monitor for signs/symptoms of active TB during and after treatment. Consider anti-TB therapy prior to Tremfya if past history of latent/active TB and adequate treatment course not confirmed. Serious hypersensitivity reaction: Includes anaphylaxis. Some serious hypersensitivity reactions occurred several days after treatment and included urticaria and dyspnoea. If occurs, discontinue Tremfya immediately and initiate appropriate therapy. Hepatic Transaminase Elevations: An increased incidence of liver enzyme elevations has been observed in patients treated with Tremfya q4w compared to patients treated with Tremfya q8w or placebo. When prescribing Tremfya q4w in psoriatic arthritis, consider evaluating liver enzymes at baseline and thereafter according to routine patient management. If increases in ALT or AST are observed and drug-induced liver injury is suspected, Tremfya should be temporarily interrupted until this diagnosis is excluded. Immunisations: Consider completing all appropriate immunisations prior to Tremfya. Do not use live vaccines concurrently with Tremfya; no data available; before

live vaccination, withhold Tremfya for at least 12 weeks and resume at least 2 weeks after vaccination. SIDE EFFECTS: Very common: Respiratory tract infection. Common: headache, diarrhoea, arthralgia, injection site reactions, transaminases increased. Other side effects: hypersensitivity, anaphylaxis, rash, herpes simplex infections, neutrophil count decreased. Refer to SmPC for other side effects. LEGAL CATEGORY: Prescription Only Medicine (POM). PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S): Pre-filled pen, x1, EU/1/17/1234/002. MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE

FROM: Janssen Sciences Ireland UC, Barnahely, Ringaskiddy, IRL - Co. Cork, P43 FA46. Prescribing information last revised: November 2020.

Adverse events should be reported. ▼ This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance Website: www.hpra.ie.

Adverse events should also be reported to Janssen Sciences Ireland UC on 1800 709 122 or at dsafety@its.jnj.com.

References:

1. Griffiths CEM, et al. Maintenance of Response Through 5 Years of Continuous Guselkumab Treatment: Results From the Phase 3 VOYAGE 1 Trial. Presented at the 16th Annual Coastal Dermatology Symposium. October 15-16, 2020.

2. McInnes IB, et al. Efficacy and Safety of Guselkumab, a Monoclonal Antibody Specific to the p19-Subunit of Interleukin-23, Through 2 Years: Results from a Phase 3, Randomized, Double-blind, Placebo-controlled Study Conducted in Biologic-naïve Patients with Active Psoriatic Arthritis. Presented at Innovations in Dermatology Conference, March 16-20, 2021. Online. 3. Griffiths C, et al. Achieving and maintaining long-term optimal improvements in patient-reported symptoms, signs, and quality of life among patients with moderate-to-severe psoriasis treated with guselkumab: 5-year data from VOYAGE 1. Presented at AAD VMX 2021. 4. Blauvelt A, et al. J Am Acad Dermatol 2017;76:405-417.

CP-297588 | Date of Preparation: February 2022

| Date of Preparation: February 2022

CP-297588

SKIN CLEARANCE

Sustained joint symptom relief proven for 2 years in PsA2

Fast4 and sustained complete clearance proven for 5 years in Ps01

Rheum to improve

Welcome to the latest edition of Update Rheumatology and Pain.

In this issue we present a wide range of expert clinical articles, as well as the latest research updates from home and abroad.

Conference-wise, this issue carries a roundup of the recent European League Against Rheumatism (EULAR) Annual Congress, as well as exclusive coverage of the Irish Society for Rheumatology (ISR) Spring Meeting. Both meetings were held in-person for the first time since 2019 following the Covid-19 pandemic and it was clear there was great joy at being able to return to the usual format.

As well as exciting new disease breakthroughs and the latest treatment findings, both meetings highlighted the current excessive waiting lists for rheumatology and the need for earlier diagnosis to maximise patient outcomes.

In Ireland, the ISR meeting heard, there is still no public access to two key biologics, belimumab and anifrolumab, for lupus patients, which has been described as “a disgrace”. In response to queries from Update as to why this was the case, the HSE said it

had not received the necessary applications for the drugs from their manufacturers. Surely it is high time that industry and the relevant professional medical bodies partner with the HSE to address this failure, so as to ensure that lupus patients, who are already a vulnerable population, often being non-Caucasian females of childbearing age, receive equal access to the latest, most promising treatment options like their counterparts in other countries and those with other rheumatic diseases such as rheumatoid arthritis (RA).

As well as access to the latest treatment options, rheumatology patients also need access to rheumatology specialists. The ISR meeting received an update on the work of the National Clinical Programme and Model of Care, which has seen public rheumatologist posts increase from 42 two years ago to 52 this year, aiming for an overall expansion to 80 posts by 2028. There is also work ongoing on changing how inflammatory arthritis is assessed, through increasing triage by physiotherapists and creating better pathways for people with suspected disease.

Demand for rheumatology care is everincreasing, however. Arthritis is the biggest cause of disability in the country and affects one million people in Ireland. According to Arthritis Ireland, the number of people living with arthritis is forecast to continue to increase in the coming decades. Key drivers are increased life expectancy, obesity, and physical inactivity – just 46 per cent of adults in Ireland are achieving the minimum level

of activity of 150 minutes per week and this figure falls to one-third for adults aged 65-74 years. It is a similar story in pain medicine.

On the more positive side, disease understanding and treatments are also continuing to improve. Among the rheumatology topics covered in this issue of Update are the latest diagnosis and management approaches to gout, ANCAassociated vasculitis, and osteoarthritis, new UK guidelines for psoriatic arthritis, a look at treat-to-target in RA, the role of advanced nurse practitioners in RA management, and the benefits of an exercise prescription for dermatomyositis.

For those interested in pain medicine, there are detailed expert clinical articles on painful diabetic neuropathy, bladder pain syndrome, and the treatment of acute pain in the community, as well as a look at the latest European and US guidelines on opioid usage in pain.

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

Thank you to 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 give any feedback or contribute an article. ■

1 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

A message from Priscilla Lynch, Editor

Editor Priscilla Lynch priscilla@mindo.ie

Sub-editor Emer Keogh emer@greenx.ie

Creative Director Laura Kenny laura@greenx.ie

Advertisements Graham Cooke graham@greenx.ie

Administration Daiva Maciunaite daiva@greenx.ie

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

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

Disclaimer

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

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

Contents 04 Irish Society for Rheumatology 2022 Spring Meeting coverage 12 EULAR Congress 2022 round-up 18 Rheumatoid arthritis: Treat-to-target 26 New UK psoriatic arthritis guideline 30 ANCA-associated vasculitis 34 Gout: Latest diagnosis and management strategies 39 Gout: Treat-to-target ULT study results 40 Osteoarthritis in review 44 An exercise prescription for dermatomyositis 47 ANP

rheumatology clinic for patients

newly-diagnosed RA 52 Opioids: New US and European guidance 54 Acute pain in focus 58 Painful bladder syndrome 61 Management of painful diabetic neuropathy: 2022 and beyond

with

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RE-USABLE: One high quality reuseable pen for the entire treatment period1

MOVYMIA 20 MICROGRAMS/80 MICROLITERS SOLUTION FOR INJECTION

Each dose of 80 microliters contains 20 micrograms of teriparatide. One cartridge of 2.4 ml of solution contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml).

Presentation: Glass cartridge. Indications: Movymia is indicated in adults. Treatment of osteoporosis in postmenopausal women and men at increased risk of fracture. In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated. Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture. Dosage: The recommended dose is 20 micrograms administered once daily. Patients should receive calcium and vitamin D supplements if dietary intake is inadequate. The maximum total duration of treatment is 24 months. The 24 month course should not be repeated over a patient’s lifetime. Following cessation of teriparatide therapy, patients may be continued on other osteoporosis therapies. Teriparatide must not be used in severe renal impairment. Use with caution in moderate renal impairment and impaired hepatic function. Teriparatide should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses.

Method of administration: Movymia should be administered once daily by subcutaneous injection in the thigh or abdomen. It should be administered exclusively with the Movymia Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions provided with the pen. The pen and injection needles are not included with Movymia. However, for treatment initiation a cartridge and pen pack should be used. Movymia must not be used with any other pen. Patients must be trained to use the proper injection techniques. Contraindications: Hypersensitivity to the active substance or excipients. Pregnancy and Breast-feeding Pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis or glucocorticoid-induced osteoporosis, unexplained elevations of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton, patients with skeletal malignancies or bone metastases. Warnings and precautions: In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide. Therefore, if blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during therapy is not required. Teriparatide may cause small increases in urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In short-term clinical studies with teriparatide, isolated episodes of transient orthostatic hypotension were observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing subjects in a reclining position, and did not preclude continued treatment. Caution should be exercised in patients with moderate renal impairment. Experience in the younger adult population, including premenopausal women, is limited. Treatment should only be initiated if the benefit clearly outweighs risks in this population. Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, teriparatide should be discontinued. The recommended treatment time of 24 months should not be exceeded. Contains sodium. Interactions: Digoxin, digitalis. Fertility, pregnancy and lactation: Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, Movymia should be discontinued. Movymia is contraindicated for use during pregnancy and breast-feeding. The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown. Driving and operation of machinery: Teriparatide has no or negligible influence on the ability to drive and use machines. Transient, orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided. Undesirable effects: Nausea, pain in limb, headache, dizziness. Refer to Summary of Product Characteristics for other adverse effects. Pack size: 1. Reporting of suspected adverse reactions: 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, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, German. Marketing authorisation number: EU/1/16/1161/001-003. Medicinal product subject to medical prescription. Date last revised: July 2019.

1. Movymia® SmPC. 2. Movymia® EPAR – public assessment report, available at: https://www.ema.europa.eu/documents/assessment-report/movymia-epar-public-assessment-report_en.pdf

3. Brixen KT et al. Basic Clin Pharmacol Toxicol. 200494(6):260–70. 4. Lyman GH et al. N Engl J Med. 2018378(21):2036–2044. 5. Janjigian YY et al. Future Oncol. 201814(23):2403–2414.* Forsteo® October 2019. 2019/ADV/TER/122H

Irish Society for Rheumatology Spring Meeting, Sligo, 19-20 May 2022

All reports by Niamh Quinlan

Waiting lists and outpatient facilities need to be tackled as a priority in rheumatology

Tackling waiting lists and obtaining off-site facilities to treat patients is top of the agenda for the Model of Care for Rheumatology on emerging from the pandemic, according to HSE National Clinical Lead for Rheumatology, Prof David Kane.

Prof Kane, Consultant Rheumatologist at Tallaght University Hospital, Dublin, told Update that during the Covid-19 pandemic, waiting lists didn’t grow significantly and became “fairly static”. “We’ve managed to maintain it by moving to virtual technology to keep our clinical appointments ticking over,” he said. “But we do have to see our patients again.”

Furthermore, the number of referrals is now growing again, but capacity is not, Prof Kane pointed out.

In the Model of Care for Rheumatology in Ireland, published in 2018, one of the objectives of the programme for access to secondary care was to reduce wait times for referrals to rheumatology.

“It’s not been an easy couple of years.

What we want to address now is getting back to normal business, optimising care for our patients and getting the waiting list down,” Prof Kane added. “We need to improve capacity, change a little bit about the way we work, and move forward with the multidisciplinary strands of our programme to deliver care through nonrheumatologists as well.”

Prof Kane is a firm advocate for taking a multidisciplinary approach to rheumatology treatment and management. “To date we have 184,000 people taken off the orthopaedic and rheumatology waiting list since the programme introduced the musculoskeletal (MSK) physio triage programme,” he said.

The National MSK Physiotherapy Triage Initiative is delivered by advanced practice physiotherapists who see referred MSK patients and triage referrals to consultant orthopaedic surgeons and consultant rheumatologists. “We’re now trying a similar initiative with occupational therapy,” he said.

Prof Kane believes rheumatology

“probably” needs an outpatient building

programme. “The other impact of the pandemic is that we’ve been to some extent squeezed-off the acute hospital sites because acute medicine was a more pressing need,” said Prof Kane. “And what we realised is that we need probably a big investment in rheumatology units nationally to build… places for us to see patients because most of us are finding it hard to get space to see patients in the existing acute hospital sites.”

He said they are looking for simple, off-site facilities and do not require any “highly technical working space”.

During his presentation at the Irish Society for Rheumatology (ISR) 2022 Spring Meeting, which took place in the Sligo Park Hotel on 19 and 20 May, Prof Kane discussed waiting times and expanding HSE rheumatologist posts from 42 two years ago to 52 this year, aiming for an overall expansion to 80 posts by 2028.

He also discussed how the Clinical Programme is working on restructuring “how we manage inflammatory arthritis and trying to create better pathways for people”.

Identifying comorbidities in axial spondyloarthritis patients

The prevalence of comorbidities in axial spondyloarthritis (AxSpA) populations is high and impacts on many facets of the patient’s disease process, as well as impacting on their response to treatment, the ISR 2022 Spring Meeting heard.

Dr Nicola Goodson, Consultant

Rheumatologist at Liverpool University Hospital, and Senior Lecturer in Rheumatology, University of Liverpool, UK, presenting via live video call, discussed ‘Comorbidities in Axial Spondyloarthritis’, a chronic, inflammatory disease, which mainly affects the spine and pelvic joints.

“The most important thing really is to identify comorbidities in axial spondyloarthritis patients,” said Dr Goodson. “Try and be a little more holistic in assessment of our patients with chronic inflammatory conditions.”

A 2020 study, published in the Arthritis

Volume 8 | Issue 6 | 2022 | Rheumatology and Pain 4

Research and Therapy journal, highlighted the various comorbid conditions in patients with AxSpA compared to a population without the condition.

“Whilst the comorbidities [in this study] are the common comorbid conditions that we see in the general population, including hypertension, dyslipidaemia, and obesity, there was also increased prevalence of conditions such as depression and osteoporosis associated with axial spondyloarthritis,” Dr Goodson explained.

AxSpA can present very early in life, and can dramatically impact a person’s quality-of-life. It is particularly associated with depression, so rheumatologists have a responsibility to look for depression in these patients, she said.

In the cited study, hypertension was 14 per cent higher in patients with AxSpA, chronic pulmonary disease was 13 per cent higher,

and depression was present in about onein-four AxSpA patients, compared to 17 per cent of non-AxSpA, Dr Goodson noted.

“An important take-home from this talk is to recognise that depression is a common comorbidity amongst our AxSpA patients, but it may not be recognised by the treating clinicians,” she said. “It does appear to be associated with worse disease activity and functional impairment.

“Where possible, offer treatment and support for patients who are affected by this comorbidity. With the hope that if we can help manage their inflammatory disease, as well as guide their treatment towards better management of their depression and anxiety, then we have a much better outcome in the long-term.”

Osteoporosis is also important to remember “as a comorbid condition associated with all of our inflammatory rheumatic diseases,

particularly our axial spondyloarthritis patients”, Dr Goodson also told the meeting.

“There are particular problems with ankylosing spondylitis, where new bone formation can lead to a very rigid spine, [and] with associated osteoporosis puts patients at risk of life-changing fractures.”

Bone density can usually be measured with DEXA imaging, however, DEXA imaging of the spine can lead to inaccurate results in AxSpA. DEXA scans of the hip are recommended instead, according to Dr Goodson, as are quantitative CT (QCT) and high-resolution peripheral quantitative CT tests, or the recently developed trabecular bone score. The trabecular bone score “basically is a computer algorithm that allows a pixelated view of the vertebral body” and shows holes in trabecular bone density. The lower the score, the lower the bone density, and the higher the increased fracture risk.

Issues in accessing biologics for lupus patients in Ireland

Irish rheumatologists are struggling to access two recently-approved biological drugs to treat lupus, the ISR 2022 Spring Meeting heard.

Dr Eoghan McCarthy, Consultant Rheumatologist at Beaumont Hospital, Dublin, gave an update on the use of biologic drugs in systemic lupus erythematosus (SLE), the most common type of lupus.

The monoclonal antibody drug belimumab, which can be used to treat patients with SLE over the age of five years and adults with lupus nephritis, has been approved for use in the EU since 2011. Another monoclonal antibody, anifrolumab, which is given to SLE patients with autoantibodies who still have moderate-to-severe disease despite standard treatment, was approved in the EU in February 2022. Neither drug are currently available in Ireland, however, he said.

“It is disease activity that you need to try and get under control as quickly as possible because those are the things that will cause damage,” Dr McCarthy told the Meeting. “But over time… the treatments that you’re actually exposing these patients to is what causes the accumulation of damage.”

“So, anything you can do to reduce damage, and therefore anything you can do to reduce the accumulative burden of steroid exposure to these patients, and reducing disease activity in a rapid manner will be associated with improved outcomes for our patients. And that’s the desperation that we all have as rheumatologists… how do you manage to do that without having to rely on such toxic medications.”

Belimumab was approved as an add-on therapy for SLE. “I think it is important that, actually, it looks like it’s a reasonably safe drug in terms of standard of care,” said Dr McCarthy. The drug is approved

for patients with active, antibody-positive SLE with a high degree of disease activity despite already receiving standard treatment.

Anifrolumab, approved only months before the ISR Spring Meeting, “looks to be quite a promising drug”, he commented. “There’s a rationale that interferon inhibitors may… reduce SLE activity.”

In SLE, a protein called type I interferon is involved in causing the immune system to attack normal cells and tissues. Anifrolumab works by blocking the action of this protein and then reduces inflammation and organ damage.

As part of showing the efficacy of biologics in the real world, Dr McCarthy spoke about the British Isles Lupus Assessment Group Biologic Register (BILAG-BR), a study underway in UK hospitals to assess the safety and effectiveness of biologic and biosimilar treatment for SLE.

“The fact that we are demonstrating efficacy

5 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

in the type of patients that are walking into your clinic is important,” he said.

“For patients, I think it’s really important to understand the application and the safety of these drugs in the real-world setting, particularly as more and more of them come through,” he added, “because all our patients are going to be receiving a kind of belimumab or anifrolumab on the background of having probably multiple courses of [other treatments].”

Dr McCarthy told Update that the main takeaway from his talk at the meeting was that: “We as treating clinicians in Ireland are unable to access either belimumab or

anifrolumab at present.”

In response to queries from Update as to why this was the case, the HSE said it had not received the necessary applications for the drugs from their manufacturers.

“Pharmaceutical companies are required to submit formal applications to the HSE if they wish their medicines to be added to the list of reimbursable items/funded via hospitals,” a spokesperson for the Executive said.

The Corporate Pharmaceutical Unit (CPU) within the HSE is responsible for accepting and considering pricing and reimbursement applications from the

pharmaceutical industry. “As of 30 May 2022, the HSE CPU can confirm that a pricing and reimbursement application has not been submitted by the pharmaceutical company (AstraZeneca) for anifrolumab.”

Regarding belimumab, the HSE Drugs Group, responsible for recommendations on pricing and reimbursement of medicines, was “unable to support the pricing approval of this medicine in 2013 due to the absence of a Health Technology Assessment (HTA)”. The HSE spokesperson said, to date, GlaxoSmithKline Pharmaceuticals has not submitted a HTA dossier for belimumab to the National Centre for Pharmacoeconomics for assessment.

New guidelines published for treatment of myositis

A standardised treatment guideline for idiopathic inflammatory myopathy (IIM), generally known as myositis, has been developed in the UK and was presented at the ISR 2022 Spring Meeting.

IIM is a multi-system autoimmune condition characterised by muscle inflammation, interstitial lung disease (ILD), and skin manifestations with an incidence of up to 19 per 1,000,000 person-years in adults and up to four per 1,000,000 person-years in children. The British Society for Rheumatology (BSR) has published a new, first of its kind, guideline on the management of paediatric, adolescent, and adult patients with IIM, which appear in the May edition of Rheumatology

Speaking during the meeting, guideline co-author Prof Hector Chinoy, Professor of Rheumatology and Neuromuscular disease at Manchester University, UK, said “there is a big unmet need in myositis. It’s rare, so it can creep up on doctors without them recognising the phenotype.”

Speaking to Update, he said: “We’re trying to put across a standardisation of the way we treat this condition, myositis, so that there’s conformity amongst physicians

treating adults and children with this difficult disease.

“We’re providing some guidance around certain ancillary aspects that we may otherwise not pay too much attention to: Paying attention to a patient’s bone health, their mental health and wellbeing, [and] recognising how their ethnicity may affect the way we treat the patients as well.”

As per the guidelines, ILD should be screened for in high-risk patients, Prof Chinoy told the Meeting. These would be patients with anti-synthetase syndrome, MDA-5 positive dermatomyositis, and scleroderma. A range of medications are recommended for this in the guidelines. He also recommended speaking to a respiratory physician or an ILD specialist.

“Risk of cancer should be considered in all adult patients,” he added. Screening should be “particularly considered” in high-risk patients: Those with dermatomyositis, moderate to severe dysphagia (difficulty swallowing), and being over the age of 40 at onset of IIM. Traits of patients at lowand medium-risk are also included in the guidelines.

Juvenile onset of IMM should be treated

by paediatric-based specialists, according to the guidelines. “Because there are differences between the two diseases,” said Prof Chinoy. “So children are more prone to get subcutaneous calcification, they don’t get so much disease damage, there’s not an association with cancer.”

For skeletal muscle inflammation in adults, the guidelines recommend methotrexate, cyclosporine, tacrolimus, and mycophenolate mofetil. For children, methotrexate and mycophenolate mofetil can be prescribed. In the case of no response to treatment, IV immunoglobin, rituximab, cyclophosphamide, and abatacept are recommended.

Other considerations such as common comorbidities related to ethnicities, testing for antibodies, bone health assessment/ fracture risk, quality-of-life, and mental health are also highlighted in the guidelines.

“It’s probably pretty obvious what you’re going to do, but we’ve written it down for you now,” Prof Chinoy concluded.

The BSR guideline can be accessed at: www.rheumatology.org.uk/practice-quality/ guidelines.

Volume 8 | Issue 6 | 2022 | Rheumatology and Pain 6

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The intersection between rheumatology and respiratory medicine highlighted at ISR meeting

Working with multidisciplinary teams (MDTs) and keeping an open mind is important in managing both interstitial lung diseases (ILD) and rheumatic diseases, the ISR 2022 Spring Meeting heard.

Dr Kate O’Reilly, Consultant in Respiratory and Acute Medicine at the Mater Misericordiae University Hospital, Dublin, told Update that working with MDTs helps to break a fixed view of a patient or disease that a physician may have.

“It’s really the multidisciplinary team: Respiratory physicians, rheumatologists, radiologists working together and being willing to reanalyse the data and change direction, rather than having a fixed view that this is the diagnosis and this is our strategy,” she said.

“In some diseases, there are very clear diagnostic criteria. But with [ILD], it’s much woollier really,” she said in her presentation.

In her talk on ILD in rheumatic diseases, Dr O’Reilly told ISR delegates that MDTs

and discussion “is key” and even “critical” in complex patients. While there may be criteria available to diagnose a rheumatic disease, “[criteria] can change in flux and there could be differences of opinion. So, it’s really important to have a team together and a team that are used to looking at these patients.”

ILDs are a complex and large category of lung diseases, the main ones being: Those with a known aetiology such as drug use or occupational exposures; granulomatous or inflammatory ILDs such as hypersensitivity pneumonia; or idiopathic interstitial pneumonias such as idiopathic pulmonary fibrosis. They can also be frequently associated with rheumatological diseases.

“Just because we’re sitting at MDT talking about somebody who’s got an ILD, it doesn’t mean that even if they don’t have a rheumatologic diagnosis now, that they won’t have one,” said Dr O’Reilly.

“You all manage lots of patients with rheumatoid arthritis,” she told the

audience. “And those patients get an awful lot of airways disease.”

Pulmonary functional tests (PFTs) can assess for progressive disease, including: Spirometry, looking for obstructive or restrictive patterns; assessing lung volume and capacity; and diffusion capacity, looking at the integrity of the alveolarcapillary membrane.

“PFTs are extremely useful in evaluating a patient with dyspnoea,” Dr O’Reilly said. “They’re very helpful in following… that patient over time, but they’re not sensitive when picking up early disease. Overall… they should be done at the time of diagnosis.”

Radiology is also “a key aspect” in managing these patients with rheumatological diseases, she noted.

Dr O’Reilly also spoke about anti-fibrotic medications, such as nintedanib and pirfenidone, citing the latest studies. “I think probably in time, you’ll see more of them in rheumatology,” she said.

The music and performance of rheumatology

The intersection between rheumatology and music was covered at the ISR 2022 Spring Meeting by Dr Ronan Kavanagh, Consultant Rheumatologist at the Galway Clinic and Bon Secours Hospital, Galway, a leading figure in the musical and arts arena.

Drawing on his own experiences with music, and his treatment of musicians in his clinic, Dr Kavanagh focused on what rheumatologists can learn from musicians in expanding their view, as opposed to “what rheumatologists can do for musicians…”.

Invoking the work of past musical geniuses, Dr Kavanagh spoke about finding “an authentic voice” and identity in working

Dr Ronan Kavanagh

in rheumatology, looking after one’s own health as a physician, and knowing when to “leave gaps” and listen to the patient.

“Medicine, as we practice it, as we think about it, is deeply informed by science, but it’s not contained by science,” Dr Kavanagh told Update. “So if you look at medicine through the lens of science, and that’s all you do for your whole career, you can see how you might miss some of the magic.

“So looking at medicine through the lens of musicianship and looking at medicine through the lens of it being a performance, just by looking at it with fresh eyes… certainly for me, brings it alive.”

Volume 8 | Issue 6 | 2022 | Rheumatology and Pain 8

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 9/L, an absolute neutrophil count (ANC) less than 1x10 9 /L or with haemoglobin less than 9 g/dL. It is recommended not to initiate dosing in paediatric patients with an absolute neutrophil count (ANC) less than 1.2 x 10 /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 moderate to severe RA who responded inadequately to, or who are intolerant to one or more DMARDs.4 bPublished as of October 2020. Clinical trial program includes patients with RA who received ≥1 XELJANZ dose across the completed 2 phase 1, 10 phase 2, 6 phase 3, 1 phase 3b/4 index studies, and 2 open-label LTE studies. 2 RA=rheumatoid arthritis; JAKi=Janus kinase inhibitor; DMARDs=disease-modifying antirheumatic drugs; IR=inadequate responder; ACR=American College of Rheumatology; MTX=methotrexate. Xeljanz in combination with MTX is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs. Xeljanz given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate. In patients over 65 years of age, patients who are current or past smokers, patients with other cardiovascular risk factors, and patients with other malignancy risk factors, XELJANZ should only be used if no suitable treatment alternatives are available. WITH RAPID RESPONSE AND THE LARGEST SEE THE DIFFERENCE XELJANZ® PP-XEL-IRL-0722 © 2022 Pfizer Inc. All rights reserved. April 2022 In ORAL Solo, XELJANZ delivered rapid reduction in the signs and symptoms of RA as early as week 2, with significant reductions at month 3 vs placebo (P<0.001).1 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

1-3,a,b

LARGEST DATASET OF ANY JAKi IN RA, CAN MAKE FROM THE START

Starting as early as 2 weeks, DMARD-IR patients with RA who received XELJANZ monotherapy demonstrated a greater ACR20 response (secondary endpoint) vs placebo (30% vs 12%; P<0.001) in a phase 3, randomised, double-blind, placebo-controlled study (N=610)1,3

At month 3, significantly more DMARD-IR patients with RA who received XELJANZ monotherapy achieved ACR20 response (primary endpoint) vs placebo (59.8% vs 26.7%; P<0.001) in a phase 3, randomised, double-blind, placebo-controlled study (N=610)1

Proven in 6 phase

trials, with >7000 patients evaluated across treatment arms in the clinical trial program2,b

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 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.

References: 1. Fleischmann R, Kremer J, Cush J, et al; for the ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl Med.2012;367(6):495-507. 2. Cohen SB, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. RMD Open. 2020;6(3):1-15. 3. Pfizer data on file. 4. XELJANZ Summary of Product Characteristics.

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

EULAR 2022 round-up

Priscilla Lynch presents a round-up of some of the most topical research presented at this year’s European Alliance of Associations for Rheumatology (EULAR) Congress, which took place in Copenhagen from June 1-4

The importance of treatment goals in PSA

Results presented at the 2022 EULAR Congress show that early achievement of minimal disease activity (MDA) in psoriatic arthritis (PsA) is associated with long-term improvements in quality-of-life. Although this highlights the importance of setting and achieving goals early on in the disease, further multinational data released from the UPLIFT study suggest the majority of PsA patients are not aligned with their healthcare provider on the topic of treatment goals. This emphasises the need to improve communication around treatment goals in order to optimise patient outcomes.

MDA is a treatment target used in PsA that takes both clinical manifestations and the patient perspective into account. Previous studies have shown that achieving MDA in the first year after diagnosis is associated with better quality-of-life. However, data

about the long-term impact of achieving MDA within the first year have been lacking. Now, new information presented at the 2022 EULAR Congress shows that PsA patients with sustained MDA have quality-of-life comparable to the general population after one, two, and three years of follow-up. However, those who did not achieve MDA in the first year after diagnosis tended to have lower quality-of-life compared to those with sustained MDA and these differences persisted over time.

Overall, the research presented by Dr Selinde Snoeck Henkemans concluded that failure to achieve MDA in the first year after PsA diagnosis is associated with worse quality-oflife outcomes that persist even despite more intensified treatment.

These insights into the significance of MDA

were complemented by another study released at the Congress, looking at findings from UPLIFT – a multinational survey among adults with a diagnosis of PsA and/or psoriasis, as well as treating rheumatologists and dermatologists. The study, presented by Prof Pascal Richette, found that rheumatologists rated disease remission or low disease activity (LDA) as the most important goals, while patients were focused on decreasing joint pain. Patients and their rheumatologists generally agreed on the top factors contributing to disease severity, treatment goals, and attributes of ideal PsA therapy. However, the majority of patients did not feel aligned with their healthcare provider on current treatment goals. These findings suggest that development of methods to discuss treatment goals and achieve alignment in perceptions are important to improving patient outcomes.

Improving treatment for lupus nephritis: New data released at EULAR Congress

Lupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE), and one of the most severe organ manifestations, affecting up to 40 per cent of patients. It constitutes an important cause of morbidity and death among patients with SLE, and leads to end-stage kidney disease (ESKD) in 17-to-33 per cent of patients after 10 years. The renal injury is the result of an immune-mediated process which involves leukocytes, immune complexes, complement, and cytokines.

Data shared at the 2022 EULAR Congress include the development of chronic kidney disease (CKD), a post-hoc analysis of voclosporin (a novel calcineurin inhibitor approved in the US for the treatment of adults with LN) data based on updated response criteria, and an integrated multilevel omics analysis that reveals pathways of potential interest for future drug targets.

Dr Konstantinos Tselios presented work

on the impact of time to remission and flares on the development of advanced CKD in LN. Using data from the Toronto Lupus Clinic database, the group showed that 15.8 per cent developed advanced CKD after 9.5 years. At baseline, these patients had a higher SLICC/Damage Index, lower estimated glomerular filtration rate, higher prevalence of hypertension, proliferative nephritis, and were more often treated with ACE inhibitors or angiotensin receptor blockers.

12 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

Importantly, complete remission within the first year from LN diagnosis strongly protected against advanced CKD. However, experiencing just one flare was associated with 2.7-fold increased risk for advanced CKD. Longer time on immunosuppressives after remission was associated with decreased risk for advanced CKD. These findings emphasise the importance of early remission as well as flare prevention with prolonged immunosuppression to maximise renal survival in LN. Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST. The optimal duration of maintenance IST for proliferative LN is unknown.

Prof Noemie Jourde-Chiche shared results of the WIN-Lupus trial, which tested whether maintenance IST discontinuation after two-to-three years in patients in remission after a proliferative LN is noninferior to IST continuation for two more years. In the per-protocol population, a relapse occurred in 10.4 per cent with IST continuation, and 25 per cent with IST discontinuation. Non-inferiority was not

demonstrated for relapse rate. Time to renal relapse did not differ between groups, and severe SLE flares (renal or extra-renal) were less frequent in patients with IST continuation compared to discontinuation, but adverse events did not differ between groups.

An abstract on integrated multilevel omics analysis revealed a set of enriched pathways of potential interest for future drug investigation in LN, with implications for proteasome inhibition. Dr Ioannis Parodis and colleagues analysed differentially expressed genes (DEGs), pathways and their druggability via the Drug Gene Interaction database (DGIdb) in 41 patients with active LN versus healthy controls. In total, 6,869 significant and validated DEGs were identified in active LN. These genes could be targeted by 203 different drugs, with the proteasome inhibitor bortezomib interfering with cathepsin B (CTSB) regulation and cyclophosphamide interfering with the regulation of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) being of particular interest.

In 2020 EULAR and the European Renal Association (ERA) published updated treatment recommendations for LN. The outline targeted reductions in proteinuria over the course of the first year of therapeutic intervention. Dr Hans-Joachim Anders reported on a post-hoc analysis of pooled voclosporin data from the AURALV and AURORA-1 studies based on these updated response criteria.

Voclosporin was approved in 2021 in the US for the treatment of adult patients with active LN in combination with background immunotherapy. Within the first three months of treatment, 78.4 per cent of patients on voclosporin and 62.4 per cent in the control group achieved ≥25 per cent reduction in urine protein creatinine ratio (UPCR). After 12 months, 52.6 per cent and 33.1 per cent of those receiving voclosporin and control, respectively, had achieved UPCR ≤0.7mg/mg. The results suggest that addition of voclosporin to a background regimen of mycophenolate mofetil and low-dose steroids in patients with LN significantly increased the likelihood of achieving the UPCR targets of therapy recommended by EULAR/ERA.

Addressing pain in rheumatic disease: Opioids and other management strategies

Pain is an important consideration for people with rheumatic and musculoskeletal diseases (RMDs), which can restrict function and limit daily activities. Indeed, low back pain has been the leading cause of disability worldwide for the past 30 years. Opioid prescribing has contributed to a North American epidemic, with increasing trends in several European countries. RMDs are one of the most common indications for prescribed opioids, but there is being little evidence on their benefit. Several abstracts presented at the 2022 EULAR Congress aimed to address this knowledge gap, and develop other pain relief strategies to reduce this chronic health burden.

Patients with RMDs often suffer from

recurrent pain, restricted function and reduction of daily activities. The current standard of intra-articular therapy is the injection of steroids, which can increase risk of infection, cartilage degeneration, and other well-known systemic side-effects. Dr Hildrun Haibel and colleagues investigated a novel approach focused on the activation of peripheral opioid receptors, using small, systemically inactive doses of morphine.

Adult patients with chronic knee arthritis and a high level of pain at baseline received a single dose of either morphine, steroid, or placebo – all delivered via intra-articular injection. The results showed that a single dose of 3mg intra-articular morphine did not lead to significant pain improvements in comparison to placebo, and was inferior

to steroid at day seven. These data do not support the use of intra-articular morphine for pain reduction in patients with chronic arthritis.

In another abstract at the Congress, Dr Joyce (Yun-Ting) Huang presented UK opioid prescribing trends in new users with one of six RMDs: Rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis, systemic lupus erythematosus, osteoarthritis, or fibromyalgia. The results show an increase in new opioid users among people with RA, PsA and fibromyalgia since 2006. However, a slight decrease in the trends of new opioid users among most RMDs after 2018 may reflect an increasing awareness of the opioid

13 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

epidemic. The high proportions of long-term opioid users in RA and fibromyalgia patients highlights the importance of exploring the safety of long-term opioid use and effective pain interventions for patients with RMDs.

In 2019, low back pain was responsible for 64 million years lived with disability (YLDs). Dr Jacek Kopec shared findings

from a microsimulation model looking at the impact of three strategies for reducing this burden: Weight loss, ergonomic interventions, and an exercise programme. The results show that a one unit reduction in body mass index (BMI) per year among overweight and obese individuals would be approximately equivalent in terms of disability reduction to an effective ergonomic

intervention in 35 per cent of at-risk workers, and an exercise intervention in 27 per cent of eligible patients with back problems over the same period. This is the first populationbased microsimulation study to compare currently available preventive strategies for low back pain in terms of YLDs averted, and to provide measures of equivalence between these strategies.

New insights into treatment effectiveness in people with axial spondyloarthritis

New evidence presented at the 2022 EULAR Congress reveals sex differences in physiology, disease presentation, and response to treatment in people with axial spondyloarthritis (axSpA), as well as the impact of non-steroidal anti-inflammatory drugs (NSAIDs) in people with radiographic disease.

Many different agents are available to treat people with axSpA, but they do not always work for everybody. Previously, pooled data from randomised controlled trials have demonstrated reduced treatment efficacy of a tumour necrosis factor inhibitor (TNFi) in females compared to males with ankylosing spondylitis.

Dr Pasoon Hellamand and colleagues sought

to validate prior studies using data from a large multinational cohort based on real-life clinical practice. In total, 6,451 axSpA patients were assessed for treatment response. Analysis of the results showed that the probability for females to have a clinically important improvement was 15 per cent lower compared to males. In addition, TNFi retention rates were significantly lower in females. Recognising these sex differences is relevant for customised patient care, and may improve patient education.

Another group working on axSpA looked at whether treatment with NSAIDs is associated with retardation of radiographic spinal progression. To date there have been conflicting reports: Previous analysis of GESPIC – the GErman SPondyloarthritis

New data on pregnancy outcomes in women with rheumatic disease

An increased risk of adverse pregnancy and neonatal outcomes has been reported for pregnancies in women with several rheumatic and systemic autoimmune diseases including RA, PsA, and SLE. New data presented at the 2022 EULAR Congress show that foetal morbidity and severe maternal morbidity occur at a higher rate in women with SLE compared to those without. An increased risk of adverse pregnancy outcomes was also

reported for women with spondyloarthritis (SpA), and shown to be associated with steroid use in women with RA. Taken together, this range of findings will help inform physicians in their management of patients with RMDs during pregnancy and planning.

At the EULAR 2022 Congress, Dr Bella Mehta presented findings from a retrospective study in over 50,000 women

Inception Cohort – showed that higher NSAID intake may retard new bone formation in radiographic axSpA. However, it remained unclear whether cyclooxygenase-2 selective inhibitors (COX2i) might have a stronger effect than non-selective ones and if the effect could also be observed in non-radiographic disease.

Dr Murat Torgutalp et al looked at 243 patients with early axSpA from GESPIC to work out the association between NSAID intake and radiographic spinal progression over two years. Overall, the results showed that higher NSAID intake is associated with lower radiographic spinal progression, particularly in patients with radiographic axSpA. COX2i might possess a stronger inhibitory effect on radiographic progression as compared to nonselective NSAIDs.

with SLE and delivery-related hospital admissions. The group’s findings show patients with SLE had a higher risk of foetal morbidity than women without SLE. This included higher risk of intrauterine growth restriction and preterm delivery. SLE patients also faced a greater risk of blood transfusion, puerperal cerebrovascular disorders, acute renal failure, eclampsia or disseminated intravascular coagulation, cardiovascular and peripheral vascular

14 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

AMGEVITA® AND ME

HOW AND WHEN IS IT GIVEN?

AMGEVITA® AND ME

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), diagram 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.

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

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

Product Characteristics (SmPC) at www.medicines.ie.

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 parent/carer can do this for you. Usually, the given every 2 weeks, but your change this to best suit what you.

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.

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

References:

Adult

• Rheumatoid arthritis

• Ankylosing spondylitis (AS)

• Axial spondyloarthritis without radiographic evidence of AS

• Psoriatic arthritis

to follow the advice of your team and ask to speak to them not feeling well.

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)

RIGHT A B C

• Crohn’s disease

• Ulcerative colitis

• Psoriasis

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

• Hidradenitis suppurativa

• Uveitis

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.

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 your AMGEVITA®, please read the

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disorders, and general medical issues than those without SLE. These important new insights will help inform the management of pregnancy in women with SLE.

In SpA, findings have not been uniform, with some studies reporting increased pregnancy risks while others have failed to identify any significant differences between women with and without SpA. Matilda Morin’s abstract shared findings from a nationwide register-based study of singleton births between April 2007 and December 2019 in women diagnosed with ankylosing spondylitis (AS) or undifferentiated SpA. Overall, women with SpA were found to be at increased risk of several adverse outcomes. In particular, there was an increased risk of gestational diabetes, elective and emergency Caesarean delivery, and preterm birth

including spontaneous preterm birth. The risk estimate for pre-eclampsia was also increased, but failed to reach significance. Infants born to mothers with SpA were not more likely to be born small for gestational age (SGA), but there was a slightly increased risk estimate of infection during their first year of life. The authors conclude that, while most pregnancies in women with SpA are uneventful, there is an increased risk for a number of adverse pregnancy outcomes.

The impact of RA and its treatment on pregnancy was also presented, in an abstract from Sabrina Hamroun and colleagues. A favourable pregnancy outcome was found in 56.5 per cent of the 92 women in the cohort. The most common unfavourable outcomes were premature birth and SGA, observed in 16.9 per cent and 20.5 per cent, respectively.

The group also ran a multivariate model, which found an association between unfavourable pregnancy outcomes and first-time deliveries, age, and exposure to corticosteroids during pregnancy.

The issue of medication use during pregnancy was also covered by Dr Dina Zucchi and colleagues, in their work on adherence to medication during pregnancy in women with systemic autoimmune disease. Overall, pregnant patients had good adherence to prescribed medication –although 25 per cent did not take therapies adequately despite close monitoring in a dedicated clinic for high-risk pregnancies and having received adequate pregnancy counselling. The findings suggest that anxiety may be a key determinant of low adherence, both in pregnant and non-pregnant women.

Osteoarthritis represents risk for variety of comorbidities across different organ systems

Three abstracts presented at the 2022 EULAR Congress shed new light on risk of a wide range of comorbidities following osteoarthritis diagnosis, and the impact of body weight on structural defects and the need for knee replacement surgery. Results suggest prevention of overweight and obesity from young adulthood could have a major impact on the burden of knee osteoarthritis, and associated healthcare costs.

Previous studies have shown that patients with osteoarthritis have a higher risk of developing comorbidities; however, much research has focused on only a few conditions, or did not consider the chronology of disease onset relative to osteoarthritis. Dr Anne Kamps and colleagues set out to determine the risk of comorbidity following knee or hip osteoarthritis using electronic health records from patients in the Netherlands.

The study population consisted of over 1.8 million patients, and examined 58 comorbidities. Overall, there was increased

risk of being diagnosed with 11 of these comorbidities after a diagnosis of knee osteoarthritis. The comorbidities were extremely varied, ranging from other rheumatic and musculoskeletal complaints such as gout, back, and neck pain, to anaemia, cataracts, chronic kidney disease, coronary heart disease, hearing loss, obesity, sleeping disorders, and thromboembolic disease.

Following the original abstract submission, Dr Kamps added an update that for 30 of the 58 studied comorbidities, exposure to knee OA showed a hazard ratio (HR) statistically significantly larger than one. Largest positive associations (HR with (99.9 per cent CIs)) were found for obesity 2.55 (2.29-2.84), fibromyalgia 2.06 (1.53-2.77), polymyalgia

1.72 (1.38-2.14), drug abuse 1.40 (1.21-1.94), and RA 1.52 (1.28-1.81). For COPD 0.80 (0.70-0.91) and tobacco abuse 0.86 (0.75-0.99) there was a statistically significant negative association (HR<1) with exposure to knee OA. All other comorbidities did not show an association with previous exposure to knee OA. For 26 comorbidities, exposure

to hip OA showed a statistically significant HR larger than one. The largest positive associations were found for polymyalgia rheumatica 1.81 (1.41-2.32), fibromyalgia

1.70 (1.10-2.63), spinal disc herniation 1.64 (1.49-1.80), thromboembolic disease 1.47 (1.28-1.70) and alcohol abuse 1.44 (1.111.88). There were no negatively associated comorbidities as for all other comorbidities the HRs of hip OA were non-significant. For people with osteoarthritis in the hip, seven comorbidities showed a statistically significant link. As for knee osteoarthritis, this included anaemia and sleeping disorders. The other linked diseases were fibromyalgia and spinal disc herniation, as well as atrial fibrillation, peripheral vascular disease, and solid malignancies. These findings suggest that the management of osteoarthritis should consider the risk of other long-termconditions, but further research on causality is needed.

In another presentation, Dr Sultana Monira Hussain showed trajectories of body mass index (BMI) from early adulthood to late

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midlife, and their correlation with the incidence of total knee arthroplasty (TKA) for osteoarthritis. The study examined almost 25,000 participants from the Melbourne Collaborative Cohort Study. Using group-based trajectory modelling, six distinct trajectories of BMI were identified. Over a period of 12.4 years, 5.4 per cent of participants had TKA. When compared to the trajectory of people with lower normal to normal BMI, the HRs for TKA increased in all other BMI trajectories. Most of the burden of TKA and associated healthcare costs occurred in those who had a normal BMI in young adulthood and transitioned to being overweight or obese in midlife. The authors estimated that 28.4 per cent of TKA

would be reduced if individuals followed the trajectory that was one lower – representing a saving to the national health system of AUD $373 million. This would require a weight difference of 6-8kg and mean that at a population level, a significant reduction in TKA and associated healthcare costs could be achieved by preventing this level of weight gain from young adulthood to midlife.

Body weight was also addressed in a study from Zubeyir Salis and colleagues. Scores from radiographic analyses of knees at baseline and at four-to-five years’ follow-up were obtained from three independent data sets in the Netherlands and the US.

Results showed that change in BMI was positively associated with both the incidence and progression of knee osteoarthritis. Change in BMI was also positively associated with narrowing of joint space on the medial, but not the lateral, side of the knee. Osteophytes of the tibial and femoral surfaces were also seen on the medial, but not the lateral, side of the knee. The group concluded that each one-unit reduction in BMI is associated with a 5-to-8 per cent decrease in the odds of the incidence and progression of the structural defects of knee osteoarthritis. This supports the idea that weight loss is of benefit in people with and at-risk of osteoarthritis.

Air pollution a key environmental exposure driving inflammatory arthritis development

Mounting evidence has shown that environmental exposures are linked to the development of inflammatory arthritis, with air pollution associated with disruption at a molecular level in the immune system, while pollutants can also have an impact on bone health. Data presented at the 2022 EULAR Congress show that chronic exposures to air pollutants are associated with incremental increases in the risk of having an autoimmune disease. Meanwhile, a second research group demonstrated that cleaning activities are underestimated sources of silica exposure in women with RA compared to the general population, and may contribute to disease development.

Two abstracts presented by Dr Giovanni Adami at the 2022 EULAR Congress looked at the issue of environmental exposures and their role in disease development. Data from over 80,000 people in a retrospective observational study in Italy found a positive association between particulate matter (PM) levels measured at local air-quality stations and the risk of autoimmune diseases. In fact, every 10μg/m3 increase in PM10 concentration was associated with an incremental 7 per cent risk of having autoimmune disease. Exposure to

PM10 above 30μg/m3 and PM2.5 above 20μg/ m3 was associated with 12 per cent and 13 per cent higher risks of autoimmune disease, respectively. When broken down by individual diseases, exposure to PM10 was associated with an increased risk of RA, but no other autoimmune diseases, whereas exposure to high levels of PM2.5 was associated with an increased risk of RA and inflammatory bowel disease. Overall, chronic exposure to particulate air pollution above the threshold for human protection was associated with a 10 per cent higher risk of developing immunemediated diseases.

The same group looked at the association between long-term exposure to PM and osteoporosis in almost 60,000 women at high risk of fracture. The results showed that exposure to PM2.5 was negatively associated with low bone mass at the top of the thigh bone and lumbar spine. Chronic exposure above 25μg/m³ for PM2.5 and 30μg/m³ for PM10 was associated with a 16 per cent and 15 per cent higher risk of having osteoporotic bone mass scores at any site. The researchers concluded that long-term exposure to air pollution was associated with higher risk of osteoporosis.

Previous studies have shown that breathing in crystalline silica is associated with the development of RA – but this research has historically focused on professional exposures and on male workers. Since substantial amounts of this pollutant are present in other environments, Dr Johanna Sigaux and colleagues set out to identify the main sources of exposure to crystalline silica in a group of RA patients regardless of their professional activity, and to assess the association between silica exposure and disease features. The results showed that in women with RA, the main sources of crystalline silica exposure were cleaning activities. For example, handling dusty clothes or talcum powder. Women involved in these activities had higher exposure compared to people in the general population. Across the whole series of RA patients, high silica exposure was independently associated with lung abnormalities such as interstitial lung disease and mediastinal lymphadenopathy. The study findings suggest that cleaning activities are underestimated sources of crystalline silica exposure that are overrepresented in women with RA compared to the general population, and may contribute to the pathogenesis of the disease.

17 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

Rheumatoid arthritis: treat-to-target approach

AUTHOR: Louise Murphy, Advanced Nurse Practitioner in Rheumatology, Cork University Hospital

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of unknown aetiology. It develops when a genetically susceptible person is exposed to an agent that triggers an inflammatory event.

Symptoms include symmetrical polyarticular arthralgia and arthritis of the metacarpal joints in the hands, wrists, elbows, shoulders, knees and metatarsal joints of the feet. Joints can be hot to touch and have a boggy feel on palpation. Patients often report early morning stiffness (EMS) in affected joints which can last for hours. Some patients report flu-like symptoms and weight loss. Fatigue is also a major issue for some individuals, with 40-to-50 per cent of patients reporting it as ‘severe’ in clinical trials.1,2,3 Symptoms typically improve after exercise and are exacerbated by rest. Extra articular symptoms vary depending on the organ affected and include subcutaneous nodules, Sjögren’s syndrome, pulmonary fibrosis, and scleritis.

Complications of RA include anaemia of chronic disease, cardiovascular disease, and osteoporosis.

RA may present at any age, affects approximately 1 per cent of the population,4,5 and is two-to-four times more common in women than men.6

Diagnosis

Early diagnosis and treatment of RA is associated with improved patient outcomes.7 Over time, untreated or poorly controlled disease causes inflammation that destroys cartilage and bone, resulting in irreversible bone damage called erosions. Erosive disease results in joint destruction and

deformity, which impacts hugely on an individual’s ability to carry out everyday tasks. Joint destruction leads to functional damage of the surrounding structures including tendons and articular cartilage, which in turn results in loss of function and range of movement in the joints. Impairment of functional ability can have a profound negative effect on an individual’s psychological mind-set, causing feelings of low self-esteem, depression, and anxiety. Impaired functional ability coupled with joint deformities can impact on a person’s ability to maintain social relationships and personal roles within the family unit, which can further impact negatively on a person’s mental health.

The American College of Rheumatology (ACR)/EULAR RA classification criteria were published in 2010 to aid RA diagnosis, but were designed primarily for the purpose of clinical trial use, to allow stratification of subjects into RA and non RA groups.8 Although the classification criteria provide a solid basis for RA diagnosis, it is the rheumatologist’s responsibility to know when these apply in clinical practice. Sometimes an RA patient can present with variable non-specific symptoms, especially in early disease, and as a result might not meet the classification criteria at that time point. Therefore, diagnosis of RA in the clinical setting is made through a full clinical assessment and detailed medical history documenting the following elements:

X Detailed history of symptoms and patterns of joint pain/stiffness/swelling/fatigue.

X Response to medications so far – most GPs will have tried non-steroidal antiinflammatory drug (NSAID) treatment,

which most RA patients will respond to. Some will have had symptom control from a course of corticosteroids.

X Joint appearance – noting colour/swelling/ deformities/nodules.

X Joint palpation – noting tenderness and any boggy feel to the joint margins.

X Range of movement exam – observing the patient while they actively perform joint movement exercises to identify flexion/ extension deformities, muscle wasting or functional disability.

X Family history – enquiring about psoriasis/ inflammatory bowel disease/uveitis/ connective tissue diseases.

X A disease assessment using a validated composite tool, for example, the Disease Activity Score (DAS), which combines a tender joint count, swollen joint count, a global health score, and an inflammatory marker such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) to give a numerical score of disease activity (see Figure 1).

The role of the rheumatology nurse in early RA Gaining trust

The role of the rheumatology nurse cannot be underestimated at this pivotal time point on the patient’s journey. Unfortunately, due to mounting waiting list times some patients wait for 24 months or more to see the rheumatology team. Some are frightened and most are in a substantial amount of pain. They may have watched a grandparent suffering brutal bouts of pain and immobility from uncontrolled RA; confined to wheelchairs with substantial joint deformities. In this case, some patients fear that this will be their disease trajectory too, so it is necessary to explore their fears and ask about any knowledge or prior

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experience they may have of the disease to dispel any anxiety. Once they are reassured that over the past 30 years the management of RA has improved dramatically and care of the RA patient has been revolutionised due to advancements in treatments and novel medications, they begin to engage with the rheumatology nurse in a more trusting way.

Education

Patient education is one of the primary roles of the rheumatology nurse at any stage of the disease course, but is especially important at the time of diagnosis. Patients require education specific to their needs and wants. The nurse should identify these needs and offer tailored information to the patient, either on a one-to-one basis or with their family/carers present, depending on the patient preference.9,10 One of the goals of patient education is to ensure the individual has all the information they require and has an understanding of their disease sufficient for them to make informed decisions about their health regarding RA treatment. Sometimes the patient or family member may need time to adjust to their diagnosis or may be in denial. A healthy therapeutic relationship between the patient and nurse will aid this adjustment and provide educational opportunities when the patient accepts their diagnosis and becomes responsive to information.

When meeting a patient at their time of diagnosis it is useful to begin with differentiating between RA and osteoarthritis (OA). Many patients confuse both and are more familiar with arthritis in terms of the mechanical form. Therefore, to help patients and family members understand RA as a separate disease entity, it is always useful to begin with the basic pathophysiology of RA and highlight that although the actual ‘trigger’ is unknown, certain environmental elements such as exposure to infections, smoking, and the gut microbiome can influence the triggering mechanism. Once the autoimmune process has been turned on, ‘drivers’ of inflammation in the form of signalling pathways such as tumour necrosis factor (TNF) alpha and cells such as T- and B-cells upregulate immune dysfunction and

activate inflammatory destructive pathways in the joint. Once patients grasp the difference between the inflammatory nature of RA and the mechanical nature of OA they begin to understand their symptoms better and the rationale for certain classes of medications to control their inflammatory disease.

Some patients have a positive serology, meaning they have rheumatoid factor (RF) or anti cyclic citrullinated peptide (anti CCP) autoantibodies. Anti CCP has greater specificity (and comparable sensitivity)

situation the rheumatology nurse should promote self-coping skills and independence, while challenging any inaccurate RA health beliefs. Patients should be taught self-management techniques for symptom control at home, such as joint protection, non-pharmaceutical pain control, relaxation techniques and good sleep hygiene to foster independence. Improving patients’ selfefficacy and confidence in their ability to control issues surrounding their disease will help with self-esteem and patient-reported outcomes.

than RF so is the preferred test in most rheumatology clinics. Positive serology alone is not diagnostic without clinical signs or symptoms. RF autoantibodies can be found in 10 per cent of healthy individuals11 and can also be found in patients with lupus, Sjögren’s, and mixed connective tissue diseases.12 Patients who fit the RA phenotype, but have no positive serology can still be diagnosed as a ‘sero negative’ RA patient.

Importance of a biopsychosocial approach to patient care

A biopsychosocial approach to managing RA takes into account the patient’s perspective on their own physical, psychological, social, and emotional health and wellbeing. It recognises the health beliefs of the patient and how these beliefs can have a positive or negative impact on their ability to self-care. Other factors that influence a patient’s ability to self-manage include attitudes towards the disease, prior experiences, level of anxiety, emotions, personal relationships and social networks. The rheumatology nurse should be cognisant that negative health behaviours such as fear-avoidance, procrastination, and catastrophising also impact on the patient’s ability to manage their disease. In this

Managing expectations

Prognosis and expectations of care should also be discussed early on in the disease pathway and goals of treatment should be identified together as part of a structured programme noting any psychosocial barriers to recovery. The general course and nature of RA should be discussed with the patient and their family, highlighting the importance of medication regimes with non-pharmacological interventions to help achieve disease control and improve qualityof-life. Newly-diagnosed patients often enquire about a ‘cure’ or suggest the disease might ‘burn itself out’. In this situation the nurse should advise that there is no cure for the disease, that medication-free remission is difficult to achieve for the majority of patients, and that if medications are abruptly stopped, two-out-of-three patients will flare within a year.13 A detailed discussion should be undertaken about the individual medications used and when they might need to dose escalate or add a drug in combination regimes, beginning with analgesia, NSAIDs, and when steroids might be required for symptom control. Once patients understand the rationale for these medications, then the discussion about disease-modifying anti rheumatic drugs (DMARDs) such

19 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

Rheumatology nurse-led treat-to-target clinics are instrumental in the achievement of best quality in clinical care for patients by adhering to evidence-based good clinical practice in rheumatology

as methotrexate can begin, highlighting the risks and benefits of treatments. A breakdown of the most common medications used in RA can be seen in Table 1. If the patient is not satisfied with the choice of medication, then the nurse must explore the barriers to treatment and if the patient makes an informed decision not to take certain medications, alternative treatment options should be explored.

Family planning

Fertility, sexuality, and family planning should be discussed and any queries regarding fertility issues relating to RA should be addressed, in particular the topic of conception and suitability of medications during pregnancy and while breastfeeding. If the patient is commencing a teratogenic medication such as methotrexate, contraception should be discussed and an appropriate method agreed to minimise risk of conception. Women are advised to discontinue methotrexate three months at least prior to conception. There is some evidence suggesting paternal low-dose methotrexate is safe, however, the strength of the evidence is low and research is limited in this area therefore some clinicians still advocate for men to cease taking the drug three months prior to conception also. Evidence suggests that the optimal time to conceive to maximise positive outcomes for both the mother and baby is when RA disease activity is quiescent.14 Furthermore, poorly-controlled RA reduces the chances of conceiving, therefore patients who express the desire to have a child must have careful pre-conception counselling about minimising disease activity.15 RA as a disease entity increases the risk of premature birth and pre-eclampsia, babies can have a lower birth weight than normal, and RA mothers often develop a postpartum flare six weeks after delivery.16

Support services

Adequate time should be given to the patient and family to discuss their anxieties, the psychological impact of the disease, and potential work-related issues. The rheumatology nurse will provide verbal and written information about support services and provide educational handouts for patients to take home. Arthritis Ireland is

a patient support organisation with regional branches situated around the country who offer support and guidance to patients with all forms of arthritis including RA. They offer group and online courses to patients such as ‘living well with arthritis’ and ‘breaking the pain cycle’, which are extremely helpful in the self-management of RA. Their website (www. arthritisireland.ie) provides up-to-date patient information material about RA. Leaflets about RA and arthritis in general are free to download at www.arthritisireland.ie/booklets.

Medications

Methotrexate is the gold standard of first-line treatment in RA and is often commenced at the first visit. It is administered on a weekly basis either in oral or subcutaneous form with folic acid (not to be taken on the same day) to reduce the risk of adverse effects. Methotrexate is administered in up to 70 per cent of RA patients.17 Regular safety blood monitoring is necessary to ensure tolerability and prevent toxicity, the frequency of which depends on the prescribing centre’s guidelines. Contraindications to methotrexate would include neutropaenia,

intravenously or subcutaneously. Efficacy of biological medications are improved when used in combination with methotrexate so they are often prescribed as dual therapy.

Biosimilar agents have come to market in the past number of years and are licensed for the treatment of RA. Biosimilars are also biological medications, but are engineered to be highly similar to a reference (or parent) drug with no clinically meaningful differences. Biosimilar agents of adalimumab, etanercept, infliximab, and rituximab are in use across Ireland currently.

The use of DMARDs, targeted DMARDs, and biologics are associated with an increased risk of infection; therefore patients must be advised to seek urgent medical advice and get guidance on their dosing regimen if they develop an active infection or viral illness while taking these medications.

liver disease, or use in women of childbearing age without contraception due to teratogenicity. On occasion if the patient has any contraindications to methotrexate or other DMARDs the clinician and patient may feel initiation of a targeted DMARD or biologic medication to be a safer option to gain disease control.

Biologic medications (or biological DMARDs) are genetically synthesised proteins derived from human or chimeric genes that target specific sites in the immune system to dampen down the autoimmune response. Biological drugs are administered

Nurse-led ‘treat-to-target’ approach Rheumatology teams often employ the ‘treat-to-target’ approach to RA management in early arthritis clinics. Treat-to-target is a set of recommendations to help optimise the care of RA patients in clinical practice.18 It is a structured programme, which aims for an achievable treatment goal (or target) of either remission or low disease activity through fast initiation and titration of DMARDs such as methotrexate while using steroid and non-steroidal anti-inflammatory medications to reach the agreed target as quickly as possible. The target should be defined pre-treatment through discussion and agreement between the nurse and patient. The patient’s functional disability is the most significant predictor of work disability.19 By adopting this model of care and defining a treatment target, short-term and long-term outcomes are improved for the patient, ie, better disease control and increased functional ability, which in turn improves work retention rates, decreasing long-term disability.

Treating patients to target necessitates regular review; up to six scheduled visits in the first year of diagnosis,20 to assess treatment efficacy and target goals. The

20 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

If the patient is commencing a teratogenic medication such as methotrexate, contraception should be discussed

For the treatment of active rheumatoid arthritis, severe recalcitrant disabling psoriasis & severe psoriatic arthritis in adult patients. Induction of remission in moderate steroid-dependent Crohn’s disease in adult patients, in combination with corticosteroids and for maintenance of remission, as monotherapy, in patients who have responded to methotrexate

THE METHOTREXATE AUTO-INJECTOR WITH THE PATIENT IN MIND

Nordimet (methotrexate) Solution for injection in pre-ﬁlled pen Please refer to the Summary of Product Characteristics (SmPC) for full prescribing information. Further information is available on request.

Nordimet (methotrexate) Solution for injection in pre-ﬁlled pen

Please refer to the Summary of Product Characteristics (SmPC) for full prescribing information. Further information is available on request.

Presentation: Pre-filled pen containing 7.5 mg (in 0.3 ml), 10 mg (in 0.4 ml), 12.5 mg (in 0.5 ml), 15 mg (in 0.6 ml), 17.5 mg (in 0.7 ml), 20 mg (in 0.8 ml), 22.5 mg (in 0.9 ml) and 25 mg (1.0 ml) methotrexate in solution for injection. Indications: Active rheumatoid arthritis in adult patients. Polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate. Severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients. Induction of remission in moderate steroid-dependent Crohn’s disease in adult patients, in combination with corticosteroids and for maintenance of remission, as monotherapy, in patients who have responded to methotrexate. Dosage and administration: Nordimet should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. Patients must be educated and trained in the proper injection technique when self-administering methotrexate. The first injection of Nordimet should be performed under direct medical supervision. Nordimet is injected once weekly, administered subcutaneously. Rheumatoid arthritis: Recommended initial dose is 7.5 mg of methotrexate once weekly. Depending on the individual activity of the disease & patient tolerability, the initial dose may be increased. A weekly dose of 25 mg should in general not be exceeded. Once the desired therapeutic result has been achieved, the dose should be reduced gradually to the lowest possible effective maintenance dose. Polyarthritic forms of severe, active juvenile idiopathic arthritis: The recommended dose is 10-15 mg/m² body surface area (BSA) per week. In therapy-refractory cases the weekly dose may be increased up to 20mg/m² BSA per week. Use in children < 3 years of age is not recommended. Psoriasis vulgaris and psoriatic arthritis: A test dose of 5 - 10 mg subcutaneously administered one week prior to

Presentation: Pre-filled pen containing 7.5 mg (in 0.3 ml), 10 mg (in 0.4 ml), 12.5 mg (in 0.5 ml), 15 mg (in 0.6 ml), 17.5 mg (in 0.7 ml), 20 mg (in 0.8 ml), 22.5 mg (in 0.9 ml) and 25 mg (1.0 ml) methotrexate in solution for injection. Indications: Active rheumatoid arthritis in adult patients. Polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate. Severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients. Induction of remission in moderate steroid-dependent Crohn’s disease in adult patients, in combination with corticosteroids and for maintenance of remission, as monotherapy, in patients who have responded to methotrexate. Dosage and administration: Nordimet should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. Patients must be educated and trained in the proper injection technique when self-administering methotrexate. The first injection of Nordimet should be performed under direct medical supervision. Nordimet is injected once weekly, administered subcutaneously. Rheumatoid arthritis: Recommended initial dose is 7.5 mg of methotrexate once weekly. Depending on the individual activity of the disease & patient tolerability, the dose may be increased. A weekly dose of 25 mg should in general not be exceeded. Once the desired therapeutic result has been achieved, the dose should be reduced gradually to the lowest possible effective maintenance dose. Polyarthritic forms of severe, active juvenile idiopathic arthritis: The recommended dose is 10-15 mg/m² body surface area (BSA) per week. In therapy-refractory cases the weekly dose may be increased up to 20mg/m² BSA per week. Use in children < 3 years of age is not recommended. Psoriasis vulgaris and psoriatic arthritis: A test dose of 5 - 10 mg subcutaneously administered one week prior to

initiation of therapy is recommended. Recommended initial dose 7.5 mg methotrexate once weekly. The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Once the desired therapeutic result has been achieved, dose should be reduced gradually to the lowest possible effective maintenance dose. In a few exceptional cases a higher dose than 25 mg might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate. Crohn’s disease (adult patients): 25 mg/week administered subcutaneously. Once patients have adequately responded to combination therapy, the corticosteroids should be tapered. Maintenance treatment: 15 mg/week administered subcutaneously, as monotherapy, if the patient has entered remission. Renal impairment, hepatic impairment or elderly patients: Please refer to SmPC. Note: When switching from oral to parenteral use, a reduction in the dose may be required, due to the variable bioavailability of methotrexate after oral administration. Contraindications: Hypersensitivity to methotrexate or to any of the excipients. Severe hepatic impairment, if serum bilirubin is > 5 mg/dl (85.5 µmol/l). Alcohol abuse. Severe renal impairment (creatinine clearance < 30 ml/min). Pre-existing blood dyscrasias (e.g. bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia). Immunodeficiency. Serious, acute or chronic infections such as tuberculosis & HIV. Stomatitis. Ulcers of the oral cavity and known active gastrointestinal ulcer disease. Pregnancy. Breast-feeding. Concurrent vaccination with live vaccines. Special warnings and precautions: Patients must be clearly advised that the therapy is to be administered once a week, and not every day. Patients receiving therapy should be appropriately monitored. Doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression. The possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with male and female patients of childbearing potential. Methotrexate contact with skin and mucosal membranes is to be avoided; in cases of contamination rinse the area with plenty of water. Interactions: Consult SmPC for detailed information on interactions. Undesirable

Serious, acute or chronic infections such as tuberculosis & HIV. Stomatitis. Ulcers of the oral cavity and known active gastrointestinal ulcer disease. Pregnancy. Breast-feeding. Concurrent vaccination with live vaccines. Special warnings and precautions: Patients must be clearly advised that the therapy is to be administered once a week, and not every day.

Patients receiving therapy should be appropriately monitored. Doses exceeding 20 mg/week can be associated with signiﬁcant increase in toxicity, especially bone marrow suppression. The possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with male and female patients of childbearing potential. Methotrexate contact with skin and mucosal membranes is to be avoided; in cases of contamination rinse the area with plenty of water. Interactions: Consult SmPC for detailed information on interactions. Undesirable

effects: See SmPCs for full list of undesirable effects. Very common: Stomatitis. Dyspepsia. Appetite loss. Abdominal pain. Nausea. Abnormal liver function tests (increased Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), alkaline phosphatase and bilirubin). Common: Leukopenia. Anaemia. Thrombopenia. Headache. Tiredness. Drowsiness. Pneumonia. Interstitial alveolitis/pneumonitis. Oral ulcers. Diarrhoea. Exanthema. Erythema. Pruritus. Uncommon: Pharyngitis. Pancytopenia. Precipitation of diabetes mellitus. Depression. Confusion. Dizziness. Enteritis. Pancreatitis. Gastrointestinal ulceration and bleeding. Cirrhosis, Fibrosis and fatty degeneration of liver. Arthralgia, myalgia, osteoporosis. Inflammation and ulceration of bladder. Renal impairment. Rare: Infection. Conjunctivitis. Sepsis. Allergic reactions. Anaphylactic shock. Hypogammaglobulinaemia. Visual disturbances. Pericarditis. Pericardial effusion. Pericardial tamponade. Thromboembolic events. Pulmonary fibrosis. Pneumocystis carinii pneumonia. Shortness of breath and bronchial asthma. Pleural effusion. Acute hepatitis. Renal failure. Anuria. Very rare: Lymphoma. Agranulocytosis. Lymphoproliferative disorders. Severe courses of bone marrow depression. Acute aseptic meningitis. Convulsions. Paralysis. Impaired vision. Retinopathy. Haematemesis. Toxic megacolon. Hepatic failure. Stevens-Johnson syndrome. Toxic epidermal necrolysis. Not known: Eosinophilia. Encephalopathy/Leukoencephalopathy. Pulmonary alveolar haemorrhage. Jaw osteonecrosis (secondary to lymphoproliferative disorders). Legal classification: POM. MA numbers: EU/1/16/1124/001 – 008. Further information available from: Nordic Pharma Ltd, 4045 Kingswood Road, Citywest Business Park, Co Dublin. Date of Prescribing Information: July 2021. Item code: IE/21/NOR/008-00.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to Nordic Pharma Ireland; info@ nordicpharma.ie or +353(0)1 4004141

Date Of Preparation: Aug 2021

IE/21/NOR/011-00

IE/21/NOR/011-00

For the treatment of active rheumatoid arthritis, severe recalcitrant disabling psoriasis & severe psoriatic arthritis in adult patients. Induction of remission in moderate steroid-dependent Crohn’s disease in adult patients, in combination with corticosteroids and for maintenance of remission, as monotherapy, in patients who have responded to methotrexate

THE METHOTREXATE AUTO-INJECTOR WITH THE PATIENT IN MIND

TYPES OF MEDICATIONS USED IN RHEUMATOID ARTHRITIS

Analgesics Corticosteroids NSAIDs

Paracetamol Solpadol Tramadol

Codeine

Prednisolone

Deltacortril

Aspirin Ibuprofen

Celecoxib Diclofenac

DMARDs Targeted DMARDs Biologics and target cytokine/cell

Methotrexate

Leflunomide

Sulfasalazine

Hydroxychloroquine

Baricitinib Tofacitinib Upadacitinib Filgotinib

Etanercept – TNF

Adalimumab – TNF

Golimumab – TNF

Certolizumab Pegol – TNF

Infliximab – TNF

Rituximab – B-cell

Abatacept – T-cell

Tocilizumab – IL6

Anakinra – IL1

X Frequent or sustained flares of RA

X Poor control of pain, fatigue, and joint stiffness

X Intolerability of medications due to toxicity or side-effects

X Deterioration in blood results from the normal values that cause concern, typically a trend over time

X Recurring bacterial or viral infections if on DMARD/targeted DMARD/biologic treatment

X Advice on withholding medications when the patient has an active infection and on an antibiotic

X Guidance on immunisation

X Rapid deterioration in functional ability

rheumatology nurse is ideally situated within the rheumatology team to offer clinical assessment, medication titration, followup support, and therapeutic management of RA patients as part of a treat-to-target programme under the guidance and governance of the rheumatology consultant.

One of the cornerstones of treat-to-target is regular assessment and monitoring of

disease activity using a validated RA outcome measure.21 Validated disease assessment tools are used to measure the level of disease activity at each visit. This will guide treatment decisions and reassure patients that measurable data is being gathered to analyse treatment responses. A number of validated and reliable assessment tools have been generated to capture levels of disease in RA patients including the DAS 28 joint count 22 (example in Figure 1), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and the Routine Assessment of Patient Index Data (RAPID). The tool of choice depends on clinician preference and access to laboratory testing. Once the same tool is used at each visit meaningful data can be generated to compare results over time and inform clinical decision making.

As part of the treat-to-target programme the nurse will provide regular advice on the non-pharmacological management of RA. Patients will be taught how to manage their disease, how to identify a flare and when to seek help. The nurse will give health promotion advice such as vaccination scheduling, medication adherence, smoking cessation, pain management techniques, problem-solving skills, and exercise advice. The nurse will also link in with the allied health professionals such as physiotherapy, occupational therapy, and nutrition and dietetics for intervention if necessary.

A key service goal in the rheumatology department is to develop a quality-driven, cost-effective service that meets the challenging and changing demographic needs of patients. Having a nurse-led treatto-target programme leads the development of individualised treatment clinics, which can promptly, safely and effectively offer advanced patient assessment, rapid symptom relief, medication titration, follow-up support, and autonomous nurse-led management of RA patients. Comprehensive nurse-led treat-to-target RA management substantially reduces disease activity and radiographic disease progression while improving patients’ physical function and quality-of-life at no extra cost to the institution 23 and is supported by European and American guidelines.24,25 Improved management of RA as a chronic illness is fully aligned with the strategic framework for health service reform.26 Implementation of nurse-led RA treat-to-target clinics is an integral component of HSE National Service Plan initiatives and is outlined

22 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

TABLE 1:Types of medications used in rheumatoid arthritis TABLE 2: When to contact the rheumatology nurse about your RA patient in general practice

As part of the treat-to-target programme the nurse will provide regular advice on the non-pharmacological management of RA

The patient is asked to rate their global health on a visual analogue scale of 0-100

The clinician documents ESR score (CRP can be used as an ESR substitute if ESR unavailable. In this situation the DAS calculator must have a CRP calculation option)

The clinician examines the patient noting how many joints out of the 28 symbolised by the red dots are tender and swollen

by the National Clinical Programme for Rheumatology (NCPR)27 in conjunction with the Irish Rheumatology Nursing Forum (IRNF).28

Benefits of treat-to-target to the patient:

X Once diagnosed immediate access to the right person in the right place, first time.

X Continuity of care during first year of diagnosis at patients’ most vulnerable time.

X The patient has direct contact with a rheumatology nurse for acute disease management.

X Tighter disease control.

X Optimisation of treatments.

X Urgent review appointments.

X Health promotion and co-morbidity screening.

X Reduction in clinical risk while on DMARD treatment.

X Improved GP access to a rheumatology professional with any issues regarding medication titration, safety, blood

How to assess for a DAS: Tender Joint Count _____ Swollen Joint Count _____ Global Health Score 0-100

ESR

Calculating the result: DAS formula = DAS28 = 0.56*√(t28) + 0.28*√(sw28) + 0.70*Ln(ESR) + 0.014*VAS Or, enter the assessment readings into any online DAS calculator and calculate result

Interpretation of results:

DAS score of <2.6: Remission

DAS score of ≥2.6, but ≤3.2: Low disease activity

DAS score of >3.2, but ≤5.1: Medium disease activity

DAS score of >5.1: High disease activity

monitoring, etc.

Benefits of treat-to-target to the rheumatology service:

X Improving patient flow through the department.

X Reducing return waiting list numbers.

X Chronic disease prevention.

X Streamlining the patient experience by improving patient outcomes.

X Improved cost efficiency.

Benefits of treat-to-target to the hospital:

X Immediate reduction in rheumatology waiting lists.

X Less public foot-fall through the outpatient department.

X Integration of service into the community in line with Sláintecare recommendations.

X Improved hospital avoidance – the rheumatology nurse will manage patients with acute flares in the community in a shared care capacity with GPs. If patients

require admission for acute flares the rheumatology nurse will coordinate with individual services in house to avoid an emergency department presentation. Rheumatology nurse-led treat-to-target clinics are instrumental in the achievement of best quality in clinical care for patients by adhering to evidence-based good clinical practice in rheumatology. The rheumatology nursing role and function is grounded in the ethos of collaboration; this extends to patients, their families and their carers. The availability of the rheumatology nurse in the appropriate location at the appropriate time improves patient flow and facilitates appropriate access to health services at the earliest possible time through the provision of urgent reviews. This also helps the integration of services between general practice and the acute setting. In centres where it is not feasible to run treat-totarget clinics, patients may not be offered regular access to a rheumatology clinician for symptom control in early disease. Consequentially, they present to their GP or practice nurse seeking assistance with symptom control. Even in established disease the rheumatology nurse should be contacted if certain ‘red flags’ become evident (Table 2). It is helpful for the rheumatology nurse or physician if specific details are noted in general practice when patients present with an issue, some of these are listed in Table 3 

Helpful information to have

Amount of tender joints (using a squeeze test)

Amount of swollen joints

Length of early morning stiffness in minutes or hours

Amount of pain on a severity scale of 0-10

Amount of fatigue on an impact scale of 0-10

Recent ESR and CRP results if available

TABLE 3: Helpful information to have when contacting the rheumatology nurse about an RA patient

23 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

FIGURE 1: Example of a Disease Activity Score (DAS) 28 tool to assess disease activity in RA (van der Heijde et al 1993), (www.das-score.nl/das28/en/)

References

1. van Hoogmoed D, Fransen J, Bleijenberg G, van Riel P. Physical and psychological correlates of severe fatigue in rheumatoid arthritis. Rheumatology 2010;49:1294-302

2. Repping-Wuts H, Fransen J, van Achterberg T, Bleijenberg G, van Riel P. Persistent severe fatigue in patients with rheumatoid arthritis. J Clin Nurs 2007;16:377-83. doi:10.1111/j.13652702.2007.02082.x

3. Pollard LC, Choy EH, Gonzalez J, Khoshaba B, Scott DL. Fatigue in rheumatoid arthritis reflects pain, not disease activity. Rheumatology 2006;45:885-9

4. Gerlag D, Norris J, Tak P. Towards prevention of autoantibody positive rheumatoid arthritis: From lifestyle modification to preventive treatment. Rheumatology 2016;55:607-14

5. Smolen J, Aletaha D, McInnes I. Rheumatoid arthritis. Lancet 2016;388:2023-38

6. McInnes IB, Schett G. Targeted treatments for rheumatoid arthritis 1: Pathogenic insights from the treatment of rheumatoid arthritis. Lancet 2017;389:2328-37

7. Burmester G, Pope J. Targeted treatments for rheumatoid arthritis 2: Novel treatment strategies in rheumatoid arthritis. Lancet 2017;389:2338-48

8. Aletaha D, Neogi T, Silman AJ, Funovitis J, Felson DT, Bingham CO, et al. 2010 Rheumatoid Arthritis Classification Criteria. An ACR/ EULAR collaborative initiative. Arthritis & Rheumatism 2010;62(9):2569-81

9. Zangi HA, Ndosi M, Adams J, Andersen L, Bode C, Boström C et al. EULAR recommendations for patient education for people with inflammatory arthritis. Ann Rheum Dis 2015;74:954-62. doi: 10.1136/ annrheumdis-2014-206807

10. Ndosi M, Adebajo A. Patient education in rheumatoid arthritis: Is the needs-based approach the way forward? Clin Rheumatol 2015;34:1827-9. doi:10.1007/s10067-0153063-2

11. Khosla P, Shankar S, Duggal L. Anti CCP antibodies in rheumatoid arthritis. J Indian Rheumatol Assoc 2004;12:143-6

12. Renaudineau Y, Jamin C, Saraux A, Youinou P. Rheumatoid factor on a daily basis. Autoimmunity 2005;38(1):11-6

13. Lenert A, Lenert P. Tapering biologics in rheumatoid arthritis: A pragmatic approach for clinical practice. Clin Rheumatol 2017;36:1-8

14. Ince-Askan H, Dolhain RJEM. Pregnancy and rheumatoid arthritis. Best Pract Res: Clin Rheumatol 2015;29(4-5):580-96

15. Ostensen M. Contraception and pregnancy counselling in rheumatoid arthritis. Current Opinion in Rheumatology 2014;26(3):302-7

16. Bandoli G, Singh N, Strouse J, Baer RJ, Donovan BM, Feuer SK, et al. Mediation of adverse pregnancy outcomes in autoimmune conditions by pregnancy complications: A mediation analysis of autoimmune conditions and adverse pregnancy outcomes. Arthritis Care & Research 2020;72(2):256-64

17. Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate in rheumatoid arthritis: Optimising therapy among different formulations. Current and emerging paradigms. Clin Ther 2014;36(3):427-35

18. Smolen JS, Aletaha D, Bijlsma JWJ, Breedveld FC, Boumpass D, Burmester G, et al. Treating rheumatoid arthritis to target: Recommendations of an international taskforce. Ann Rheum Dis 2010;69:631-7. doi:10.1136/ard.2009.123919

19. Tillett W, Shaddick G, Cooper A, Creamer P, Clunie G, Helliwell PS et al. Factors influencing work disability in psoriatic arthritis: First results from a large UK multicentre study. Rheumatology 2015;54(1):157-62. doi: 10.1093/ rheumatology/keu264

20. Harrington N. Manorhamilton rheumatology department site approval application to the Nursing and Midwifery Board of Ireland (NMBI). Personal Communication 2014

21. Vermeer M, Kuper HH, Bernelot Moens HJ, Hoekstra M, Posthumus MD, van Riel PLCM, et al. Adherence to a treat to target strategy in early rheumatoid arthritis: results of the DREAM remission induction cohort. Arthritis Res Ther 2012;14(6):R254. doi: 10.1186/ar4099

22. van der Heijde DM, van’t Hof M, van Riel PL, van de Putte LB. Development of a disease activity score based on judgement in clinical practice by rheumatologists. J Rheumatol 1993;20(3):579-81

23. Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance RM, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis. Lancet 2004;364:263-69

24. Smolen JS, Landewe R, Bijlsma JWJ, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2016;76:960-77. doi: 10.1136/ annrheumdis-2016-210715

25. Singh JA, Saag KG, Bridges SL, Akl EA, Bannuru RR, Sullivan MC et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016;68(1):1-26

26. Department of Health, Ireland. Future Health. A Strategic Framework for Reform of the Health Service 2012-2015. Available at: https://health.gov.ie/wp-content/ uploads/2014/03/Future_Health.pdf

27. National Clinical Programme for Rheumatology (NCPR) Model of Care for Rheumatology in Ireland (2018). Available at: www.hse.ie/eng/about/who/cspd/ncps/ rheumatology/resources/model-of-care-forrheumatology-in-ireland1.pdf

28. Minnock P, Ryan AM. Rheumatology advanced nurse practitioners, treat to target person centred care: Ireland's policy framework [Abstract presentation] on behalf of the Irish Rheumatology Nursing Forum (IRNF) 2018. doi: 10.1136/annrheumdis-2018eular.4010

24 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

OTEZLA® has an established efficacy and safety profile for up to 5 years†1,2

No contraindications for concurrent use with live vaccination

Minimise frequency of clinical appointments

OTEZLA® (apremilast) 10mg, 20mg and 30mg film coated-tablets Brief Prescribing Information. Refer to the Summary of Product Characteristics (SPC) before prescribing. Further information is available upon request. Presentation: 10mg, 20mg and 30mg film coated-tablets. Indications: Psoriatic arthritis: OTEZLA, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated 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 DMARD therapy. Psoriasis: OTEZLA is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA). Dosage and administration: Treatment with OTEZLA should be initiated by specialists experienced in the diagnosis and treatment of psoriasis or psoriatic arthritis. The recommended dose of OTEZLA is 30mg twice daily taken orally in the AM and PM, approximately 12 hours apart, with no food restrictions. The film-coated tablets should be swallowed whole. An initial dose titration is required per the following schedule: Day 1: 10mg in the AM; Day 2: 10mg in the AM and 10 mg in the PM; Day 3: 10mg in the AM and 20mg in the PM; Day 4: 20mg in the AM and 20mg in the PM; Day 5: 20mg in the AM and 30mg in the PM; Day 6 and thereafter: 30mg twice daily in the AM and PM. No re-titration is required after initial titration. If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for their next dose, the missed dose should not be taken and the next dose should be taken at the regular time. Patients with severe renal impairment: The dose of OTEZLA should be reduced to 30mg once daily in patients with severe renal impairment (creatinine clearance of less than 30mL per minute estimated by the Cockcroft-Gault equation). For initial dose titration in this group, it is recommended that OTEZLA is titrated using only the AM doses and the PM doses be skipped. Paediatric population: The safety and efficacy of OTEZLA in children aged 0 to 17 years have not been established. No data is available. Contraindications: Hypersensitivity to the active substance(s) or to any of the excipients. OTEZLA is contraindicated in pregnancy. Pregnancy should be excluded before treatment can be initiated. Special warnings and precautions: Diarrhoea, nausea and vomiting: Severe diarrhoea, nausea, and vomiting associated with the use of OTEZLA have been reported. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalized. Patients 65 years of age or older may be at a higher risk of complications. Discontinuation of treatment may be necessary. Psychiatric disorders: OTEZLA is associated with an increased risk of psychiatric disorders such as insomnia and depression. Instances of suicidal ideation and behaviour, including suicide, have been observed in patients with or without history of depression. The risks and benefits of starting or continuing treatment with OTEZLA should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with OTEZLA. Severe renal impairment: See dosage and administration section. Underweight patients: OTEZLA may cause weight loss. Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered.

Lactose content: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Interactions: Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of OTEZLA, which may result in a loss of efficacy of OTEZLA. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine,

No warnings regarding risk of serious infection2

A short half-life of 9 hours

Means that OTEZLA® is rapidly cleared from the body if administration needs to be stopped2

Immunomodulatory mode of action

Confidence not compromise in immune response, down-regulation of proinflammatory cytokines and up-regulation of anti-inflammatory cytokines

phenytoin and St. John’s Wort) with OTEZLA is not recommended. In clinical studies, OTEZLA has been administered concomitantly with topical therapy (including corticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy. OTEZLA can be co-administered with a potent CYP3A4 inhibitor such as ketoconazole, as well as with methotrexate in psoriatic arthritis patients and with oral contraceptives. Pregnancy, lactation and fertility: Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment. OTEZLA should not be used during breast-feeding. No fertility data is available in humans. Undesirable effects: Psychiatric disorders: In clinical studies and post-marketing experience, uncommon cases of suicidal ideation and behaviour, were reported, while completed suicide was reported post-marketing. The most commonly reported adverse reactions with OTEZLA in these indications are gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. Adverse reactions reported in the psoriatic arthritis and/or psoriasis clinical trial programme and post marketing experience include: very common (≥ 1/10) diarrhoea*, nausea*; common (≥1/100 to <1/10) bronchitis, upper respiratory tract infection, nasopharyngitis*, decreased appetite*, insomnia, depression, migraine*, tension headache*, headache*, cough, vomiting*, dyspepsia, frequent bowel movements, upper abdominal pain*, gastroesophageal reflux disease, back pain*, fatigue; uncommon (≥1/1,000 to <1/100) hypersensitivity, suicidal ideation and behaviour, gastrointestinal haemorrhage, rash, urticaria, weight loss; not known (cannot be estimated from the available data) angioedema. *At least one of these adverse reactions was reported as serious. Please consult the SPC for a full description of undesirable events. Pharmaceutical

Precautions: Do not store above 30°C. Legal category: POM. Presentation and Marketing

Authorisation Numbers: Initiation pack containing 27 film coated tablets (4 x 10mg, 4 x 20mg, 19 x 30mg) - EU/1/14/981/001; 30mg film coated tablets in a pack size of 56 tablets - EU/1/14/981/002.

Marketing Authorisation Holder: Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin D09 TX31. OTEZLA is a trademark owned or licensed by Amgen Inc., its subsidiaries, or affiliates. Date of preparation: April 2020 (Ref: IE-OTZ-2000019).

Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse events should also be reported to Amgen Limited on +44 (0)1223 436441.

† Otezla met the primary endpoint of the pivotal trials in psoriasis: PASI-75 response vs placebo at 16 weeks. ESTEEM 1: 33.1% (N=562) vs 5.3% (N=282); ESTEEM 2: 28.8% (N=274) vs 5.8% (N=137), P<0.0001. OTEZLA met the primary endpoint of the pivotal trials in Psoriatic Arthritis: ACR 20 response vs placebo at 16 weeks. PALACE 1: 38% (N=168) vs 19% (N=168), P≤0.001. PALACE 2: 32% (N=162) vs 19% (N=159) P≤0.01; PALACE 3: 41% (N=167) vs 18% (N=169) P≤0.001.2

References: 1. Kavanaugh et al. Arthritis Research & Therapy 2019: 21;118. 2. OTEZLA (apremilast). Summary of Product Characteristics.

OTEZLA® can offer solutions to the challenges in this new environment

Make OTEZLA® the positive choice for your psoriasis and psoriatic arthritis patients

laboratory pre-screening, and no drug specific blood monitoring required

BSR launches new psoriatic arthritis guideline

AUTHOR: Priscilla Lynch

The British Society for Rheumatology (BSR) has launched a new guideline for the treatment of psoriatic arthritis (PsA). The updated guideline includes information on biologic and targeted drugs to help clinicians understand how effective they are, when they can work, and the impact on other associated conditions.

The BSR’s original guideline for PsA was published in 2012 and focused specifically on TNF inhibitors as they were the only biologic

disease-modifying anti-rheumatic drugs (bDMARDs) available. Since that time, there have been significant advances in therapeutic options available for PsA and drugs with different modes of action are now available, including IL17, IL12/23, IL23 p19, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4Ig), Phosphodiesterase-4 (PDE4), and Janus kinase (JAK) inhibition (i).

Dr William Tillett, who co-led the

development of the guideline with Dr Laura Coates, says: “Since the last guidelines were published in 2012 there has been a rapid expansion in the number of therapeutic options available and an improved understanding of treatment strategy to improve the way we treat psoriatic arthritis. This guideline helps everyone understand when and how to use these medications and their impact on comorbidities.”

Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

FIGURE 1: Summary algorithm (abbreviated) for the treatment of PsA with b/tsDMARDs. BSR 2022

Dr Coates adds: “We’ve put patients at the centre covering treatment selection, treatto-target approaches, lifestyle modifications and we’ve addressed some of the challenging areas we see in routine practice such as switching and tapering.”

As well as members from rheumatology, the working group who created the guideline included patients, dermatologists, gastroenterologists, and ophthalmologists to ensure comprehensive representation.

“In areas where there was an absence of evidence, we’ve reached out to experts in other fields to fill the gaps,” explains Dr Tillett. “Our hope is that these guidelines will be accessible for everyone involved in the care of psoriatic arthritis patients.”

The new NICE-approved guideline includes a flow chart which allows clinicians to gain an overview of treatment at a glance (See Figure 1).

PSA

PsA is a chronic, inflammatory, musculoskeletal disease affecting approximately one-quarter of people with the skin condition psoriasis. PsA is a highly heterogeneous disease, encompassing diverse musculoskeletal manifestations or ‘domains’ resulting from disease activity in different tissues. These include peripheral arthritis, spondylitis (axial inflammation), dactylitis (inflammation of the whole digit), and enthesitis (inflammation where a tendon, ligament or joint capsule insert to the bone). There is thus significant variability in clinical presentation of PsA.

PsA is a potentially debilitating and destructive disease, with half of people developing irreversible joint damage within two years. This results in significant functional limitations, depression and anxiety, as well as negatively impacting on education, work capacity, and social participation.

Furthermore, PsA is associated with extra-articular manifestations, including inflammatory bowel disease (IBD) (Crohn’s disease and ulcerative colitis) and uveitis. In addition, metabolic syndrome (obesity,

diabetes, hypertension, hyperlipidaemia, fatty liver disease), and cardiovascular disease are more common compared with the prevalence in the general population.

All of these factors may influence treatment selection and potentially modifiable risk factors such as obesity and smoking, which can impact therapeutic response and prognosis, should be addressed within the management plan.

As individuals with PsA may have different domains involved and drugs have different levels of effectiveness on each domain, it is therefore essential that clinical guidelines for the treatment selection in PsA include disease phenotype and differential effect of medication, according to the BSR.

Overarching BSR generic recommendations

Therapeutic decisions need to be individualised and should be based on shared decision making between people with PsA and their clinicians [strength of agreement (SoA) 98 per cent].

All medication decisions in people with PsA should take into account: Disease presentation with activity in the different domains, previous medication use, associated conditions such as psoriasis, uveitis, and IBD, other comorbidities, and patient preference (SoA 97 per cent).

When a range of clinically suitable and equivalent treatments are being considered by people with PsA and their clinicians, select the least expensive, taking into account administration costs, dosage, price per dose, and commercial arrangements (SoA 88 per cent).

If people with PsA have an inadequate response to a biologic or targeted synthetic DMARD (b/tsDMARDs), consider potential factors that could be addressed including: Confirming correct diagnosis, adherence, pain due to other causes, drug levels, and immunogenicity (SoA 95 per cent).

Treat-to-target

There is strong evidence that a treat-to-target (T2T) approach to PsA management, aiming

for remission or low disease activity, results in better clinical, radiographic and patientreported outcomes, according to the BSR’s new guidelines. Significant advances in therapeutic options available for PsA now mean a target of remission is an achievable goal. Despite PsA being a highly heterogeneous disease, most physicians apply the same step-up therapy to all people with peripheral arthritis, owing to the lack of comparative evidence. Initially a single conventional systemic DMARD (csDMARD) is used, with methotrexate typically being prescribed first-line. This is followed by use of an alternative single csDMARD or combinations of csDMARDs, prior to biologic use if the previous treatment step is unsuccessful.

Up to half of people with PsA require b/ tsDMARD therapy. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and local corticosteroids are frequently used, which although not optimal for long-term use, do offer quick, short-term symptomatic relief, while DMARDs take effect.

In practice, biologics require use for a minimum of 12 (eg TNFi) or 16 weeks (eg, IL-17Ai), before response can be evaluated, the BSR noted. A proportion of people do not respond to the first-line drug chosen (primary non-response), while other people respond well initially, but subsequently lose response (secondary non-response). For these reasons, as well as adverse events encountered by some people, switching therapy is required to achieve and maintain treatment targets, the BSR says.

Full details of the new BSR 2022 guideline for the treatment of psoriatic arthritis with biologic and targeted synthetic DMARDs is available at www.rheumatology.org.uk/practicequality/guidelines. 

Reference

Tucker L, Allen A, Chandler D, Ciurtin C, Dick A, Foulkes A, et al. The 2022 British Society for Rheumatology guideline for the treatment of psoriatic arthritis with biologic and targeted synthetic DMARDs. Rheumatology (Oxford). 2022 May 31:keac295. doi: 10.1093/ rheumatology/keac295

27 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

Manage as lowat 12 guidelines. levels

The cardiovascular Hepatic baseline management. elevation is liver this vein been Use Risk and surgery DVT/PE promptly. by CYP3A4 be with dose treatment details. Upadacitinib is childbearing contraception of parents/ the while during for adverse acne. bronchitis, anaemia, pain, CPK/ALT/AST, monitoring. information. suspected website:

disorders. Manage hyperlipidaemia as cholesterol, lowlipoprotein (HDL) at 12 international guidelines. pre-treatment levels is limited. The cardiovascular determined. Hepatic enzymes at baseline management. enzyme elevation is drug-induced liver interrupted until this thromboembolism: Deep vein (PE) have been upadacitinib. Use DVT/PE. Risk age, obesity and major surgery features of DVT/PE treat promptly. metabolised mainly by affected by CYP3A4 daily should be treatment with once daily dose chronic treatment for full details. Upadacitinib is childbearing contraception the final dose of their parents/ to contact the menarche while be used during human fertility has Refer to SmPC for common adverse infections, acne. <1/10): bronchitis, influenza, anaemia, abdominal pain, CPK/ALT/AST, additional monitoring. safety information. any suspected Pharmacovigilance; website:

RINVOQ the 15mg once-daily oral selective & reversible JAK inhibitor

indicated for the treatment of adult patients with moderate to severe active RA, active PsA and active AS who have inadequately responded or are intolerant to one or more DMARDs (RA/PsA) or conventional therapy (AS)1

RINVOQ INRA

RINVOQ IN PSA

RINVOQiNAS

MARKETING PRESENTATION:

Calendar blister

MARKETING Deutschland GmbH Ludwigshafen, Germany. AbbVie Limited, 14 Dublin 24, Ireland. PI-1404-005

Autoimmune processes:

Stop treatment positive antibodies

Consider the long halfClosely monitor to respond to fixed fibrotic Serious infections some of which had these patients. when Humira was with use as other biologic TNF-antagonists and lactation: pregnancy if needed. consider the use of for at least five administration of live Humira in utero for 5 treatment during breast-feeding. Adverse tract Infections tract infection, nasopharyngitis and neutropenia and increased, headache, liver enzymes, pain, injection erythema). Serious, been reported. infections, allergic reactivation and lymphoma and haematological, have also been pancytopenia, aplastic demyelinating events and Stevens-Johnson SmPC for the

Category: POM EU/1/03/256/013, information:

Citywest Business any suspected Pharmacovigilance; website: November 2020,

MARKETING PRESENTATION: blister MARKETING GmbH Germany. 14 Ireland. processes: treatment antibodies halfmonitor to fibrotic infections had patients. was as biologic TNF-antagonists lactation: needed. of five live for 5 during Adverse Infections infection, and and headache, enzymes, injection Serious, reported. allergic and and haematological, been aplastic and Stevens-Johnson the POM EU/1/03/256/013, information: Business suspected website: 2020,

demonstrated greater and durable* remission rates† vs adalimumab (both treatment groups + MTX) through 3 years in a head-to-head study 2

*Consistent with earlier time points (from Week 8), greater proportions of patients (MTX-IR) achieved remission at 3 years with RINVOQ vs adalimumab (both treatment groups + MTX).2,3

†Remission as measured by DAS28 (CRP) <2.6: at Week 12, nominal P≤0.001 RINVOQ vs adalimumab (both treatment groups + MTX);1,3,4 at Week 156, nominal P<0.001 RINVOQ vs adalimumab (both treatment groups + MTX).2

EMA primary endpoint met: DAS28 (CRP) <2.6 at Week 12, P≤0.001 RINVOQ vs placebo (both treatment groups + MTX): multiplicity-controlled comparison.1,3

demonstrated rapid and sustained joint efficacy with ACR20 response observed as early as Week 2‡1,5,7 and maintained through Week 56§1,8,9

‡Week 2 data, RINVOQ vs placebo – SELECT-PsA 1 (non-bDMARD-IR) and SELECT-PsA 2 (bDMARD-IR): P<0.001 and P≤0.05 respectively (both nominal P values).6,7

§All patients randomised to placebo were switched to 15mg or 30mg once-daily upadacitinib at Week 24. Upadacitinib 30mg is not a licensed dose in rheumatology.1

ACR20 responses maintained through Week 56.1,8,9

Primary endpoint of SELECT-PsA studies met: ACR20 response at Week 12 RINVOQ vs placebo, P≤0.001 (multiplicity-controlled comparison).1

demonstrated greater disease control with ASAS40 response seen as early as Week 2¥10 and maintained through 2 years11

¥P≤0.0002 RINVOQ vs placebo (NSAID-IR): nominal P-value.10

Patients were NSAID-IR. Placebo arm switched to active treatment with upadacitinib 15mg once-daily at Week 14 as part of the open label extension.11

Primary endpoint met: ASAS40 response at Week 14, P≤0.001 RINVOQ vs placebo: multiplicity-controlled comparison.1

RINVOQ demonstrated a CONSISTENT SAFETY PROFILE across RA, PsA and AS populations in the SELECT clinical trial programme12

8,500 patient-years of exposure inclusive of patients in the RINVOQ treatment arms of six RA trials, two PsA trials and one AS trial12

In the placebo-controlled clinical trials for RA, PsA and AS, the most commonly reported adverse reactions with RINVOQ were upper respiratory tract infections, blood creatine phosphokinase (CPK) increased, alanine transaminase increased, bronchitis, nausea, cough, aspartate transaminase increased, and hypercholesterolaemia.

The most common serious adverse reactions were serious infections.1

ACR20, Improvement of at least 20% in the American College of Rheumatology core criteria; AS, Ankylosing Spondylitis; ASAS40, Assessment of Spondylo Arthritis international Society 40% response; csDMARD, Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug; DAS28 (CRP), Disease Activity Score with 28-Joint Count (C-Reactive Protein); (b)DMARD, (biologic) Disease-Modifying Anti-Rheumatic Drug; EMA, European Medicines Agency; EOW, Every Other Week; IR, Inadequate Responder; JAK, Janus Kinase; MTX, Methotrexate; NSAID, Non-Steroidal Anti-inflammatory Drug; PsA, Psoriatic Arthritis; QD, Once-Daily; RA, Rheumatoid Arthritis.

References:

1. RINVOQ (upadacitinib) Summary of Product Characteristics, available at www.medicines.ie

2. Fleischmann R, Mysler E, Bessette L, et al. RMD Open. 2022; 8(1): e002012. doi: 10.1136/rmdopen-2021-002012. 3. Fleischmann R, Pangan AL, Song IH, et al. Arthritis Rheumatol. 2019; 71(11): 1788-1800. 4. Fleischmann RM, Genovese MC, Enejosa JV, et al. Ann Rheum Dis. 2019; 78(11): 1454-1462. 5. McInnes IB, Anderson JK, Magrey M, et al N Engl J Med. 2021; 384(13): 1227–1239. 6. McInnes I, Anderson J, Magrey M, et al. Ann Rheum Dis. 2020; 79: 16–17. 7. Mease PJ, Lertratanakul A, Anderson JK, et al. Ann Rheum Dis. 2020; 80(3):

Abstract 1691. Arthritis Rheumatol. 2021; 73 (suppl 10).

312–320. 8. McInnes IB, Kato K, Magrey M, et al RMD Open. 2021; 7(3): e001838. 9. Mease PJ, Lertratanakul A, Papp KA, et al. Rheumatol Ther. 2021; 8(2): 903–919. 10. van der Heijde D, Song IH, Pangan AL, et al. Lancet. 2019; 394(10214): 2108–2117. 11. van der Heijde D, Deodhar A, Maksymowych W, et al. Abstract 0924. Arthritis Rheumatol. 2021; 73 (suppl 10). 12. Burmester G, Cohen S, Winthrop K, et al.

Prescribing Information is available on the facing page. IE-UPAD-210033 April 2022 | www.abbviepro.com

ANCA-associated vasculitis

AUTHOR: Dr Richard Conway, Consultant Rheumatologist, St James’s Hospital, and Clinical Associate Professor, Trinity College Dublin

CASE STUDY

A 58-year-old man presents with sinus congestion, bloody nasal discharge, cough and dyspnoea. Inflammatory markers are elevated and he is treated for sinusitis and a respiratory tract infection with a course of antibiotics. His symptoms do not improve with this or with a second antibiotic and he is sent to the emergency department for further evaluation. A chest radiograph reveals a number of pulmonary nodules and he is admitted for further investigation. A needle biopsy of the largest pulmonary nodule reveals

ANCA-associated vasculitis (AAV) encompasses three different and variably related conditions. The two major subtypes are the closely related and overlapping GPA and microscopic polyangiitis (MPA). The third condition typically included in this group is eosinophilic granulomatosis with polyangiitis, however, this is a distinctly different condition characterised by eosinophilic infiltration and will not be discussed further here. GPA and MPA are relatively rare conditions with a combined prevalence of 50-to-200 cases per million people. They show marked geographical variation, with GPA more common in Northern Europe, and MPA more common in Southern Europe and in Asia. These two conditions could be conceptualised as two ends of a seesaw with their relative frequency alternating based on uncertain factors, but likely to include genetic predisposition and environmental factors.

Clinical features

AAV can affect multiple organ systems either simultaneously in a variety of combinations or in isolation. This makes the diagnosis challenging and requires a vigilant maintenance of a high degree of clinical suspicion. It remains important to remember

granulomatous inflammation with necrosis. Laboratory testing reveals a positive antineutrophil cytoplasmic antibody in a cytoplasmic pattern (c-ANCA) with a proteinase 3 (PR3)-ANCA titre of 65. He is referred to rheumatology for further evaluation. Further history elucidates the presence of recurrent otitis media with hearing loss, and bilateral ankle pain and stiffness. A non-blanching petechial rash was present on the lower limbs, and urine dipstick was normal. He was diagnosed with granulomatosis with polyangiitis (GPA).

that the majority of cases where a diagnostic possibility of AAV is raised ultimately do not have a final diagnosis of AAV. Equally, in true cases of AAV, diagnosis is frequently delayed, with potential negative consequences in terms of irreversible damage.

Constitutional symptoms such as pyrexia, weight loss, anorexia, and malaise are common in AAV, but non-specific. In GPA ENT manifestations are frequently seen; nasal crusting, epistaxis, sinusitis, and otitis media leading to hearing loss are most common. Long-standing disease can lead to the characteristic, but not pathognomonic, saddle nose deformity. Subglottic stenosis leading to stridor and airway compromise merits special mention as it can occur in early disease, and may sometimes be the main presenting feature.

Pulmonary manifestations include recurrent chest ‘infections’, haemoptysis, pulmonary nodules, interstitial lung disease, infiltrates, and diffuse alveolar haemorrhage. Renal disease is frequently minimally symptomatic in the early stages and characterised by acute kidney injury with an active urinary sediment (blood and protein on dipstick) signifying a nephritic syndrome due to

glomerulonephritis. Red cell casts on microscopy are an important clinical sign. Renal histology demonstrates a pauciimmune glomerulonephritis.

Diagnosis

While there are useful laboratory and tissue diagnostic adjuncts in AAV, these are far from perfect. The diagnosis of AAV remains a clinical one. Arguably the most important aspect of this is recognition of the possibility of AAV in an individual presenting with a consistent symptom constellation. This should lead to further clinical assessment and if clinical suspicion remains extended, investigation to confirm or refute the diagnosis.

Laboratory testing

Patients with AAV typically have elevated inflammatory markers. Depending on the organs involved, other manifestations may be seen. Urinalysis – dipstick for blood or protein followed if positive by microscopy and protein quantification is crucial. The key laboratory investigation, however, is ANCA testing. The identification of ANCAs is a twostage process. Indirect immunofluorescence involves visualisation of a staining pattern on neutrophils under the microscope. This may localise to the cytoplasm (c-ANCA), peri-nuclear (p-ANCA), or elsewhere (atypical ANCA, usually not related to AAV). Enzyme-linked immunosorbent assay (ELISA) identifies antibodies to PR3 or myeloperoxidase (MPO). These two testing methodologies have concordant patterns – c-ANCA and PR3 co-segregate as do p-ANCA and MPO. GPA and MPA are ANCA-associated diseases with the presence of antibodies to PR3-ANCA or MPO-ANCA in >90 per cent of patients; however, some individuals do not have identifiable ANCA. The identification of both PR3 and MPO in the same individual or the presence of discordant immunofluorescence and ELISA

30 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

results, ie PR3-ANCA+ with a p-ANCA or MPO-ANCA+ with a c-ANCA should prompt evaluation for another aetiology such as drugs (both prescribed and recreational) or infection.

Biopsy

The value of tissue biopsy in AAV varies significantly based on the organ involved. This ranges from being of significant value with renal involvement, to moderate value with lung involvement, and of limited to no utility in nasal and skin involvement. There is a common axiom that ‘tissue is the issue’, but this must be balanced against practicalities and pragmatism, biopsy does not always shift the diagnostic dial sufficiently to be essential. Biopsy findings include granulomatous inflammation, multinucleate giant cells, necrotising vasculitis, and a pauci-immune glomerulonephritis.

Management

The management of AAV is stratified based on disease extent and severity. The key distinction is the presence of organ or lifethreatening disease. A vital component of this is the recognition of what constitutes organ-threatening disease. Some facets of this are obvious; acute kidney injury due to glomerulonephritis or respiratory failure due to diffuse alveolar haemorrhage. However, other ‘organs’ should not be neglected. Mononeuritis multiplex is significantly debilitating and generally either irreversible or associated with very slow improvement. Sinonasal disease can also result in significant tissue destruction, and in such cases should be considered as a more severe manifestation. In the absence of such severe manifestations, AAV is frequently referred to as ‘limited’ disease. Generally this signifies combinations of skin, joint, and muscle involvement, or milder sinonasal disease. This terminology is contentious as even such disease can be associated with significantly morbidity.

The treatment approach is divided into two phases; a more intensive induction phase aimed at achieving disease remission and a less intensive maintenance phase aimed at the prevention of further disease flares.

A management algorithm is outlined in Figure 1.

Induction treatment

Irrespective of whether an individual patient has organ-threatening disease or not, the induction treatment of AAV is a combination treatment approach with glucocorticoids used for their initial efficacy, but in as short a duration and as low a dose as possible. Multiple recent studies have been informative in illustrating that traditional glucocorticoid regimes resulted in higher cumulative doses of glucocorticoids than necessary, with an attendant increase in side-effects. There are a number of different steroid regimes utilised at present, the most commonly used in clinical practice is the reduceddose steroid protocol from the PEXIVAS trial.1 This appears to be sufficient for the majority of patients, however, careful observation of clinical response to these reduced glucocorticoid regimes is warranted as a small number of patients, particularly those with very severe disease, may require dose increases.

Induction treatment for organ- or life-threatening AAV entails either cyclophosphamide or rituximab in addition to glucocorticoids. Multiple large clinical trials have established the equivalence of these two treatment regimes. 2,3 Most practitioners favour rituximab in the majority of settings due to convenience and better tolerance. Rituximab also appears more efficacious in those who are PR3+ or with relapsing disease. 2 If cyclophosphamide is used the intravenous formulation is generally favoured due to a significantly lower rate of adverse events (due to lower cumulative cyclophosphamide dose), albeit at the expense of a possible slight increase in subsequent flare rate. For patients without organ- or life-threatening disease, methotrexate or azathioprine are generally used as induction treatments; even in this setting rituximab is becoming more utilised however. The induction treatment phase should continue for three-to-six months until remission is achieved.

Maintenance treatment

Following successful induction treatment a maintenance treatment phase is required to prevent subsequent disease relapse. The MAINRITSAN trial demonstrated the superiority of rituximab over azathioprine for remission maintenance.4 Subsequent studies have aimed to clarify the dose and interval of ongoing rituximab treatment. There is still uncertainty here with successful regimes varying from 500mg every six months to 1,000mg every four months; most experts will currently adopt a tailored approach to this. Tailored redosing strategies based on surrogate laboratory markers continue to attract attention, but require further evaluation. Despite the superiority of rituximab as a maintenance strategy, it does have potential adverse events, and methotrexate or azathioprine are also frequently used as alternative maintenance agents. If a patient with limited disease has been induced with methotrexate or azathioprine these are generally continued as remission maintenance agents. Glucocorticoids are generally also employed as part of remission maintenance regimes; while glucocorticoid regimes prioritise as rapid a tapering as possible this is generally until a dose of 5mg prednisolone, which most practitioners will continue longer-term; the current TAPIR trial is aimed at answering the clinical question as to whether this sustained glucocorticoid use is needed. The optimal duration of maintenance therapy remains uncertain; the MAINRITSAN 3 trial demonstrated that 18 months is superior to shorter durations.5 When dealing with a disease with high relapse rates, which can be potentially catastrophic, most will err on the side of caution and continue maintenance treatment indefinitely in the absence of treatment-related adverse events.

Other treatments

A variety of other treatments have been trialled or utilised in AAV and merit some discussion. Plasma exchange was commonly employed in the past in patients with severe AAV. The PEXIVAS trial subsequently demonstrated no benefit to the use of plasma exchange in AAV.1 More nuanced interpretation of the results suggest that

31 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

Organ/Life threatening disease

Limited Disease

Glucorticoids AND Cyclophosphamide OR Rituximab

Rituximab OR Methotrexate OR Azathioprine

while there is no effect on mortality, in patients with severe acute kidney injury there may be some benefit with regards to prevention of progression to end-stage kidney disease, but at the expense of increased infections. Plasma exchange is now mainly reserved for critically-unwell treatment-refractory patients. One important caveat to this is patients with AAV who have concurrent anti-GBM antibodies (approximately 5 per cent); these antibodies are believed to be directly pathogenic and therefore removal by plasma exchange is beneficial.

Intravenous immunoglobulin appears to have efficacy in AAV. There are a dearth of comparative studies, but most would consider it as a less efficacious treatment than our other options. However, it may have a role where there are contraindications to other treatments (such as active current infection) and in patients with refractory disease.

Mycophenolate mofetil has been demonstrated to be inferior to azathioprine as maintenance treatment in AAV.6 This was surprising and disappointing given how effective a treatment it is in other similar diseases such as systemic lupus erythematosus (SLE). It may still have a limited role as a treatment in those unable to use azathioprine or methotrexate and in those with MPO+ disease.

Avacopan is an orally administered complement C5a receptor antagonist that has

Glucocorticoids AND Methotrexate OR Azathioprine OR Rituximab

Methotrexate OR Azathioprine OR Rituximab

been approved for use in AAV in the US and Japan. It has demonstrated efficacy in a novel very low-dose glucocorticoid clinical trial. Its potential role in treatment algorithms remains unclear as does its reimbursement and cost in Ireland.

All of the previously discussed treatments are immune-modulators. Frequently damage will occur in the course of AAV, particularly at presentation, which cannot be reversed with such treatments. It is important to manage these features appropriately and not escalate immunosuppression in settings where there is no possibility of such a strategy being effective. For example, people with AAV can frequently have chronic sinusitis and nasal crusting despite full disease remission; in this setting treatments such as nasal glucocorticoid sprays and sinus rinses are vital to symptomatic control.

Personalised medicine

AAV are a heterogenous group of diseases with complex treatments and varied responses to management strategies. Despite important advances, considerable uncertainty remains regarding many aspects of management. It is important to contextualise any potential treatment approach in terms of the individual patient. Given the balance between desired remission maintenance and potential treatment-related adverse events, it is important to adopt a shared-decision making approach with the person who is living with this disease. Ongoing research will

inform our strategies further in due course, but an informed collaborative approach to treatment will remain crucial.

Summary

AAV are complex diseases with varied presentations. A high vigilance for the potential diagnosis followed by prompt investigation and management is crucial to optimising disease outcomes. Given the intensity of treatment approaches, and considerable uncertainty particularly regarding longer term management strategies, it is crucial that people with AAV are informed partners in treatment decisions. 

References

1. Walsh M, Merkel PA, Peh CA, Szpirt WM, Puéchal X, Fujimoto S, et al. Plasma exchange and glucocorticoids in severe ANCAassociated vasculitis. NEJM. 2020;382(7):62231

2. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. NEJM. 2010;363(3):221-32

3. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. NEJM. 2010;363(3):211-20

4. Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, et al. Rituximab versus azathioprine for maintenance in ANCAassociated vasculitis. NEJM. 2014;371(19):177180

5. Charles P, Perrodeau É, Samson M, Bonnotte B, Néel A, Agard C, et al. Longterm rituximab use to maintain remission of antineutrophil cytoplasmic antibody–associated vasculitis. Ann Intern Med 2020;173(3):179-87

6. Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: A randomised controlled trial. JAMA . 2010;304(21):2381-8

32 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

FIGURE 1: Management approach to AAV

Strength of Balance

JYSELECA – a preferential JAK1 inhibitor for moderate to severe RA1

Balancing sustained efficacy2-6 with acceptable tolerability1,7

Indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti-rheumatic drugs.1 May be used as monotherapy or in combination with methotrexate.1

*This is based on biochemical assays, the clinical consequence of this is unknown.

Refer to Summary of Product Characteristics (SmPC) before prescribing, and for full prescribing information.

JYSELECA® filgotinib 100 mg or 200 mg film-coated tablets.

Indication: Jyseleca is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX).

Dosage: Adults: 200 mg once daily. Taken orally with/without food. It is recommended that tablets are swallowed whole. Laboratory

Monitoring: Refer to the SmPC for information regarding laboratory monitoring and dose initiation or interruption. Elderly: A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited. Renal impairment: No dose adjustment required in patients with estimated creatinine clearance (CrCl) ≥ 60 mL/min. A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min). Not recommended in patients with CrCl < 15 mL/min. Hepatic impairment: Mild/moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Children (< 18years): Safety and efficacy not yet established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy. Warnings/Precautions: See SmPC for full information. Immunosuppression: Combination use, with immunosuppressants e.g. ciclosporin, tacrolimus, biologics or other Janus kinase (JAK) inhibitors is not recommended as a risk of additive immunosuppression cannot be excluded. Infections: Infections, including serious infections such as pneumonia and opportunistic infections e.g. tuberculosis (TB), oesophageal candidiasis, and cryptococcosis have been reported. Risk benefit should be assessed prior to initiating in patients with risk factors for infections (see SmPC). Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. Treatment should be interrupted if the patient is not responding to antimicrobial therapy, until infection is controlled.

Lipids: Treatment with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and highdensity lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not

There is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population. Tuberculosis: Patients should be screened for TB before initiating filgotinib, and filgotinib should not be administered to patients with active TB. Viral reactivation: Cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see SmPC). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed. Malignancy: Immunomodulatory medicinal products may increase the risk of malignancies. Malignancies were observed in clinical studies (see SmPC). Fertility: In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see SmPC). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. Haematological abnormalities: Do not start therapy, or temporarily stop, if Absolute Neutrophil Count (ANC) <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL. Temporarily stop therapy if these values are observed during routine patient management. Vaccinations: Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. Lipids: Treatment with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and highdensity lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not

Learn

Learn more at strengthofbalance.co.uk

take filgotinib. Pregnancy/Lactation: Filgotinib is contraindicated in pregnancy. Filgotinib should not be used during breast-feeding. Women of childbearing potential must use effective contraception during and for at least 1 week after cessation of treatment. Driving/ Using machinery: No or negligible influence, however dizziness has been reported. Side effects: See SmPC for full information. Common (≥1/100 to <1/10): nausea, upper respiratory tract infection, urinary tract infection and dizziness. Uncommon (≥1/1000 to <1/100): herpes zoster, pneumonia, neutropenia, hypercholesterolaemia and blood creatine phosphokinase increase. Serious side effects: See SmPC for full information Legal category: POM Pack: 30 film-coated tablets/ bottle Price: UK Basic NHS cost: £863.10; Ireland: POA Marketing authorisation number(s): Jyseleca 100mg film-coated tablets EU/1/20/1480/001 EU/1/20/1480/002 Jyseleca 200mg film-coated tablets EU/1/20/1480/003 EU/1/20/1480/004 Further information: Galapagos UK, Belmont House, 148 Belmont Road, Uxbridge UB8 1QS, United Kingdom 00800 7878 1345 medicalinfo@glpg.com Jyseleca® is a trademark. Date of Preparation: January 2022 IE-RA-FIL-202112-00003 Additional monitoring required

Adverse events should be reported.

For Northern Ireland, reporting forms and information can be found at yellowcard.mhra.gov.uk or via the Yellow Card app (download from the Apple App Store or Google Play Store). Adverse events should also be reported to Galapagos via email to DrugSafety.UK.Ireland@glpg.com or 00800 7878 1345

Adverse events should be reported.

For Ireland, reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971. Adverse events should also be reported to Galapagos via email to DrugSafety.UK.Ireland@glpg.com or 00800 7878 1345

3. Genovese MC, et al. JAMA 2019;322 (4):315–325. 4. Westhovens R, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219213. 5. Combe B, et al. Arthritis Rheumatol 2021;73(suppl 10). https://acrabstracts.org/abstract/clinical-outcomes-up-to-week48-of-filgotinib-treatment-in-an-ongoing-long-term-extension-trial-of-rapatients-with-inadequate-response-to-mtx-initially-treated-with-filgotinib-or-adalimumab-during-th/. Last accessed: February 2022.

Genovese MC, et al. JAMA 2019;322 (4):315–325. 4. Westhovens R, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219213. 5. Combe B, et al. Arthritis Rheumatol 2021;73(suppl 10). https://acrabstracts.org/abstract/clinical-outcomes-up-to-week48-of-filgotinib-treatment-in-an-ongoing-long-term-extension-trial-of-rapatients-with-inadequate-response-to-mtx-initially-treated-with-filgotinib-or-adalimumab-during-th/. Last accessed: February 2022.

6. Buch MH, et al. Arthritis Rheumatol 2021;73 (suppl 10). https://acrabstracts.org/abstract/clinical-outcomes-up-to-week-48-of-ongoing-filgotinib-ra-long-term-extension-trial-of-biologic-dmard-inadequateresponders-initially-on-filgotinib-or-placebo-in-a-phase-3-trial/. Last accessed: February 2022. 7. Winthrop K, et al. Arthritis Rheumatol 2021;73(suppl 10). Available at: https://acrabstracts.org/abstract/integratedsafety-analysis-update-for-filgotinib-in-patients-with-moderately-to-severely-active-rheumatoid-arthritis-receiving-treatment-over-a-median-of-2-2-years/. Last accessed: February 2022.

February 2022 IE-RA-JY-202201-00016

more at strengthofbalance.co.uk

2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214. 3.

1. JYSELECA SPC. Available at: www.medicines.ie. Last accessed: February 2022.

References: 1. JYSELECA SPC. Available at: www.medicines.ie. Last accessed: February 2022. 2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214.

JYSELECA shows more than 5x greater potency for JAK1 over JAK2/3 and TYK21*

Gout: Latest diagnosis and management approaches

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

Gout is a common systemic condition caused by the deposition of monosodium urate crystals (MSU) in articular and nonarticular structures. Although presenting as an intermittent flaring condition, gout is a chronic disease. It is a painful and debilitating condition with a high prevalence and associated morbidity.10 Increased serum uric acid (SUA) above a specific threshold is a requirement for the formation of uric acid crystals, and hyperuricaemia is the greatest risk factor for the development of gout.1, 2 Gout occurs in response to the presence of MSU crystals in joints, soft tissues, and bones. It is characterised by sudden, severe attacks of pain, swelling, redness and tenderness in one or more joints, most often in the big toe, but other commonly affected joints include the ankles, knees, elbows, wrists, and fingers. It may result in recurrent flares of inflammatory arthritis, chronic gouty arthropathy, the accumulation of urate crystals in the form of tophaceous deposits, uric acid nephrolithiasis, and chronic nephropathy. Long-term complications of gout include joint damage and renal stones.3, 5, 8, 10

Serum urate is regulated by urate transporters in the kidney and gut. Activation of the NLRP3 inflammasome by monosodium urate crystals with release of IL-1β plays a major role in the initiation of gout flares, and aggregated neutrophil extracellular traps are important in the resolution phase.1

Although hyperuricaemia is the main pathogenic defect in gout, many people with hyperuricemia do not develop the condition, or form uric acid crystals. Only 5 per cent of people with hyperuricaemia above 9mg/dL develop gout, and other factors

including genetic predisposition share in its occurrence.2,4

Worldwide, the incidence of gout is increasing gradually due to poor dietary habits such as processed foods, lack of exercise, increased incidence of obesity, and metabolic syndrome. Reports of the prevalence and incidence of gout vary widely according to the population studied and methods employed, but range from a prevalence of <1-to-6.8 per cent and an incidence of 0.58-to-2.89 per 1,000 person-years.3 According to Arthritis Ireland, it is estimated that up to one-in-40 people are affected by gout.14 Factors affecting SUA levels include age and gender. It occurs more often in men than women (3-to-6 per cent in men and 1-to-2 per cent in women in Western countries), however, SUA levels in postmenopausal women can rise to the same levels as in men. Prevalence can rise to 10 per cent in men and 6 per cent in women over the age of 80 years.

Rarely, gout can occur in children and young adults who have inborn errors of purine metabolism.2,3 Deficiency of enzymes involved in purine metabolism leads to overproduction

of uric acid. Lesch-Nyhan syndrome is an inborn error of metabolism resulting from deficiency of an enzyme (hypoxanthineguanine phosphoribosyltransferase) involved in uric acid metabolism. It is a genetic X-linked recessive disorder with varying degrees of severity according to the type of mutation. Lesch-Nyhan syndrome involves neurological abnormalities such as dystonia, chorea, cognitive dysfunction, compulsive injurious behaviour, self-mutilation, and articular manifestations (early-onset gout), in addition to renal stones. If left untreated, it may lead to tophi formation and renal failure.3

Another enzymatic abnormality that causes gout in the young is the super activity of phosphoribosyl pyrophosphate synthetase. It is an X-linked dominant inherited disorder. The syndrome has two clinical forms; a severe early onset form in children, and a mild late juvenile or early adult onset form. It includes neurological abnormalities such as sensorineural hearing loss, hypotonia, and ataxia in the severe form. The mild form manifests as uric acid renal stones and arthritis. These enzymatic disorders constitute less than 10 per cent of cases of overproduction of urates.3

Risk factors

Hyperuricaemia is the leading cause of gout. Factors implicated for gout and/or hyperuricaemia include older age, male sex, obesity, purine diet, alcohol, medications, comorbid diseases, and genetics.5

Foods rich in purines such as cooked or processed food, especially from animal and seafood origin, is a key element of

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Worldwide, the incidence of gout is increasing gradually due to poor dietary habits such as processed foods, lack of exercise, increased incidence of obesity and metabolic syndrome

increasing uric acid precursors. Alcohol is a well-known risk factor for gout. Certain medications including low-dose aspirin, thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors and beta blockers can increase uric acid levels, as can the use of anti-rejection drugs prescribed for people who have undergone an organ transplant. Increased endogenous production of uric acid occurs in accelerated cellular turnover such as in malignancies, haematological and inflammatory diseases, and increased purine production may also result from chemotherapy and tissue damage. Genomewide association studies have found several genes associated with gout including SLC2A9, ABCG2, SLC22A12, GCKR, and PDZK1.5, 8 Increased body weight and obesity leads to enhanced production of uric acid aggravating the risk of hyperuricaemia. Leptin is also found to increase serum levels of urate.3

The prevalence of gout is higher among individuals with chronic diseases and comorbidities such as hypertension, chronic kidney disease, diabetes mellitus, obesity, congestive heart failure, and myocardial infarction. Every condition that causes alterations in extracellular urate concentration can trigger a flare-up of gout. These include stress (recent surgery or

trauma), dietary factors (eg, fatty food, beer, wine, and spirits), and medications such as aspirin and diuretics. 5, 8

Presentation and diagnosis

Patients usually present with acute onset of joint pain. Gout flares are more common at night and in the early morning. The pain is often sudden, waking the person from their sleep or may develop gradually over a few hours, with the maximum intensity of pain at 24 hours. Signs of inflammation usually extend beyond the joint involved. The pain is severe, and even lightly touching the joint can be excruciatingly painful. Gout flare-ups often incite local inflammation, which presents as erythematous, swollen, and a warm joint. Systemic features of joint inflammation may include fever, general malaise, and fatigue.5, 9

Gout flare is usually mono-articular, often occurring in the lower extremities. The most commonly involved joint is the first metatarsophalangeal joint. In some cases, the talar, subtalar, ankle, and knee can be involved. Other joints, specifically those with underlying osteoarthritis, can also be affected. Periarticular structures such as tendons and bursa may also be affected. Gout can occur in axial joints such as sacroiliac joints and the spine, although much less common than peripheral involvement, leading to diagnostic

confusion. Polyarticular gout flares are more likely to occur in patients with long-standing disease. Initial presentation of polyarticular gout is more frequent in patients in whom gout and hyperuricaemia arise secondary to lymphoproliferative or myeloproliferative disorder, or in organ transplant recipients receiving tacrolimus or cyclosporine.6, 7

Physical examination findings usually align with the patient’s history. The affected joint is usually red, swollen, warm, and tender. In patients with chronic gout, the flare-up may involve multiple joints. Tophi, which are subcutaneous depositions of urate that form nodules, can also be found in patients with persistent hyperuricaemia. Tophi typically occur in the joints, ears, finger pads, tendons, and bursae.5,9

Investigations usually reveal elevations in the white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) during a gout flare-up, however, these features are non-specific and do not confirm the diagnosis. The serum urate level should be repeated in patients with an uncertain gout diagnosis after the resolution of the flare-up. Hyperuricaemia is helpful in the clinical diagnosis of gout in symptomatic patients, but hyperuricaemia alone does not definitively confirm the

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FIGURE 1: Gout tophi

Eight updated EULAR recommendations for the diagnosis of gout

1. Search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of MSU crystals allows a definitive diagnosis of gout

2. Gout should be considered in the diagnosis of any acute arthritis in an adult. When synovial fluid (SF) analysis is not feasible, a clinical diagnosis of gout is supported by the following suggestive features: Mono articular involvement of a foot (especially the first metatarsophalangeal, MTP) or ankle joint; previous similar acute arthritis episodes; rapid onset of severe pain and swelling (at its worst in <24 hours); erythema; male gender and associated cardiovascular diseases and hyperuricaemia. These features are highly suggestive, but not specific for gout

3. It is strongly recommended that synovial fluid aspiration and examination for crystals is undertaken in any patient with undiagnosed inflammatory arthritis

4. The diagnosis of gout should not be made on the presence of hyperuricaemia alone

5. When a clinical diagnosis of gout is uncertain and crystal identification is not possible, patients should be investigated by imaging to search for MSU crystal deposition and features of any alternative diagnosis.

6. Plain radiographs are indicated to search for imaging evidence of MSU crystal deposition, but have limited value for the diagnosis of gout flare. Ultrasound scanning can be more helpful in establishing a diagnosis in patients with suspected gout flare or chronic gouty arthritis by detection of tophi not evident on clinical examination, or a double contour sign at cartilage surfaces, which is highly specific for urate deposits in joints

7. Risk factors for chronic hyperuricaemia should be searched for in every person with gout, specifically: Chronic kidney disease; overweight, medications (including diuretics, low-dose aspirin, cyclosporine, tacrolimus); consumption of excess alcohol (particularly beer and spirits), non-diet sodas, meat, and shellfish

8. Systematic assessment for the presence of associated co morbidities in people with gout is recommended including obesity, renal impairment, hypertension, ischaemic heart disease, heart failure, diabetes, and dyslipidaemia

diagnosis. Asymptomatic hyperuricaemia is not uncommon in the general population. Persistently low serum urate concentrations make the diagnosis of gout less likely. In patients suspected of gout based on clinical features, elevated serum urate level (>6.8mg/ dL) can support the diagnosis, but is neither diagnostic nor required to establish the diagnosis. The most accurate time for assessing serum urate levels to establish a baseline value is two weeks or more after a gout flare completely subsides.5

Monosodium urate crystal identification is the gold standard for gout diagnosis. Gout flare-up is marked by the presence of MSU crystals in synovial fluid obtained from affected joints. Synovial fluid during a gout flare-up is usually yellow in colour and cloudier in appearance, and contains crystals and white blood cells with neutrophil predominance. Synovial fluid in patients with septic arthritis is usually opaque, with a yellow-green appearance.

Under microscopic examination, synovial fluid for septic arthritis will have a higher WBC count than in gout and a positive gram stain.5

Although not routinely used, ultrasonography and dual-energy CT (DECT) can assist in diagnosing gout. Monosodium urate deposition will be apparent on ultrasound as a hyperechoic enhancement over the cartilage.5

In 2018 EULAR published updated evidence-based recommendations for the diagnosis of gout, which supersede the 2006 recommendations. There are eight updated recommendations (see Table 1).16

The updated recommendations centre mainly on clinical presentation, imaging tools, and evaluation of comorbidities. They discard recommendations for renal excretion rate and septic arthritis, and reformulate, but maintain,

recommendations for a gold-standard diagnosis based on microscopic synovial fluid analysis, which is mandatory for any acute arthritis. The 2018 EULAR recommendations include a conceptual change from the previous recommendations, reinforcing that gout can be the cause of any kind of acute arthritis, rather than suggesting that typical clinical presentations are highly suggestive of gout. In addition, they outline specific clinical features suggestive of typical gout flares. An interaction between clinical features and imaging findings allowed for formulation of a new staging of gout, known as ‘subclinical gout’ or urate crystal deposition without gout symptoms.19

Treatment and management

The choice of drug therapy depends on timing, contraindications, the patient’s previous experience with treatments, and the number and type of joints affected.12 Urate-lowering therapy (ULT) is started at a low dose to monitor the side-effects and response to treatment. During ULT initiation, there is an increased risk of gout flare-ups, so anti-inflammatory medications or colchicine prophylaxis is recommended to reduce the risk.5

Long-term ULT leads to the dissolution of monosodium urate crystals, ultimately resulting in the prevention of gout flares and tophi, and improved quality-of-life.1 Xanthine oxidase inhibitors (XOI) work by inhibiting uric acid synthesis. This class includes allopurinol and febuxostat.5 Allopurinol is the recommended first-line pharmacologic ULT in gout. It is not an analgesic, and does not have any effect during a gout attack. It works by lowering the level of uric acid in the blood, and can take two-to-three months to become fully effective. It needs to be taken every day to keep the uric acid level normal to prevent gout attacks.11 Febuxostat is also effective in preventing gout flares by keeping uric acid levels low, however, it has side-effects, and is usually reserved for people who are unable to take allopurinol.11

The American College of Rheumatology (ACR) published an updated set of guidelines for the management of gout in 2020.17,18 Strong recommendations include initiation

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TABLE 1: 2018 EULAR update of evidence-based recommendations for diagnosis of gout16

Treatment of gout

1. Acute gout flares should be treated as soon as diagnosed

2. First-line options identified for acute flare include: Colchicine, loading dose of 1mg, 0.5mg on day one, or a NSAID, oral corticosteroids (equivalent prednisolone dose of 30-35mg/ day for 3-5 days), or joint aspiration with intraarticular injection of corticosteroids. Avoid colchicine and NSAID administration in patients with renal impairment

3. Interleukin (IL)-1 blockers should be considered in patients with both frequent disease flares and contraindications to receiving colchicine, NSAIDs, or corticosteroids

4. Urate-lowering therapy (ULT) should be accompanied by prophylaxis in the first six months of treatment. Colchicine is recommended at a dose of 0.5-1mg/day, with adjustments for renal impairment. When colchicine is not tolerated well or is contraindicated, prophylaxis with NSAIDs at a low dosage can be considered

5. Patients with definitive gout diagnosis and ≥two gout flares/year, tophi, urate arthropathy, or recurrent kidney stones should be considered for ULT. Patients who are <40 years old or who have SUA levels >8mg/dL (480µmol/L), or other comorbidities should receive early ULT

6. SUA targets of <6mg/dL (360µmol/L) should be targeted with ULT therapy, SUA targets of <5mg/dL (300µmol/L) may be appropriate in patients with severe gout. Long-term SUA levels of <3mg/dL are generally not recommended

7. Initiation of low-dose ULT is recommended, with upward titration until SUA goal is attained

8. Allopurinol is recommended by the taskforce as the first-line ULT, beginning with 100mg/ day and increasing by 100mg increments every two-to-four weeks if needed to attain SUA goal. Febuxostat or a uricosuric should be started if allopurinol alone cannot be used to attain target SUA, or if it is not well tolerated

9. Creatinine clearance should be used to adjust allopurinol maximum daily doses for patients with renal impairment

10. When target SUA levels cannot be attained in patients with debilitating chronic tophaceous gout and crystal-proven disease, pegloticase is indicated

11. If a patient presents with gout and is on loop or thiazide diuretics, it is recommended that the diuretic be switched. Losartan or calcium channel blockers should be considered to replace diuretic indicated for hypertension and a statin should be considered for hyperlipidaemia

of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100mg/day, and lower in CKD) or febuxostat (<40mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate measurements, with a serum urate target of <6mg/dl. When initiating ULT, concomitant anti-inflammatory prophylaxis therapy for a duration of at least three-tosix months is strongly recommended. For management of gout flares, colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids (oral, intra-articular, or

intramuscular) are strongly recommended.

The current EULAR recommendations for the management of gout (2016),12 contain three overarching principles and 11 key recommendations (see Table 2).12 For the treatment of flare, colchicine, NSAIDs, oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, and an interleukin-1 (IL-1) blocker should be considered. In addition to education and a non-pharmacological management approach, ULT should be considered from the first presentation of the disease, and SUA levels should be maintained at <6mg/dL (360µmol/L) and <5mg/dL (300µmol/L) in those with severe

gout. Allopurinol is recommended as firstline ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric, or combining an XOI with a uricosuric, should be considered. For patients with refractory gout, pegloticase is recommended. Because of the high cost of IL-1 blockers and an increased likelihood of infection, EULAR recommends they be prescribed only for patients who have contraindications to colchicine, NSAIDs, and corticosteroids.12

A proton-pump inhibitor (PPI) may be required to protect the stomach lining of patients taking NSAIDs. Contraindications for the use of NSAIDs include active duodenal or gastric ulcer, cardiovascular disease, NSAID allergy, and CKD.5 Colchicine should not be given to patients with kidney impairment or those receiving strong P-glycoprotein and/ or CYP3A4 inhibitors such as cyclosporin or clarithromycin.12 Adverse effects of colchicine include abdominal cramping and diarrhoea.5

Non-pharmacological management such as rest with topical application of ice packs combined with medications can help reduce inflammation.5 Most people continue to have further flares. These can be prevented by a combination of lifestyle modification such as losing weight, changing diet, reducing/ eliminating alcohol, and medicines to reduce urate levels.10

EULAR recommends that every person with gout should be systematically screened for associated comorbidities and cardiovascular risk factors, including renal impairment, coronary heart disease, heart failure, stroke, peripheral arterial disease, obesity, hyperlipidaemia, hypertension, diabetes, and smoking, which should be addressed as an integral part of the management of gout.12,13

Patient education is also a key aspect of gout management, and patients must be kept informed and involved in the management of their condition. All patients with gout should receive advice regarding lifestyle management; weight loss if appropriate, and avoidance of alcohol, especially beer and spirits,

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TABLE 2: EULAR 2016 gout management recommendations

and sugar-sweetened drinks, heavy meals and excessive intake of meat and seafood. Low-fat dairy products should be encouraged and regular exercise should be advised.12 Patients should receive information regarding gout pathophysiology, triggers, treatment options, burden of comorbidities, general medical management of acute attack management, and the lifelong need to reduce SUA to target levels.13,14

For detailed information about gout and sleep and fatigue, exercise, work and lifestyle information, patients can download the Living with Gout booklet or contact the Arthritis Ireland Helpline at 081 8252846 or email: helpline@arthritisireland.ie.14

Outlook

Although gout is a treatable disease, its management is still not optimal in a large proportion of patients. Studies report that less than half of patients with gout receive ULT, and that when prescribed, it is often at an insufficient dose to effectively lower the SUA levels to target.3,12 Studies also suggest that fewer than a half of patients adhere to treatment.3 Many gout risk factors exist, including obesity, dietary factors and comorbid conditions. As well as a firmly established increased risk of cardiovascular disease and CKD, associations with other comorbidities have been reported, including erectile dysfunction, atrial fibrillation, obstructive sleep apnoea, osteoporosis, and venous thromboembolism. Increasing prevalence and incidence of obesity and comorbidities are likely to contribute substantially to the rising burden of gout.3

Continued emphasis on patient and clinician education, and attempts to standardise international medical approaches regarding gout, outcome measures, staging and its management are important strategies. Investigating the possible role of the microbiome in gout parallel to its metabolic counterparts, and intensive studies in genomics and proteomics, may also lead to a better understanding of disease predisposition and susceptibility to drug adverse effects, and offer potential therapeutic breakthroughs for the future treatment and management of gout.1

Researchers at Washington State University and elsewhere recently identified a new therapeutic target for the treatment of gout, with their work published in the journal Cellular and Molecular Immunology. The study suggests that blocking a signalling molecule known as TAK1 can suppress inflammation caused by gout. This research lays the foundation for the development of potential new treatment strategies that could significantly improve the quality-of-life of millions of people around the world.15

References

1. Dalbeth N, Gosling A, Gaffo A, Abhiskek A. (2021). Gout. Lancet ; Volume 397; Issue; 10287; pp 1843-1845; March 2021. doi: 10.1016/S01406736(21)00569-9

2. Ragab G, Elshahaly M, Bardin T. (2017). Gout: An old disease in new perspective – A review. J Adv R, 8(5), 495–511

3. Dehlin M, Jacobsson L, Roddy E. (2020). Global epidemiology of gout: Prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020 Jul;16(7):380-390. doi: 10.1038/s41584-020-0441-1

4. Dalbeth N, Merriman T, Stamp L. Gout. Lancet. 2016; 388(10055):2039–2052

5. Fenando A, Rednam M, Gujarthi M. (2021). Gout. In StatPearls Publishing. Available at: www.statpearls.com/ArticleLibrary/ viewarticle/22376

6. Komarla A, Schumacher R, Merkel P. (2013). Spinal gout presenting as acute low back pain. Arthritis Rheum. 2013 Oct;65(10):2660. doi: 10.1002/art.38069

7. Lumezanu E, Konatalapalli R, Weinstein A. (2012). Axial (spinal) gout. Current rheumatology reports. PubMed PMID: 22318623

8. Mayo Clinic. (2022). Gout. Available at: www.mayoclinic.org/diseases-conditions/gout/ symptoms-causes/syc-20372897

9. HSE. (2022). Gout. Health Service Executive. Available at: www2.hse.ie/conditions/gout/

10. NICE (2020). Guideline scope Gout: Diagnosis and management. National Institute for Health and Care Excellence. Available at: www.nice. org.uk/guidance/gid-ng10151/documents/finalscope-2

11. Patient. (2022). Gout. Patient info. Available at: https://patient.info/foot-care/gout-leaflet

12. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheumatic Dis 2017; 76:29-42

13. Sison C. (2016). EULAR releases updated gout management guidelines. Rheumatology Advisor. Available at: www.rheumatologyadvisor. com/home/topics/gout/eular-releases-updatedgout-management-guidelines/

14. Arthritis Ireland. (2022). Gout. Arthritis Ireland. Available at: www.arthritisireland.ie/gout

15. Science Daily. (2019). Potential new target for treatment of gout. Available at: www. sciencedaily.com/releases/2019/10/191029095629. htm

16. EULAR. (2018). EULAR publishes 2018 update of evidence-based recommendations for diagnosis of gout. Available at: www. eular.org/sysModules/obxContent/files/ www.eular.2015/1_42291DEB-50E5-49AE5726D0FAAA83A7D4/pr_gout_final.pdf

17. Wiley online Library. (2020). 2020 American College of Rheumatology Guideline for the Management of Gout. doi: 10.1002/art.41247

18. Chaplin S. (2021). Summary of the ACR guideline on the management of gout. Prescriber. Wiley Clinical Healthcare Hub. Available at: https://wchh.onlinelibrary.wiley. com/doi/full/10.1002/psb.1887

19. Pérez-Ruiz F. (2019). The 2018 updated EULAR recommendations for the diagnosis of gout: What’s new, what’s changed, and what’s gone? Medicine Matters. Available at: https://rheumatology.medicinematters. com/gout/diagnosis-and-screening/neweular-recommendations-for-diagnosis-ofgout/17152630

20. Crowley S. (2021). Gout in the 21st Century. Medical Independent. pp 1-5, January 2021

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

Study finds treat-to-target ULT strategy manages gout effectively and safely with no cardiovascular toxicity

AUTHOR: Priscilla Lynch

New research presented at ACR Convergence 2021, the American College of Rheumatology’s (ACR) annual meeting, held online in November, shows that allopurinol and febuxostat may effectively lower urate levels when used in a treat-to-target approach.

Importantly, both urate-lowering therapies (ULT) were very effective with 90 per cent of patients reaching target urate levels. Additionally, both appeared safe, with no evidence of increased cardiovascular toxicity (Abstract #1900).

ULT is a cornerstone treatment for gout management, but there is a lack of data to support the comparative efficacy and safety of the two major oral ULTs, allopurinol and febuxostat, when prescribed in a treat-totarget approach. There is also an urgent need to determine if these ULTs are safe and effective in gout patients with chronic kidney disease, a common comorbidity. Researchers conducted this multicentre, randomised, double-blind, non-inferiority trial to compare the safety and efficacy of these two therapies for gout management.

“Our trial is the first to compare allopurinol to febuxostat using the recommended treatto-target, urate level approach. This trial demonstrates that both agents are highly effective and safe when used in this way and, importantly, this was true in patients with chronic kidney disease as well,” said Dr James R O’Dell, Chief, Division of Rheumatology, at the University of Nebraska Medical Centre in Omaha and the study’s co-author.

For the 72-week trial, 940 patients with gout and a serum urate concentration of 6.8mg/dl or higher were randomised to receive either allopurinol or febuxostat between 2017 and 2019. Patients with persistent elevated uric acid levels in the blood, despite allopurinol treatment (300mg/dl or less), were eligible;

by design over one-third of patients had chronic kidney disease, stage III. The trial had three phases: ULT titration from week 0-24, maintenance therapy from week 25-48, and observation with continued, stable ULT from week 49-72.

Patients received initial doses of either 100mg of allopurinol with maximum titration to 800mg, or 40mg of febuxostat with maximum titration to 120mg (reduced to 80mg in 2019 at the request of the US Food and Drug Administration (FDA)). Patients also received anti-inflammatory treatments selected by the site investigator until the start of the third phase.

The primary outcome was the proportion of patients who had one or more gout flares during the third phase.

Similarly, effectiveness and tolerability of the two drugs in stage III chronic kidney disease patients were examined, as were serious sideeffects, and the proportion of patients who achieved a serum urate of less than 6mg/dl by the end of the second phase of the trial.

During the third phase, 35 per cent of patients

taking allopurinol had one or more gout flares compared to 42 per cent of patients taking febuxostat. Overall, 80 per cent of patients in the trial achieved a serum urate level of less than 6.0mg/dl, and 92 per cent achieved a level of less than 6.8mg/dl during the second phase, with no difference between the two treatments. There were also no differences in serious side-effects between the two treatment groups, including the percentage of patients with cardiovascular events in people with or without chronic kidney disease. That final finding is important, because nearly one in every two gout patients suffers from renal insufficiency.

Allopurinol was found to be non-inferior to febuxostat when prescribed as part of a treat-to-target approach in people with gout, providing two effective, safe treatment options for managing serum urate levels long-term, the study’s findings show.

“Gout is a common and increasing cause of morbidity in patients, as well a major cause of work loss,” said Dr O’Dell. “This trial shows that if a treat-to-target, uric acidlevel approach with either allopurinol or febuxostat is widely adopted, chronic gout could be essentially wiped out.” 

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Gout (inflamatory arthritis)

Osteoarthritis in focus

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

Osteoarthritis is a chronic degenerative joint disorder characterised by cartilage loss. It is a leading cause of pain and disability, affecting 3.3-to-3.6 per cent of the global population and is the most common form of arthritis worldwide. Osteoarthritis affects approximately 400,000 Irish people and is the most common joint disease in Ireland.

Osteoarthritis presents with joint pain and loss of function; however, the disease is widely variable and can present from an asymptomatic incidental finding to a permanently disabling disorder. Osteoarthritis is a heterogeneous disease caused by multiple factors. Risk factors for developing osteoarthritis include increasing age, female gender, obesity, anatomical factors, muscle weakness and joint injury, particularly from occupational and sports activities.

The prevalence and incidence of osteoarthritis increase with age, with a majority of individuals over the age of 65 affected. The occurrence of osteoarthritis is progressively rising, due to increased life expectancy and population ageing together with a rise in obesity. Excess weight compounds the problem by putting extra strain on damaged joints.

Osteoarthritis is more common and often more severe in women, especially in the knees and hands. It often starts after the menopause. Certain occupations can place excessive loads on the joints resulting in osteoarthritis in later years. Occupations with repetitive knee-bending can result in knee osteoarthritis, while heavy manual labour may predispose to hip osteoarthritis.

Although complex, the genetic contribution to osteoarthritis is significant. The roles of genes and signalling pathways in

osteoarthritis pathogenesis have been demonstrated by ex vivo studies using tissues derived from osteoarthritis patients and in vivo studies using surgically-induced osteoarthritis animal models and genetic mouse models.

Nodal osteoarthritis is one common form of osteoarthritis that runs strongly in families, and particularly affects the hands of middleaged women. In other common forms of osteoarthritis, heredity plays a small part compared with obesity, ageing and joint injury. There are some very rare forms of osteoarthritis that start at a young age and run in families and these are linked with single genes that affect collagen, which is an essential component of cartilage.

Osteoarthritis is a disease of the entire joint and is recognised as a low-grade inflammatory disease involving cartilage degradation, bone remodelling, osteophytes and synovitis. The chronic low-grade inflammation found in osteoarthritis contributes to disease development and progression. During osteoarthritis progression, the entire synovial joint, including cartilage, subchondral bone, and synovium, are involved in the inflammation process.

Osteoarthritis can be classified into two categories: Primary osteoarthritis and secondary osteoarthritis. Primary osteoarthritis is the most common subset and is diagnosed in the absence of predisposing trauma or disease.

Primary osteoarthritis can be localised or generalised, the latter more commonly found in postmenopausal women, with development of Heberden’s nodes.

Secondary osteoarthritis occurs with a pre-existing joint abnormality. Predisposing conditions include trauma or injury, congenital joint disorders, inflammatory

arthritis, avascular necrosis, infectious arthritis, Paget’s disease, osteopetrosis, osteochondritis dissecans, metabolic disorders, haemoglobinopathy, EhlersDanlos syndrome, or Marfan syndrome.

Symptoms

The presentation and progression of osteoarthritis varies greatly from person to person. The triad of symptoms are joint pain, stiffness and locomotor restriction. Patients can also present with muscle weakness and problems with balance. Pain is usually related to activity and resolves with rest. For patients in whom the disease progresses, pain is more continuous and affects activities of daily living, eventually causing severe limitations in function. Patients may also experience bony swelling, joint deformity and instability.

Osteoarthritis typically affects proximal and distal interphalangeal joints, first carpometacarpal joints, hips, knees, first metatarsophalangeal joints, and joints of the lower cervical and lumbar spine, and can be mono or poly articular in presentation. Shoulder and elbow joints are also susceptible to osteoarthritis although this is much rarer. Joints can be at different stages of disease progression.

Typical exam findings include bony enlargement, crepitus, effusions, and a limited range of motions. Tenderness may be present at joint lines, and there may be pain upon passive motion. Classic physical exam findings in hand osteoarthritis include Heberden’s nodes, Bouchard’s nodes, and ‘squaring’ at the base of the thumb.

Diagnosis

A thorough history and physical examination with a focused musculoskeletal exam should be carried out. Differential

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diagnosis can include rheumatoid arthritis, psoriatic arthritis, crystalline arthritis, haemochromatosis, bursitis, avascular necrosis, tendinitis, and radiculopathy, among other soft tissue abnormalities.

There are no specific blood tests for diagnosing osteoarthritis, however, blood tests including FBC, ESR, rheumatoid factor, and anti-nuclear antibodies can be ordered to rule out inflammatory arthritis.

X-rays of the affected joint can show findings consistent with osteoarthritis, such as marginal osteophytes, joint space narrowing, subchondral sclerosis, and cysts, however, radiographic findings do not correlate to the severity of the condition and may not be present early in the disease. MRI is not routinely indicated for osteoarthritis workup; however, it can detect osteoarthritis at earlier stages than normal radiographs.

Ultrasound can also identify synovial inflammation, effusion, and osteophytes, which can be related to osteoarthritis.

Treatments

Current therapeutic options are aimed at keeping the associated pain, inflammation, and degeneration of synovial joint tissues manageable in order to minimise the structural and symptomatic progression of osteoarthritis. Management of the disease involves both pharmacological and nonpharmacological therapies.

Pharmacotherapy involves oral, topical, and/or intra-articular options. Paracetamol and oral NSAIDs are usually the initial choice of pharmacological treatment. Topical NSAIDs are less effective than their oral counterparts, but have fewer gastrointestinal and other systemic sideeffects. A proton pump inhibitor (PPI) may

also be prescribed at the same time as oral NSAIDs to reduce the risk of damage to the stomach lining. Capsaicin cream may also be prescribed for osteoarthritis of the hands or knees, if topical NSAIDs have not been effective in easing pain. Capsaicin cream works by blocking the nerves that transmit pain in the treated area.

Intra-articular joint injections can be an effective treatment for osteoarthritis. Glucocorticoid injections have a variable response, however, and there is ongoing controversy regarding repeated injections. Although corticosteroid injections can ease osteoarthritis symptoms, they have limitations. They cannot repair damaged cartilage or slow the progression of osteoarthritis, and relief is only temporary. There are also some risks involved with glucocorticoid joint injections including; injury to the joint tissues, mainly with repeated injections; thinning of cartilage; weakening of the ligaments of the joint; inflammation in the joint caused by a corticosteroid that has crystallised; irritation of the nerves; infection; and whitening or thinning of the skin at the injection site.

Non-pharmacologic therapy includes avoidance of activities that exacerbate pain, exercise to improve strength, weight loss if applicable, wearing suitable footwear and occupational therapy for unloading joints. Malalignment of joints should be corrected via mechanical means such as a realignment knee brace or orthotics. Weight loss is an important intervention in patients who are overweight and obese. Regular exercise that keeps a person active, builds up muscle, and strengthens the joints usually helps to improve symptoms. Patients should, however, be advised to avoid exercise that puts strain on joints and forces them to bear an excessive load, such as running and weight training. Activities such as swimming and cycling, where strain on joints is more controlled, are advisable.

In addition to lifestyle changes and pharmacology, patients may benefit from a number of supportive treatments that can help reduce pain and make everyday

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FIGURE 1A and 1B : Normal joint versus joint with osteoarthritis Source: www.arthritisireland.ie/osteoarthritis A normal joint Capsule and ligaments

Bone Bone

Thickened joint capsule Bone thickens and spreads out (osteophytes) Cartilage Cartilage thins further Thinning cartilage Synovial fluid Synovial membrane More advanced osteoarthritis The early stages of osteoarthritis

tasks easier. Not using joints can cause muscles to waste and increase the stiffness caused by osteoarthritis. Manual therapy is a technique where a physiotherapist uses their hands to stretch, mobilise and massage the body tissues to keep a patient’s joints supple and flexible. Applying hot or cold packs to the affected joints can also help relieve the pain and symptoms of osteoarthritis in some people. Transcutaneous electrical nerve stimulation (TENS) if advised by a doctor or healthcare professional may help ease the pain caused by osteoarthritis, by numbing the nerve endings in the spinal cord which control pain. For osteoarthritis in the lower limbs, such as hips, knees or feet, special footwear or insoles for shoes may be helpful. Footwear with shock-absorbing soles can help relieve some of the pressure on the leg joints when walking, and special insoles may help spread weight more evenly. Leg braces and supports also work in the same way. For osteoarthritis in the hip or knee that affects mobility, the use of a walking aid, such as a stick or cane, may be beneficial. Occupational therapists can provide help and advice about using assistive devices in the home or workplace.

Osteoarthritis can affect any joint in the body, but the most common areas affected are the knees, hips and small joints in the hands. For patients with knee or hip osteoarthritis for whom pharmacological and non-pharmacological treatments have failed, joint replacement surgery/ arthroplasty is the next option. Failure rates for both knee and hip replacements are quite low, and joint replacement can provide pain relief and increased

functionality. The timing of surgery is important. Poor functional status and considerable muscle weakness may not lead to improved postoperative functional status versus those undergoing surgery earlier in the disease course. Most patients who undergo joint replacement tend to have a good prognosis with success rates of over 80 per cent. However, most prosthetic joints wear out in 10-to-15 years, and repeat surgery is required. A newer type of joint replacement surgery called resurfacing uses only metal components and may be more suitable for younger patients.

If a joint replacement is not a suitable option, an operation to fuse the joint in a permanent position, known as an arthrodesis, may be carried out. The joint will be stronger and less painful; however, the patient will no longer be able to move it. For patients with osteoarthritis of the knees who are unsuitable for knee replacement surgery, an osteotomy may be performed. This involves adding or removing a small section of bone either above or below the knee joint. This helps realign the knee so weight is no longer focused on the damaged part of the knee. An osteotomy can relieve symptoms of osteoarthritis, although the patient may still need knee replacement surgery in the future.

Outlook

The prognosis for osteoarthritis patients depends on the joint involved, how many joints are affected, and the severity of the disease. There is currently no cure for osteoarthritis, and all available treatments are directed towards reducing symptoms. Although significant research has been

carried out and progress made in recent years, the molecular mechanisms of osteoarthritis initiation and progression is still not fully understood. The last decade has seen significant advances however, in understanding the processes that contribute to osteoarthritis and over the coming years these new insights will hopefully lead to better treatment options. Further research and a better understanding of the molecular mechanisms could accelerate the development of novel therapeutic strategies for osteoarthritis.

Traditional osteoarthritis management approaches often result in varying treatments, evidence practice gaps, and delayed treatment due to over demand and long waiting lists. Despite the considerable societal, economic, and personal burden associated with osteoarthritis, the condition is often overlooked in healthcare strategic plans for chronic disease management. A shift is needed to promote evidence-based management of osteoarthritis and address the underutilisation of core recommended treatments and over-reliance on surgery and pharmacological agents.

Model of Care ‒ ENACt Project

Osteoarthritis does not feature alongside other chronic diseases such as asthma or diabetes and there is currently no specific model of care for osteoarthritis in primary care in Ireland. The ENACt research project (2020-2024), led by researchers at the RCSI, hopes to change that and is in the process of developing a model of care for osteoarthritis in primary care to deliver best practice nationwide. The ENACt project is developing a model of care for osteoarthritis specifically tailored to the Irish healthcare system, with the goal of implementing and evaluating it on a large scale national level. The research, to be carried out in three work packages over four years, aims to identify current primary care management of osteoarthritis in Ireland and develop a model of care focusing on core interventions, education, exercise and weight loss. 

References on request

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The last decade has seen significant advances however, in understanding the processes that contribute to osteoarthritis and over the coming years these new insights will hopefully lead to better treatment options

An exercise prescription for dermatomyositis

AUTHOR: Andrew Dunne , Chartered Physiotherapist and Clinical Exercise Specialist, Personal Health Medical Exercise Clinic, Rathmines, Dublin, www.personalhealth.ie

Dermatomyositis is a chronic inflammatory disorder of the skin and muscles with characteristic cutaneous findings. It is autoimmune in origin. Adult onset can happen at any age with females being affected three times as frequently as males. This systemic disorder may also affect the joints, oesophagus, lungs, and less commonly the heart.

Exercise assessment for case report patient

The initial assessment was in April 2020 and as result was performed remotely via Zoom. This was a limiting factor for objective measurement. As a result, the online assessment only included two outcome measures – TUG and 30-second ‘Sit-to-Stand’ test. Risk stratification was completed and discussion focused on exercise intensity, frequency, and gradual progressions. Measurements such as body composition, sub-maximal Vo2 aerobic testing, and dynamometry were postponed until July of the same year when the patient could be seen in person.

In July 2020, the patient presented in clinic and was assessed for upper limb strength levels using hand-held dynamometry. Submaximal VO2 testing was performed on a recumbent watt bike. SpO2 levels were 97 per cent and pre-exercise assessment BP was 131/82.

A musculoskeletal screening assessed for joint mobility and range of motion globally, noting reductions in range of motion bilaterally on cervical spine rotation, left shoulder abduction, lumbar extension, hip abduction, and flexion bilaterally.

CASE REPORT

A 58-year-old female was referred by a clinical nurse specialist (CNS) in rheumatology for a clinical exercise prescription in April 2020. The patient was not coping well with comorbidity including dermatomyositis, hyperlipidaemia (statin intolerant), and extensive musculoskeletal history with surgical intervention. The referral was received at the height of early Covid-19 restrictions and as a result the initial consultations were done online via Zoom. There were some key issues around fatigue, pain management, and resultant fear-avoidance coping strategies. The patient was mobilising independently, but very carefully, around her family home. She had lost confidence in her ability to achieve anything beyond the basic activities of daily living. She was frustrated and desperate to improve her quality-of-life.

Background and diagnosis

The patient was diagnosed with dermatomyositis in 2013, confirmed on muscle biopsy with lung involvement. She had multiple interventions in the next five years including surgery for cervical spondylosis and a bilateral hip replacement in 2018. She was motivated to maintain an active lifestyle following her initial dermatomyositis diagnosis in 2013, however, a seemingly endless cascade of medical, surgical, and rehabilitation periods had gradually overwhelmed the patient.

Psychosocial impact

On presenting for initial assessment the patient described the gradual, but corrosive impact that poor health had on her lifestyle. She had reluctantly retired as a small business owner, had given up playing tennis, and no longer tended to her garden, which she was very passionate about. While she was aware that medication was a necessary part of her treatment plan, she also felt some drugs were contributing to a more persistent low mood. The patient had developed a complex relationship with her pain levels and this was having a negative impact on her perceived rehabilitation potential.

Ongoing medical management

The patient is being seen twice yearly by a consultant rheumatologist. She is taking a combination of 20mg methotrexate with folinic acid and folic acid once weekly. She is also taking vitamin D3 and a proton pump inhibitor (lansoprazole). Finally, she takes a range of analgesics (etoricoxib, Solpadeine, tapentadol, and diazepam PRN). She is statin intolerant and her total cholesterol is currently 8.1, despite a healthy diet. She has been referred to a cardiologist to assess her suitability for an alternative lipid-lowering medication. She has no cause for imaging in recent history.

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Dermatomyositis is a rare chronic inflammatory disorder of the skin and muscles

Flexible and collaborative exercise programming

There are currently no American College of Sports Medicine (ACSM) recommendations explicitly for dermatomyositis. Exercise participation may be a daily struggle for individuals living with rheumatological disease. Given that a rheumatology patient may have systemic inflammatory markers up to 100 times those of a healthy adult it is a unique challenge that needs to encourage, convince and reassure the patient all at once.

Exercise specialists play a central role in this through a mix of motivational interviewing and clinical education. It is vital that the patient feels safe, in control, and understood. Following these principles it is also paramount that the patient is educated around the benefits of low-intensity training initially.

A typical exercise prescription has four key pillars; aerobic, strength training, flexibility/ mobility, and neuromotor. In the case of rheumatology presentations, it is often

helpful to start with gentle mobility work in order to establish trust and a ‘feel-good’ factor around the looming spectre of exercise. Anecdotally, many of these patients will have been exposed (at some stage) to exercise progressions at a rate they could not tolerate, and as such, further developed unhelpful beliefs around the efficacy of regular movement. In good time, exposure to low-intensity strength and conditioning can be introduced and appropriately progressed in collaboration with the patient.

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FIGURE 1

At the outset it is also important to clearly define what the heart rate (HR) parameters are at varying levels of intensity. In this case we used the Tanaka method to establish multiple zones whereby the patient had a keen sense of the low-moderate exertion levels required. The patient purchased a Polar chest strap HR monitor due to its greater accuracy vs wrist wearables. We then

focused initially on zones one-to-three (very light-moderate) for the first six weeks of the exercise programme.

Exercise progressions post week six and beyond

Following a sustained period of mobility work whereby the patient noted significant improvements in joint range of motion

without any aggravation, it was now appropriate to introduce strength and conditioning principles.

Aerobic: Two-to-four days per week at lowmoderate intensity (or 8-12 on RPE Borg scale of exertion). The aerobic activity was not lower than 15-minute bouts in duration. Aerobic work was initially focused on low impact work to preserve excessive joint loading. We encouraged a mixture of cycling (static bike), swimming, and elliptical trainer. The many benefits of outdoor walking were also encouraged with some vigilance around duration and walking speed.

Strength training: One strength session per week was introduced using body weight resistance exercises across eight major muscle groups. The patient did these sessions online (via Zoom) supervised by a chartered physiotherapist.

Neuromotor: By week 12, higher-impact loading such as dynamic agility drills (ladder drills for improved footwork and balance) were being safely negotiated and enjoyed.

Patient update

After a 32-week supervised and personalised exercise programme the patient made statistically-significant improvement in almost all areas measured. A notable change saw a gain in lean muscle mass of 1.4kg. Cardiorespiratory fitness had improved significantly, meaning the patient was now considered ‘above average’ as per age-related normative data. The patient was walking outdoors regularly, had rekindled her passion for gardening, and was generally feeling a positive shift in overall quality-of-life. Her strength levels had also improved, with hand-held dynamometry being a clinical marker for improved vitality and reduced all-cause mortality. She is still realistic and cautious around management of her condition alongside triggers such as excessive workload, stress, anxiety, and fatigue. However, she has renewed confidence in making these issues less prevalent and destructive

her

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daily life.  July 2020 Feb 2021 WEIGHT (KG) 59kg 60.7kg LEAN MUSCLE (KG) 34.8kg 36.2kg CARDIORESPIRATORY FITNESS (VO2 MAX – ML/KG/MIN) 24 (below average) 33 (above average) STRENGTH – HH dynamometry RH - 14.5 LH - 13.1 RH - 22.6 LH - 21.1 6MWT (metres) 316 702 FIGURE 3:

programme

outcomes

Case report patient exercise

assessment

FIGURE 2: Case report patient exercise and exertion measurements

The many benefits of outdoor walking were also encouraged with some vigilance around duration and walking speed

Development of a new rheumatology ANP clinic for the management of patients with newly diagnosed rheumatoid arthritis. Barriers, facilitators, and results of a pilot programme

In 2017 the Sláintecare report was published by the Department of Health (DOH).1 It outlined a 10-year programme to transform our health and social care services and saw nursing as one of the main solutions to existing challenges in healthcare. It acknowledged that the DOH must support and enable nursing professionals to maximise their full potential and operate to the full of their license. The Sláintecare programme also recognised the need to develop healthcare services to be delivered in the community setting away from the acute hospital setting. Its focus is on co-ordinated integrated care between acute hospitals and community health, utilising a whole system approach based on person-centred models promoting patient selfmanagement and self-care in the community.

As part of healthcare service reform to improve patient care pathways, the demonstrator project initiative was also established that year by the DOH.2 This initiative outlined a novel approach to creating a critical mass of advanced nurse practitioners (ANPs) in Ireland across a number of disciplines including rheumatology. The aim of this initiative was to maximise the utilisation and application of nursing resources to optimise patient outcomes and improve services nationwide.2

The following year (2018) the National Clinical Programme for Rheumatology published the Model of Care for Rheumatic and MSK Disorders, 3 outlining a chronic disease model of care to

facilitate ‘the right person in the right place, first time’ method to rheumatology service delivery. This model proposed a ‘treat-to-target’ approach to services for patients with rheumatological disorders based on evidence-based practice in keeping with international standards of care in early rheumatoid arthritis (RA).4,5 Treatto-target is an internationally endorsed set of recommendations for optimising the care of patients with early inflammatory arthritis using a shared decision-making framework between the patient and practitioner.6 It is a structured treatment and management programme that aims for an achievable treatment ‘target’ of either low disease activity or remission through fast initiation and titration of disease-modifying medications with concomitant (short-term) use of non-steroidal anti-inflammatory medications and/or glucocorticoids as bridging agents to reach the treatment target as quickly as possible. By adopting this strategy and defining a target of treatment, short-term and long-term outcomes are improved for the patient; ie, better disease control, maintenance of independence, maintained functional ability, and a reduction in the risk of long-term disability.

In response to the demonstrator project initiative, the senior nursing management team in collaboration with the lead rheumatology clinical nurse specialist (CNS) in Cork University Hospital (CUH) submitted an expression of interest for a rheumatology candidate ANP post, which

was filled in September 2017 with the successful registration of the candidate in June 2019. Detailed discussion was undertaken, led by the local rheumatologists including the candidate ANP and business management teams, as to how best to utilise this new advanced practice post to optimise patient care in line with Sláintecare recommendations. It was agreed that the rheumatology ANP, once registered, would seek to develop the first Irish communitybased rheumatology ANP-led treat-to-target clinic for the management of patients with early RA.

Development and initiation

To get Executive Management Board (EMB) approval for service development, the ANP was tasked with producing a business case with supporting evidence detailing the service need through audit, projected service costs with anticipated logistical issues, beginning with a pilot of six patients. This began with defining the caseload. It was agreed that the ANP would accept the care of newly-diagnosed patients with RA for the first year after their diagnosis. Clinic capacity per annum was identified at 60 patients from discussion with other rheumatology ANPs who were delivering this service in the acute setting based on their new, return, and urgent reviews, and other ANP non-clinical commitments. Inclusion and exclusion criteria were outlined and a referral form was developed for use.

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AUTHORS: Louise Murphy, Advanced Nurse Practitioner, Department of Rheumatology, Cork University Hospital; Dr Sinead Harney, Consultant Rheumatologist, Department of Rheumatology, Cork University Hospital; and Elmar Cronin , BSc Physio, Primary Care Development Officer, Cork/Kerry Community Healthcare, HSE, St Mary’s Primary Care Centre, Gurranebraher, Cork

An audit of all newly-diagnosed RA patients in CUH over a one-year period (October 2018-October 2019) was undertaken by the ANP. This demonstrated a total number of 59 patients. Each patient’s home address was plotted on a map of Cork county and the wider Munster region to assess geographical spread and identify a potential pilot city location plus three county locations suitable for patients who would typically travel long distances.

To capture each visit on the hospital’s electronic patient management system the ANP liaised with the local medical records department to create an ANP clinic profile and subsequently a clinic code. Administration help was sought by the ANP for pulling of notes prior to clinics, but was declined. A digital dictation licence was approved by the business manager for ANP clinic letters as part of the business case workup. Clinical governance was agreed upon by all rheumatologists. To maintain GDPR guidelines it was agreed that the ANP would use a HSE laptop with access to patient labs, diagnostics, and file letters while off-site until a system was in place to deliver patient charts to the community settings. The business case was presented at EMB and approved on a cost-neutral basis.

It was initially envisaged by the ANP that clinic rooms in GP practices would be of most benefit to patients and would fully integrate the ANP service into the community. Preliminary meetings were held with two major GP practices in Cork county. Although each GP saw the value of the service and were eager to facilitate the ANP clinic, financial reimbursement for the use of GP rooms was a barrier to progression. After further discussion with hospital management it was suggested to liaise with the chief officer of Cork-Kerry Community Healthcare (CKCH) to seek a clinic location. Contact was made and the ANP was directed to the Primary Care Development Officer for Cork North who has a key role in developing HSE integrated services in the community setting. The business case illustrating the clear benefits to patient care and smooth integrated care service delivery was readily accepted. Further visits to the large CKCH

Primary Care Centre included discussions involving the ANP, the Assistant Director of Nursing, and the Business Manager from the medical directorate to clarify patient care pathways, clinical governance, logistics, and the selection of a suitable clinic consulting room, to enable the commencement in early 2020 of the pilot ANP-led clinic.

Barriers

On the 29 of February 2020 the first case of Covid-19 was confirmed in Ireland7 and during the months that followed hospital outpatient services and community clinics were forced to operate virtually with minimal patient face-to-face contact to protect service users and staff. The forced and rapid transition from face-to-face care coupled with the immediate reconfiguration of services to accommodate Covid-19 wards and emergency assessment areas caused major disruption to services.8 Many nursing and medical staff who were advised to ‘cocoon’ were not replaced nor were staff members on sick leave or those who were redeployed to Covid-19 units. Those who could work from home did so, but not every service could facilitate this option. Due to the increasing concern of Covid-19 at the time and the temporary ceasing of face-to-face reviews the ANP chose to postpone the clinic for six months. During this time due to the aforementioned issues with staffing, allied rheumatology CNS posts became vacant and so the ANP assumed responsibility for both CNS caseloads for the duration of 12 months. This increase in workload inhibited progression of the ANP community clinic due to onsite service demands. The main barrier to the initiation of this clinic was the Covid-19 pandemic. The impact of the virus on the health service was unprecedented and could not have been foreseen.

Barriers continue to inhibit escalation of numbers to maximum capacity – the current patient clinic number is 30. This is due to a number of reasons. Staff shortages continue to hamper progression. The ANP is often needed to assist at consultant-led clinics if NCHD attendance is low. Nursing shortages due to recruitment issues continue, however, additional qualified staff will commence in

the next few weeks. Not having the medical notes to hand in the community setting can impair the patient-nurse consultation if the patient has any queries regarding written documentation, test results filed in the physical chart, or correspondence from other services, etc. During the first year of the ANP clinic access to nursing management to present clinic data was difficult due to the demands on senior management in the acute hospital setting and the obvious need to address more pressing, urgent pandemicrelated issues. A standardised process of reporting to senior nursing management for service evaluation is lacking, however, this may be as a result of continued pressure on the acute services due to recovery of the health service from the pandemic. A report published by Brady et al in 2020, which evaluated the demonstrator policy implementation9 identified the lack of standardised reporting processes to be a national issue, but more worryingly, reports this issue as being a substantial barrier to the long-term sustainability of the nurse practitioner role.

Facilitators

The successful initiation of this clinic was made possible primarily as a result of the trust and support provided by the rheumatologists in CUH. Their understanding of the role fully aligned with the ANPs’ vision for nurse-led community-based services to help alleviate the mounting congestion of the outpatient department (OPD) clinics. Their unwavering commitment and enthusiasm towards the success of the ANP community clinic is noteworthy and should be commended.

The support from the Director of Nursing (DON) was also a substantial facilitator in the initiation of this clinic. The DON’s immediate understanding of the benefits to patient care, to our nursing profession and the organisation as a whole was instrumental in achieving EMB approval. The ANP maintains good communication with the DON’s office and monitors key performance indicators (KPIs) as set out by the business plan. The ANP also maintains good levels of communication and liaises regularly with the service line manager regarding any

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operational issues that may arise. A method of standardising KPI reporting and the accurate capturing of clinical data to include nurse-specific interventions is lacking, however, new data reporting and analytic systems are being explored by the Nursing and Midwifery Planning and Development Unit in collaboration with the Office of the Nursing and Midwifery Services Director to resolve this.

CKCH were key stakeholder partners and continue to express their openness to initiatives that strengthen person-centred integrated care between acute hospitals and community healthcare and promote hospital avoidance. Good communication was achieved with a mix of formal and informal discussions coupled with local practical knowledge to implement essential logistical and operational elements, which ensured that this clinical initiative commenced with relative ease. Stakeholder buy-in and

effective communication are critical enablers in ensuring a smooth transition to the community-based rheumatology service and are a huge factor in the long-term sustainability of the service.

The Irish Rheumatology Nursing Forum (IRNF) is a professional organisation which represents and promotes the vital role of nurses working in rheumatology throughout Ireland. The IRNF provides collegial support and promotes evidence-based practice and research through facilitating regular educational meetings and forums. In 2014 the IRNF submitted a business proposal to the national Clinical Programme for Rheumatology.10 It outlined key issues in the clinical pathway for patients with inflammatory arthritis in Ireland and provided nurse-led solutions to address these issues. It called for a phased increase in the number of rheumatology ANPs and CNSs nationally, with evidence highlighting the

benefits to service delivery and sustainability, and identified potential savings by the HSE through nurse-led treat-to-target clinics. The IRNF business proposal was used as a framework to produce the business case for the ANP community clinic in Cork as it provided the critical evidence to support its approval at local EMB level. The extraordinary ambition, motivation, and dedication of the IRNF to produce this document must also be commended.

Pilot audit

In January 2021 the first patient was seen in the rheumatology ANP community clinic. Staff shortages continued to slow the growth of referred numbers but during 2021 a slow and steady increase was observed. At six months a report was produced outlining the outcomes for the first six pilot patients. All patients achieved between 25-to-49 per cent improvement in disease activity scores (Graph 1) and a steady decline in fatigue (Graph 2) and early morning stiffness (Graph 3). There was one hospital avoidance episode, six prescriptive episodes, and three unscheduled urgent reviews for flaring disease where two of the three patients couldn’t make contact with their respective GP.

Of note, two medication errors were identified and rectified by the ANP within two weeks. These involved one patient not taking the correct dose of methotrexate and another discontinuing it completely. Both errors would have gone unchecked for four months without ANP intervention.

Patients’ verbal feedback to the ANP on exiting the programme is wholly positive with the majority seeking to be reinstated. Many comment on how spacious the clinic room is and that the peaceful environment of the

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Disease activity scores Visit number PtA PtB PtC PtD PtE PtF Visit 1 3.92 6.43 5.41 6.91 4.62 5.83 Visit 2 3.42 7.67 6.17 5.62 3.91 4.92 Visit 3 2.67 3.28 3.14 4.2 2.94 3.14 DAS Disease level >5.1 High 5.1-3.3 Moderate <3.2 Low <2.6 Remission

GRAPH 1: Disease activity scores (DAS) over the pilot period

clinic location helps the flow of conversation and ultimately improves the quality of the patient-nurse interaction. Continuity of care is maximised by meeting the same practitioner at each visit.11 A trusting professional relationship builds up between the nurse practitioner and patient where shared decision-making becomes the norm. Patients regard a nurse-led person-centred approach to care as therapeutic and empowering.11

The next step

ANPs are highly skilled autonomous practitioners who deliver safe, effective, high quality care. The International Council of Nurses describes ANPs as nurses who develop an expert knowledge base, acquire complex decision-making skills, and achieve clinical competencies for extended practice.12 The benefits of ANP-led treat-to-target clinics are outlined in Table 1. Additional benefits, efficacy and safety of ANP-led care have been widely documented in the literature,13,14,15 and were replicated in the demonstrator project policy evaluation report.9 During the study’s evaluation period (as a result of either candidate or registered ANP intervention), on average 4.6 patients were removed from a rheumatology specialist list per week, and on average 1.7 rheumatology patients avoided hospital admission per week. Patients reported that they received high levels of individualised care that was delivered in a highly professional manner with high levels of follow-up support.

Much has been done to drive advanced nursing practice in Ireland, especially in rheumatology, however, a wider understanding of the role including clinical autonomy,16 role clarity,17 and role expansion18 needs to be achieved. ANPs are pivotal players in developing innovative nurse-led services and to achieve successful implementation of services, especially in the community, support is required from all key stakeholders at senior management levels across both the acute and community sectors. This article serves to demonstrate that rheumatology ANP-led community clinics are achievable and sustainable if the nurse practitioner has organisational, clinical, and professional support structures in place.

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

GRAPH 2: Fatigue scores over the pilot period

Fatigue scores – Likert scale 0-10 Visit number PtA PtB PtC PtD PtE PtF Visit 1 6 5 9 10 8 3 Visit 2 5 8 9 8 7 3 Visit 3 2 5 5 3 2 2 Early morning stiffness – calculated in hours Visit number PtA PtB PtC PtD PtE PtF Visit 1 3 2 2 4 1 1 Visit 2 1 3 2 3 0.75 1 Visit 3 0.75 0.33 1 1 0 0.66

GRAPH 3: Early morning stiffness scores over the pilot period

Patient benefits

Improved understanding of disease and satisfaction with service

Tighter disease control

Improved medication adherence

Identification of comorbidities

Structured support system and improved patient advocacy

Less distance to travel for review appointments

Service benefits

Meeting international best practice standards of care

Urgent review clinics for early RA patients facilitated by ANP freeing up NCHD time

New AHP referral pathways and improved MDT collaboration

Evidence-based ANP pathway for future candidates

Improved GP communication with direct access to ANP for GPs

Integration of service via nurse-led clinics

TABLE 1: Benefits of community ANP-led treat-to-target clinics

References

1. Committee on the Future of Healthcare Sláintecare Report. (2017). Houses of the Oireachtas Committee, Dublin: Department of Health. www.gov.ie/pdf/?file=https://assets. gov.ie/165/270718095030-1134389-SlaintecareReport-May-2017.pdf#page=11

2. Department of Health. (2019). A policy on the development of graduate to advanced nursing and midwifery practice. www.healthgov.ie

3. National Clinical Programme for Rheumatology (NCPR). Model of Care for Rheumatology Ireland (2018). www.hse.ie/eng/about/who/cspd/ncps/ rheumatology/resources/model-of-care-forrheumatology-in-ireland1.pdf

4. Fraenkel L, Bathon JM, England BR, et al (2021). 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis & Rheumatology, 73(7):11081123

5. Smolen JS, Landewé R, Bijlsma J, et al (2017). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis, 76:960-977

6. Smolen JS, Breedveld FC, Burmester GR, et al (2015). Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international taskforce. Ann Rheum Dis, 75:3-15. doi: 10.1136/annrheumdis-2015-207524

7. Health Protection Surveillance Centre.

RTÉ News. 1 March 2020. www.rte.ie/news/ coronavirus/2020/0229/1119357-coronavirusireland/

8. Frawley T, Van Gelderen F, Somanadhan S, et al (2021). The impact of Covid-19 on health systems, mental health, and the potential for nursing. Ir J Psychol Med, 38(3):220-226. doi: 10.1017/ipm.2020.105

9. Brady AM, Drennan J. (2020) Evaluation of the impact of implementing a draft policy to develop advanced nurse practitioners (cANPs/ RANPs) to meet health service needs. University College Cork; Trinity College Dublin; Health Service Executive. http://hdl.handle.net/10147/629382

10. Irish Rheumatology Nursing Forum. (2014) Business proposal for advanced nurse practitioner and clinical nurse specialist posts. Submitted to the National Clinical Programme for Rheumatology. https://irnf.ie/wp-content/ uploads/160115-FINAL-Business-Case.pdf

11. Sweeney AT, McCabe C, Flurey CA, et al. (2020) The patient perspective of nurse-led care in early rheumatoid arthritis: A systematic review of qualitative studies with thematic analysis. J Clin Nurs, 30. doi: 10.1111/jocn.15531

12. International Council of Nurses. (2021) Definition and characteristics of the role. Nurse practitioner and advanced practice roles. http:// international.aanp.org/Practice/APNRoles

13. Woo BFY, Lee JXY, Tam WWS. (2017) The

Organisational benefits

Freeing OPD clinic appointments for return patients

Reduction in waiting list numbers for return patients

Improved patient flow

Improved hospital avoidance

Impacting on national ANP policy development

Progression of rheumatology integrated care into the community

impact of the advanced practice nursing role on quality of care, clinical outcomes, patient satisfaction, and cost in the emergency and critical care settings: A systematic review. Hum Resour Health 15:63. doi: 10.1186/s12960-0170237-9

14. Laurant M, van der Biezen M, Wijers N, et al (2018) Nurses as substitutes for doctors in primary care. Cochrane Database Syst Rev 2018, Issue 7 Art No: CD001271. doi: 10.1002/14651858.CD001271.pub3

15. Collins D. (2019) Assessing the effectiveness of advanced nurse practitioners undertaking home visits in an out-of-hours urgent primary care service in England. J Nurs Manag 27(2):450-458. doi: 10.1111/jonm.12680

16. Lockwood EB, Lehwaldt D, Sweeney MR, et al (2022) An exploration of the levels of clinical autonomy of advanced nurse practitioners: A narrative literature review. Int J Nurs Pract 28(1), e12978. doi: 10.1111/ijn.12978

17. Cooper MA, McDowell J, Raeside L, et al (2019) The similarities and differences between advanced nurse practitioners and clinical nurse specialists. Br J Nurs 28(20):1308-1314

18. Fealy GM, Casey M, O’Leary DF, et al. (2018) Developing and sustaining specialist and advanced practice roles in nursing and midwifery: A discourse on enablers and barriers. J Clin Nurs 27:3797– 3809. doi: 10.1111/ jocn.14550

51 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

Opioids: New US and European guidelines

AUTHOR: Priscilla Lynch

In February this year the US Centers for Disease Control and Prevention (CDC) published a new draft Clinical Practice Guideline for Prescribing Opioids for public consultation.

The draft clinical practice guideline updates and expands the CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016, and provides evidence-based recommendations for clinicians who provide pain care, including those prescribing opioids, for outpatients age 18 years and older with acute pain, subacute pain, or chronic pain not including sickle cell disease-related pain management, cancer pain treatment, palliative care, and end-of-life care. Release of the final updated guideline is anticipated in late 2022.

The draft guideline has been welcomed by US medical bodies, who say that misapplication of the 2016 guideline by outside stakeholders including payers, legislators, medical boards, healthcare systems, and pharmacy benefit plans (PBMs) continues to negatively impact patients and the ability of pain management physicians to provide evidence-based and humane care.

“We applaud the CDC for a shift to a more ‘whole-person’ patient-centred pain medicine approach with recommendations for a more holistic, multimodal treatment paradigm, which is evidence-based and risk-stratified in the proposed 2022 updated draft. Many of our initial concerns that were disregarded are now the foundation for an improved draft guidance that more clearly balances the clinical distinction between the careful initiation of opioid therapy for acute, subacute, and chronic pain with understanding of the unique needs of those patients already managed and stable on chronic opioid therapy (legacy patients) as part of their treatment plan,” said the American Academy of Pain Medicine.

However, the fact also remains that opioid abuse is a leading cause of premature death in the US. Provisional CDC data indicates that there were an estimated 107,622 drug overdose

deaths in the US during 2021, an increase of nearly 15 per cent on 2020, when threequarters of these deaths were cited as involving an opioid. The number of drug overdose deaths in the US increased by nearly 30 per cent from 2019 to 2020 and has quintupled since 1999.

To allay concerns over an opioid crisis, as in the US, the European scientific community has also reviewed evidence on using opioids to treat chronic non-cancer pain (CNCP). In 2021, under the umbrella of the European Pain Federation (EFIC), a gathering of nine European scientific societies and a leading patients’ organisation launched new clinical recommendations for opioid use in treating CNCP.

Opioid prescriptions have increased over the past decade in some European countries, which has caused concerns. The new recommendations, therefore, aim to provide safer and more effective care for people with CNCP, to improve communication between clinicians and people with chronic pain about the benefits and harms of using prescription opioids for chronic pain, and to give guidance to doctors on appropriate opioid use as well as decrease harmful opioid use.

The new recommendations advise that opioids should not be prescribed for people with chronic primary pain as they do not work for these patients. Moreover, opioids should also not be used as a ‘first-line therapy’ for chronic secondary pain syndromes. Instead, doctors should first use non-opioid medications, or established non-pharmacologic therapies (eg, exercise, psychological therapies), and only consider prescribing opioids if these first-line therapies do not work, are not tolerated, or contra-indicated.

The recommendations state that, before prescribing opioids, clinicians should establish treatment goals with patients, including realistic goals for daily physical function and pain. In addition, before starting – and

regularly throughout the opioid therapy –doctors should discuss the known harms and realistic benefits of opioid therapy (and of alternatives) with their patients. And if opioids are used to treat chronic secondary pain, they should always be combined with non-opioid painkillers and non-opioid therapies.

Doctors should closely monitor patients after starting treatment with opioids and the therapy should only continue if there is clinically meaningful improvement in pain and physical function that outweighs the risks to their patient’s safety.

EFIC’s recommendations advise starting low and going slow. At the outset, clinicians should prescribe the lowest effective dose: Less than 50 morphine milligram equivalents (MME) a day. They should also avoid increasing the dosage above 90 MME/day, or carefully justify any decision to do so.

Opioid therapy should stop if the goals agreed at the beginning of the treatment are not being met, or if intolerable adverse events happen. Treatment should also stop if the goals can be achieved through other non-opioid treatments, or if there are concerns about a patient becoming dependent.

The paper’s lead author, Prof Winfried Häuser, commented: “The debate on opioidprescribing for chronic non-cancer pain has become polarised: Opioids are either seen as a dangerous risk for all patients, leading to addiction and deaths or they are promoted as [the] most potent painkillers for any type of pain. This paper seeks to navigate the scientific and clinical evidence and provides recommendations for when opioids could be beneficial and when not for chronic noncancer pain. Opioids are still important in the management of chronic non-cancer pain – but only in some selected chronic pain syndromes and only if established non-pharmacological and non-opioids analgesics have failed or are not tolerated.” 

52 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

Acute pain in focus

AUTHOR: Mr Eamonn Brady, MPSI

Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage”. Pain may also occur in the absence of tissue damage or any identifiable pathophysiological cause. Pain can be considered more than just a symptom of disease and is sometimes classed as a disease state in itself. Pain is universal, however, pain perception varies and is affected by the likes of cultural backgrounds and genetic differences.

The 2006 National Disability Survey Ireland (CSO, 2008) stated that pain was one of the most common disability types reported. Almost 50 per cent of individuals reported pain as the main cause of their disability and of those, 34 per cent cited arthritis as being the most common cause of injury or illness. Almost 20 per cent stated their pain disability was caused by an accident or injury.

For the purpose of this article, I will discuss the types of acute pain often seen in community and GP settings. The management of acute pain from severe trauma (eg, RTAs) that requires management with likes of opioids and sedation in hospital settings is outside the scope of this article.

Causes of pain

The cause of pain is sometimes difficult to determine and there are often many aspects to consider. Chronic pain can be more difficult to determine the cause; acute pain more often has a clearly identifiable cause, eg, muscle injury. It is the indeterminate nature that can present the biggest obstacle to health professionals to establishing proper diagnosis of the condition.

Acute pain

Acute pain starts quickly and lasts a short period of time. The definition of acute pain is pain that improves within one-to-three months of onset. Pain that lasts longer than six months is considered chronic pain and will require more specialist treatment from a pain expert. The period between three and six months is classified as the time of transition from acute pain to chronic pain. Patients require more specialist evaluation and treatment at this stage rather than just taking painkillers to avoid transitioning into chronic pain.

Common examples of acute pain:

X Headaches;

X Sprains and strains;

X Dental work;

X Surgery;

X Broken bones;

X Burns or cuts;

X Childbirth.

Acute pain can be difficult to diagnose and treat, especially when caused by injuries that are not visually evident like a fractured rib, a herniated disc, or a pinched nerve. Pain can develop to be more than a physical sensation. For example, it can develop to become an emotional problem, such as fear, or anxiety related to a traumatic event that triggered the pain. For example, a person may avoid driving after suffering severe injuries in a car accident.

Reasons for acute pain

The majority of acute pain episodes arise from causes that can be categorised as musculoskeletal conditions.

Pain is a sensation experienced through the nervous system (nerves, spinal cord, and brain). Reflexes are the nervous system’s immediate response to acute pain. This is demonstrated by when a hot plate is touched, it takes milliseconds for the nervous system and muscles to coordinate and make the hand move away immediately; ie, a reflex reaction.

In addition to reflexes, the nervous system has more sophisticated mechanisms for processing pain. The brain releases neurotransmitters that influence pain levels and have an influence on mood, which is one of the reasons why depression can occur in response to pain. Pain and depression can create a vicious cycle in which pain worsens the symptoms of depression and then the resulting depression worsens feelings of pain.

Symptoms of acute pain

Acute pain can be felt in a specific body area, such as the neck or back, or the patient may have widespread pain with conditions such as a viral illness.

Acute pain may be described as:

X Sharp;

X Dull;

X Stabbing;

X Throbbing (sign of inflammation);

X Shooting or shock-like (sign of nerve involvement).

Diagnosis for acute pain

The reason for the pain may not be visually obvious. Diagnostic tests are helpful and include:

X Blood tests;

X Imaging studies (x-ray, CT, MRI, nuclear scans);

X Local anaesthetic injections;

X Dye-injection studies, such as a diskogram to identify painful disks in the spine or

54 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

Figure 1 on reported causes of pain from the PRIME study, National University of Ireland Galway (NUIG) 2011, illustrates the problem further.

myelogram to identify areas of spinal nerve compression;

X Electromyography and nerve conduction studies to identify nerve abnormalities.

Chronic pain versus acute pain

Chronic pain can be defined as pain which lasts longer than what is considered a ‘normal’ healing time, perhaps as part of recovery from illness or injury – generally more than three months.

Chronic pain may be attributable to an event, such as an accident, developing from acute pain. Opinion differs as to whether previous acute pain is always the root cause of chronic pain or simply appears, sometimes without an initial cause. In some cases, especially in relation to sports injury in contact sports, the underlying chronic pain may appear some time after an event. Pain may also be related to another condition. Surveys show that in Ireland, 35 per cent of reported chronic pain is arthritis related. It may be site-specific, ie, back, knee, and wrist, however, 80 per cent of sufferers in Ireland report that their pain relates to more than one site.

Types of pain

Pain can be classified either by type of pain, or by body region. Pain types include:

X Nociceptive pain: Aching, boring, worse on movement, anatomically defined, fluctuates in severity.

X Neuropathic pain: Burning sensation, sharp stabbing type, tingling, transient limb pain (shooting), associated with allodynia (experience of pain from a non-painful stimulation of the skin, such as light touch), hypersensitivity, or other sensory changes.

X Mixed nociceptive and neuropathic pain: Combination of symptoms.

X Visceral pain: Dull, non-specific, difficult to pinpoint.

X Autonomic symptoms: Physiological changes (colour, temperature), sweating.

Treatment

Aims of treatment are to:

X Reduce intensity of the pain;

X Enhance physical functioning;

X Improve mood;

X Promote the return to work or school and/ or role within family and society;

X Improve quality-of-life;

X Support pain-management planning decisions;

X Reduce need for healthcare services.

First-line treatment options include:

X Resting the affected area;

X Applying ice or heat;

X Paracetamol or non-steroidal antiinflammatory drugs (NSAIDs) such as aspirin, ibuprofen, or naproxen;

X Exercise;

X Physiotherapy;

X Stress reduction;

X Bioelectric therapy (ie, local electrical stimulation like a transdermal electronic nerve stimulation (TENS) machine for moderate pain); opioid medication, such as codeine or morphine;

X Muscle relaxant medications.

Second-line treatment options include:

X Antidepressants: Some tricyclics such as amitriptyline have a role in nerve pain and some antidepressants may be needed for mood and insomnia issues exacerbated by pain;

X Anticonvulsants: More often used for nerve pain;

X Nerve blocks: Local anaesthetics to block nerve activity;

X Trigger point injections: To treat muscle spasms;

X Steroid injections: To reduce tissue inflammation.

Overview of pain medications

A successful outcome from general practice visits should be a pain management plan. It is highly likely that as part of this, some form of pain-relieving medication will be prescribed.

Ideally, advise on promotion of self-help, self-management, and other treatments to help improve their condition and add value to the benefit offered by medication.

Given the wide and varied nature of acute and chronic pain, there is a myriad of medication options. The effectiveness of medication depends on the nature and severity of the pain.

Regarding treatment of acute pain caused by headache (ie, migraine), in addition to standard paracetamol and NSAIDs, triptans are considered the most effective option to combat acute attacks if ordinary analgesics do not work.

These include:

X Almotriptan;

X Frovatriptan;

X Sumatriptan; X Zolmitriptan; X Eletriptan; X Naratriptan,

All are prescription-only medicines (POM), apart from sumatriptan, which has an over-the-counter (OTC) version available in Ireland.

55 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

FIGURE 1: ‘Reported cause of pain’ from the PRIME study. NUIG 2011

Musculoskeletal Headache and/ or migraine

Osteoarthritis

Rheumatoid arthritis

Osteomyelitis

Osteoporosis

Ankylosing spondylitis

Myofascial diseases

Polymyalgia rheumatica

Polymyositis

Fractures

Chronic or repetitive overuse

Carpel tunnel syndrome

Muscular strains

Faulty posture

Mechanical low-back pain

Cluster headaches

Migraine

Trigeminal neuralgia

Giant cell (temporal) arteritis

Glaucoma

Smoking

Alcohol

Temporo-mandibular joint dysfunction

Drug or substance overuse or misuse

Neurological Psychological causes

Diabetic sensorimotor polyneuropathy

(up to 25 per cent of diabetics)

Spinal stenosis

Brachial plexus

traction injury

Thoracic outlet syndrome

Post-herpetic neuralgia

Multiple sclerosis

Alcoholism

Thyroid disease

Pernicious anaemia

Infections (ie, HIV), polyneuropathies

Polyradiculopathies

Efficacy of OTC painkillers

Cochrane reviews (39 in total) of randomised controlled trials on effectiveness of OTC analgesics in acute pain found reliable evidence to indicate that simple, inexpensive, and common analgesics give good pain relief to many patients with acute pain, such as headache, toothache, sprains, and strains. Data demonstrated the most efficacious OTC drugs used were ibuprofen/paracetamol combinations in respective 400mg/1,000mg and 200mg/500mg doses.

These formulations gave effective relief in seven-out-of-10 patients. Fastacting ibuprofen 200mg and 400mg was effective in at least five-out-of-10 patients. Paracetamol alone was effective in fourout-of-10 patients.

World Health Organisation (WHO) analgesic ladder

The WHO analgesic ladder (introduced in 1986) was developed to help clinicians decide cancer pain treatment. It was developed for chronic pain, but the principles apply to the management of

acute pain. OTC painkillers can be used for mild pain according to this tool, starting with a non-opioid (eg, paracetamol or aspirin) for mild pain then trialling an opioid plus a non-opioid (eg, co-codamol) for mild-to-moderate pain. Despite its origin to manage cancer-related pain, the WHO analgesic ladder now acts as a useful guide for pain control in both acute and chronic pain from malignant and non-malignant causes. As pain is a subjective experience, the stepwise approach of the WHO analgesic ladder is not always appropriate for managing intense pain.

Guidance on musculoskeletal injures

The American Academy of Family Physicians (AAFP) and American College of Physicians (ACP) guidelines published in 2020 (after a review of 13 million patients) recommend topical NSAIDs as first-line therapy for patients experiencing pain from musculoskeletal injuries (excluding lower back pain). The guidelines recommend that clinicians not prescribe opioids except in cases of severe injury or if patients cannot tolerate firstline therapeutic options.

Depression

Anxiety

Personality disorders

Sleep disturbances

The recommendations state that topical NSAIDs were the only intervention that improved all outcomes in patients with acute pain from non-lower back musculoskeletal pain. They found that topical NSAIDs were also among the most effective options for treatment satisfaction, pain reduction, physical function, and symptom relief, and were not associated with a statistically-significant increased risk of adverse effects.

Oral NSAIDs were shown to be effective in reducing pain within two hours and one-to-seven days after treatment and were associated with greater likelihood of symptom relief. However, oral NSAIDs also were associated with an increased risk of gastrointestinal adverse events.

Self-help

Pain management programme

The Pain Management Programme (PMP) is a psychologically based rehabilitative treatment for people with persistent pain. It is delivered in a group setting by a multidisciplinary team of experienced healthcare professionals working closely

56 Volume 8 | Issue 6 | 2022 | Rheumatology and Pain

TABLE 1: General classification of pain causes

Pain type

Lower back pain

Tension-type headache

Migraine (must be medically diagnosed before OTC medication can be recommended)

Sprains and strains

Evidence-based recommended analgesic

NSAIDs, (eg, ibuprofen 400mg three times per day) at the lowest possible dose for the shortest possible time. Do not offer paracetamol alone

Aspirin (300mg three times per day), paracetamol or NSAID, taking account of patient preference and comorbidities

Combination of triptan (eg, sumatriptan no more than two 50mg tablets in 24 hours), NSAID or triptan, and paracetamol. If the patient prefers one drug only, consider monotherapy with oral triptan, or NSAID (eg, ibuprofen) or paracetamol alone, considering comorbidities. Opioids should not be used for the acute treatment of migraine

Paracetamol (500mg to 1g four times per day, with a maximum 4g in 24 hours) or topical NSAID (eg, ibuprofen or diclofenac gels) are recommended first-line. Consider oral NSAID (eg, ibuprofen 400mg three times per day) 48 hours after the initial injury if needed

Period pain NSAID (eg, ibuprofen or naproxen) unless contraindicated. Paracetamol can be used if a NSAID is contraindicated or provides insufficient pain relief

with patients. The main aim is to teach a group of patients with similar problems about pain, how best to cope with it, and how to live a more active life. Referral to a PMP is usually through the GP to the local pain clinic.

There are public PMPs in*:

X St Vincent’s University Hospital, Dublin.

X Tallaght University Hospital, Dublin.

X Mater Misericordiae University Hospital, Dublin.

X Mercy University Hospital, Cork.

*This list not exhaustive.

Private hospitals also have pain clinics. For example, the Beacon Hospital in Dublin operates an acute pain service and a chronic pain service.

Physical therapy

Physical therapy covers a number of different treatment types, which can be beneficial for chronic pain, especially pain due to musculoskeletal disorders.

X Hot or cold (ice) pack treatment;

X Ultrasound;

X Peripheral nerve stimulation/TENS.

A chartered physiotherapist can help with manual therapy, which helps to increase tissue extensibility and range of movement, thereby decreasing pain. Manual therapy

can also help with alignment and joint mechanics issues, which in itself can also help alleviate pain.

Therapeutic exercise such as hydrotherapy, can restore joint movement and flexibility and strengthen and condition muscles to help movement, thereby reducing pain.

Patient education can support physical therapy in a self-help or home-based manner. Reading and learning about their condition can assist in management of patients’ own pain.

Exercise – staying active can be the key to improving chronic pain symptoms. Any activity that increases mobility can have not only a positive physical benefit, but also an affirming mental health benefit also.

Cognitive behavioural therapy (CBT)

CBT is a proven ‘talk therapy’, the primary aim of which is to teach the patient how to recognise and manage negative thinking or unhelpful beliefs that lead to increased distress. Generally delivered on a one-to-one basis, the participant is taught techniques and strategies to enable them to challenge their thoughts and change their attitude, leading to a change in future behaviour. Through regular

attendance, confidence builds, leading to positive goal setting. These goals should relate to achieving resumption of activities previously restricted by pain.

Learning problem-solving strategies and stress reduction techniques will help achieve a successful outcome.

General practice

The patient’s needs will affect treatment choice so GPs and primary care teams should have available (and understand) a range of guidance and literature to best advise patients about the most effective treatment for them.

Regular review of the continued suitability of all medications used by those with both acute and chronic pain is vital. For many, beyond the pharmacy, the GP surgery is the first port of call when a pain-related problem arises. Using some of the ideas regarding questions, pain diary, etc, will really help in enabling people to make better-informed decisions about their own next step.

Becoming familiar with local resources like physios, support groups, condition-specific charities, etc, and signposting these will only add value to a positive perception. 

References on request

57 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

TABLE 2: Common acute pain conditions and the recommended, OTC, evidence-based analgesia Reference: National Institute of Health and Care Excellence (UK)

Bladder pain syndrome/ interstitial cystitis

AUTHORS: Prof Barry O’Reilly, Obstetrician/Gynaecologist, Sub specialist in Urogynaecology, Mater Private Hospital and University Hospital Cork; and Dr Yair Daykan , Urogynaecology Subspecialty Fellow, Cork University Hospital

Bladder pain syndrome, also known as interstitial cystitis, involves bladder pain or discomfort that can profoundly impact quality-of-life.

Bladder pain syndrome is challenging to diagnose, prevent, and treat because its basic science and pathophysiology are poorly understood. The prevalence of bladder pain syndrome varies widely and is estimated to be from 1-to-20 per cent.

It is estimated that 90 per cent of people with interstitial cystitis are women.

The symptoms of bladder pain syndrome are discomfort with a frequent and often urgent need to pass urine. The findings of interstitial cystitis are suprapubic or retropubic pain, pressure, or discomfort related to the bladder. The pain usually increases with intensity during bladder filling and may persist or disappear after voiding.

To date, there is no curative treatment and the primary goal of management is to provide symptom relief to achieve an adequate qualityof-life. There are many therapeutic approaches for bladder pain syndrome, none of which have been proven helpful for all patients.

Women with bladder pain syndrome also have other associated urinary symptoms and a higher prevalence of specific systemic diseases (eg, inflammatory bowel disease).

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FIGURE 1 : Pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS)

People with interstitial cystitis may have many of the following symptoms:

X An urgent need to urinate, both in the daytime and at night.

X A frequent need to urinate as many as 20 times a day or more.

X Pressure, pain, and tenderness around the bladder, pelvis, and perineum may increase as the bladder fills and relieves as the bladder empties.

X The sensation that they can’t hold as much urine as before.

X Pain during sexual intercourse.

Risk factors

X Sex: Women are diagnosed with interstitial cystitis more often than men.

X Age: Most people with interstitial cystitis are diagnosed during their 30s or older.

X Chronic pain disorder: Interstitial cystitis may be associated with other chronic pain disorders, such as irritable bowel syndrome or fibromyalgia.

X Stimulatory foods/drinks: Spicy foods and caffeine.

Pathophysiology

The pathophysiology of interstitial cystitis is complex and includes a number of different possible aetiologies. The main points are epithelial dysfunction, immune system activation (mast cells), neurogenic inflammation, autoimmunity, and occult infection. One of the most common findings is the thinning of the bladder epithelium, suggesting injury and damage to the blood supply.

Other changes seen include increased histamine (produced due to the inflammation process) and increased nerve cells in the bladder wall. An autoimmune response (when antibodies are made that act against a part of the body, such as in rheumatoid arthritis) may also be the cause in some people.

The urothelium, which is the inner surface of the urinary bladder, acts as a barrier between urine and the underlying bladder. The bladder mucus is a critical component

of this function and is composed of glycosaminoglycans (GAGs), which are highly hydrophilic and trap water at the cell’s outer layer. The primary pathology of the disease is a disruption of the urothelial barrier, the penetration of the urinary solutes (potassium), causing injury to the nerves and muscles.

Evaluation

Normal Epithelium Bladder Muscle

Normal GAG layer

Dysfunctional Epithelium

Dysfunctional GAG layer

Clinical symptoms: This condition is suspected in patients who have pain in the urinary bladder for a few weeks. Specific findings include frequent urination to avoid discomfort, with bladder distension and pelvic tenderness on examination.

Physical examination: Tenderness or tightness of the pelvic floor muscles, which can be identified by palpation of the levator muscles on pelvic examination, is consistent with the diagnosis.

Findings on examination that require workup for other diagnoses include significant pelvic prolapse, urethral diverticulum, uterine/cervical mass, and eroded/exposed vaginal mesh.

An abnormal GAG layer allows penetration of potassium-rich urine, causing stimulation of pain receptors and other inflammatory symptoms

Additional testing

"Pain" "Urgency" Nerve

Nerve "Frequency"

Bladder Muscle

Urine tests: Urinalysis and post void residual (PVR) urine volume.

Urinalysis with microscopy is performed to rule out infection and check for haematuria. A urine culture should be performed if urinalysis results suggest urinary tract infection. A PVR of urine can be measured by ultrasound

Cystoscopy: Cystoscopy is not a mandatory tool to make the diagnosis of interstitial cystitis. However, it may be performed to exclude other aetiologies either on initial presentation or in patients who do not respond to treatment with oral medications, and can help in the treatment. Over 50 per cent of patients may experience some symptom relief, but this will rarely last longer than six months. Cystoscopy can be used for cystodistension of the bladder and fulguration of Hunner’s ulcers/lesions.

There are typical findings of lesions related to interstitial cystitis during cystoscopy:

X Hunner’s lesions (reddened lesions on the

59 Rheumatology and Pain | Volume 8 | Issue 6 | 2022

FIGURE 2: Urothelial dysfunction

bladder mucosa with attached fibrin deposits; typically bleed after hydrodistension) in 5-to10 per cent of patients, and are highly specific. To identify Hunner’s lesions, cystoscopy is performed with direct visualisation before and after hydrodistension, and biopsies are taken of suspected lesions (see Image 1).

X Glomerulations (punctuate petechial haemorrhage), which appear after hydrodistension (see Image 2).

Both can be found in a patient with interstitial cystitis, but not all patients with interstitial cystitis will have them (not reliable criteria).

Histology

Increased numbers of mast cells on histologic examination of bladder biopsy specimens.

Biomarkers of interstitial cystitis

X GB-51.

X HB-EGF.

X APF (anti proliferative factor) is emerging as the best candidate for a biomarker for interstitial cystitis, but further studies and trials are needed. Excluding other aetiologies is essential.

Diagnosis

The American Urological Association (AUA) guidelines use the following definition of interstitial cystitis/painful bladder syndrome: “An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes.”

The clinical diagnosis requires a careful history, physical examination, and laboratory testing to document the disorder’s basic symptoms and exclude infections or other disorders.

Differential diagnosis

X Bladder or urethral cancer.

X Infections.

X Benign pelvic abnormalities.

X Intravesical pathology.

X Urethral diverticulum.

X Neurologic conditions.

X Chronic pelvic pain syndromes.

Treatment

There is no curative treatment for interstitial cystitis and the main goal is to manage symptomatic relief in order to achieve an adequate quality-of-life. Effective pain management is an essential component and may require a multidisciplinary, multimodal approach.

There are many therapeutic approaches, none of which have been proven helpful for all patients. The decision to start pharmacological treatment must be individualised after shared decision-making considering the severity of symptoms, the frequency of flares, patient preference, and the potential adverse effects of continued reliance on analgesic use.

Behavioural/non-pharmacologic treatments

X Patient education.

X Evaluate for comorbid conditions.

X Self-care and lifestyle modification –dietary modification: Avoid acidic foods, coffee, tea, soda, spicy foods, artificial sweetener, and alcohol.

X Pelvic floor myofascial physical therapy.

Pharmacological treatments

X Pain management agents (eg, urinary analgesics, paracetamol, NSAIDs, opioid/nonopioid medications).

X Amitriptyline, cimetidine, pentosan polysulfate sodium (PPS), hydroxyzine.

X Antihistamines for patients with allergic disorders.

X Neuropathic pain agents.

Intravesical instillations

X Sodium hyaluronate (Cystistat), heparin, or lidocaine may be administered as intravesical treatments.

X Cystoscopy under anaesthesia with shortduration, low-pressure hydrodistension may be considered.

X If Hunner’s lesions are present, fulguration (with electrocautery) and injection of triamcinolone/Botox should be performed in a second-step procedure.

X Intra-detrusor botulinum toxin may

be administered if other treatments have not provided adequate improvement in symptoms and quality-of-life.

Take home message about interstitial cystitis

X Interstitial cystitis is essentially an inflamed or irritated bladder wall.

X The cause of interstitial cystitis is unknown, and antibiotics are not the treatment.

X Symptoms include changes in urination such as frequency and urgency; pressure, pain, and tenderness around the bladder, pelvis, and the area between the anus and vagina or anus and scrotum; and pain during sex.

X There is no best way to diagnose interstitial cystitis.

X A variety of tests may be needed.

X Cystoscopy may be helpful for the diagnosis and treatment

X Treatments are aimed at easing symptoms.

X Lifestyle changes may be advised, and various medications and procedures are available. 

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IMAGE 1: Hunner’s ulcer/lesion IMAGE 2: Glomerulations, which appear after hydrodistension

Management of painful diabetic neuropathy: 2022 and beyond

AUTHOR: Prof Dominic A Hegarty, Consultant in Pain Management and Neuromodulation, Mater Private Hospital, Cork; Associate Professor in Pain Medicine, University College Cork; and Clinical Director, Pain Relief Ireland, www.painreliefireland.ie

Diabetic neuropathy (DN) represents a common, disabling and, until recently, largely neglected problem affecting approximately 50 per cent of patients with diabetes at some point. According to the International Diabetes Federation, 425 million people world-wide aged 20 years had diabetes in 2017, and this number is expected to increase to 629 million by 2045. Approximately one-in-three people with diabetes experience painful diabetic neuropathy (PDN).

Ignoring PDN is no longer acceptable because the impact it has on an individual’s quality-of-life once established can lead to several costly complications, including persistent neuropathic pain, ulcers, Charcot foot, and an increased risk of amputations associated with increased mortality. A recent cohort study reported that patients with PDN were twice as likely to use opioids and over 16 times more likely to have an amputation than patients with diabetes mellitus without neuropathy.

Until recently, medical management was the only option available and it would often fail to control the situation. That is likely to change with the recent research and subsequent approval by the US FDA of the use of spinal cord stimulation (SCS) to treat painful diabetic peripheral neuropathy.

Defining diabetic neuropathy

A broad and simple definition of DN is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with

diabetes after the exclusion of other causes”. DN is among other factors attributable to hyperglycaemia, hyperglycaemia-associated metabolic derangement, dyslipidaemia, and micro vessel alterations.

The most common form of DN is a chronic symmetrical length-dependent sensorimotor polyneuropathy, termed diabetic polyneuropathy, which accounts for 75-to-90 per cent of all DN cases. Other types of DN include autonomic neuropathy, diabetic radiculoplexopathy (formerly called diabetic amyotrophy), mononeuropathies, and treatment-induced neuropathies.

The remainder of this review will focus on PDN.

Aetiology of PDN

Painful neuropathy is a common but inconsistent feature of chronic diabetes. Clinical studies have yet to offer robust clues to the pathogenesis of pain in diabetic patients, so there are no targeted prophylactic therapies.

Animal studies in diabetic rodents have suggested that over-expression of sensory receptors and ion channels in primary afferents can exaggerate or modify sensory input from the periphery. This is followed by amplification of sensory processing at the spinal cord level via sensitisation and disinhibition mechanisms.

There is also an emerging appreciation that the higher nervous system is not spared in

diabetes, so that amplifier or generator sites for pain may be located within the brain and project pain sensations to the periphery. The developing appreciation of the pathogenesis of pain in animal models of diabetes has offered mechanistic validations for some therapies in current clinical use, such as gabapentanoids, low-dose lidocaine, and alpha-lipoic acid while also highlighting new sites for intervention that may offer greater specificity and a reduced side-effect profile. It also raises questions regarding the use of bioelectric management to modify the transmission of pain in order to provide early symptom relief.

Diagnosis and management of PDN

Diabetic neuropathies are complex diseases, and no robust definition or gold standard exist that fully encompass the complexity and changing course of nerve fibre damage in PDN. The hierarchical classification of PDN by the Toronto criteria into ‘possible’,

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Ignoring PDN is no longer acceptable because the impact it has on an individual’s quality-of-life once established can lead to several costly complications

Source: Jingxuan L, et al (2021). Different Drugs for the Treatment of Painful Diabetic Peripheral Neuropathy: A Meta-Analysis. Front Neurol. 12:682244

‘probable’ or ‘definite’ addresses this issue by these criteria:

a) Possible PDN requires symptoms of decreased sensation (eg, numbness or pricking feeling in the toes, feet or legs) or signs (ie, symmetric decreased sensation or decreased or absent ankle reflexes).

b) Probable PDN requires symptoms and signs, including two or more of the following: Neuropathic symptoms, decreased distal sensation, or decreased or absent ankle reflexes.

c) Definite PDN requires abnormal nerve conduction studies or an abnormal validated measure of small fibre damage in combination with a symptom or a sign. QST added substantial information in this area.

Importantly, these criteria permit for the changing course of nerve fibre damage in PDN, but at the same time they also illustrate the clinical challenge that there is no specific measure to diagnose PDN in any individual at all times throughout the course of PDN.

The examination for PDN starts at the ‘bedside’ with simple assessments of signs of neuropathy ( Figure 2 ). In addition, the examination should include foot inspection, joint mobility testing and evaluation of motor function. A number of scoring systems have been developed for the screening of PDN. Two examples

include the Toronto Clinical Neuropathy Scoring System, and the Diabetic Neuropathy Symptom Score.

Present medical management options

Over the past 12 years there have been many reports on the effects of different drugs for the treatment of PDN. A meta-analysis in 2021 where the pain score was used as the main result and 30 per cent and 50 per cent pain reduction and adverse events were used as secondary results, identified 37 relevant studies. The key agents are listed in Table 1. In summary, pregabalin and duloxetine showed good therapeutic effects on painful PDN, but adverse events, which were not unexpected, were also significant. Tapentadol was found to have a good analgesic effect, but due to possible risk of opioid addiction, it needs to be very cautiously approached in clinical use.

The analgesic effects of ABT-894 and gabapentin need to be further studied with longer and larger randomised controlled trials (RCTs). Although lacosamide, mirogabalin, and capsaicin are more effective than placebo, the therapeutic effect is weaker than pregabalin.

Spinal cord stimulation as a treatment option

Neuromodulation or modulation of nerve fibre activity at the spinal cord (SCS) is an established treatment option for neuropathic pain, such as failed back surgery syndrome and complex regional

pain syndrome. In July 2021 the US FDA approved the use of SCS to treat PDN especially for those who have not responded to traditional medical management and in whom their diabetes is under reasonable control. For the first time, individuals with PDN now have a treatment that can have a meaningful improvement on activities of daily living (ADL).

The concept of SCS is that it provides focused electrical current on the dorsal column to counter balance the painful signals thereby providing symptom relief. It does not eliminate the pain source, but it changes the way the brains perceives the pain. The devices themselves can be

FIGURE 1: SCS uses either (a) lowfrequency current to replace the pain sensation with a mild tingling feeling called paraesthesia or (b) high-frequency or burst pulses to mask the pain with no tingling feeling. This inhibits the transmission of painful sensations to the brain based on the ‘Gate Control Theory’ Source: https://mayfieldclinic.com/pe-stim.htm

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Agent RR 95% CI P 12 Pregabalin 1.32 1.10-1.58 < 0.003 44% Duloxetine 1.34 1.01-2.02 < 0.004 76% Tapentadol 1.38 1.12-1.71 < 0.003 0% Capsaicin 0.99 0.73-1.36 0.97 0% Gabapentin 2.39 0.57-10.00 0.23 87%

TABLE 1: Summary of key medications for treatment of PDN

FIGURE 2: Diabetic polyneuropathy (DPN). Beside tools for testing cutaneous sensation, both large fibre function: 10-g monofilaments, vibration with 128-Hz turning fork, touch and joint position, and small fibre function: Cols and warm sensation, and pinprick

Source: Gylfadottir et al. J Diabetes Investig 2019; 10: 1,148-1,157

VAS; all showing beneficial effects of SCS compared with BMT for patients with PDN.

Ability to personalise treatment

The use of conventional SCS parameters should also provide pain control, and the introduction of Differential Targeted Multiplexed (DTM) SCS programming that involves stimulation for the glial cells in the dorsal column could also provide another useful control point in the pain pathway.

Although the effectiveness of conventional paraesthesia inducing SCS for PDN has been demonstrated, its cost-effectiveness has not yet been established. A cost-utility analysis from a societal perspective should be conducted based on the outcomes of SCS.

Planning for the future: 2022 and beyond

Diabetes is expected to increase in the population and it will bring with it an expected increase in diabetic-related complications. PDN is one such predictable complication that needs to be considered. Pro-active management of diabetes has been shown to help reduce long-term complications. These step could include:

programmed to influence the pain pathway personalising the therapy ( Figure 1).

Evidence of clinical improvement

Overall SCS has shown a mean reduction in pain intensity of 23.13 (95% CI 24.19 to 22.08) for the management of PDN with SCS when compared with basic medical therapy (BMT). Statistically-significant differences were also observed for the proportion of patients achieving at least a 50 per cent pain reduction, EQ-5D utility index, and EQ-5D

The ability of SCS devices to deliver different types of stimulation patterns is an important advancement. This ability greatly increases the chance of improving outcomes for those with PDN. For example, RCTs evaluating high-frequency SCS at 10kHz for PDN have shown a greater improvement in the proportion of patients with at least a 50 per cent reduction in lower-limb pain without a clinically meaningful neurological deficit compared with baseline at three months (SCS (86 per cent), when compared with patients receiving conventional medical management alone (5 per cent). Encouraging results have also been reported in a case series and a small crossover RCT evaluating burst SCS for PDN. RCT evidence is required to ascertain the effectiveness of burst SCS for PDN.

a) Screening for early features of PDN should be included in the bi-annual screening programmes presently available. The prevalence of DN often preceeds other complications so regular clinical screening for PDN could be crucial. This would permit the inclusion of suitable analgesics early and before peripheral sensitisation becomes irreversible.

b) An awareness campaign should be also be provided to all primary care centres and to all healthcare providers who manage individuals with diabetes. Actively engaging with patient-focused diabetes groups would be a practical way to highlight the issues and the solutions. Supporting podiatry services with equipment to undertake simple noninvasive sensory assessments (QST) would allow for early and effective identification of those who could benefit from advanced treatments and prevent complications.

c) Commencement of suitable analgesics should be considered sooner. The evidence suggests that refractory cases (ie, those cases who failure to respond to basic medical

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Encouraging results have also been reported in a case series and a small cross-over RCT evaluating burst SCS for PDN

management) should be considered for SCS as soon as possible. Personalised drugfree technology centred treatment could improve an individual’s quality-of-life by 50 per cent in a matter of weeks.

d) The National Clinical Programme for Diabetes (NCPD) published A Practical Guide to Integrated Type 2 Diabetes Care (2016) outlining the proposed pathway to “integrated” healthcare. While this publication dealt with the management of the diabetic foot and outlined an algorithm of treatment options, unfortunately, management of PDN was not mentioned in the document nor was there any mention of the possibility of a pain management referral as part of the “integrated” approach. Hopefully this can be rectified when the next document is prepared so that the pain

management can be included and the new, proven technology-centred therapy options can be recommended and provided in a timely fashion. 

Acknowledgement

If you feel you have individuals who could benefit from QST assessment, SCS or other possible treatment options please contact info@painreliefireland.ie for an appointment.

References

1. Abbott CA, Malik RA, van Ross ERE, et al. Prevalence and characteristics of painful diabetic neuropathy in a large communitybased diabetic population in the UK. Diabetes Care 2011;34:2220–4

2. Aekplakorn W, Chariyalertsak S, Kessomboon P, et al. Prevalence and management of diabetes and metabolic risk factors in Thai adults: The Thai National Health Examination Survey IV, 2009. Diabetes Care 2011; 34: 1980–1985

3. Boulton AJ, Malik RA, Arezzo JC, et al. Diabetic somatic neuropathies. Diabetes Care 2004; 27: 1458–1486

4. Boulton AJ. Diabetic neuropathy and foot complications. Handb Clin Neurol 2014; 126: 97–107

5. Bowling FL, Rashid ST, Boulton AJ. Preventing and treating foot complications associated with diabetes mellitus. Nat Rev Endocrinol 2015; 11: 606–616

6. Callaghan BC, Cheng HT, Stables CL, et al. Diabetic neuropathy: Clinical manifestations and current treatments. Lancet Neurol 2012; 11: 521–534

7. Culcutt N. Biology and pathophysiology of painful diabetic neuropathy. Painful Diabetic Polyneuropathy 2013

8. Davies M, Brophy S, Williams R, et al. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 2006; 29: 1518–1522

9. Duarte R, Nevitt S, Maden M, et al. Spinal cord stimulation for the management of painful diabetic neuropathy: A systematic review and meta-analysis of individual patient and aggregate data. Pain 2021; 162: 2635–2643

10. Dyck PJ, Overland CJ, Low PA, et al. Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs NPhys trial. Muscle Nerve 2010; 42: 157–164

11. Gibbons CH, Freeman R. Treatmentinduced neuropathy of diabetes: An acute, iatrogenic complication of diabetes. Brain 2015; 138: 43–52

12. Gylfadottir S, Weeracharoenkul D.,Anderson S, et al. Painful and nonpainful diabetic polyneuropathy: Clinical characteristics and diagnostic issues. J Diabetes Investig 2019; 10: 1148–1157. doi: 10.1111/ jdi.13105

13. International Diabetes Federation. IDF Diabetes Atlas 2018. Available from www.idf. org/ Accessed August 14, 2018

14. Jingxuan L, Litian M, Jianfang F (2021) Different drugs for the treatment of painful

diabetic peripheral neuropathy: A metaanalysis. Front Neurol. 12:682244. doi: 10.3389/ fneur.2021.682244

15. Kiyani M, Yang Z, Charalambous LT, et al. Painful diabetic peripheral neuropathy: Health care costs and complications from 2010 to 2015. Neurol Clin Pract 2020;10:47–57

16. Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ 2014; 348: g1799

17. Pertersen E, Struss T, et al. Effect of high-frequency (10-kHz) spinal cord stimulation in patients with painful diabetic neuropathy: A randomised clinical trial. JAMA Neurol. 2021; 78(6):687-689 doi:10.1001/ jamaneurol.2021.0538

18. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic 944. Neuropathy: A position statement by the American Diabetes Association. Diabetes Care 2017; 40: 136–154

19. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352: 341–350

20. Tesfaye S, Vileikyte L, Rayman G, et al. Painful diabetic peripheral neuropathy: Consensus recommendations on diagnosis, assessment and management. Diabetes Metab Res Rev 2011; 27: 629–638

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The prevalence of DN often preceeds other complications so regular clinical screening for PDN could be crucial

COMPLETE SKIN CLEARANCE

DEMONSTRABLE JOINT EFFICACY

PROVEN DURABILITY*

Most patients who started on TREMFYA® stayed on TREMFYA® long-term1,2

Durability*, also known as patient retention or drug survival is a combination of efficacy, safety, tolerability and patient satisfaction or preference.

DISCOVER-2 was a Phase 3, double-blind, multi-centre, placebo-controlled study that evaluated the efficacy and safety of TREMFYA® in bio-naïve patients with active PsA.1

Tremfya▼ 100 mg solution for injection in pre-filled pen PRESCRIBING INFORMATION.

FROM: Janssen Sciences Ireland UC, Barnahely, Ringaskiddy, IRL - Co. Cork, P43 FA46. Prescribing information last revised: November 2020.

Adverse events should also be reported to Janssen Sciences Ireland UC on 1800 709 122 or at dsafety@its.jnj.com.

References:

References: 1. Griffiths CEM, et al. Maintenance of Response Through 5 Years of Continuous Guselkumab Treatment: Results From the Phase 3 VOYAGE 1 Trial. Presented at the 16th Annual Coastal Dermatology Symposium. October 15-16, 2020.

Sustained joint symptom relief proven for 2 years in PsA2

Fast4 and sustained complete clearance proven for 5 years in Ps01