EMJ 8.4 2023

Volume 8.4

Flagship Journal

Winter 2023

Editor's Pick

Ambiguous Effects of Obesity on Cancer Prognosis and Treatment Response: A Narrative Review Interviews

Aurore Girard, Dame Clare Gerada, and Dirk Devroey share insights into primary care

Article

An Observational Evaluation of Primary Care Online Resources emjreviews.com

Contents 4

Editorial Board

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Welcome

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Foreword

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Congress Feature Can COVID-19 Help Us Deliver Whole-System Holistic Healthcare?

Ada Enesco

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Symposium Reviews New Horizons in IgA Nephropathy: A Focus on Current Treatment and Emerging Solutions

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Spasticity Matters: A Call to Action Following an Acute Stroke

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Becker Muscular Dystrophy: Could Altering the Natural History of Decline Help Tackle Unmet Medical Need?

Interviews 41

Exploring Methotrexate Route of Administration Decisions for Adults with Rheumatoid Arthritis

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Perimenopause and Menopause: An Opportunity to Engage, Inform, and Empower Women to Live Well

54 57 60

Aurore Girard

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Dame Clare Gerada Dirk Devroey

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Articles Editor's Pick: Ambiguous Effects of Obesity on Cancer Prognosis and Treatment Response: A Narrative Review Pandita

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An Observational Evaluation of Primary Care Online Resources Millares Martin and Millares-Bobet

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Hansen’s Disease with Pure Nerve Involvement and Perineural Abscess Mistaken for Peripheral Nerve Sheath Tumour Sultan et al.

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Spontaneous Subcapsular Hepatic Haematoma: A Rare Case Report Burrows-O'Donoghue et al.

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An Atypical Case of Hepatitis B-Associated Vasculitis

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Post-operative Dressing for Paediatric Hypospadias Repair

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Redefining Renal Cell Carcinoma: A Molecular Perspective on Classification and Clinical Implications

Ren et al.

Kaya et al.

Raghavan et al.

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Effect of Liraglutide on Weight Loss and BMI Among Patients Who Are Overweight and Obese with Type 2 Diabetes: A Systematic Review and Meta-analysis Zorampari et al.

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Editorial Board Editor-in-Chief Prof Markus Peck-Radosavljevic

Klinikum Klagenfurt am Wörthersee, Austria

Editorial Board Dr Pierfrancesco Agostoni

St. Antonius Hospital, the Netherlands

Dr Fernando Alfonso

Hospital Universitario de La Princesa, Spain

Dr George Anifandis

University of Thessaly, Greece

Dr Emanuele Angelucci

IRCCS Ospedale Policlinico San Martino, Italy

Dr Riccardo Autorino

Virginia Commonwealth University, USA

Prof Ahmad Awada

Jules Bordet Institute, Belgium

Prof Sorin T. Barbu

“Iuliu Hațieganu” University of Medicine and Pharmacy, Romania

Prof Andrew Bush

Imperial College London, UK

Dr Abdullah Erdem Canda

Yildirim Beyazit University, Türkiye

Prof Ian Chikanza

Harley Street Clinic, London

Dr Lorenz Räber

Bern University Hospital, Switzerland

Prof Lászlo Vécsei

University of Szeged, Hungary

Dr Mátyás Benyó

University of Debrecen, Hungary

Dr Hassan Galadari

United Arab Emirates University, United Arab Emirates

Dr Amir Hamzah Abdul Latiff

Pantai Hospital, Malaysia

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Aims and Scope EMJ is an online only, peer-reviewed, open access general journal, targeted towards readers in the medical sciences.

We aim to make all our articles accessible to readers from any medical discipline.

EMJ allows healthcare professionals to stay abreast of key advances and opinions across Europe.

EMJ aims to support healthcare professionals in continuously developing their knowledge, effectiveness, and productivity.

The editorial policy is designed to encourage discussion among this peer group.

EMJ is published quarterly and comprises review articles, case reports, practice guides, theoretical discussions, and original research.

EMJ also publishes 18 therapeutic area journals, which provide concise coverage of salient developments at the leading European congresses. These are published annually, approximately 6 weeks after the relevant congress.

Further details can be found on our website: www.emjreviews.com Editorial Expertise EMJ is supported by various levels of expertise: • • • •

Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.

Invited contributors are recognised authorities from their respective fields.

Peer review, which is conducted by EMJ’s Peer Review Panel as well as other experts appointed due to their knowledge of a specific topic.

An experienced team of editors and technical editors.

Peer Review On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review.

We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com To submit a paper, use our online submission site: www.editorialmanager.com/e-m-j Submission details can be found through our website: www.emjreviews.com/contributors/authors Reprints All articles included in EMJ are available as reprints (minimum order 1,000). Please contact hello@emjreviews.com if you would like to order reprints.

Distribution and Readership EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields across Europe.

Indexing and Availability EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®; selected articles are indexed in PubMed Central®.

EMJ is available through the websites of our leading partners and collaborating societies.

EMJ journals are all available via our website: www.emjreviews.com Open Access This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license.

Congress Notice

Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.

Staff members attend medical congresses as reporters when required.

All peer review is double blind.

Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.

ISSN 2397-6764

Editorial staff have final discretion over any proposed amendments.

All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible.

However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. The cover photo is of Brussels, Belgium, the location of work for two of the interviewees.

Submissions We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects.

We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.

This Publication

EMJ is published four times a year. For subscription details please visit: www.emjreviews.com

Front cover and contents photograph: Brussels, Belgium © bbsferrari / stock.adobe.com

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NOW APPROVED IN PsA AND axSpA

LEAVE PSORIASIS BEHIND WITH THE OPPORTUNITY FOR COMPLETE, FAST AND LASTING SKIN CLEARANCE* 1

THE OPPORTUNITY TO

*84% of patients achieved co-primary endpoints of PASI 90 and IGA 0/1 at Week 16 and 71% achieved PASI 75 at Week 4 following first dose.

58% of patients also achieved PASI 100 at Week 16 and 88% of those who did maintained it at Week 52.1 BIMZELX® is indicated for the treatment of: moderate to severe plaque psoriasis in adults who are candidates for systemic therapy; active PsA, alone or in combination with methotrexate, in adults who have had an inadequate response, or who have been intolerant, to one or more DMARDs; active nr-axSpA with objective signs of inflammation as indicated by elevated CRP and/or MRI, in adults who have responded inadequately, or are intolerant, to non-steroidal anti-inflammatory drugs (NSAIDs); and active AS in adults who have responded inadequately or are intolerant to conventional therapy.

References: 1. BIMZELX® EU SmPC. Moderate to severe plaque psoriasis. https://www.ema.europa.eu/en/documents/product-information/bimzelx-epar-product-information_en.pdf.

Accessed November 2023; 2. Reich K, Papp KA, Blauvelt A, et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial. Lancet. 2021;397(10273):487-498; 3. Gordon KB, Foley P, Krueger JG, et al.

Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY): a multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial. Lancet.

2021;397(10273):475-486; 4. Warren RB, Blauvelt A, Bagel J, et al. Bimekizumab versus adalimumab in plaque psoriasis. N Engl J Med. 2021;385(2):130-141.

EXPECT EXCEPTIONAL Based on efficacy data vs placebo, adalimumab and ustekinumab in pivotal phase III trials.2–4

Click here for prescribing information AE reporting This medication is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare Professionals are asked to report any suspected adverse reactions.

AS, ankylosing spondylitis; axSpA, axial spondyloarthritis; CRP, C-reactive protein; IGA, Investigator Global Assessment; PASI, Psoriasis Area and Severity Index; MRI, magnetic resonance imaging; nr-axSpA, nonradiographic-axSpA; PsA, psoriatic arthritis.

EU-BK-2300276 Date of preparation: November 2023 © UCB Biopharma SRL, 2023. All rights reserved. BIMZELX® is a registered trademark of the UCB Group of Companies.

EU-BK-2300276 PSO BKZ SL2 Journal Ad EU_149x210.indd 1

Stay up to date with new advancements across European healthcare Visit EMJ for our comprehensive collection of peerreviewed research articles, latest interviews, and features across a range of therapeutic disciplines.

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28/11/2023 15:2

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Welcome letter Editor Evgenia Koutsouki Editorial Manager Anaya Malik Copy Editors Noémie Fouarge, Kirsty Hewitt

Evgenia Koutsouki

Editorial Co-ordinator Natasha Meunier-McVey Editorial Assistants Lucy Anderson, Victoria Antoniou, Abigail Craig, Ada Enesco, Evan Kimber, Darcy Richards Design Manager Stacey Rivers

It is with great pleasure that I welcome you to our final issue of the EMJ flagship journal for 2023. With this highly engaging journal containing outstanding content, we are delighted to finish the year by showcasing the importance of primary health, whilst focusing on key topics across several disciplines.

The diabetologists amongst you will find our feature covering a holistic approach to diabetes care, and discussing the telemedicine aspects, a particularly insightful piece of content that hones in on challenges and opportunities around the use of telemedicine following the pandemic.

Senior Designer Roy Ikoroha Designer Steven Paul Junior Designers Dillon Benn Grove, Shanjok Gurung

This issue also features insightful interviews, with key experts discussing the challenges in primary care, the multifaceted aspects of the role of general practitioners, and the ever-increasing importance of the patient in the decision-making process.

Head of Sales Robert Hancox Chief Content Officer Justin Levett Chief Operating Officer Dan Scott Chief Commercial Officer Dan Healy Founder and Chief Executive Officer Spencer Gore

Editor

The Editor’s pick for this issue is a compelling review that sheds light on conflicting evidence regarding the role of obesity in cancer prognosis and survival outcomes, highlighting recent studies that have indicated positive responses to certain types of immunotherapies for patients with cancer and obesity. Oncology is also the focus of a review summarising key pathologic and clinical characteristics of the molecularly-defined renal cell carcinoma subtypes, incorporated in the new 2022 World Health Organization (WHO) classification system.

In addition, you will be able to read case reports in rheumatology and radiology, among other clinical areas.

I would like to close by thanking our amazing contributors, and Editorial Board for ensuring the high standards of content in this issue.

As always, our reviewers played a pivotal role in ensuring that the articles published were of the highest quality. Until our next issue in March 2024, I hope you have a peaceful new year ahead!

Contact us Editorial enquiries: editor@emjreviews.com Sales opportunities: salesadmin@emjreviews.com Permissions and copyright: accountsreceivable@emjreviews.com

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Reprints: info@emjreviews.com Media enquiries: marketing@emjreviews.com

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Have you diagnosed a patient with NMOSD or gMG? Our new infographic provides updates in: • Neuromyelitis optica spectrum disorder (NMOSD) • Generalised myasthenia gravis (gMG) This infographic is detailed with: • Prevalence statistics • Symptoms and challenges • Primary treatment goals

Learn more Publication of this infographic was supported by Alexion.

M/INT/NP/0071

December 2023

Foreword Dear Colleagues, Welcome to the latest issue of EMJ, featuring engaging content spanning a variety of therapeutic areas. The focus of this journal is centred around primary care, and topics cover online care resources, associations between obesity and cancer prognosis, Hansen’s disease, and post-operative dressings for hypospadias repair, amongst others.

My Editor’s Pick for this issue is the article, entitled ‘Ambiguous Effects of Cancer Prognosis and Treatment Response: A Narrative Review’, which focuses on an analysis of the relationship between obesity and cancer prognosis. This article presents a comprehensive literature review of the mechanisms that may influence survival outcomes.

Also included within this issue is an article evaluating the quality of primary online care resources, a highly relevant piece, as patient– doctor interactions continue to occur virtually post-COVID-19. The authors set out to establish

the online presence of general practices through time, and their quality of services.

This final 2023 issue of EMJ also showcases case reports on atypical hepatitis B-associated vasculitis, and spontaneous subcapsular hepatic haematomas, respectively.

Alongside these captivating articles, interviews were also conducted with Aurore Girard, Vice President of Société Scientifique de Médecine Générale (SSMG), Brussels, Belgium; Dame Clare Gerada, President of the Royal College of General Practitioners, London, UK; and Dirk Devroey, Dean of the Department of Family Medicine and Chronic Care, Faculty of Medicine, Vrije Universiteit Brussels (VUB), Belgium.

As always, I would like to extend my appreciation to all the authors, reviewers, interviewees, and Editorial Board members for their contribution and dedication, which have made publishing this edition of EMJ possible. I hope that this issue proves to be an enveloping and inspiring read for all healthcare professionals.

Prof Lászlo Vécsei Head of Neuroscience Research Group, Department of Neurology, University of Szeged, Hungary

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Can COVID-19 Help Us Deliver Whole-System Holistic Healthcare?

Authors:

Ada Enesco, EMJ, London, UK

Citation:

EMJ. 2023;8[4]:10-13. DOI/10.33590/emj/10304838. https://doi.org/10.33590/emj/10304838.

The 7ᵗʰ Joint Symposium between the European Association for the Study of Diabetes (EASD) and the Asian Association for the Study of Diabetes (AASD) took place on the 2ⁿᵈ–6ᵗʰ October in Hamburg, Germany. In an engaging session examining the impact of COVID-19 on new healthcare models, experts provided insights into whole-system approaches for diabetes, and opportunities for improvement in patient outcomes via telemedicine.

A WHOLE-SYSTEM APPROACH FOR DIABETES CARE Marc Evans, University Hospital Llandough, Cardiff, UK, opened the session by highlighting the growing costs and prevalence of diabetes worldwide. In the face of these increasing challenges, Evans drew attention to the way COVID-19 brought a new system-wide perspective to healthcare, in which all stakeholders were aligned to meet a single objective: save lives, and protect the integrity of the healthcare system. Evans explained that this holistic model is highly relevant, and valuable, for the management and treatment of diabetes.

“Diabetes does not exist as a sole entity: it is a component of the entire healthcare system, in which there are many different stakeholders,” he emphasised.

A single intervention can have an impact on all stakeholders and the entirety of a system, enabling solutions to many problems at once.

For instance, optimising strategies for glycaemic control in people with diabetes reduces the burden of complications, which translates into an improved quality and length of life, lower personal and healthcare costs, and less pressure on the healthcare system. Evans quoted: “To reduce cost, the best approach is often to spend more on some services to reduce the need for others.”1 In addition to this system-based thinking, Evans highlighted the importance of addressing inertia, and implementing strategies

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at an early stage, as seen with early lockdowns during the COVID-19 pandemic to reduce transmission and healthcare pressures. “Inertia is something that is very present in diabetes […] If we address inertia from a system-wide perspective, there are huge value gains,” stated Evans. He added that a total-system approach to decision-making would also have profound social, economic, and environmental impacts.

THE RISE OF TELEMEDICINE FOR DIABETES On behalf of Andrea Luk, Chinese University of Hong Kong, Hong Kong, Juliana Chan, from the same institution, spoke about the rise of digital health technologies during COVID-19, and the potential for telemedicine to reshape the future of diabetes care. Telemedicine is described by the World Health Organization (WHO) as the “delivery of healthcare services using information and communication technologies with the aim of diagnosing, treating, and preventing diseases and injuries.” Chan explained that, before COVID-19, telemedicine was mainly applied in order to help overcome access barriers, so as to reach patients in remote areas through teleconsultations. For diabetes, telemonitoring was established early on for the real-time transmission of glucose data to healthcare professionals (including continuous glucose monitoring), to make recommendations on insulin dosage.

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A 2016 meta-analysis across more than 9,000 participants with Type 1 or 2 diabetes examined the mean difference in attained HbA1c in patients exposed to telemedicine or conventional care.2 Overall, the telemedicine group had a larger reduction in HbA1c levels than those undergoing conventional care. Furthermore, a 2020 metaanalysis of over 5,000 pregnant females with gestational diabetes found that telemedicine was associated with better maternal and fetal outcomes, including a lower incidence of Caesarean section, pre-eclampsia, premature rupture of membranes, and macrosomia.3 Nevertheless, Chan emphasised that the heterogeneity of telemedicine studies, such as variation in approach, sample size, and follow-up duration, is a challenge for drawing conclusions on the effectiveness of this new care model.

“No studies have yet examined how telemedicine may impact long-term diabetes complications,” she stated.

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Chan also spoke about the Hong Kong healthcare experience, where the Hospital Authority provides healthcare for 90% of the Hong Kong population, and a single electronic medical record system has provided clinical care for all patients since 2000. The Hospital Authority launched a one-stop mobile platform in 2019, ‘HA Go’, which provides teleconsultation services to improve the healthcare experience of patients.

However, Chan explained that many barriers to teleconsultation still remain in Hong Kong, such as the absence of legislation for the regulation of virtual services, which raises concerns about potential medicolegal consequences for misdiagnosis. “Many healthcare systems, like in Hong Kong, are at a crossroads […] We still don’t know if telemedicine is here to stay,” stated Chan. While some systems continue to expand their telemedicine platforms and services, others have reverted back to conventional modes of care.

“Diabetes does not exist as a sole entity: it is a component of the entire healthcare system, in which there are many different stakeholders.”

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TELEMEDICINE POST-PANDEMIC: LESSONS AND CHALLENGES COVID-19 not only prompted the global uptake of telemedicine, but also provided an opportunity to assess its effectiveness in a real-world setting, identifying areas of development to support the ongoing use of telemedicine post-pandemic.

Chan emphasised that, ultimately, the goal for telemedicine is to ensure quality care. She cited the guidelines from the Institute of Medicine Committee on Quality of Health Care in the USA, which provides strategies for the redesign of healthcare systems.

Firstly, telemedicine should achieve comparable safety and effectiveness to conventional care, and may also require a different quality reporting system, which should evaluate impact at a system-wide level. “Evaluation of telemedicine services should keep pace with the rapid change of the technology landscape,” explained Chan. Secondly, telemedicine should be efficient and timely, providing improved access to care for people living in remote areas, and using healthcare resources more efficiently than conventional care. Thirdly, telemedicine

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should be patient-centred and equitable. Chan highlighted the risk for telemedicine to increase, rather than decrease, health inequities: “We have to ensure that there is internet access in remote areas; develop tools to assist people with motor, visual, or audial impairments; and increase help for population segments with limited language proficiency, or low digital literacy,” she advised. Chan spoke about the telemedicine experience in India, where 65% of the population has no internet access.

To ensure equitable access to health, the government introduced ‘eSanjeevani’, a virtual appointment platform where patients living in remote villages are aided by a local healthcare worker with internet access to connect with physicians.

Chan went on to present valuable insights into the current strengths and limitations of telemedicine after COVID-19. A 2022 study including half a million patients with diabetes, found that conventional care performed slightly better in medication-based measures, while telemedicine performed better in testing-based measures (90.8% versus 85.6% of patients had HbA1c levels tested).4 Chan explained that the

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initiation of medication may require more in-depth discussion with patients, which may not be as readily achievable through teleconsultation. In parallel, the absence of physical examinations in teleconsultations may prompt healthcare professionals to order more extensive patient testing. In another study, 64% of people with diabetes in Italy stated they were willing to continue using telemedicine after lockdown, with females and elderly patients less likely to continue with it, and graduates and unemployed people more likely to.5 People with greater perceived ability in self-management, mostly the younger population, generally had a higher willingness to continue using remote services, and perceived these services as of higher quality.

References 1.

2.

3.

Su D et al. Does telemedicine improve treatment outcomes for diabetes? A meta-analysis of results from 55 randomized controlled trials. Diabetes Res Clin Pract. 2016;116:136-48.

Xie W et al. Effectiveness of

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CONCLUSION COVID-19 has presented the opportunity to apply and evaluate new systems and perspectives for healthcare. These are highly relevant for the treatment of diabetes, a complex disease with increasing prevalence and challenges. Ultimately, the integration of telemedicine to routine healthcare delivery will require system-level interventions, to ensure equitable access to care, and increase the quality, safety, and efficiency of virtual services.●

telemedicine for pregnant women with gestational diabetes mellitus: an updated meta-analysis of 32 randomized controlled trials with trial sequential analysis.

BMC Pregnancy Childbirth.

2020;20(1):198.

Porter ME. What is value in health care? N Engl J Med. 2010;363(26):2477-81.

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Baughman J et al. Comparison of quality performance measures for patients receiving in-person vs telemedicine primary care in a large integrated health

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system. JAMA Netw Open.

2022;5(9):e2233267.

5.

Maietti E et al. The experience of patients with diabetes with the use of telemedicine and teleassistance services during the COVID-19 pandemic in Italy: factors associated with perceived quality and willingness to continue. Diabetes Res Clin Pract.

2021;180:109047.

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Symposium Review

New Horizons in IgA Nephropathy: A Focus on Current Treatment and Emerging Solutions Presentations took place on 9th September 2023 as part of the Nephro Update Europe Congress, held in Prague, Czechia Speakers:

Vladimir Tesař,1 An De Vriese2 1. Department of Nephrology, Charles University, Prague, Czechia 2. Department of Internal Medicine, Division of Nephrology and Infectious Diseases, AZ Sint-Jan, Brugge, Belgium

Disclosure:

Tesař served as a consultant for AstraZeneca, Bayer, Boehringer-Ingelheim, Calliditas Therapeutics, Novartis, Omeros, Otsuka, and Travere Therapeutics.

De Vriese has received research support from Amgen; and served as a consultant for Bluestar, Confo Therapeutics, CSL Vifor, Goldfinch Bio, Liberium, Nipro Digital Technologies, Novartis, Pfizer, and Xeltis.

Both speakers received fees from CSL Vifor for this symposium.

Acknowledgements:

Writing assistance was provided by Eleanor Roberts, Beeline Science Communications Ltd., London, UK.

Disclaimer:

The views and opinions expressed are those of the faculty and not necessarily those of Vifor (International) AG.

Support:

The publication of this article was funded by CSL Vifor.

Keywords:

Angiotensin, endothelin, glomerulonephritis, IgA nephropathy (IgAN), optimised supportive care, proteinuria, sparsentan.

Citation:

EMJ. 2023;8[4]:14-23. DOI/10.33590/emj/10303661. https://doi.org/10.33590/emj/10303661.

Meeting Summary IgA nephropathy (IgAN) is a common form of glomerular disease, with wide heterogeneity of symptom occurrence and progression. Diagnosis is based on kidney biopsy findings. IgAN initiates in the mucosa with development of galactosedeficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies, leading to deposition of these complexes in glomerular mesangium with resulting fibrosis, inflammation, tubulointerstitial scarring, and glomerular injury. This can lead to chronic kidney disease (CKD), kidney failure, and death. IgAN treatment involves optimised supportive care, including individualised strategies to address symptoms, such as high blood pressure control and cardiovascular risks. Drug treatment includes renin-angiotensin-aldosterone system (RAAS) inhibitors and immunosuppressant therapies. While the latter can successfully lower proteinuria, and have a positive effect on estimated glomerular filtration rate (eGFR), adverse effects can limit treatment duration, and increasing proteinuria and decreasing eGFR can return following treatment discontinuation. New formulations of immunosuppressant therapies include delayed-release budesonide with targeted release in the lower

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part of the small intestine where Gd-IgA1 production occurs. Although treatment with this drug can reduce proteinuria and sustain eGFR levels, similar to other immunosuppressant therapies, effects seem to be predominantly limited to the active treatment period. Targeting a different mechanism, sparsentan is a dual endothelin A receptor (ETA) and angiotensin II receptor type 1 (AT1) blocker that targets endothelin-1 (ET-1) and angiotensin II, both involved in IgAN progression.

Initial Phase III trial results show significant differences, favouring sparsentan, compared with the AT1 blocker irbesartan, on proteinuria, with similar adverse event profiles. These agents, and several other drugs in development, will widen the armamentarium of therapies for people with IgAN, which, when used in combination, can target different aspects of IgAN pathogenesis for a more individualised treatment approach.

Introduction IgAN, which can lead to CKD and kidney failure, is the most common form of primary glomerulonephritis, predominantly, though not exclusively, occurring in young adults.1,2 Prevalence of IgAN, and associated CKD is higher in people of East Asian ancestry.3 While IgAN progression can be slow in some patients, occurring over 20–25 years, in many, progression can be rapid. This means that early diagnosis and treatment is key, as even in patients where development is slow, IgAN occurrence in a young adult can mean progression in their middle age.2,4 Symptoms are heterogeneous, and can range widely from asymptomatic microscopic haematuria to sustained proteinuria and rapid renal function decline.1,2 Diagnosis of IgAN necessitates a kidney biopsy to ascertain the ‘MEST-C’ score, based on a combination of five histological components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S), interstitial fibrosis/tubular atrophy (T), and crescents (C).5 Results from MEST-C assessment can be incorporated into prognosis predictions, but, according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, “there is insufficient evidence to support the use of the MEST-C score in determining whether immunosuppression should be commenced in IgAN.”4 At the Nephro Update Europe 2023 Congress, An De Vriese, Department of Internal Medicine, Division of Nephrology and Infectious Diseases, AZ Sint-Jan, Brugge, Belgium; and Vladimir

Tesař, Department of Nephrology, Charles University, Prague, Czechia, discussed IgAN pathogenesis, current treatments, and how, with the development of several new treatments, IgAN therapy should be individualised according to each patient’s needs.

Pathogenesis of IgA Nephropathy De Vriese explained how the basic pathogenesis of IgAN can be encompassed within the “fourhit hypothesis.”1,2 In this model, the initiating hit is when elevated circulating levels of Gd-IgA1 occur following a mucosal infection due to, often inherited,6 abnormalities in IgA1 production. The second hit, development of autoantibodies, occurs as Gd-IgA1 lacks galactose residues around the hinge region needed to clear IgA1, and this area is exposed as an autoantigen.1,2,7,8 The third hit occurs when Gd-IgA1 and anti-GdIgA1 autoantibodies combine to form immune complexes, leading to the fourth hit, deposition of these complexes in glomerular mesangium.

This can result in inflammation and fibrosis, due to the stimulation of mesangial cells; activation of the complement pathway; and secretion of chemokines, cytokines, and extracellular matrix proteins, leading to glomerular injury and tubulointerstitial scarring.1,2,7

Current Treatment of IgA Nephropathy With regard to the four-hit hypothesis, De Vriese noted: “It is important to realise that all four

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hits must occur for clinically relevant disease to develop. This implies that solely targeting one factor in treatment will not work; instead, you need a comprehensive approach that targets all the relevant factors.” De Vriese also explained how “you need to judge in an individual patient which element of the pathophysiology is determining the clinical effects you see. Is this proteinuria because of chronical scarring and incomplete restoration of the glomerular filtration barrier, or is this proteinuria the consequence of active inflammatory disease? This will determine which drug(s) you will choose.”

considered following discussion of potential adverse events. However, it is noted in the guidelines that “clinical benefit of glucocorticoids in IgAN is not established and should be given with extreme caution or avoided entirely in patients with a number of conditions.” These conditions include eGFR <30 mL/min/1.73 m2, diabetes, obesity, latent infections, and severe osteoporosis. For patients who remain at high risk of progressive kidney disease despite maximal supportive care, KDIGO guidelines suggest they “should be offered the opportunity to take part in a clinical trial.”4

Another difficulty when assessing and treating IgAN, De Vriese explained, is that “there’s an extreme heterogeneity in clinical presentation and prognosis of patients, from isolated microscopic haematuria with very low risk of progressive disease that just requires annual follow-up to, on the other end of the spectrum, rapidly progressive glomerulonephritis that has a dire prognosis that should be treated aggressively. The problem,” De Vriese continued, “is that a large majority of patients are somewhere along this spectrum, and it can be difficult to figure out where exactly they are at.”1,2,9 De Vriese explained how “the challenge in the approach to IgAN is not only to assess the risk of progressive disease, but to try to figure out if a patient has active inflammatory disease, and will likely respond to a course of immunosuppressive treatment.”

These recommendations are partly based on the Toronto Glomerulonephritis registry study, showing that proteinuria is one of the most important modifiable indicators of renal survival in patients with IgAN. This study showed that in patients with <1 g/day proteinuria, rate of renal decline was 90% slower than the mean rate, but increased in patients with higher proteinuria levels.10 This means that, according to Tesař, “if we are able to reduce proteinuria, we should be able to modify the course of the disease.”

Indeed, the Valiga study, conducted by Tesař and colleagues, showed that for patients receiving RAAS blockade with or without glucocorticoids, those achieving proteinuria of <1 g/day had more favourable outcomes than patients not achieving this level.11 As such, Tesař said, “we should aim for low proteinuria.” Additionally, Tesař continued, “the longer proteinuria remission is, the better the outcome of the patients.” Decreasing this risk may take a number of years, but once achieved and maintained, the long-term outcome, said Tesař, should be favourable.12

To aid IgAN management, the KDIGO Glomerular Diseases Work Group provided updated IgAN treatment guidelines in 2021. These state that “the primary focus of management should be optimised supportive care.” Such care includes individualised strategies for the patient that involve, as needed, blood pressure control, cardiovascular risk minimisation, dietary counselling, smoking cessation, weight control, and exercise.4 Medical management for IgAN in KDIGO guidelines is predominantly based on proteinuria levels. If proteinuria is >0.50 g/day, RAAS inhibitors should be prescribed, regardless of presence of hypertension. If proteinuria is >0.75– 1.00 g/day, despite at least 90 days of optimised supportive care, a patient is considered to be at high risk of IgAN progression, and a 6-month course of glucocorticoid treatment can be

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However, while prescribing immunosuppressive treatment based on proteinuria level is useful, De Vriese suggested the importance of “incorporating the presence of persistent microscopic haematuria in your decisionmaking.” Although this is not proposed in KDIGO guidelines, De Vriese also suggested taking the MEST-C score into account, as the results of one study showed that adding MEST-C to baseline assessments, such as proteinuria, can improve prediction of 50% decrease in eGFR or kidney failure.4 For example, while proteinuria at biopsy between 1.0–1.5 g/day with M0 and T0 has a 90.6% risk of composite renal outcome, for those with M1 (mild) and T1 or T2 (mild or moderate), the risk is 73.5%.13

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To illustrate this, De Vriese discussed two cases which, on first examination may appear similar; both were 45-year-old males with proteinuria levels of 1.5 g/day (Figure 1). “From the perspective of the KDIGO guidelines,” said De Vriese, “you would need to approach these patients in a similar way. However, the first patient does not have persistent microscopic haematuria, nor does he have any signs of active disease in the kidney biopsy, while the second patient does.”4 This means, De Vriese continued, that “these patients have a different risk of progressive disease, and it’s highly unlikely that this first patient will respond to a course of immunosuppressive drugs.”

Current Treatment for IgA Nephropathy As immunosuppressant agents are currently the main treatment choice when optimised supportive care does not reduce proteinuria, a handful of trials have been carried out to assess the utility of this approach. In the ‘Therapeutic Evaluation of Steroids in IgA Nephropathy Global’ (TESTING) trial, 6−9 months’ treatment with methylprednisolone (n=257) was compared with placebo (n=246); both study groups included optimised supportive care.14 Over the 6-year trial and follow-up period, cumulative incidence of the primary endpoint (40% decline in eGFR, kidney failure, or death due to CKD) was significantly lower (p<0.001) in the methylprednisolone group compared with placebo (hazard ratio: 0.53; 95% confidence interval [CI]: 0.39–0.72].14

Figure 1: Two cases of IgA nephropathy with differences in haematuria and MEST-C score.

Patient 1

Patient 2

45-year-old male

45-year-old male

Proteinuria: 1.5 g/d

Proteinuria: 1.5 g/d

Haematuria: absent

Haematuria: present

M1 E0 S1 T1 C0

M1 E1 S1 T1 C1

C: crescents; E: endocapillary hypercellularity; M: mesangial hypercellularity; S: segmental glomerulosclerosis; T: tubular atrophy/interstitial fibrosis.

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However, De Vriese pointed out, supplementary data showed that following initial proteinuria decline during the active treatment period in the methylprednisolone group, proteinuria levels rose during the follow-up period. Conversely, eGFR levels initially rose with methylprednisolone treatment, but the slope of decline following discontinuation was similar to that of the placebo group.14

in the group that discontinued MMF use. For proteinuria, percentage decrease from baseline was significantly greater in the MMF group compared with the optimised supportive care group (p<0.001). At the end of the post-trial period, gains over the optimised supportive care group disappeared in the MMF group that discontinued treatment, but were retained in those who continued treatment.16

In the 3-year ‘Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy’ (STOP-IgAN) trial, 6 months’ glucocorticoid treatment combined with optimised supportive care was compared to optimised supportive care alone. At the 6-month timepoint, there was a decrease in proteinuria in the combined treatment group; however, once treatment was withdrawn, any advantages over optimised supportive care alone were not sustained at 36 months. At all timepoints, reported de Vriese, there was no beneficial effect with combined therapy on eGFR.1

One drug highlighted in this session was a delayed-release formulation of the corticosteroid budesonide,17-19 which has received conditional approval from the European Medicines Agency (EMA),20 and accelerated approval from the U.S. Food and Drug Administration (FDA)21 for adults with IgAN at high risk of progressive disease (proteinuria >1.5 g/day). This drug, explained De Vriese, “has been designed to selectively affect the immune cells in the gut, located in the Peyer’s patches, that are thought to be responsible for Gd-IgA1 and anti-Gd-IgA1 autoantibodies generation.”17,20,22,23 Budesonide has been formulated into triple-coated beads inside an enteric coated starch capsule. Together, they provide delayed-release only once the capsule is exposed to the pH of the intestine (around pH 5−8),17,20 in the area where Peyer’s patches are most abundant, the final 25 cm segment of the distal ileum.2 As only a small percentage of the active drug reaches the systemic circulation, compared to systemic glucocorticoids, it is postulated to have a lower toxicity profile.17,20

The ‘Effect of Mycophenolate Mofetil on Renal Outcomes in Advanced Immunoglobulin A Nephropathy’ (MAIN) trial compared the immunosuppressive agent mycophenolate mofetil (MMF; n=85) with optimised supportive care (n=85) for at least 18 months, with a followup period of up to 3 years from baseline. At the end of the trial, primary composite endpoint outcomes (doubling of serum creatinine levels, kidney failure, or death due to kidney or cardiovascular cause) were significantly different between the groups (log-rank p=0.008).16 De Vriese noted though, that while the majority of MMF group participants discontinued treatment at the end of the trial phase (n=66), 14 MMF group participants remained on treatment throughout the post-trial follow-up, and differences were found in eGFR and proteinuria, according to whether or not participants discontinued or remained on treatment. Over the entire study period, in the optimised supportive care only group, eGFR steadily decreased from around 50 mL/min/1.73 m2 to around 30 mL/ min/1.73 m2. In the MMF group, eGFR declined to around 47 mL/min/1.73 m2 by the end of the initial trial period; this was retained throughout the post-trial period in the group that continued taking MMF. However, eGFR declined to levels similar to the optimised supportive care group

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The ‘Efficacy and Safety of Nefecon (delayedrelease budesonide) in Patients with Primary IgA Nephropathy’ (NefIgArd) study was a Phase III trial that compared delayed-release budesonide (n=182) with placebo (n=182) in patients with IgAN and persistent proteinuria, all of whom received optimised supportive care.25,26 Results showed that over 9 months of treatment, mean change from baseline in eGFR in the delayedrelease budesonide group was 0.66 mL/min/1.73 m2 (95% CI: -0.80–2.15) compared with -4.56 mL/ min/1.73 m2 (95% CI: -5.86–-3.22) in the placebo group. Mean change from baseline in proteinuria was -33.6 (95% CI: -39.6–-27.0) in the delayedrelease budesonide group compared with -5.2 (95% CI: -13.7–4.3) in the placebo group.24 However, noted De Vriese when examining the observational follow-up period, “after withdrawal of budesonide, proteinuria slowly starts to creep up again and, after an initial rise in eGFR, the

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slope of decline runs in parallel with the placebo group.”25 With all of the studies of glucocorticoids in mind, De Vriese noted that, in simple terms, they showed that “glucocorticoids work for as long as you give them, and when you stop giving them, you’re back to where you came from.”

Another treatment discussed in this session was the addition of a sodium/glucose cotransporter-2 (SGLT-2) inhibitor to RAAS inhibitors. SGLT-2 inhibitors enhance urinary glucose excretion by reducing renal proximal convoluted tubule glucose reabsorption, and have an effect on efferent arteriolar tone. As SGLT-2 inhibitors affect afferent arteriolar tone, the combination of these two agents can reduce intraglomerular pressure in an additive manner.25,26

New Treatment Opportunities in IgA Nephropathy A number of agents are being trialled that target IgAN along different stages of its four-hit pathogenesis. These include agents that target the kidney, including AT1 and ETA blockers; those that block production of Gd-IgA1 and anti-GdIgA1 autoantibodies in the gut through B-cell/ antibody suppression; as well as complement inhibitors (Table 1).9 De Vriese discussed how now, or shortly, “for IgAN pathogenesis, there is budesonide and other drugs in development [such as the] anti-a proliferation-inducing ligand and/or anti-B-cell activating factor, and antiCD38 inhibitors/antibodies. For inflammation you have the systemic immunosuppressants and complement inhibitors, and for fibrosis you have RAAS inhibition and sparsentan.”

Sparsentan for IgA Nephropathy Optimised supportive care, discussed Tesař, may soon include drugs that target the endothelin receptor, as such agents are currently in Phase III trials for IgAN.29-31 The vascular endothelin system is comprised of endothelins-1, -2, and -3. Receptors for ET-1, primarily ETA but also ETB, are both expressed in the kidneys. ET-1 has a variety of effects

on vascular and renal cells, and is associated with CKD pathophysiology. For example, in the vasculature, ET-1, via ETA receptors, contributes to vasoconstriction, platelet activation, and endothelial dysfunction, with overexpression leading to hypertension and/or atherosclerosis.

In the kidney, ET-1 actions, also via ETA receptors, include those on podocyte-related proteinuria, cytoskeletal remodelling, and foot process effacement; in mesangial cells, ET-1 has a role in glomerulosclerosis, extracellular matrix accumulation, and cell hypertrophy; and in renal tubules, ET-1 is linked to tubulointerstitial fibrosis.

These actions may all lead to CKD.40 With the actions of ET-1 in mind, it is of interest for IgAN treatment that ETA blockade can lead to reductions in proteinuria, blood pressure, and salt and water retention, along with decreases in reactive oxygen species, fibrosis, and inflammation. Such blockade is associated with reductions in hypertension, proteinuria, and diabetic micro- and macrovascular complications.39 Studies of ETA and ETB receptor antagonists show that while some drugs, such as avosentan, are non-ET-1 receptor selective, others, including sparsentan and atrasentan, are much more selective for ETA.42 There are a number of interactions between the ET-1 system and the RAAS. For example, while angiotensin II can stimulate ET-1 release in renal cells43 and enhance ET-1induced vasoconstriction,44 ET-1 can stimulate aldosterone secretion, inhibit juxtaglomerular apparatus renin release, and stimulate angiotensin II formation in pulmonary endothelial cells.43 Sparsentan is a first-in-class dual ETA and AT1 receptor antagonist that can bind to these receptors in podocytes, mesangial cells, and other renal cell types, preventing binding of ET-1 and angiotensin II, respectively.43,45,46 It recently received accelerated approval by the FDA39 in the USA and marketing authorisation is currently being evaluated in Europe. Studies evaluating sparsentan have shown that it can prevent actions such as vasoconstriction and endothelial dysfunction in renal vessels; glomerulosclerosis, mesangial cell proliferation, and extracellular matrix production in the glomeruli; and proteinuria, podocyte apoptosis, and increased glomerular permeability, that can lead to inflammation and fibrosis, in the tubulointerstitial compartment.43,47

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Table 1: Agents in development or newly approved for treatment of IgA nephropathy.9

Agent

Mechanism of action

Trial

Phase

AT1 and ETA blockers Sparsentan*

Dual AT1 blocker/ETA receptor antagonist

PROTECT29,30

Phase III

Atrasentan

ETA receptor antagonist

ALIGN31

Phase III

B-cell/antibody suppression Atacicept

BAFF/APRIL inhibitor

ORIGIN 332

Phase III

Telitacicept

BAFF/APRIL inhibitor

Phase II trial33

Phase II

BION-1301/zigakibart

Anti-APRIL antibody

BEYOND34

Phase III

Sibeprenalimab

Anti-APRIL antibody

VISIONARY35

Phase III

Complement inhibition LNP023/iptacopan

Complement factor B inhibitor

APPLAUSE-IgAN36

Phase III

OMS721/narsoplimab

MASP-2 inhibitor

ARTEMIS-IgAN37

Phase III

IMAGINATIO38

Phase III

Ligand-conjugated antisense IONIS FB LRx/RO7434656 oligonucleotide targeting complement factor B

*Recently received FDA accelerated approval.39 APRIL: a proliferation-inducing ligand; AT1: angiotensin II receptor type 1; BAFF: B-cell activating factor; ETA: endothelin receptor type A; FDA: U.S. Food and Drugs Administration; IgAN: immunoglobulin A nephropathy; MASP-2, mannan-binding lectin serine protease 2.

In the Phase III, international, multicentre, randomised, double-blind, active-controlled PROTECT trial, 400 mg/day sparsentan (n=202) was compared with maximum dose (300 mg/day) of the AT1 blocker irbesartan (n=202) in adult participants with IgAN and persistent proteinuria, despite maximum angiotensin-converting enzyme inhibitors or AT1 blockers.29,30 Patients were predominantly male (70%), White (67%), and had a history of hypertension (70%). The initial double-blind trial period was for 110 weeks, followed by 4 weeks of standard of care without study medications. There is an ongoing, optional,

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open-label extension period of up to 156 weeks.

The primary efficacy endpoint was change in urinary protein-to-creatinine ratio (UP/C) at Week 36. Secondary endpoints include the rate of change in eGFR from baseline to 110 weeks, as well as eGFR rate of change following the initial acute effects of randomised therapy, that is, from Week 6 to Week 58, and to Week 110.29,30 In the interim analysis at Week 36, there was a -49.8% (95% CI: -55.0–-44.0) change in UP/C for the sparsentan group compared to a -15.1% (95% CI: -23.7–-5.4) change in the irbesartan group.

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This represented a 41% relative reduction in UP/C ratio and a significant difference, favouring sparsentan (p<0.0001). Significant differences were shown as early as Week 4, with an initial large change in UP/C in participants receiving sparsentan, followed by further decreases over the trial period.30 Also observed at Week 36 was complete proteinuria remission (urinary protein excretion <0.3 g/day) in 21% of participants in the sparsentan group, and 8% of participants in the irbesartan group (odds ratio: 3.1; 95% CI: 1.6–5.8; p=0.0005). Partial proteinuria remission (urinary protein excretion <1.0 g/day) was observed in 70% of participants in the sparsentan group, and 44% of participants in the irbesartan group (odds ratio: 4.5; 95% CI: 2.7–7.6; p<0.0001). Baseline subgroup analysis, assessing several variables, such as sex, eGFR level, urine protein, and age, showed that higher proteinuria reductions were consistent across subgroups. Tesař also observed that there were limited differences between the two treatment groups with regard to blood pressure,30 meaning that proteinuria remission was not solely caused by the effect of sparsentan on blood pressure.

Treatment emergent adverse events in the sparsentan and irbesartan groups were similar, and included peripheral oedema (14% and 9% of participants, respectively), hypotension, (14% and 6%), hyperkalaemia (13% and 10%), and dizziness (13% and 5%).

Treatment emergent adverse events leading to treatment discontinuation were reported in 7% of participants in the sparsentan group and 5% of participants in the irbesartan group. New diuretic use occurred in 18% of participants in the sparsentan group and 19% of participants in the irbesartan group. No participant in either

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Magistroni R et al. New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Kidney Int. 2015;88(5):974-89.

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group discontinued treatment due to oedema, there was no evidence of heart failure, and there were no serious adverse events associated with treatment-related fluid retention. Where liver enzyme elevations >3x the upper limit of normal occurred (2% of participants in each group), they were asymptomatic, reversible, and without concurrent elevation in total bilirubin.30,48 Tesař concluded with the reminder that “even with all these treatments we now have available, still a significant proportion of patients progress to kidney failure, partly because they can’t take a medication that may work for a long time due to adverse events. Based on the interim analysis of the PROTECT trial, it seems that combined inhibition of AT1R and ETAR, is a promising strategy, although we need to have the data from the full study to see if the effect on proteinuria is translated to a beneficial eGFR effect.”

Conclusion A significant proportion of patients with IgAN show a progressive disease course. Current treatment recommendations primarily include RAAS inhibition, immunosuppressant treatment, and lifestyle alterations, but a ‘one size fits all’ approach may not target all symptoms in every patient.1,2,4 Delayed-release budesonide17-19 and the dual ETA and AT1 receptor antagonist sparsentan,43-46 which recently received accelerated FDA approval,39 are now available in some countries for people with progressive IgAN, and there are several other drugs in development. The availability of such drugs should mean that each of the four hits of IgAN pathogenesis can now be targeted, depending on the individual symptoms of each patient.

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12. Canney M et al. Quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy. J Am Soc Nephrol. 2021;32(2):436-47.

13. Barbour S et al. The MEST score provides earlier risk prediction in lgA nephropathy. Kidney Int. 2016;89(1):167-75.

14. Lv J et al. Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial.

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15. Rauen T et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med. 2015;373(23):2225-36.

16. Hou F et al. Effectiveness of mycophenolate mofetil among patients with progressive IgA nephropathy: a randomized clinical trial. JAMA Netw Open.

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17. Watts P, Smith A. TARGIT technology: coated starch capsules for site-specific drug delivery into the lower gastrointestinal tract. Expert Opin Drug Deliv. 2005;2(1):159-67.

18. Calliditas Therapuetics. Highlights of prescribing information, Tarpeyo (budesonide). 2021. Available at: https://www.accessdata. fda.gov/drugsatfda_docs/ label/2021/215935s000lbl.pdf. Last accessed: 21 November 2023.

19. STADA Arzneimittel AG. Kinpeygo 4mg modified-release hard capsules. 2023. Available at: https://www.ema.europa.eu/en/ documents/product-information/

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kinpeygo-epar-productinformation_en.pdf. Last accessed: 21 November 2023.

20. European Medicines Agency (EMA). Kinpeygo. 2023. Available at: https://www.ema.europa.eu/en/ medicines/human/EPAR/kinpeygo.

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21. U.S. Food and Drugs Administration (FDA). FDA approves first drug to decrease urine protein in IgA nephropathy, a rare kidney disease. 2021.

Available at: https://www.fda. gov/drugs/fda-approves-firstdrug-decrease-urine-protein-iganephropathy-rare-kidney-disease.

Last accessed: 21 November 2023.

22. Griebel PJ, Hein WR. Expanding the role of Peyer's patches in B-cell ontogeny. Immunol Today.

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23. Barratt J et al. Why target the gut to treat IgA nephropathy? Kidney Int Rep. 2020;5(10):1620-4.

24. Van Kruiningen H et al. Distribution of Peyer's patches in the distal ileum. Inflamm Bowel Dis. 2002;8(3):180-5.

25. Lafayette R et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet.

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26. Barratt J et al. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int. 2023;103(2):391-402.

27. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus.

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28. Herrington WG et al. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPAKIDNEY study. Clin Kidney J. 2018;11(6):749-61.

29. Travere Therapeutics, Inc. A study of the effect and safety of sparsentan in the treatment of patients with IgA nephropathy (PROTECT). NCT03762850. https://www.clinicaltrials.gov/ study/NCT03762850.

30. Heerspink H et al. Sparsentan in patients with IgA nephropathy:

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a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial.

Lancet. 2023;401(10388):1584-94.

31. Chinook Therapeutics U.S., Inc. Atrasentan in patients with IgA nephropathy (ALIGN).

NCT04573478. https://www. clinicaltrials.gov/ct2/show/ NCT04573478.

32. Vera Therapeutics, Inc. Atacicept in subjects with IgA nephropathy (ORIGIN 3). NCT04716231. https:// www.clinicaltrials.gov/study/ NCT04716231.

33. RemeGen Co., Ltd. A study of telitacicept in patients with primary IgA nephropathy. NCT05799287. https://www.clinicaltrials.gov/ct2/ show/NCT05799287.

34. Chinook Therapeutics, Inc. A study of BION-1301 in adults with IgA nephropathy. NCT05852938. https://www.clinicaltrials.gov/ study/NCT05852938.

35. Otsuka Pharmaceutical Development & Commercialization, Inc. Visionary study: phase 3 trial of sibeprenlimab in immunoglobulin A nephropathy (IgAN). NCT05248646. https:// www.clinicaltrials.gov/study/ NCT05248646.

36. Novartis Pharmaceuticals. Study of efficacy and safety of LNP023 in primary IgA nephropathy patients (APPLAUSE-IgAN). NCT04578834. https://www.clinicaltrials.gov/ study/NCT04578834.

37. Omeros Corporation. Study of the safety and efficacy of OMS721 in patients with immunoglobulin A (IgA) nephropathy. NCT03608033. https://www.clinicaltrials.gov/ct2/ show/NCT03608033.

38. Hoffmann-La Roche. A study to evaluate the efficacy and safety of RO7434656 in participants with primary immunoglobulin A (IgA) nephropathy at high risk of progression (IMAGINATION).

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39. Travere Therapeutics. Travere Therapeutics announces FDA accelerated approval of FILSPARI™ (sparsentan), the first and only non-immunosuppressive therapy for the reduction of proteinuria in IgA nephropathy.

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immunosuppressive-Therapy-forthe-Reduction-of-Proteinuriain-IgA-Nephropathy.html. Last accessed: 21 November 2023.

40. Kohan D. Endothelin, hypertension and chronic kidney disease: new insights. Curr Opin Nephrol Hypertens. 2010;19(2):134-9.

41. Jandeleit-Dahm K, Watson A. The endothelin system and endothelin receptor antagonists. Curr Opin Nephrol Hypertens. 2012;21(1):6671.

system and endothelin-1 in treatment of chronic kidney disease. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R87784.

44. Lin Y et al. Angiotensin II enhances endothelin-1-induced vasoconstriction through upregulating endothelin type A receptor. Biochem Biophys Res Commun. 2014;451(2):263-9.

42. Davenport A et al. Endothelin.

Pharmacol Rev. 2016;68(2):357418.

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43. Komers R, Plotkin H. Dual inhibition of renin-angiotensin-aldosterone

46. Travere Therapeutics. Highlights of prescribing information,

Filspari (sparsentan) tablets.

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47. Trachtman H et al. Dual angiotensin II AT1 receptor blocker and endothelin ETA receptor antagonist, treatment of focal segmental glomerulosclerosis, treatment of IgA nephropathy.

Drugs Future. 2020;45(2):79.

48. Radhakrishnan J et al. Proteinuria reduction with sparsentan in immunoglobulin A nephropathy (IgAN): PROTECT study interim results. Abstract 333. NKF Spring Clinical Meeting, 11-15 April, 2023.

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Spasticity Matters: A Call to Action Following an Acute Stroke This non-promotional, industry-sponsored symposium took place during the 15th World Stroke Congress (WSC) held in Toronto, Canada, 10th–12th October, 2023 Chairpeople:

Sean Savitz,1 Ted Wein2

Speakers:

Ganesh Bavikatte,3,4 Sean Savitz,1 Ted Wein2 1. Institute for Stroke and Cerebrovascular Diseases, University of Texas Health Science Center at Houston (UTHealth Houston), USA 2. McGill University, Montréal, Quebec, Canada 3. Walton Centre NHS Foundation Trust, Liverpool, UK 4. University of Liverpool, UK

Disclosure:

As an employee of UTHealth, Savitz has served as a site investigator in clinical trials sponsored by Athersys, KM Pharma, ReNeuron, and San Bio, and has provided consultation to ArunA, AbbVie, Neurexcell, Neurastasis, Lumosa, Deck Therapeutics, and Simcere. Wein has received grants and/or research support from AbbVie, Ipsen, Canadian Institutes of Health Research (CIHR), and Servier; honoraria from AbbVie, Ipsen, and Servier; consulting fees from AbbVie, Ipsen, Servier, and Novartis; and has served on steering committees for AbbVie and Ipsen. Bavikatte has attended sponsored meetings and received honoraria from AbbVie, Ipsen, and Merz. The speakers’ institutions do not endorse any AbbVie products, and the speakers are not responsible for the accuracy of the content of this article.

Acknowledgements:

Writing assistance was provided by Nicola Humphry, Nottingham, UK.

Support:

The publication of this article was funded by AbbVie. The views and opinions expressed are exclusively those of the speakers.

Keywords:

Early identification, post-stroke spasticity, spasticity, stroke.

Citation:

EMJ. 2023;8[4]:24-32. DOI/10.33590/emj/10304502. https://doi.org/10.33590/emj/10304502.

Meeting Summary More than half of survivors of stroke experience some degree of motor impairment, and spasticity can develop within days of the initial event. Patients with post-stroke spasticity (PSS) report a lower quality of life than those without spasticity, and they require regular long-term follow-up and monitoring within the healthcare system.

This symposium supported a non-promotional discussion regarding the prevalence, burden, consequences, and need for identification of PSS. The benefits of PSS identification within 3 months of stroke were discussed by a panel of key opinion

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leaders, including Ted Wein, Neurologist and Assistant Professor of Neurology and Neurosurgery at McGill University, Montréal, Quebec, Canada; Ganesh Bavikatte, Consultant and Clinical Lead in rehabilitation medicine at the Walton Centre, Liverpool, and Honorary Senior Clinical Lecturer at the University of Liverpool, UK; and Sean Savitz, Professor of Neurology and Physical Medicine and Rehabilitation, Frank M. Yatsu MD Chair in Neurology, and Director of the Institute for Stroke and Cerebrovascular Diseases, University of Texas Health Science Center at Houston (UTHealth), Texas, US. These key opinion leaders explained that early prediction of PSS could be improved by increased awareness of the associated risk factors and tools, such as the Post-Stroke Checklist (PSC), the Spasticity Screening Tool, and the PSS Referral Tool. Finally, potential barriers to the early identification of PSS were presented, alongside strategies to overcome these barriers.

Early Identification of Post-stroke Spasticity: What Could it Mean for Patients?

Many patients experience impairment following a stroke, including motor or cognitive impairment, urinary incontinence, dysphagia, language impairment, and psychological disturbances.1 Motor impairments are the most common poststroke complication, experienced by 50–83% of patients.1 Spasticity is a common consequence of stroke,2,3 and is characterised as disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles.4 Spasticity may lead to hypertonicity, disability, reduced function, and associated pain.5 Spasticity primarily affects the elbows, wrists, and ankles,6 though it has also been reported in other locations, such as the finger and toe flexors, and shoulder and thigh adductors (Figure 1).2,7 Around 63% of patients with PSS experience both upper and lower limb spasticity.8 Approximately 100 million people are living with stroke worldwide, of whom 22% are individuals between 15–49 years of age.11 The prevalence of PSS increases over the first 6 months poststroke,12 and estimates anticipate a 27% increase in the demand for post-stroke rehabilitation in the European Union (EU) over the next 3 decades.13 It was emphasised that spasticity can have a broad impact on a patient’s functional recovery and general wellbeing, potentially leading

to contractures, pain, insomnia, depression, pressure ulcers, compromised mobility, increased dependency on others, difficulty maintaining sexual relations, poor self-esteem, and difficulty maintaining hygiene.3,14,15 Mobility limitations and limb impairments may result in serious physical and emotional burdens for patients and caregivers. For example, a lack of motor control can result in frequent falling,3 caregivers may need to provide postural support management. Assistance with hygiene and dressing is frequently required.3,16 In addition, patients' and caregivers' ability to work may be affected.17 A prospective study reported that 3 months after ischaemic stroke, patients reporting spasticity (n=54) had significantly lower health-related quality of life scores compared with patients not reporting spasticity (n=274), indicating that patients with PSS may experience psychological and emotional issues.18 Further studies have demonstrated that significantly more patients with PSS (n=18) experienced pain at a median of 16 weeks post-stroke, compared to patients without PSS (n=65; 72.0% versus 1.5%; p<0.001),6 and between 35–48% of patients with PSS (n=273) reported that pain resulted in moderate-to-extreme work interference.12 The incidence of spasticity, particularly severe/ disabling spasticity, generally increases over time following the initial stroke.19 A systematic review and meta-analysis of 23 studies indicated that in the first month following a stroke, 4–46% of patients experienced spasticity, and 2–3% experienced severe/disabling spasticity. At 3–6 months following a stroke, these figures increased to 7–63% and 8–16% of patients, respectively.19

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Figure 1: Common postures of spasticity in upper and lower limbs.

Adducted shoulder with internal rotation

Flexed wrist

Flexed elbow

Flexed fingers

Adducted thigh

Plantar flexed foot/ankle

Pronated forearm

Thumb-in-palm

Flexed knee

Equinovarus foot

Clenched fist

Extended knee

Striatal toe

Flexed toe

Images reproduced from Simpson DM et al.9 and Esquenazi A et al.,10 open-access articles under the terms of the Creative Commons Attribution 4.0 International Licence (https://creativecommons.org/licenses/by/4.0/).

Several studies have shown that PSS can develop in a matter of days after a stroke, with one study reporting that spasticity was present in 25% of patients at Day 3;20 another that spasticity was present in 21% of patients at an average of 5.4 days following stroke;7 and a third that 25% of patients showed an increase in muscle tone in at least one joint in the first 14 days after stroke.6 If PSS is left untreated, a vicious cycle can develop, in which unopposed contraction causes abnormal limb posture, leading to soft tissue shortening, further biomechanical changes in contracted muscles, and prevention of muscle lengthening, thus perpetuating further tonicity.3 Management options available for PSS include pharmacological treatment (e.g., oral treatments, injectables such as botulinum toxin type A [BoNT/A]), physical rehabilitation (e.g., physical

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and occupational therapy with a multidisciplinary team),3 and surgical approaches (e.g., destructive and orthopaedic procedures).21 BoNT/A is a long-acting, focally-administered neuromodulator that is recommended for the treatment of PSS.22 BoNT/A therapy should be considered when spasticity interferes with the goals of patients, caregivers, or healthcare teams, regardless of the time since diagnosis,23 and studies have indicated that early intervention with BoNT/A within 3 months after onset, rather than later, may deliver a greater reduction in muscle tone,24 and may minimise the risk of developing contractures.25 A meta-analysis of six studies reporting the effects of BoNT/A treatment less than 3 months after stroke onset indicated that early treatment with BoNT/A resulted in a significant treatment effect (p=0.0002), in terms of reduction in

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hypertonicity compared to controls.5 Furthermore, a multicentre, longitudinal cohort study indicated that BoNT/A treatment for PSS initiated within 3 months of stroke onset may result in greater reductions in muscle tone at Months 1 and 3 of follow-up, compared with treatment initiated later.24 This study was conducted in patients who have had a stroke with PSS, who received BoNT/A for the first time, according to routine practice, within 12 months of stroke onset (n=83). Results showed that the odds of increased muscle tone in patients treated with BoNT/A more than 90 days after stroke onset versus patients treated within 90 days were 2.1-fold greater at Month 1 of follow-up (p=0.044), 2.9-fold greater at Month 3 of follow-up (p=0.002), and 1.1-fold greater at Month 6 of follow-up (p=0.747).24 In addition, a randomised controlled trial indicated that patients who developed spasticity within 6 weeks of a first stroke (n=93), who received BoNT/A injections versus placebo, were shown to have a significantly greater passive range of motion in the wrist at 6 weeks post-treatment (75.6 degrees versus 63.8 degrees, respectively [p=0.004]).25 It was concluded that spasticity is a common consequence of stroke,2 and patients with PSS report significantly lower health-related quality of life scores than patients with stroke without spasticity.18 The incidence of spasticity increases over time, potentially reaching up to 46% of the stroke population within 1 month since stroke,19 and early BoNT/A treatment (<3 months after stroke) may result in improved outcomes for patients with PSS.5,24,25

What Tools Can Be Used to Identify and Assess Post-stroke Spasticity Early?

Early identification and prompt treatment of PSS is important because spasticity may evolve less than 3 months after stroke,5 and early treatment with BoNT/A can improve muscle tone,24 spasticity-related pain,5 and passive range of motion.25 Recognition of the risk factors associated with PSS can enable the early prediction of PSS in a patient who has had a stroke.12 In the acute phase (the first week) following stroke, risk factors include a low Barthel Index score and EQ5D,6 hemihypaesthesia,8 severe paresis,6,8,26,27 and

increased muscle tone.6 In the post-acute phase, risk factors include a low Barthel Index score,6,8 paresis (particularly if limited to one side of the body),6,28 extensive stroke lesions on CT28 and MRI,29 a National Institutes of Health Stroke Scale (NIHSS) score indicative of severe stroke,31 and a low Motricity Index.30 Alterations in the modulating influence of descending fibre tracts on local spinal networks are widely accepted as relevant pathophysiological changes in patients with PSS. However, not all ischaemic brain lesions result in PSS.29 Several studies have indicated that consideration of the site and size of stroke lesions measured on MRI may help to predict PSS development.29,31,32 In one retrospective analysis of MRI data from patients with stroke with (n=39) and without (n=59) PSS, lesions over 3 cm3 in diameter, located within the middle cerebral artery territory with involvement of the pyramidal tract and/or internal capsule, were found to be predictive of PSS (odds ratio: 28.48).29 In another retrospective study, voxel-based lesion symptom mapping with MRI images from patients who have had a stroke (n=45) found that the involvement of the striatum and white matter tracts influenced the development of spasticity in the upper and lower limbs.32 Several tools are available to support the early identification of PSS, including the Moving Beyond Stroke initiative, to empower patients and caregivers to speak to their healthcare practitioners (HCP).33 The PSC is designed to be completed by patients, and links patientreported problem areas, including spasticity, pain, mobility, mood, and activities of daily living to a specific referral, such as a primary care physician, rehabilitation/spasticity specialist, or speech language therapist.34 The Spasticity Screening Tool is a brief, patient-reported questionnaire designed to identify muscle stiffness, tightness, or spasms experienced over the past month; it can be used in general practice and specialist settings to enhance the identification and appropriate referral of patients with spasticity.35 The PSS Referral Tool is an aid to identify and triage patients who are at risk of developing PSS, and to provide guidance on patient management.36,37 The PSS Referral Tool was developed from consensus recommendations

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Figure 2: Post-stroke spasticity referral tool.

A) Mildly increased muscle stiffness is a Modified Ashworth Scale (MAS) 1 or +1, while moderately is MAS 2, markedly is MAS 3, and severe is MAS 4. B) Measured using the FMUE scale. C) Muscle contractions may occur due to spasms, disturbed reciprocal inhibition, or spastic dystonia, and should be differentiated from contractures. D) Visual inattention includes hemianopsia, scotoma, or visual neglect. E) Can be measured with the Barthel Index (low score) and EQ-5D (low score).

Figure adapted from Bavikatte G et al.,38 an open-access article under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/).

FMUE: Fugl-Meyer Upper Extremity; MDT: multidisciplinary team.

for spasticity management and rehabilitation in clinical practice, and was created by a panel of expert specialists. The expert consensus panel agreed that identification of spasticity and its risk factors, and a lack of subsequent referral to rehabilitation or specialist spasticity services, is a key unmet need. The PSS Referral Tool aids the categorisation of patients who have had a stroke into three levels of risk: red (urgent referral), amber (routine referral), and green (periodic monitoring; Figure 2).37

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The tool is recommended for use by clinicians and physiotherapists when evaluating patients who have had a stroke, both in primary and secondary care. Ideally it should be used within 12 weeks of the stroke event, and it should also be used at regular follow-up visits.36,37 It was explained that the PSS Referral Tool could be used to aid patient triage; to highlight early identification of PSS in clinics and/or institutions that do not currently consider it a main focus; to define referral strategies based on severity of spasticity; and to increase awareness of PSS symptoms, and the different referral options.

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Figure 3: Strategies to help drive the early identification of post-stroke spasticity in the acute stroke setting.

Education to recognise spasticity in early acute care1 Availability of tools to support the early identification of PSS2,3

Development of clearer referral pathways1

Training on effective communication and integrated teamwork1 Post-stroke management requires an MDT1,4

Patients who have had a stroke need long-term follow-up and monitoring5

HCP: healthcare professional; MDT: multidisciplinary team; PSS: post-stroke spasticity; QoL: quality of life.

A global inter-rater reliability study has recently been completed to validate the PSS Referral Tool, to ensure that the tool possesses sufficient sensitivity and specificity for meaningful use by clinicians, regardless of experience and region of practice.38 In Part A, investigators videoed the clinical assessment of 30 patients with varying degrees of spasticity using a semi-structured script based on the PSS Referral Tool. In Part B, the videos were classified by an expert global panel using the PSS Referral Tool, and in Part C, inter-rater reliability was performed virtually on 15 of the videos (five for each referral category) by stroke rehabilitation clinicians from six global regions. It was noted that data from this study is currently being analysed, and that it is hoped that results will lead to validation of the tool within the target audience, 6-monthly reviews post-stroke becoming standard practice, and long-term improvements in disease awareness of PSS amongst the relevant HCPs. A mobile app has also been developed to host the PSS Referral Tool, and to support HCPs in the early identification of PSS and appropriate referral. The PSS: Early ID™ app (AbbVie, North Chicago, Illinois, USA) aims to provide the healthcare community with access to on-

demand educational content, which may help with awareness and early identification of PSS, both through the PSS Referral Tool and through the ‘My Clinic’ section of the app, which includes hypothetical patient case studies. The app also has the potential to understand how confident HCPs are at identifying PSS (Bavikatte, personal communication). The target audience for the app includes neurorehabilitation consultants, physical medicine and rehabilitation physicians, primary care physicians, neurologists, stroke physicians, acute physicians, physical therapists, nurses, and occupational therapists.

In conclusion, PSS may be predicted and triaged at an early stage by looking out for certain risk factors in patients, and there are tools available to support the early identification and prompt management of PSS, which are self-explanatory, and easy to use. New tools are being developed to support the classification of PSS risk for referral purposes, and to increase awareness of PSS among HCPs. The panel emphasised the importance of actively involving patients in their care and wellbeing, and underscored the value of tools like the PSC, to support communities which are underserved, or do not have good access to medical care.

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What Can We Do to Help Drive the Early Identification of Post-stroke Spasticity in the Acute Stroke Setting?

Rehabilitation and recovery is a key aspect of the continuum of stroke care,39 and often includes passive stretching and/or repetitive task practice.3 However, there is limited data available to support guidelines for this stage of care,3,39 and it was stressed that spasticity detection is often not addressed in the acute care setting for patients who have had a stroke.

There are several potential barriers that may be responsible for this situation (Figure 3): •

Lack of understanding: HCPs, patients, or caregivers may not recognise the symptoms of spasticity, and patients may be unaware of the possible impact of spasticity and/or more concerned by other symptoms post-stroke.40

•

Transition from acute care: Acute-care therapists may not assess spasticity, and there is a focus on early supported discharge41 (Savitz, personal communication).

•

Logistical challenges: There may be delayed access to specialist referral from acute care, and patients may find it difficult to access rehabilitation centres or physiotherapy.40

•

Attitudes towards spasticity: At the acute care level, there may be a lack of communication among the multidisciplinary team, and in the chronic phase of stroke, spasticity symptoms may not be considered by HCPs to be the most important complication of stroke.40

Strategies that may help to support the early identification of PSS in the acute care setting include the education of HCPs to recognise spasticity in early acute care; the development of clearer referral pathways; training on effective communication and integrated teamwork; 40 and increased availability of tools to support the early identification of PSS (Figure 3).34,35 Following a stroke, patients can experience a variety of symptoms which may affect their life, including pain and spasticity; problems with cognition, communication, mood, and mobility; incontinence; and activities of daily living.42 Secondary stroke prevention is also important.43

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Because of the wide range of potential poststroke symptoms and considerations, it was explained that a transdisciplinary approach is needed in the post-stroke setting. This may include rehabilitation nurses, stroke neurologists, speech and language therapists, social workers, physical therapists, vocational counsellors, occupational therapists, psychologists, physical medicine and rehabilitation specialists, and the patient and their family.3,40,43 It was emphasised that concerted effort by a multidisciplinary team is necessary to help ensure optimal post-stroke patient care (Figure 3).40,43 The long-term follow-up and monitoring required by patients after a stroke is being implemented through guidelines by healthcare providers and stroke organisations.39,41,44 For example, the World Stroke Organization (WSO) recommends that stroke rehabilitation should begin in the sub-acute phase,44 the American Stroke Association recommends that the provision of comprehensive rehabilitation programmes should be a priority,41 and the Canadian Best Practice Recommendations for Acute Stroke Management state that patients with stroke and neurological impairments that could impact daily functioning should be referred to an appropriate rehabilitation specialist.39 Working towards an early diagnosis of PSS could lead to increased awareness of signs and symptoms of PSS, an increase in early referral and treatment of PSS, and an increase in positive functional outcomes and quality of life for patients.37,40 Together, these changes have the potential to decrease the PSS-related burden on caregivers and the healthcare system (Figure 3).13,40 Finally, the panel asked that HCPs make the following pledge to help to overcome the barriers to early identification of PSS in the acute stroke setting: I am committed to becoming better educated in recognising the signs and symptoms of PSS; if I do not have the expertise to manage spasticity, I will refer my patients to specialists with appropriate expertise; and I will aim to refer appropriate patients with PSS to clinical studies in the future.

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Summary and Closing Remarks The prevalence of PSS increases in the first 6 months following stroke, and that BoNT/A treatment within 3 months of stroke may result in improved patient outcomes, including the prevention of secondary complications, such as contractures. It was clarified that certain risk factors can help to predict PSS at an early

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30. Ryu JS et al. Factors predictive of spasticity and their effects on motor recovery and functional outcomes in stroke patients. Top Stroke Rehabil. 2010;17(5):380-8.

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31. Lindenberg R et al. Predicting functional motor potential in chronic stroke patients using diffusion tensor imaging. Hum Brain Mapp. 2012;33(5):1040-51.

32. Lee KB et al. Which brain lesions produce spasticity?

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stroke spasticity (PSS): the PSS risk classification System. Poster 1358661. 92nd Congress of the German Society for Neurology (DGN) Congress 2019, 25-28 September, 2019.

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38. Wissell J et al. Design of a global inter-rater reliability study of the post-stroke spasticity referral tool.

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Becker Muscular Dystrophy: Could Altering the Natural History of Decline Help Tackle Unmet Medical Need?

This symposium took place on 8th October 2023, as part of the 28th International Annual Congress of the World Muscle Society (WMS), held in Charleston, South Carolina, USA Chairperson:

Joanne Donovan1

Speakers:

Erik Niks,2 Sam Collins,1 Barry Byrne3 1. Edgewise Therapeutics, Boulder, Colorado, USA 2. Leiden University Medical Center (LUMC), the Netherlands 3. Powell Gene Therapy Center, University of Florida (UF), Gainesville, USA

Disclosure:

Niks has been a participant in advisory boards for Edgewise, Italfarmaco, Sarepta, Epirium, Regenxbio, and Janssen; has been a principal investigator at the Leiden University Medical Center (LUMC) for clinical trials from Edgewise, Italfarmaco, Sarepta, Fibrogen, NS Pharma, Reveragen, Santhera, BioMarin, ML Bio, Janssen, ArgenX, and Alexion; received reimbursements by LUMC; and has also received grants from Pfizer, the European Union, Duchenne Parent Project, Prinses Beatrix Spierfonds, Association Française contre les Myopathies, Dutch Research Council, and Spieren voor Spieren. Collins is the Vice President of Clinical Development at Edgewise Therapeutics. Byrne is an investigator for clinical trials from Italfarmaco, Sarepta, and Pfizer. Donovan is Chief Medical Officer at Edgewise Therapeutics.

Acknowledgements:

Medical writing assistance was provided by Amanda Barrell, Brighton, UK.

Disclaimer:

The opinions expressed in this article belong solely to the named speakers.

Support:

The publication of this article was supported by Edgewise Therapeutics.

Keywords:

Becker muscular dystrophy (Becker), creatinine kinase, Duchenne muscular dystrophy (Duchenne), dystrophin, dystrophy, EDG-5506, fast muscle fibre, genetic disorder, muscle contraction injury, myosin, rare disease.

Citation:

EMJ. 2023;8[4]:33-40. DOI/10.33590/emj/10300460. https://doi.org/10.33590/emj/10300460.

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Meeting Summary This symposium was held as part of the 28th International Annual Congress of the World Muscle Society (WMS), held in Charleston, South Carolina, USA. Speakers reviewed the natural history of Becker muscular dystrophy (Becker), outlined the top line, 12-month data from the ARCH open label study of investigational agent EDG-5506, and aimed to put those results into clinical context.

Becker is a serious rare disease with significant physical, emotional, financial, and social impact on the affected individuals and their caregivers. Once function begins to decline, males affected by the progressive X-linked genetic disorder continue to irreversibly lose muscle, ultimately leading to the loss of ambulatory and cardiopulmonary function.

After discussing the aetiology of the condition, Erik Niks, Paediatric and Adult Neurologist, Leiden University Medical Center (LUMC), the Netherlands, presented the findings of natural history studies. They showed that while the age at which decline begins varies, once it does start, patients tend to experience a consistent decline in function equivalent to around 1.2–1.3 North Star Ambulatory Assessment (NSAA) points each year. This finding, combined with data on using MRI as a biomarker of disease progression, provides an evidence-based framework for clinical trial design, he argued. Sam Collins, Vice President of clinical development, Edgewise Therapeutics, Boulder, Colorado, USA, then presented topline 12-month data from the ARCH study. It found that EDG-5506 was well tolerated, and, importantly, recorded the stabilisation of functional assessments, including the NSAA, with a trend towards improvement, as well as rapid, sustained, and significant decreases in biomarkers of progression, including those related to muscle damage.

Putting the ARCH study data into context, Barry Byrne, Director of the Health Center for Advanced Therapeutics and Powell Gene Therapy Center, University of Florida (UF), Gainesville, USA, explained exactly how declining NSAA status translated into life-altering function loss. Stabilising function, or even reducing the speed of decline, was an important goal for patients, he said, adding that meeting it could help to address significant unmet medical need.

Background First described by German physician Peter Emil Becker in the 1950s, Becker is an X-linked genetic recessive disorder.1 Like Duchenne muscular dystrophy (Duchenne), it is caused by a mutation in the gene that produces dystrophin, a protein that links the sarcolemma to the cytoskeleton in the muscle fibres.2 The 79 exons of the dystrophin gene include several internal promoters that give rise to shorter isoforms, and a central region that encodes for the binding domain of neuronal nitric oxide synthase. In general, in-frame mutations lead to Becker, while out of frame mutations lead to a Duchenne phenotype, with both conditions being part of a spectrum of dystrophinopathies. While in

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Duchenne exon deletions tend to completely block dystrophin production, in Becker the proteins are usually shortened, and only partially functional.2 “The dystrophin itself is located at the periphery of all the muscle fibres. Its expression is clearly reduced in patients with Becker, and nearly absent in Duchenne,” said Niks, describing Becker as being “on the same spectrum” as Duchenne, which has an earlier onset and faster progression.2 The dystrophin protein can be quantified using Western blot analysis, “but it is important to realise that levels of dystrophin are very variable both in healthy controls, as well as in patients with Becker,” said Niks.3 The absence or reduction of dystrophin results in a dystrophic

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Symposium Review

pattern on muscle biopsy, with increased fibrotic tissue and increased fatty replacements being clearly visible on MRI.3 The natural history of Becker is highly variable between individuals.4 Patients will usually experience slowly progressing proximal and paraspinal weakness, and a mixture of progressive muscle hypertrophy and atrophy.4,5 Many, but not all, males with Becker tend to remain ambulant beyond the age of 16 years.5 Muscle pain and cramps are common, and cardiomyopathy can occur later in life.4 Clinicians employ a number of approaches to measure disease activity and progression, including the NSAA, which has been validated for use in clinical trials.6 It consists of 17 items related to everyday activities, such as walking, rising from a chair, and climbing stairs. Each item is scored from 0–2, depending on whether the patient is unable to perform the task (0 points), can perform the task with difficulty or assistance (1 point), or can perform the task independently (2 points). It yields a maximum score of 34 points, with the lowest scores representing the highest levels of function loss.6

of publication, he said 36 patients with Becker aged between 18–67 years were followed up for 3 years, with annual functional assessments, and an optional muscle MRI at visits one and three. Eleven participants had one of the most common Becker mutations,8 deletions of exons 45–47, and based on the mutation, the neuronal nitric oxide synthase binding site was predicted to be involved in 21 cases. The study recorded no clear differences in decline between these two subpopulations, leading Niks to say there was “still much to learn about the genotype/ phenotype correlations.”

“While we saw patients with a maximum score at baseline who remained basically stable for the entire course of the study, there was a quite consistent decline in the NSAA score over 3 years, mainly in those who had a baseline value between 10 and 32,” he said. The 10 metre walk/ run velocity results showed higher variability, an absent genotype/phenotype correlation, and a much less consistent decline, even over 3 years of follow-up.

MRI as a Biomarker in Becker Muscular Dystrophy

Natural History An Italian natural history study, published in 2016, followed 69 patients between the ages of 6–69 years for 12 months.7 A total of 28 participants had a deletion ending on exon 45, 10 had a deletion of only exon 48 (del 48), 10 had a deletion ending on exon 51 (del x-51), and 21 were classified as ‘other’. The mean NSAA at baseline was 25.3, with a standard deviation (SD) of 10.8. The mean change at 12 months was -0.9, with an SD of 1.6 (p<0.001). Interestingly, participants with the del 48 and del x-51 mutation recorded almost maximum NSAA scores at baseline (del 48: NSAA of 33.9 and SD of 0.32; del x-51: NSAA of 33.7 and SD of 0.95) and little decline over the follow-up period (del 48: -0.3 and SD of 0.50; del x-51: 0.0 and SD of 0.00). In contrast, those with the deletion ending on exon 45 had lower NSAA at baseline (NSAA of 20.9 and SD of 11.10), and a higher degree of change at 12 months (-1.3 and SD of 1.70).7 Niks’ team has recently concluded a similar study in the Netherlands. Presenting the data ahead

Fat fraction (FF), as measured by MRI, may be a useful biomarker of disease progression for use in clinical trials. However, it differs both between and within muscles.9 As part of a study

by Niks’ group, MRI and clinical assessments were performed at baseline (n=24) and 24 months (n=20). They used the Dixon method to quantify FF.9 Researchers manually delineated images of 12 thigh and seven lower leg muscles into 23 slices each, calculating FF values for the three central slices, as well as the whole muscle.

The functional tests NSAA, 6-Minute Walk Test (6MWT), and 10-metre run velocity were also conducted. “We noticed quite a consistent increase in FF over 24 months, with the median whole muscle FF increasing by between 0.2% and 2.6%, depending on the muscle,” said Niks, adding that increases occurred both in muscles with a relatively low, and higher FF, at baseline.

“It could be a biomarker that captures disease progression across the range of the phenotypes,” he added.9

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In terms of functional assessment results over the 24 months, the median change in NSAA was -2.5 points (range: -12.00–1.00; p=0.002), and, in 10-metre run velocity, -0.22 m/s (range: -1.40– 0.25; p=0.014). This was consistent with figures recorded in previous natural history studies, Niks explained. Next, the researchers conducted a stepwise analysis of the full dataset to identify the optimal MRI biomarker. “Whole thigh FF was very sensitive, reproducible, and also relatively practical to put into an MRI protocol, with standardised response means of around one,” said Niks.9 Summing up, he said: “High clinical variability and slow disease progression does not facilitate the conduction of clinical trials [...] but we are able to capture changes in motor function when following these patients for 12 months or longer.

When you select subpopulations, for example, those with a baseline NSAA of 10 to 32, you are able to capture progression over the duration of a clinical trial, with a feasible number of patients.”

Targeting Contraction-Induced Muscle Damage Biomarkers of muscle damage can also be useful in clinical trials. Contraction damages muscles in everyone, but in Duchenne and Becker, the lack of dystrophin results in excessive contraction-induced damage, leading to excessive degeneration and muscle membrane leak.10 This is evidenced by elevated levels of creatine kinase in the blood of people with Becker and Duchenne.11 Data comparing levels of fast skeletal muscle troponin I and slow skeletal muscle troponin I in the blood of healthy controls with people with Becker and Duchenne have also demonstrated that the muscle damage primarily affects the fast muscle fibres in those living with the conditions.11 Explaining how this data has informed the development of the investigational agent EDG-5506, Collins said: “As the sequence of damage continues, it exhausts the regenerative processes, and fat infiltration and fibrosis occur; but if you could protect the muscle against that excessive degeneration, you could help preserve function and, ultimately, muscle function.”

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ARCH Study of EDG-5506 Collins went on to outline the 12-month top line results from the ARCH study of EDG-5506, an orally administered, allosteric, selective, fast myofiber (Type II) myosin inhibitor (unpublished data, presented at WMS 2023).12 The compound has been designed to protect the muscle fibres against contraction-induced damage, and the associated loss of function.13 The open-label, single-centre trial enrolled 12 males with Becker aged between 18–55 years, with a dystrophin mutation, a Becker phenotype, and the ability to complete a 100 m timed test (unpublished data, presented at WMS 2023).12 “We were looking at the safety and tolerability of EDG-5506, but we could also measure biomarkers of muscle damage, and carry out functional assessments throughout the course of the study,” said Collins, adding that ARCH had now been extended for an additional year.

After screening, participants were treated with a daily 10 mg dose of EDG-5506, escalating to 15 mg after 2 months, and 20 mg after a further 4 months.12 At baseline, participants had significant functional impairment, with a median NSAA of 15.5 (range: 4–31),12 showing they were in the functional decline phase of disease course, as defined by previous natural history data (unpublished data, presented at WMS 2023).7 They had decreased muscle mass and substantial elevation of creatine kinase, a biomarker of muscle injury (Table 1).

The compound was well tolerated at all doses, and no dose reductions due to adverse events (AE), treatment discontinuations, or serious AEs were reported.12 Over the 12 months, the most common AEs were dizziness, COVID-19, and arthralgia, with each occurring in four (33%) participants. There was no increase in the incidence of these AEs as dose increased (unpublished data, presented at WMS 2023).12 EDG-5506 led to a sustained decrease in biomarkers of muscle damage over the 12 months of treatment. The study recorded an overall 37% (p=0.001) reduction in serum creatine kinase, and a 79% (p<0.0001) reduction in fast skeletal muscle troponin I.12 The observation that biomarkers of muscle damage decreased during the trial suggests treatment decreased contraction-induced injury, said Collins.

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Table 1: Baseline characteristics of ARCH study participants.

Characteristic

Participants with Becker (n=12)

Age normative values

Age (SD)

32.8 (8.1) years

N/A

10 m walk/run

8.4 sec

<4 sec

Rise from floor

6/12 could perform

<12

NSAA

15.5 (range: 4–31)

N/A

Serum creatinine (mean, mg/dL)

0.44

0.92–1.16

Serum CK (mean, U/L)

1,390

<210

DXA % lean mass

54.9%

>75%

Functional measures (median)

Becker: Becker muscle dystrophy; CK: creatinine kinase; DXA: dual energy X‐ray absorptiometry; N/A: not applicable; NSAA: North Star Ambulatory Assessment; SD: standard deviation.

Over the course of the 12 months, 75% of NSAA scores either stabilised or improved, and there was a mean 0.4 point improvement (unpublished data, presented at WMS 2023),12 compared with the -1.2 point decline predicted by natural history data (Figure 1).7,9 “It is certainly starting to move away from what you might expect to see in Becker individuals over that kind of time frame,” said Collins, adding that the data pointed to a functional benefit of improving contractioninduced injury.

In addition, there was no decline from baseline in 100m timed test velocity.12 “We were very pleased to see this. These patients decline over time, so stability in a functional test over a year is a good outcome,” explained Collins.

A positive downward trend in patient-reported pain scores was also observed during 12 months of treatment, though it is important to note that the ARCH study was not placebo-controlled.12 “In future studies, we are interested in collecting more data about pain, because it can have a big impact on patients’ day-to-day lives,”14 he went on. “In conclusion, EDG-5506 was well tolerated

at all doses; demonstrated rapid, sustained, and significant decreases in multiple biomarkers of disease progression; and resulted in stabilised functional assessments, with a trend towards improvement.”12 Maximal biomarker response was observed at the lowest administered dose of 10 mg (unpublished data, presented at WMS 2023).12 Edgewise (Boulder, Colorado, USA) is now recruiting for GRAND CANYON, a global, 18-month pivotal trial to evaluate the safety and efficacy of EDG-5506 in adults living with Becker.15 Participants will be ambulatory males aged between 18–50 years, with a genetic diagnosis of Becker, and an NSAA of between 5–32. The primary endpoint will be change in NSAA at 18 months in patients receiving EDG5506 10 mg once per day versus placebo.

Secondary endpoints include timed function tests, change in fat fraction assessed by MRI, muscle damage biomarkers, and patientreported outcomes.15

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Figure 1: Improvement of North Star Ambulatory Assessment during 12 months of treatment with EDG-5506.

NSAA Change 15 mg

10 mg

20 mg

3

Change in NSAA

2 1

+0.4

0 -1

-1.2 Becker natural history average decline Dashed lines shows 95% CI on linear regression

-2 0

2

4

6

8

10

12

EDG-5506: month of treatment

Means±95% CI. Source: data on file.

Natural history based on data presented by Bello et al.7 and van de Velde NM et al.9 Becker: Becker muscle dystrophy; CI: confidence interval; NSAA: North Star Ambulatory Assessment.

North Star Ambulatory Assessment: What Constitutes a Meaningful Difference?

Byrne described dystrophinopathies as a spectrum that includes both Duchenne and Becker. “Decreasing levels of dystrophin lead to significant impairment, and, ultimately, loss of ambulatory and cardiopulmonary function,”16 he said, adding that there was significant unmet need across the lifespan of both conditions.

Explaining how the reductions in NSAA scores over time translated into an impact on everyday activities, he said losing the ability to run, hop, and jump stopped patients from playing sports, while the inability to stand on their heels hindered attempts to walk on uneven ground or cycle, for example. If someone cannot stand on one leg, they can have difficulty dressing themselves, and if they cannot stand from a chair, they can have difficulty using a toilet independently, getting out of bed themselves, or using public transport.

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Data from baseline assessments of ARCH and CANYON participants show how patients with Becker move through NSAA stages, first developing compensation strategies before losing function in 15 of the score’s domains (unpublished data, presented at WMS 2023).12 “When we look at this, based on the functions that are lost, and where compensation comes into play, it gives us a better idea of how progression occurs over the years,” said Byrne.

The 39 study participants were segregated into those with a NSAA of ≥30 (Group 1), between 20–29 (Group 2), between 10–19 (Group 3), and those with the most impairment, or NSAA <10 (Group 4) (unpublished data, presented at WMS 2023).12 Once disease decline has started, natural history data have suggested that patients can expect to move from the midpoint of Group 1 to the midpoint of Group 2 over the course of around 5 years; from the midpoint of Group 2 to that of Group 3 over around 8 years; and from the midpoint of Group 3 to the midpoint of Group 4 over around another 8 years, Byrne explained.7,9

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In Group 1, patients could complete all 17 assessed functions, though a small proportion (approximately 10%) had lost the ability to stand on their heels.12 There was also some weaknessrelated compensation in domains such as standing up from a chair, rising from the floor, and hopping on the right leg (unpublished data, presented at WMS 2023).12 Those in the NSAA 20–29 group could complete most functions, though compensation was recorded in many domains, reflecting the progressive loss of muscle and progressive weakness.12 “The compensation is particularly evident in standing up from a chair, which is one of the telltale early signs that bring patients to medical attention,” Byrne said. More than 80% showed compensation in either leg when descending or ascending a box step, 80% had difficulty with walking and running, and 100% had compensation for rising from the floor.12 At NSAA 10–19, which reflects the baseline function of those involved in the ARCH study, patients were unable to complete most functions, and needed to compensate for almost

all functions (Figure 2).12 “This really reflects the progressive loss and progressive weakness as the disease continues and as individuals get older. At this point, 40% exhibit compensation during standing, all are having difficulty with standing from a chair, and some have lost that ability altogether,” said Byrne. 12 Patients in Group 4, who had a recorded NSAA of 0–9 points at baseline, had lost function in most domains.

This cohort showed minimal ability to complete the activities, and was nearly non-ambulatory (unpublished data, presented at WMS 2023).12 All the NSAA domains have a direct impact on a person’s ability to live their life well, Byrne said. “These activities obviously have real world implications for Becker patients, and their ability to participate in social activities, sports, and so on.”

As such, stabilising function and reducing the rate of decline is “an important life goal” for people living with Becker. Being able to provide this would help to address a significant unmet medical need in this condition, he concluded.

Figure 2: Loss of function and compensation at baseline in patients with North Star Ambulatory Assessment 11–20 (Group 3) enrolled in ARCH. Compensating

Loss of function

ch air ts to sit no tin St ne g an leg do -r n Cl igh on im el t bb eg ox -l ef ste Cl t im pbb De r igh sc ox en t ste db p ox -l De ef ste sc t en p db -r i gh ox t ste plef t Lif th ea d Ju Wa mp lk/ ru n( 10 Ris m) ef ro m St flo an or do nh ee ls Ho plef Ho t prig ht

ro m

Ge

do

an

St

St an

du

pf

St

Wa lk

100 90 80 70 60 50 40 30 20 10 0 an d

% of patients

Group 3: Baseline NSAA 10-19

NSAA domain NSAA: North Star Ambulatory Assessment.

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References 1.

2.

Duan D et al. Duchenne muscular dystrophy. Nat Rev Dis Primers.

2021;7(1):13.

3.

Beekman C et al. Use of capillary Western immunoassay (Wes) for quantification of dystrophin levels in skeletal muscle of healthy controls and individuals with Becker and Duchenne muscular dystrophy. PloS One. 2018;13(4):e0195850.

4.

5.

6.

Study, The Association Française contre les Myopathies (AFM), The DMD Italian Group, and The Collaborative Trajectory Analysis Project (cTAP). Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls. Neuromuscul Disord.

2022;32(4):271-83.

Becker PE, Kiener F. [A new x-chromosomal muscular dystrophy]. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr. 1955;193(4):427-48. (In German).

Thada PK et al., Becker Muscular Dystrophy [Internet] (2023) Treasure Island: StatPearls.

Available at: https://www.ncbi.nlm. nih.gov/books/NBK556092/. Last accessed: 8 November 2023.

Darras BT et al.

“Dystrophinopathies,” Darras BT, Royden Jones Jr H, Ryan MM, De Vido DC (eds.), Neuromuscular Disorders of Infancy, Childhood, and Adolescence (2019) 2nd edition, Academic Press, pp.55192.

Muntoni F et al.; North Star Clinical Network, PRO-DMD-01

7.

Bello L et al. Functional changes in Becker muscular dystrophy: implications for clinical trials in dystrophinopathies. Sci Rep. 2016;6:32439.

8.

Ameziane-Le Hir S et al.

Dystrophin hot-spot mutants leading to Becker muscular dystrophy insert more deeply into membrane models than the native protein. Biochem.

2016;55(29):4018-26.

9.

van de Velde NM et al.

Selection approach to identify the optimal biomarker using quantitative muscle MRI and functional assessments in Becker muscular dystrophy. Neurology.

2021;97(5):e513-22.

10. Batti B et al. Duchenne muscular dystrophy: disease mechanism and therapeutic strategies. Front Physiol. 2023;14:1183101.

11. Barthel BL et al. Elevation of fast but not slow troponin I in the circulation of patients with Becker and Duchenne muscular dystrophy.

Muscle Nerve. 2021;64(1):43-9.

12. Collins S et al. P255 Effects of EDG-5506, a fast myosin modulator, on function and biomarkers of muscle damage in adults with Becker muscular dystrophy (BMD). J. Neuromuscul.

Dis. 2023;33:S146-7.

13. Russell AJ et al. Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy. J Clin Invest.

2023;133(10):e153837.

14. Jacques MF et al. Frequency of reported pain in adult males with muscular dystrophy. PloS One. 2019;14(2):e0212437.

15. Edgewise Therapeutics, Inc. Phase 2 study of EDG-5506 in Becker Muscular Dystrophy (GRAND CANYON). NCT05291091. https://clinicaltrials.gov/study/ NCT05291091.

16. Gao Q, McNally EM. The dystrophin complex: structure, function and implications for therapy. Compr Physiol. 2015;5(3);1223-39.

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Interview

Exploring Methotrexate Route of Administration Decisions for Adults with Rheumatoid Arthritis Interviewee:

Roberto Caporali1,2 1. Department of Clinical Sciences and Community Health, University of Milan, Italy 2. Department of Rheumatology and Medical Sciences, ASST Gaetano Pini-CTO, Milan, Italy

Disclosure:

Caporali has served on the speakers bureau for AbbVie, Bristol Myers Squibb (BMS), Fresenius, Galapagos NV, Eli Lilly, Pfizer, and UCB; has been a consultant for AbbVie, Accord Healthcare, Galapagos NV, and Pfizer; and has been on the advisory board for AbbVie, BMS, Eli Lilly, Galapagos NV, Pfizer, and UCB.

Acknowledgements:

Medical writing assistance was provided by Hannah Moir, EMJ, London, UK. The interviewee was given the opportunity to review the article.

Disclaimer:

The views and opinions expressed in this article belong solely to the named interviewee and do not necessarily reflect those of Accord Healthcare.

Support:

The publication of this article was funded by Accord Healthcare.

Accord Healthcare suggested the topic and author and carried out full medical approval on all materials to ensure compliance with regulations. The sponsorship fee included honoraria for the author.

Keywords:

Drug administration, methotrexate, oral methotrexate, patient preference, rheumatoid arthritis, rheumatologist, subcutaneous methotrexate.

Citation:

EMJ. 2023;8[4]:41-46. DOI/10.33590/emj/10308161. https://doi.org/10.33590/emj/10308161.

Interview Summary Methotrexate is a common first-line treatment for rheumatoid arthritis, yet its widespread and habitual usage often leads physicians to overlook the choice of administration route when planning management strategies. A recent survey involving 30 consultant rheumatologists from France, Germany, Italy, Poland, Spain, and the UK, identified variation in the utilisation and perceptions regarding oral versus subcutaneous delivery for methotrexate.

In November 2023, EMJ interviewed Roberto Caporali, Professor of Rheumatology at the University of Milan, and Head of the Department of Rheumatology and Medical Sciences at Gaetano Pini Hospital, Milan, Italy. Caporali's expertise is in clinical practice, teaching, and research in rheumatology, mainly rheumatoid arthritis and other immune-mediated inflammatory diseases, with a focus on prognostic factors, biomarkers, and treatment for patients with moderate-to-severe active rheumatoid arthritis.

During this interview, Caporali discussed the decision-making process for treating rheumatoid arthritis, with a particular focus on the use of methotrexate. The purpose

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Interview was to gain insights from a rheumatology expert regarding the prevalence and management goals of the disease, and available treatment options.

The interview considered key decision-making drivers and barriers to healthcare professionals when selecting the route of administration. Caporali suggested that the efficacy and safety profile of methotrexate when delivered subcutaneously may be the optimal choice for patients, often resulting in higher adherence compared to oral dosing. Caporali recommended education and re-evaluation of local guidelines to improve patient outcomes by better understanding the optimal use and efficacy of methotrexate.

THE ROLE OF METHOTREXATE IN THE TREATMENT OF RHEUMATOID ARTHRITIS Rheumatoid arthritis is a chronic disease that causes pain and inflammation of the joints.

Methotrexate is a synthetic disease-modifying antirheumatic drug (DMARD) that is considered the ‘anchor drug’ for rheumatoid arthritis because of its favourable efficacy, safety profile, and low cost.1,2 The mechanism by which methotrexate reduces disease activity and controls the progression of rheumatoid arthritis is not well understood.

Methotrexate may act through several pathways, such as folate antagonism, extracellular adenosine signalling, generation of reactive oxygen species, decrease in adhesion molecules, alteration of cytokine profiles, and interaction with T and B lymphocytes.3 Studies also suggest that methotrexate may suppress the JAK-STAT pathway.4 Methotrexate is the recommended first-line treatment for rheumatoid arthritis.2,5-7 The American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) guidelines recommend methotrexate monotherapy, or in combination with low-dose short-term glucocorticoids.2,5 It should be noted that methotrexate is contraindicated in patients with renal impairment or early intolerance.5 It is important to tightly control rheumatoid arthritis at the beginning of the disease. For adults, early diagnosis and the ‘treat-to-target’ strategy are crucial in achieving remission or low disease activity.2 Caporali considered treatto-target as “the most important strategy” for patients with rheumatoid arthritis. He also stated

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that the “window of opportunity” to diagnose and treat the patient is approximately 90 days, with check-ups every 1–3 months, a response expected within 3 months, and achievement of remission within 6 months.2,6,7

PATTERNS OF METHOTREXATE USE FOR RHEUMATOID ARTHRITIS: TREATMENT VARIATIONS ACROSS EUROPE Caporali outlined a web-based survey that was conducted across six European countries (France, Germany, Italy, Poland, Spain, and the UK), to understand the patterns of methotrexate use. The survey included 30 consultant rheumatologists (Accord Healthcare, data on file UK-05568) and examined the drivers of decisionmaking, and barriers influencing the choice of route of methotrexate administration.

The survey identified differences across the European countries, reporting that 42% of patients with rheumatoid arthritis on average were using oral methotrexate, while 58% of patients were using subcutaneous methotrexate.

The UK demonstrated the highest first-line oral methotrexate use (94% of patients), and Poland showed a preference for first-line oral administration (68% of patients). When excluding the UK data, on average, 66% of patients use subcutaneous methotrexate compared to oral use (34% of patients initiated first-line oral [Accord Healthcare, data on file UK-05568]).

Italian rheumatologists preferred subcutaneous administration, with the highest rate of firstline subcutaneous methotrexate use (94% of patients), followed by Germany (83% of patients), and Spain (58% of patients; Figure 1 [Accord Healthcare, data on file UK-05568]).

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Figure 1: Percentage of patients initiated onto oral versus subcutaneous methotrexate as first-line treatment, by country (Accord Healthcare, data on file UK-05568).

P e r c e n t ag e ( % ) of p at i e n t s

100%

94%

94%

90%

Patientsinitiated initiated on oral methotrexate Patients MTX

80%

Patientsinitiated initiated on subcutaneous subcutaneous MTX Patients methotrexate

83%

68%

70% 60%

58%

56%

50%

44%

40%

42%

32%

30% 17%

20% 10% 0%

6%

4% UK

Poland

France Spain C ou n t r y br e ak dow n

Influencing Factors on Methotrexate Choice in Rheumatoid Arthritis Treatment According to the survey, the majority of rheumatologists perceived the route of methotrexate administration as important, and both options allow them to individualise treatment.

Caporali suggested that in the UK, the high prevalence of oral methotrexate is in line with the local National Institute for Health and Care Excellence (NICE) guidelines, which recommend oral methotrexate as the primary first-line option.6,7 This may also be due to the lower cost of oral methotrexate compared to the subcutaneous form. The EULAR guidelines recommend considering the individual, medical, and societal costs associated with rheumatoid arthritis.5 The NICE guidelines consider both cost-effectiveness and a treat-to-target strategy when making recommendations.6,7 When two equally suitable treatments are available for a particular patient, the less expensive option is favoured.5-7 This recommendation also extends to the choice between oral and subcutaneous methotrexate.2,5 While the EULAR guidelines do not specify the most suitable

Germany

Italy

form of methotrexate administration,5 the ACR recommends starting with oral administration, and then switching to subcutaneous if the target is not achieved.2 Caporali noted that the cost difference between oral versus subcutaneous is relatively small in contrast to the overall rheumatoid arthritis treatment cost, suggesting this should be a consideration for guidelines. Utilising subcutaneous methotrexate earlier may delay the transition to more expensive biologics.8 The survey found that Italian rheumatologists prioritise subcutaneous methotrexate administration from the outset of the disease, which was attributed to perceived efficacy (identified by 67% of consultant rheumatologists from all countries); better adherence; and improved facilities for self-injection, with the easy-to-use auto-injectors availability (Accord Healthcare, data on file UK-05568). Caporali noted the subcutaneous delivery injectors enabled patients to receive the exact and correct dose.

Caporali also asserted that subcutaneous delivery is “more active than the oral

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administration,” advocating for its early use.9 He suggested subcutaneous administration may be more effective due to higher bioavailability, whereas oral administration may be less effective for medium to high methotrexate doses (more than 15 mg per week).9 Caporali also suggested that patient adherence to subcutaneous administration may be higher compared to oral use.10 Put simply, Caporali said: “One subcutaneous injection once per week compared to six to eight pills,” for 15 mg or 20 mg doses, respectively, may be preferred by patients.

misconceptions, refuting misinformation sourced from Internet searches, and providing accurate information about the true nature and efficacy of methotrexate in rheumatoid arthritis. Methotrexate was originally used as a cancer treatment; some patients may hold the misconception that they are receiving high-dose anti-cancer chemotherapy, and the risks associated with this, rather than a DMARD. Caporali emphasised the significance of dispelling this misconception at the earliest opportunity.

Patient Preference on Route of Methotrexate Administration

SIDE EFFECTS ASSOCIATED WITH THE ROUTE OF METHOTREXATE ADMINISTRATION

Caporali emphasised that when considering route choice, physicians often neglect to question the real difference between the two options, overlooking factors such as efficacy and bioavailability. He stated that physicians tend to prioritise perceived patient preference when selecting between oral and subcutaneous methotrexate.

The survey identified that patient preference was a major factor for oral methotrexate. However, this preference could be influenced by healthcare professionals who recommend oral methotrexate based on their own perceptions. After all, it is understandable that most patients would favour an oral tablet over an injection. Nevertheless, this perspective does not take into account potential differences in outcome benefits for patients in terms of efficacy, tolerability, and even pill burden experienced by patients. However, patient preference did not appear to be a major factor in the choice of administration route in the UK (Accord Healthcare, data on file UK-05568).

Caporali identified a potential lack of education among physicians regarding methotrexate use, particularly among newer physicians who may prescribe almost ‘automatically’ based on local practices, rather than thoughtful consideration.

Caporali believed newer rheumatologists exhibit more awareness and curiosity for more modern alternatives, such as biologics.

Caporali further contended that patient adherence to treatment is likely to improve when patients are comfortable with the chosen drug administration method from the outset. Additionally, he also addressed patient

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Caporali noted that subcutaneous administration has a preferable tolerability profile, presenting fewer gastrointestinal side effects.9 This was supported by the survey findings, where 73% (n=22) of consultant rheumatologists cited that subcutaneous injections were associated with fewer side effects. He stated that subcutaneous administration may be more favourable for patients due to reduced incidence of gastrointestinal complaints, whereas oral methotrexate may be preferable to those averse to injections. Despite needle phobia (cited by 47% [n=14] of rheumatologists) and injection site reactions (cited by 27% [n=8] of rheumatologists) being the main disadvantages to subcutaneous use, Caporali noted that, in Italy, patients who avoid subcutaneous use due to needle phobia or self-injection are, in his opinion and experience, minimal (fewer than 10%).

Caporali identified that other side effects, including transaminase elevation and flulike symptoms, were noted to be similar between the two administration methods.9 To address gastrointestinal side effects, the ACR recommends adjusting the dose, or increasing the folic acid intake.2

SWITCHING DYNAMICS BETWEEN ROUTES OF METHOTREXATE ADMINISTRATION The survey found that 26% of patients who started on oral methotrexate switched to subcutaneous methotrexate, due to issues with

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low efficacy and tolerability, such as nausea and gastrointestinal complaints. The timeframe for switching typically occurs within 3–6 months, as per guidelines,2,6,7 but can be longer in the UK (Accord Healthcare, data on file UK-05568).

Caporali explained that the UK had a longer timeframe for switching, whereas other European countries tended to react faster to treatment switching. The prevalence of switching from oral to subcutaneous was particularly prevalent in France (48% of patients) and Poland (41% of patients [Accord Healthcare, data on file UK-05568]).

Conversely, very few patients switched from subcutaneous to oral methotrexate (12% of patients), with patient request being the primary reason (Accord Healthcare, data on file UK05568). Of note, very few patients reverted back to oral methotrexate after switching to subcutaneous (1–2% of patients [Accord Healthcare, data on file UK-05568]).

Caporali noted that, in his experience, switching from subcutaneous to oral is rare, and usually only due to injection site reactions, which are uncommon. In cases where patients do not show improvement with oral methotrexate, Caporali recommended switching to subcutaneous methotrexate instead of another conventional DMARD or biologic, as recommended by the ACR Guideline.2

FUTURE DIRECTIONS AND EDUCATIONAL NEEDS FOR METHOTREXATE USE Caporali emphasised that patient education is essential in addressing misconceptions about methotrexate use. He also identified the importance of early communication with patients about their rheumatoid arthritis diagnosis and treatment, particularly regarding methotrexate use.2 There is a need, he went on, to improve rheumatologist awareness and education regarding the similarities and differences in

efficacy, safety, and bioavailability between oral and subcutaneous methotrexate administration.

Caporali believes this should be a major driver of choice, which is currently not the case.

Caporali also noted that the longstanding and frequent use of methotrexate means physicians often prescribe automatically, without stopping to consider the route of administration. For example, NICE guidelines may drive choice in the UK, but they do not consider efficacy and patient preference. The challenge lies in motivating physicians to engage with educational initiatives, as they may believe they possess sufficient knowledge of a drug that has been widely used since its introduction in the 1950s, said Caporali.

Addressing this challenge is crucial for ensuring informed and deliberate prescribing practices among healthcare professionals, he added.

Caporali also identified that guidelines should provide clearer recommendations on dosage adjustments, managing side effects, and transitioning between administration routes.

Further research is needed to evaluate the effectiveness and safety of different strategies, such as dose reduction or discontinuation, in patients with long-standing remission. The challenge, however, lies in raising questions that make physicians realise they may not know as much as they thought about this highly used and long-established therapy.

SUMMARY Caporali believes education and rethinking around methotrexate and route of administration choice are necessary to prompt changes in guidelines, optimise treatment, and improve patient outcomes. Re-evaluating and updating local guidelines may be necessary to better reflect evidence on efficacy and optimal methotrexate use. Education of both rheumatologists and patients is important to optimise methotrexate treatment decisions and adherence.

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All adverse events should be reported. Reporting forms and information can be found in your local country. Adverse events should also be reported to Accord using the contact details dependant on the country you are based.

UK/IE: Accord UK-LTD on +44 (0) 1271 385 257 or email medinfo@accord-healthcare.com.

Rest of EU: safety.eu@lambda-cro.com.

UK Adverse events reporting forms and information can also be found at www.mhra.gov.uk/ yellowcard.

UK-05505 Date of preparation: November 2023

References

One. 2015;10(7):e0130078.

1.

Pincus T et al. Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21(5 Suppl 31):S179-85.

2.

Fraenkel L et al. 2021 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924-39.

3.

4.

Friedman B, Cronstein B. Methotrexate mechanism in treatment of rheumatoid arthritis.

Joint Bone Spine. 2019;86(3):3017.

Thomas S et al. Methotrexate is a JAK/STAT pathway inhibitor. PLoS

5.

Smolen JS et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.

Ann Rheum Dis. 2023;82(1):3-18.

6.

Deighton C et al. Management of rheumatoid arthritis: summary of NICE guidance. BMJ. 2009;338:b702.

7.

Allen A et al. Diagnosis and management of rheumatoid arthritis in adults: summary of updated NICE guidance. BMJ. 2018;362:k3015.

8.

Sharma P, Scott DGI. Optimizing methotrexate treatment in rheumatoid arthritis: the case for subcutaneous methotrexate prior to biologics. Drugs.

2015;75(17):1953-6.

9.

Bianchi G et al. Methotrexate and rheumatoid arthritis: current evidence regarding subcutaneous versus oral routes of administration. Adv Ther.

2016;33(3):369-78.

10. Senbel E et al. Benefits of switch from oral to subcutaneous route on adherence to methotrexate in patients with rheumatoid arthritis in real life setting. Patient Prefer Adherence. 2021;15:751-60.

FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Perimenopause and Menopause: An Opportunity to Engage, Inform, and Empower Women to Live Well Interviewees:

Rossella E. Nappi,1,2 Katrin Schaudig3 1. Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Italy 2. Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy 3. Centre for Gynaecological Endocrinology, Hormone Hamburg, Germany

Disclosure:

Nappi has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck & Co, Novo Nordisk, Organon & Co, Shionogi Limited, Theramex, and Viatris. Schaudig has received honorary for advisory boards and lectures from aidhere, Astellas, Bayer-Jenapharm Healthcare AG, Besins Health Care, Exeltis GmbH, Gedeon Richter Pharma GmbH, Hexal AG, Laborarztpraxis Rhein-Main, Novo Nordisk, Organon Health Care GmbH, Theramex, and Viatris.

Acknowledgements:

Medical writing assistance was provided by Amanda Barrell, Brighton, UK.

Support:

The publication of this article was funded by Astellas Pharma.

Keywords:

Disease prevention, healthy ageing, hormones, hot flashes, lifestyle advice, menopausal transition, menopause, menopause management, perimenopause, postmenopause.

Citation:

EMJ. 2023;8[4]:47-53. DOI/10.33590/emj/10306944. https://doi.org/10.33590/emj/10306944.

Interview Summary While awareness of the issues facing women leading up to, during, and following the menopause has increased in recent years, it remains a condition of significant unmet need. Reasons include a stigma around asking for help, and a lack of awareness of the symptoms and associated risks among women and healthcare professionals alike. Standard medical training includes limited education on perimenopausal and post-reproductive healthcare, meaning clinicians are often ill-prepared to intervene.

However, there is much that healthcare professionals, regardless of their specialty, can do to help women entering their post-reproductive years, say Rossella Nappi, Chief of the Research Centre for Reproductive Medicine and Director of the Gynecological Endocrinology and Menopause Unit at IRCCS San Matteo Foundation, University of Pavia, in Italy; and Katrin Schaudig, co-founder of the Centre for Gynaecological Endocrinology, Hormone Hamburg, Germany, and President of the German Menopause Society. Moreover, perimenopause represents an important opportunity to engage, inform, and empower women to take charge of their health for years to come.

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In this key opinion leader interview, Nappi and Schaudig explain the physiological changes associated with menopause, their clinical manifestations, and their associated risk factors. They talk about the need to tackle the stigma that is often attached to this phase of life, and why healthcare professionals have a duty to work with women to spot the signs of menopausal transition from an early stage. They argue that holistic care, which focuses as much on the prevention of chronic disease as it does on the treatment of menopausal symptoms, is key to ensuring women stay physically and mentally fit and healthy as they get older.

A NATURAL EVENT Menopause is the last menstruation in a woman's life. It corresponds to the cessation of ovarian function, comprising loss of reproductive hormone production, and the irreversible loss of fertility.1 It is a natural event that occurs in all women, but Nappi said there were a “wide rainbow of possibilities” in terms of phenotypes.

In Western countries, early menopause is defined as occurring between the ages of 40–45 years, and menopause before the age of 40 years as premature menopause or premature ovarian insufficiency.1,2 In some women, menopause is induced by surgical removal of the ovaries, or pharmacological interventions delivered with the aim of temporarily or permanently stopping the production of reproductive hormones.

It is usually not a sudden occurrence. Women tend to enter the menopausal transition slowly, and “it can be a long journey,” said Schaudig.

Perimenopause is defined as the time between the onset of menstrual irregularities and 12 months after the last menstrual period, which is the official definition of menopause.3 It tends to start between the ages of 45–55 years and, on average, lasts for about 7 years.4 Twelve months after the last menstrual period, the woman enters postmenopause.

Explaining the physiology of the process, Schaudig said that a woman’s life could be divided into three chapters: childhood, a reproductive stage, and a post-reproductive stage. At puberty, women have around 300,000 ovarian follicles.5 During this time, a feedback loop between the hypothalamus, the pituitary gland, and the ovaries is established,6 resulting in a single follicle, containing a single oocyte, being released each month. This process is responsible for the release of reproductive hormones, including oestradiol and progesterone,7 as well

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as anti-Müllerian hormone (AMH).8 By the age of around 37 years, the number of ovarian follicles, which are the source of AMH secretion, will have reduced to around 25,000. As the follicle reservoir depletes, so do AMH levels, leading to an increase in follicle-stimulating hormone (FSH), resulting in fluctuations in hormone production and irregular cycles.5,9 “The production of sexual hormones becomes like a roller coaster,” said Schaudig. “During the perimenopause, we can sometimes see two or even three developing follicles in 4 weeks with untimely ovulations, even during menstruation.

There may also be months without a complete follicle maturation at all. It means there might be periods of oestradiol deficiency, followed by periods of elevated oestradiol levels, all accompanied by an elevation in FSH, as the body tries to normalise the cycle. At the same time, the secretion of progesterone that usually takes place after ovulation is impaired, which may lead to a dominance of oestradiol and bleeding disorders.” The eventual exhaustion of the follicle reservoir leads to the almost complete depletion of oestradiol, progesterone, and AMH in the postmenopausal stage (Table 1).5,6

SYMPTOMS AND RISK FACTORS Menopause symptoms vary between individuals,1 as well as the stage of transition.5 During the early stage of perimenopause, when there is fluctuating ovarian hormone production, women may experience symptoms related to oestrogen excess (such as breast tenderness, menorrhagia, migraine, nausea, or a shorter cycle length), oestrogen insufficiency, or a mixture of both.5 Oestrogen deficiency symptoms, which can include vasomotor symptoms (VMS) like hot flashes and night sweats, and urogenital symptoms like vaginal dryness,

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Table 1: Menopausal stages.5,9

Early perimenopause

Late perimenopause

Postmenopause

Menstrual cycle flow/ length

Variable cycles (>7 days in cycle length, or <60 days in duration of amenorrhoea)

Cycles >60 days

Ceased

Symptoms

Likely

More likely

Very likely

Serum FSH/oestradiol

FSH increased or normal, oestradiol and ovarian reserve variable

FSH increased, oestradiol low, ovarian reserve low

FSH elevated, oestradiol low, ovarian reserve very low to undetectable

FSH: follicle-stimulating hormone.

urinary tract infections, and urge incontinence, are more common in the later stages and postmenopause.10,11 In perimenopause, women may experience ‘cognitive fog’, fatigue, irritability, disturbed sleep, joint pain, anxiety/depressive moods, and loss of libido.5 Such symptoms can be insidious in nature, explained Nappi. “It is not a sleep disorder, or depression, it’s more that you just do not feel yourself; you do not feel okay,” she said, adding that some women may have the appearance of having severe premenstrual syndrome.

Such symptoms can have a significant impact of health-related quality of life and wellness, Nappi went on.12 She explained that the symptoms impacted on multiple domains of health-related quality of life, including working capacity, social activity, sport/exercise, emotional wellbeing, and pain, as well as self-esteem and self-perception.

The peri- and postmenopausal stage of life is associated with a range of evolving risk factors.

Some of these are linked to changes in hormone levels, and others to simply getting older. Women may also experience iron deficiency as a result of heavy and irregular menstrual periods during the transition phase.13 Furthermore, the fall in oestradiol levels has a number of adverse metabolic effects. During the reproductive stage of life, reproductive hormones help to balance bone loss, but their depletion at menopause can contribute to the

risk of osteoporosis and fractures. Women tend to experience increases in insulin resistance, dyslipidaemia, and endothelial dysfunction, as well as an increase in abdominal fat deposition.14 Such changes increase the likelihood of conditions, including cardiovascular diseases (CVD) and Type 2 diabetes.5,14 The CVDprotective effect of oestrogen is lost around 10 years after the onset of menopause.14 Cancers, both age- and hormone-related, are another important consideration. While menopause is not directly related to cancer, the risk increases with age15 and obesity,16 explained Schaudig.

With CVD and cancer being the leading causes of mortality worldwide,17 she went on, understanding and working to mitigate such risks, is key.

Nappi added that the age of onset of menopause was another element to the risk profile. Early menopause, for example, is associated with a reduced risk of breast cancer, but increased risks of premature osteoporosis, CVD, and premature death.2

CHANGING PERCEPTIONS Traditionally, perimenopausal and postmenopausal healthcare has not received the attention it deserves, due in part to the stigma of the condition and of asking for help. Menstrual bleeding is often a symbol of femininity for women, and many perceive their inability to

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cope with symptoms on their own as a sign of weakness, said Nappi. “Sometimes, women do not want to ask for help because they do not want to be judged,” she added.

High-profile awareness campaigns have, in recent years, gone some way to raising awareness and dispelling the stigma, but there is still work to be done. Schaudig said women in their mid-40s were often shocked when she told them they could be perimenopausal. “They say they are too young for that. They think that being menopausal means to be grumpy, and unattractive, and that it is synonymous with being old,” she said. While it is, of course, still possible for women going through perimenopause to become pregnant, “it can be hard for women to accept they may not be fertile anymore,” she went on.

However, menopause does not mean “the end,” said Nappi, describing it instead as the “start of a new era.” “Menopause is a natural part of being a woman. Longevity has increased so much that women of this age are active members of society, they have jobs and young children. They should not be ashamed of menopause symptoms, and they need to be aware that some of them will not just go away; in fact, they may go on for a long time. So why should they have to suffer?”

Yet, even when women do ask for help, it may not always be forthcoming. Healthcare professionals tend to receive limited training on post-reproductive health, meaning they do not always feel qualified to intervene, explained Nappi and Schaudig. As such, many will wait until 12 months after the last menstrual bleeding, i.e., until the person has entered the postmenopause period, before offering advice or treatment.

Nappi said: “This is a common but important mistake. You need to start taking care of your patient as soon as you realise that they are experiencing perimenopause.” Early intervention, both in terms of helping women to cope with the direct symptoms and to manage their future health, is critical.

THINK PERIMENOPAUSE Nappi advised healthcare professionals to “think about perimenopause,” and ask about

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bleeding cycles in all women over 40. It is important to note, she went on, that they may present with symptoms such as mood or sleep disturbances, having no idea they could be related to the perimenopause.

According to the Stages of Reproductive Aging Workshop (STRAW) staging system, if the length of a woman’s consecutive cycles differs by 7 days or more over at least 10 months, she is likely to be in the early stage of perimenopause.18 In this phase, FSH may still be in the normal range, which may lead to the incorrect assumption that the woman has not yet entered early perimenopause. AMH levels are already low in this phase, and so is the antral follicle count.18 The STRAW system further defines late stage perimenopause as amenorrhoea of 60 days or longer, with a now increased FSH level, increased variability in cycle length, extreme fluctuations in hormonal levels, and the increased prevalence of anovulation.18 Hormonal tests, however, are not always recommended to diagnose menopause, particularly in those aged over 45 years.5 The 2023 Practitioner’s Toolkit for Managing Menopause, which has been endorsed by the International Menopause Society (IMS), explains the tests are uninformative in those using systemic hormonal contraception that suppress ovulation, have a progestin intrauterine device, or have been prescribed progestogen following an endometrial ablation, for example.5 The toolkit states that hormonal measurements “may be useful” in women aged between 4 0–45 years, and amenorrhoeic women with subtle or fluctuating symptoms, such as mood changes, with no or few VMS.5 However, it also notes that a single observation of normal FSH and oestradiol would not exclude perimenopause, a period during which hormone levels are known to fluctuate.5 It recommends hormonal testing when there is a suspicion of premature ovarian insufficiency (menopause before the age of 40 years), and explains that elevated FSH and low oestradiol on at least two occasions between 4–6 weeks apart is indicative of premature menopause.5 Depending on clinical assessment, healthcare professionals will also need to exclude other causes of amenorrhoea, such as pregnancy,

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hypothalamic amenorrhoea, hyperprolactinaemia, or thyroid disease.5 In those experiencing fatigue, changes in mood, and hot flashes, Nappi also recommended measuring thyroid stimulating hormone for thyroid disease, haemoglobin for iron deficiency, and fasting blood glucose for Type 2 diabetes.5 “It is important that healthcare professionals recognise when women are in the perimenopause so that they can offer help, and at least give them a clue as to what is going on,” said Schaudig. While some issues will require specialist gynaecological input, there is much that can be done in primary care to help women remain physically and mentally healthy as they transition to postmenopause. Symptoms such as vaginal dryness, for example, “can, and should” be treated relatively simply. Just being able to reassure women that symptoms, such as cognitive fog or low mood, are part of the process, rather than signs of a more serious underlying condition like dementia or depression, can be critical to their wellbeing, Nappi and Schaudig agreed.

HEALTHY AGEING Nappi referred to this period as a “golden moment” to engage women to focus on primary prevention. Schaudig agreed. “It is the perfect opportunity to ask women to reflect on what they want from the next, often longest, stage of their lives,” she said, adding that most will answer that they want to live long and healthy lives. “Explain that there is nothing to be scared of, but that they are at a turning point; that the reproductive hormones that have protected them from some chronic conditions for the last 35 years or so are no longer there,” Nappi went on.

She highlighted a care pathway from the European Menopause and Andropause Society (EMAS), which recommends a battery of screening and investigations aimed at assessing an individual’s risk of long-term health conditions.3 Smoking status, diabetes history, blood pressure, and cholesterol levels, as well as the family history can be used to estimate CVD risk, while BMI and waist-to-hip ratio are useful for predicting the risk of metabolic syndromes.3 Not only will this information help to inform prevention strategies, but it will also

guide any decisions on menopausal hormone therapy (MHT).3 Peri- and postmenopausal women should also be stratified for fracture risk, using, in those over the age of 40 years, the FRAX® calculator (University of Sheffield, UK).3 Thresholds for bone mineral density assessment by dual-energy X-ray absorptiometry vary by country.3 In the UK, for example, all postmenopausal women >65 years of age should be screened.3 Clinicians, Nappi said, should follow their own national guidelines. The EMAS pathway also states that older postmenopausal women can experience an age-related decline in muscle strength and mass, and decreased physical performance.3 Handgrip strength, gait speed, and the SARC-F questionnaire are useful sarcopenia evaluations, she went on.3 Clinicians have an important educational role to play, said Schaudig, referencing a 2004 survey that found 35% of women identified breast cancer as their most important health threat,19 despite the condition carrying survival rates of up to 93%.20 “The data is quite old now, but I think it still holds true,” Schaudig said, adding that while breast cancer was the most common cancer in women, mortality was low.

Conversely, just 13% of survey respondents thought they would die from CVD, despite it being one of the leading causes of death in men and women, worldwide.17 Based on these assessments, healthcare professionals can engage, inform, and empower women to manage their long-term health, both doctors argued. “If you are around 50, you may live until you are 90 or 100, which means you still have 40 or 50 years,” said Schaudig. It makes it a good time for women to consider, with their healthcare professional, what they can do to improve their quality of life, and reduce their risk of conditions such as CVD and cancer. “There are all kinds of things we can do in terms of lifestyle: physical exercise, nutrition, minimising alcohol, and stopping smoking.” Clinicians should also encourage women to undergo regular blood pressure checks and engage with national cancer screening campaigns, including for breast and colon cancer,5 which account for more than 40% of malignancies in women across Europe.21

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Prevention advice, Nappi argued, should be “first-line.” “We should empower women by informing them of the best things they can do around the time of menopause,” she said.

PERI- AND POSTMENOPAUSE MANAGEMENT Managing menopause symptoms starts with a conversation about which are the most burdensome, both Nappi and Schaudig agreed.

“I call it the fairy godmother question,” said Schaudig. “I ask, ‘if you had one wish, which symptom would you make disappear?’ Then, ‘what if you had two wishes?’ and so on, until we have a list.” This, combined with a holistic understanding of women, their lifestyle, and their goals, will help to build a treatment plan.

According to the 2023 Practitioner’s Toolkit for Managing Menopause, the most robust menopause clinical practice guidelines support MHT as the most effective treatment to alleviate VMS, and individual risk factors will guide selection of the most appropriate approach.5 “When we think that the lack of hormones is the reason for many of these symptoms, it is quite logical to at least think about replacing these hormones,” said Schaudig. “However, this is tricky in the perimenopausal period, when the levels are going up and down.”

For some perimenopausal women, combined hormonal contraceptives can be useful for regulating hormonal cycles and, therefore, relieving symptoms.5 However, it will not be suitable for those who wish to become pregnant, and the appropriate type of agent will depend on the individual’s risk factors.5 For women with contraindications for combined hormonal contraceptives, progestin-only pills, in combination with transdermal oestradiol during periods of oestrogen depletion symptoms, can be useful. Bleeding disorders can be treated with levonorgestrel intrauterine devices.

Non-hormonal interventions often mirror those employed for the prevention of chronic conditions, and include a focus on diet and exercise, as well as removing VMS triggers, such as caffeine and alcohol (Table 2). Being overweight and smoking are risk factors for VMS, for example, so encouraging weight reduction and smoking cessation can help.2,5 Exercise, yoga, mindfulness-based stress reduction techniques, and relaxation may improve sleep, and, by extension, fatigue, mood, and general wellbeing.2 Food supplements,1,2 such as black cohosh, calcium, and vitamin D, may have a “mild effect,” said Schaudig. Cognitive behavioural therapy may also be useful for VMS, and may also provide benefits in terms of sleep and mood.1 Gabapentin, as well as some antidepressants, such as venlafaxine and paroxetine, can sometimes be efficacious.2

Table 2: Lifestyle advice for the management of menopausal symptoms, and for prevention of chronic disease associated with ageing and the menopause.3

Domain

Intervention

General advice

Wear lighter clothing, sleep in a cooler room, use fans; control VMS triggers, such as spicy foods, caffeine, and smoking; reduce stress with relaxation techniques, such as deep breathing, guided visualisation, and progressive muscle relaxation

Physical activity

Reduce sedentary behaviour as much as possible; aerobic exercise: ≥150 mins moderate intensity or 75 mins of vigorous intensity per week; musclestrengthening activities: ≥2 days a week, or as often as possible

Diet

Increase intake of complex carbohydrates; increase protein intake; increase intake of mono- and polyunsaturated fats; Mediterranean diet

Supplementation

Increase calcium intake through diet or supplements; increase vitamin D intake through diet or supplements

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Nappi said there were also a number of novel non-hormonal agents for VMS, one of which has now been approved by the FDA (Food and Drug Administration).22,23,24,25 These neurokinin B receptor antagonists target the KNDy neurons, which are involved in the release of gonadotropin-releasing hormone and temperature regulation. 22,23,24,25 This new class of drugs will help those women who are considered unsuitable for MHT, or for those who are simply averse to its use, said Nappi.

References

MAKING A DIFFERENCE Summing up, both doctors offered their topline advice to clinicians. “Don’t miss the early signs of menopause; don’t leave women to their fate,” said Schaudig. “At the beginning there will be cycle irregularities, mood swings, a lack of concentration, depressive mood, and sleeplessness, but without hot flashes. These come later.” Nappi said they should not miss any opportunity to talk about menopause and healthy ageing, because “it will always be time well spent.”

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10. Avis NE et al. Vasomotor symptoms across the menopause transition: differences among women. Obstet Gynecol Clin North Am. 2018;45(4):629-40.

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Davis SR, Baber RJ. Treating menopause-MHT and beyond. Nat Rev Endocrinol. 2022;18(8):490502.

11. Angelou K et al. The genitourinary syndrome of menopause: an overview of the recent data.

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Lambrinoudaki I et al. Menopause, wellbeing and health: a care pathway from the European Menopause and Andropause Society. Maturitas. 2022;163:1-14.

12. Whiteley J et al. The impact of menopausal symptoms on quality of life, productivity, and economic outcomes. J. Womens Health (Larchmt). 2013;22(11):983-90.

National Institute on Aging (NIA).

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Available at: https://www.nia.nih. gov/health/what-menopause. Last accessed: 10 November 2023.

13. Munro MG et al. The relationship between heavy menstrual bleeding, iron deficiency, and iron deficiency anemia. Am J Obstet Gynecol. 2023;299(1):1-9.

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Davis SR et al. The 2023 practitioner’s toolkit for managing menopause. Climacteric. 2023;DOI :10.1080/13697137.2023.2258783.

14. Nappi RE et al. Menopause: a cardiometabolic transition.

Lancet Diabetes Endocrinol.

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Baskind NE, Balen AH. Hypothalamic-pituitary, ovarian and adrenal contributions to polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol.

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15. White MC et al. Age and cancer risk: a potentially modifiable relationship. Am J Prev Med. 2014;46(3 Suppl 1):S7-15.

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Holesh JE et al. Physiology, Ovulation [Internet] (2023) Treasure Island: StatPearls.

Available at: https://www.ncbi.nlm. nih.gov/books/NBK441996/. Last accessed: 10 November 2023.

Kollmann Z et al. Anti-Müllerian hormone and progesterone levels produced by granulosa cells are higher when derived from natural cycle IVF than from conventional gonadotropin-stimulated IVF. Reprod Biol Endocrinol 2015;13:21.

Santoro N. Perimenopause: from research to practice. J Womens Health (Larchmt). 2016;25(4): 332-9.

16. Pati S et al. Obesity and cancer: a current overview of epidemiology, pathogenesis, outcomes, and management. Cancers (Basel).

2023;15(2):485.

17. World Health Organization (WHO).

Cardiovascular diseases (CVDs).

2021. Available at: https://www. who.int/news-room/fact-sheets/ detail/cardiovascular-diseases(cvds). Last accessed: 14 November 2023.

18. Harlow SD et al.; For the STRAW+ 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop+ 10: addressing the unfinished agenda of staging reproductive aging.

Climacteric. 2012;15(2):105-14.

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19. Mosca L et al.; American Heart Association. Tracking women’s awareness of heart disease: an American Heart Association national study. Circulation.

2004;109(5):573-9.

20. Dafni U et al. Breast cancer statistics in the European Union: incidence and survival across European countries. Breast Care (Basel). 2019;14(6):344-53.

21. Dyba T et al. The European cancer burden in 2020: incidence and mortality estimates for 40 countries and 25 major cancers.

Eur J Cancer. 2021;157:308-47.

22. Bayer. A study to learn more about how well elinzanetant works and how safe it is for the treatment of vasomotor symptoms (hot flashes) that are caused by hormonal changes over 52 weeks in women who have been through the menopause (OASIS-3).

NCT05030584. https://classic. clinicaltrials.gov/ct2/show/ NCT05030584.

23. Simon JA et al. Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dosefinding clinical trial (SWITCH-1).

Menopause. 2023;30(3):239-46.

24. Johnson KA et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocrinol Metab. 2023;108(8):1981-97.

25. Lederman S et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet.

2023;401(10382):1091-1102.

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Interviews EMJ spoke with Aurore Girard, Dame Clare Gerada, and Dirk Devroey. The experts shared insights into fascinating topics, including key challenges faced by general practitioners, misconceptions in primary care, and the integration of technology into the field.

Aurore Girard Vice President of Société Scientifique de Médecine Générale (SSMG), Brussels, Belgium; President of the World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians (WONCA) European Conference Host Organizing Committee 2023.

EMJ. 2023; DOI/10.33590/emj/10302075. https://doi.org/10.33590/emj/10302075.

Citation:

Q1

What initially attracted you to primary care as a specialism?

The first thing is probably the holistic approach to care. Primary care provides care for people for a large part of their life, and we can have a real impact on people’s health.

As we follow our patients long-term, we provide advice that may impact their health for many years. The second thing is the independence and capacity to create our own network, linked to our patients’ needs. Primary care is integrated to the community and local network. Finally, each general practitioner (GP) may develop their own expertise and competencies linked to their interest and patient’s needs.

"Primary care is still less valued than hospital practice in patients’ minds in a lot of countries."

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Q2

Do you feel that there are any misconceptions about the discipline of primary care?

Sometimes, GPs are seen as other specialists’ secretaries, or as an obligatory checkpoint to see other doctors. Primary care is still less valued than hospital practice in patients’ minds in a lot of countries, but also in other specialists’ minds.

General practice is also sometimes seen as a less technical speciality. Some people see a GP practice as a ‘by the way’ practice, which does not really need a framework.

Q3

Medicine compliance is a key issue for primary care physicians to consider.

Have you seen much improvement in addressing this challenge over the last few years?

I do not think that there are really big changes in practice. General practice always has a privileged place in a patient’s health. If you

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take a look at explanatory notes for medication, it can be very anxiety-provoking. So, one challenge is to explain side effects without creating anxiety.

Some patients take inadequate initiatives to stop or to modify their treatment, which is why one of our major tasks is to help the patient adhere to their treatment, and to co-construct it.

Q4

Another growing challenge that primary care physicians are encountering increasingly frequently is how the environment impacts patient health. Can you discuss why this can be so challenging for general medical specialists to address?

The lack of medications in Europe is a big challenge. GPs need to manage their prescriptions, and provide responsive prescriptions while thinking about their impact on the environment. A second challenge is increasing antibiotic resistance. This changes the way GPs should prescribe, while taking into consideration the environmental impact of our prescriptions. This is currently a changing mindset in GP practices. A third challenge is patient movements. The environmental impact of movement to access care is a real challenge.

Some patients have to travel miles to access examinations, or a hospital consultation. Another challenge is medical waste management and sorting inside practices and clinics, which is a challenge to implement.

Q5

As President of the World Organization of National Colleges, Academies and Academic Associations of

General Practitioners/Family Physicians (WONCA) European Conference 2023, you oversaw a congress theme of ‘Making choices in primary care’. Can you talk about what this theme meant, and how it shaped the organisation of the congress?

GPs need to make choices every day, especially the ‘good choice’. We need to provide the best clinical examination, and the appropriate clinical management linked to evidence-based practices.

We also have to link our choices with patients’ preferences, possibilities, and opportunities, with special attention to their autonomy. Finally, we need to make choices to find an optimal balance between professional and personal challenges.

"There is a huge diversity between health system and remunerations."

Q6

Can you tell our readers about your personal highlights from the WONCA European Conference 2023 scientific programme?

I will remember the lecture given by Els Torreele, University College London (UCL), UK, entitled ‘Why are our medicines so expensive?’, and another by France Légaré, University Laval, Quebec, Canada, who presented on ‘The multiple facets of shared decision making in primary care’.

In my opinion, those will stay the highlights of my WONCA week.

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Q9

Health systems in Europe are very different in each country. So, even if the diseases are the same, the resilience of each system is very different, as are the means of action levels. There is a huge diversity between health system and remunerations, which is very challenging.

AI is a new help for diagnosis in consultation and monitoring. The add-on of primary care stays human contact, and we have the capacity to adapt support and treatment to the context and needs of each patient. A big challenge is the ethical framework of using AI, while continuing to protect the patient’s safety.

Q8

Q10

What is the biggest challenge that WONCA faces in their goal to ‘facilitate professional development and research in and on general practice and on the premises of general practice?’

You are a member of several general medicine associations, including WONCA and the Société Scientifique de Médecine Générale (SSMG). What work do these associations do to prioritise diversity in terms of the age and gender of their member GPs? At SSMG, we try to create a welcoming virtuous circle. We take care to implement mentorship in each part of our organisation to promote young GPs. Each department is based on a junior–senior model to build confidence in leadership capacities.

We pay special attention to positive and respectful communication, and stay open to every member’s suggestions to construct our development model based on real GP life. We are also very attentive to preserving a real respect between professional and private life.

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How do you see the advent and integration of new technology, such as artificial intelligence (AI) and machine learning, impacting the field of primary care?

What are the most significant changes you have seen in the field of primary care during your time working in the field?

The mentality of GPs and the mentality of care have changed in recent years. GPs have transferred from a vocational model to a professional model. While they still work with the same passion and devotion, they now set more limits to protect their private life and mental health, so the link to work is not the same any more. This creates new needs and challenges.

In patients, we now observe more impatient and consumerist attitudes, as this new framework creates more aggression and misunderstanding.

Dr Google is not very helpful to our practice, and very anxiogenic to patients. ●

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Dame Clare Gerada DBE Royal College of General Practitioners President, Clinical Chair of the NHS Assembly, Senior Medical Advisor to the Department of Health, and Director of Primary Care for the National Clinical Governance, London, UK

Citation:

EMJ. 2023; DOI/10.33590/emj/10303143. https://doi.org/10.33590/emj/10303143.

Q1

You initially trained in psychiatry, and focused on treating patients with addiction. In the time you have worked in this field, how do you think the approach of the medical community has changed and improved?

When I started out way back in the 1980s, addiction was predominantly dealt with by psychiatrists in hospitals, psychiatrists in the private sector, and a few general practitioners (GP) and psychiatrists in private practice.

It was not systematically delivered to high standards, there was little use of evidence-based interventions, and we did not have shared care.

Now, the mainstay of addictions is carried out

by GPs in partnership with the third sector, so the voluntary sector. Paradoxically, psychiatry has less of a part to play. I am not saying that is a good thing, but that is what has changed.

GPs now do the mainstay of chronic disease management, and addiction is a chronic disease; as with other chronic diseases, it has moved into general practice. Sadly, the resources have not also moved with it! However, there is much safer and better care now than when I started out.

Q2

Do you feel there are any misconceptions about the role of a GP, and what do you think can be done to address these misconceptions?

I think the GP's role has essentially become that of a hospital doctor in the community. This morning, I saw 18 patients, and had to move between being a consultant paediatrician, cardiologist, respiratory physician, psychiatrist, and so on, sometimes in the same patient. Yet,

I had to do each of those in under 10 minutes, and on my own. My job as a GP, which is essentially first contact care and managing risk and uncertainty, is rapidly playing second place in managing complexity and chronic disease.

The misconception is that while the GP is well placed within the community, this does not mean we should be doing all the work. For example, approximately 1 million children, every day, do not go to school, mostly due to minor illness. If we were allowed to do our job properly, parents would have the space, and we would have the space and the time to help them answer whether their child is too sick, or well enough to go to school. But we cannot do this, because we are managing complexity, and have no time to offer what I think is basic general practice. And I think that is where the misconception is: people do not understand my skills. I am perfectly skilled at managing chronic schizophrenia, depression, or respiratory disease. But my real skill is managing risk and uncertainty, and answering that basic question 10,000 times an hour (which is how many children consult with their GP in London): “Is my child well enough to go to school?” And GPs can do that because we have skills in dealing with children who are well, as well as children who are sick. I keep reminding people that I am not a hospital doctor in disguise. I am a GP with skills in generalism, uncertainty, and continuity.

Q3

What do you feel are the greatest challenges currently facing GPs, both in the UK and across the world?

Across the world, there are not enough GPs. The industrialisation of healthcare has increased

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"The industrialisation of healthcare has increased the number of ultra-specialists." the number of ultra-specialists, with fewer and fewer generalists able to deal with the whole person. The challenge here is that nobody is happy because the ultra-specialist is not happy just seeing a small part of the human body, and generalists are not happy at having to deal with so much complexity. The challenge also facing GPs across the whole world is the number of us, as there are fewer and fewer of us, and we are doing more and more. But it is also the broader issue of the industrialisation of healthcare, which is turning healthcare into a production line, rather than a relationship between a patient and their doctor.

Q4

In 2022, you authored a paper entitled, ‘Doctors' identity and barriers to seeking care when unwell’. What were the findings of this paper, and how do you think these challenges can be addressed moving forwards?

I hypothesise that everybody has an identity; in fact we have many, depending on our current role or position. For example, your identity now is that of a journalist, but you might also be a parent, and as such your identity is fluid depending on your situation. The identity of a doctor is one of the strongest identities. It has formed even before starting medical school, as those wanting to study medicine have preconceived ideas of what it is to be a doctor, and try and emulate them (studying hard at school, being altruistic by working for charitable organisations, and so on). Once in training, the identity is strengthened by our long training, where we don’t really mix with those outside medicine. A doctor’s identity is made up of two parts; it is made up of our individual identity, that is, ‘I am a doctor’, but also our group identity, the identity of medicine. It is a very strong identity, and on the whole, there is little space for another identity. Even an identity as a mother gets pushed out. Also, what gets denied is the identity of being a patient, as the identity of a doctor means denying vulnerability; it is those on the other side of the consulting room who are vulnerable, and have illnesses. We wear magic white coats because that is what

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our identity tells us. And, of course, we do not wear magic white coats, and we get ill, but it both prevents us from seeking help, and creates a sense of invincibility. If you ask me what I am, I am a doctor. It is not just a job, it is something I am. So that is my hypothesis. I wrote the book ‘Beneath the White Coat: Doctors, Their Minds and Mental Health’, which elucidates all of this.

Q5

You are the current President, and previous Chair, of the Royal College of General Practitioners (RCGP). Can you tell our readers a little bit about the work the RCGP does, and what these roles mean to you?

I am proud that I am the second woman to hold the Chair and the President. I am also very proud of my college. It is the largest, but one of the youngest, of all the Royal Colleges, and has achieved an awful lot. It has achieved, in front of the scenes, the development of our education and training to support us professionally, but also, behind the scenes, stopping things from happening, which therefore never see the light of day, such as having to sit a compulsory exam every 5 years, which was muted as part of revalidation requirements. This will end for me this year on the 17th of November, after 25 continuous years on council. It is a poignant moment, but I am ready to leave and see what else comes next. The college has provided me with support, friends, and opportunities to develop my career, and it has probably been the most important part of my professional life.

Q6

How do you feel that the development and integration of technology into primary care has changed the field? Has this resulted in a benefit for doctors and patients in terms of quality of care?

I think it is vital that we have a mix of face-toface and remote consultations, and I think the future will lean towards remote-first. Think of banking. The idea of going into a bank every time you want to put a cheque in, or get money, has gone out with the ark, and the same is going

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to happen to medicine. I am a front-runner on technology, and I used email with my patients and their relatives 20 years ago, when email was still a sort of wind-up clock with no guidance.

I also used social media to communicate with people on a broader scale. My practice has developed a tool called e-consult, a digital triage tool, and it is life-changing for me as a doctor because I can understand what might be wrong with my patients before I consult with them. I can start thinking about how much time I might need with them, whether I need more information, or need to ask for help. And they themselves can access me in a much easier way.

I have also started to experiment with artificial intelligence (AI). I have been using ChatGPT for about 3–4 months personally to help me research things, but I have also started using it clinically when I have time, and when I consult remotely. I do not think, for now, it is helpful for the patient to use, as the AI response always ends in asking the patient to consult with their GP or doctor. But for me, it is helpful because it helps me think of things I had not thought of. I think we are about 18 months–2 years away from a healthcare transformation. But we do need funding, because we need to get double running systems. So, we have had the cottage industry, the industrial revolution, and now we have the digital revolution.

Q7

You were awarded an MBE for your services to medicine and substance misuse in the Millennium Birthday Honours.

Can you tell our readers a little more about the amazing work you did you achieve that award?

In 2000, I was leading drug misuse for the Department of Health, and I think I saved more lives doing that than anything else I have

"I think it is vital that we have a mix of face-to-face and remote consultations." ever done. I set up a shared care scheme, got some funding to train GPs, as well as funding to do supervised ingestion for drug users on methadone, and worked really hard in transforming the way substance misuse is managed. I got a damehood in 2020 for my services to physician health by setting up a service for the mental health of doctors and dentists. I set up practitioner health, which has now seen about 17,000 health professionals with mental health problems. So top and tail of the two ends of my career, I am really very proud of that.

Q8

You are reaching the end of your tenure as RCGP President. Where can we expect to see your focus lie in the coming years?

I have always done two or three jobs simultaneously. I am currently running a gambling service for problem gamblers. I am also president of the Royal College of GPs, and I am patron of a charity called Doctors in Distress, as well as doing my clinical work in practice. I am going to be a grandmother in November, and my other son is getting married very shortly. So, I do see a real change in my life and my personal life going forward. But I have applied to support Jersey healthcare, and I am also going to carry on doing the gambling support, so I won't be redundant, that's for sure. ●

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Dirk Devroey Dean of the Department of Family Medicine and Chronic Care, Faculty of Medicine, Vrije Universiteit Brussels (VUB), Belgium; Member of the Scientific Committee for the 28th World Organization of Family Doctors (WONCA) European Conference

EMJ. 2023; DOI/10.33590/emj/10304915. https://doi.org/10.33590/emj/10304915.

Citation:

Q1

With your vast experience in the disciplines of primary care and family medicine, could you tell our readers what initially attracted you to specialise and practice in this area?

I undertook my university courses at University Hospitals, and at several other hospitals in Belgium, but I also had some training in general practice. From the start, I felt much better in these small practices that were outside of the city, and very close to the patients. It was a very diverse experience, as the general practice experience is not about one specialism.

The combination of diseases also very much attracted me, as well as the very close long-term contact that the general practitioner (GP) has with patients. This attracted me so much that I started a practice in the very small town where I was born and lived as a child, so I still have patients who knew my mother and father, and were there when I was born, and who even knew me when I was born! So, all these aspects of being very close to the patient attracted me so much that I never doubted my choice of primary care as a GP.

Q2

Do you feel that there are any key misconceptions about the specialism of primary care? What impact do you feel these misconceptions can have?

Before I started my university studies, the misconception was that GPs were those who could not specialise. They were the ones who had to choose to be a GP because they thought that they were not clever enough, or they could not arrange a place for specialisation, and so on.

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I think that is a very important misconception.

During my studies, I was not the best student in my year, but other very good students, who were much cleverer than I was, chose to be GPs when they had the opportunity to specialise, but did not want to. They made a positive choice to be a GP. Another important misconception is that we as GPs are there to deal with very common diseases, the easy diseases, even the self-curing diseases; or that we are there to write sick notes, to do the admin, or to do blood tests. I think that is a very important misconception, because we are here to manage complex patients with multiple comorbidities, and the complex patients who are very old, and cannot go to the hospital anymore. Currently, we deal with patients with complex diseases who cannot get appointments with specialists because there are not enough specialists, or the waiting lists are too long. I think this makes our profession as a primary care doctor very, very attractive now, although very challenging.

Q3

In 2022, you co-authored a paper, entitled ‘Diabetes and Cardiovascular Diseases Risk Assessment in Community Pharmacies: An Implementation Study’. Can you enlighten our readers about some of the key findings from the study of this pilot project?

This was a part of a bigger study where we tried to find out how we could better organise care for outpatients with pharmacies. First, we tried to study self-testing, such as which kind of self-tests were interesting for patients, and what role the pharmacists could play. We

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had to do research with pharmacists, GPs, and psychologists. However, this was not that successful, so we had to try to find another way of studying diabetes and cardiovascular risk assessment in community pharmacies, and to find out how it could be implemented in pharmacies.

The study started several years ago but was published in 2022. With the COVID-19 pandemic, COVID-19 vaccinations, and COVID-19 testing, pharmacists have massively progressed in their role in primary healthcare in Belgium, and in other European countries as well. I think that this has also contributed to the place that the pharmacist could take in primary healthcare, especially in delegating certain tasks from GPs to pharmacists. The results of this study opened the door for collaboration between both.

"We especially looked at their mental health, and traumatic stress experienced during the hunger strike."

I must admit that COVID-19 has opened a lot of doors, and that without the study, the same doors would still have been opened. We started this study several years before COVID-19, but we are happy with where we are now with regard to the tasks that pharmacists can now do in Belgium. In other countries, such as France and the UK, pharmacists already did many more of these tasks than the pharmacists did in Belgium, where doctors were very protective of primary care: no other people, no nurses or pharmacists, could interfere with their primary care. However, these doors were opened with the study.

"My focus will be to try to give family medicine a predominant place in healthcare in Belgium."

Q4

You also recently contributed to a fascinating article entitled ‘Between Sympathy, Fascination, and Powerlessness.

The Experiences of Health Professionals During the Medical Monitoring of a Hunger Strike Among Undocumented Migrants’. Can you explain to our audience the importance of a study like this, and how it relates to larger issues faced by primary care physicians, such as patient non-conformance and physician mental health?

This is very complex question, and it was also a very complex study that was part of a PhD study on undocumented migrants on hunger strikers.

There is a very unique and challenging situation in Belgium, where undocumented people embark upon hunger strikes to attain documents, or at least to get authorisation to stay in the country.

One of the ways to stay in the country is to get so sick that you need medical treatment, and so undocumented migrants will try hunger strikes to get sick, and to get these documents. There are many personal and political views on this phenomenon, but with this study we tried to have a medical view. These people risk their lives and their health to get these documents and there were many problems that we encountered when trying to monitor them. We never tried to influence the people, the politics, or the hospitals. We were simply just trying to help the people. They could irreversibly damage their health, and we did not want that.

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The first time I encountered undocumented migrants was in 2009, when we had about 150 hunger strikers in one of the car parks of our university. We had to organise the medical care for these hunger strikers. But we also learned more about these people. We understood what the problem was, and how they were driven into this situation.

When trying to help them, we found that there were no guidelines. When should someone stop the hunger strike? What kind of hunger strikes were there? Were they not eating or drinking, or were they only drinking sugar water and so on?

It was very interesting to find out there were no guidelines, and that there were only guidelines for prisoners, where they were obliged to take some food and drink. We never forced the hunger strikers to eat or drink, but we tried talking with them to help them. From there, we tried to start developing guidelines surrounding how to manage the people who were on hunger strike.

Secondly, we did follow-up studies to see what had happened to the individuals 5 years after the hunger strike, in a social context, but also in a medical and mental health context. In this study, we especially looked at their mental health, and also the traumatic stress that they experienced during the hunger strike, and in the period after it. It was so fascinating, but we are very happy that this is no longer a technique that is being used by undocumented refugees. We are still trying to take care of them as much as possible.

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Q5

As a researcher and practitioner in the primary care field, where can we expect to see your focus lie in the coming years?

I will turn 60 in November, and I am now Dean of the Faculty of Medicine at Vrije Universiteit Brussels (VUB), which I am very honoured by.

I am now in charge of all the personnel in the medical faculty. At the University Hospital, we have a Chief Executive Officer, but I also take part in the governing of the hospital. It is a recognition that GPs can also have an important position in the faculty, and in a university.

My focus will be to try to give family medicine a predominant place in healthcare in Belgium, and maybe in the world, as there are still so many problems to solve. But, at my age, I think it is important to stimulate young researchers, and GPs in particular, to try to conduct high quality research in primary care, and also in collaboration with other specialties. I think it is important that we do research on integrated care with all kinds of specialists, where primary care also has its place. It is important that I can stimulate this in young researchers, and also encourage young, high-potential students to get a PhD. This is important in primary care, because we still do not have enough young people with PhDs. I would also like to encourage these young researchers to get funding for their work. I was funded by the University, so I did not have external funds; however, I think that things have changed, and we need now to get the external

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funding, which is important for your place at university, and in the faculty.

The healthcare system is important, and we should keep the patient-centric approach in all the work that we do. The patient is still the most important thing in medicine, but for me, what is also important is the sustainability of medicine: the planet’s health, global health, and our carbon footprint in medical industry, especially the pharmaceutical industry. I think the importance of this can sometimes be underappreciated.

At the World Organization of Family Doctors (WONCA) conference, I had the opportunity to discuss this with a lot of young colleagues, and I am happy, and hopeful, to hear that sustainability is important to them. Perhaps in the future we will drive more of our research to look at sustainability.

Q6

You played a role in the organisation of the 28th WONCA European Conference. Can you talk about the ways in which WONCA aims to empower patients and create a dialogue aimed at optimal healthcare benefits?

For one, I think that patient-centeredness is one of the most important things. Patientcenteredness has always been important as an approach to healthcare. I have participated in WONCA for 30 years, and 30 years ago decisionmaking was mostly done by the GP alongside the specialists. However, the patient can now take part in that decision-making. I think that is one of the most important things that WONCA tries to stimulate. I also think that health education and promotion are important. Patient education to improve health outcomes is one of the focuses, especially as chronic conditions are becoming more common. Lifestyle choices are important for patients, and these are decisions that the patients can make themselves. I think that WONCA is very open in discussing these topics and this goes fluidly with the shared decision-making.

I am very happy that we have already discussed hunger strikes, as WONCA is also advocating patient rights, and plays an important role. Health literacy is another one of the important things that WONCA tries to promote, and recognises as an important part of patient empowerment.

Q7

Over the years that you have been practising as a primary care physician and researcher, how have you seen the field evolve in terms of changing practices, and advancements to the technology used?

I remember my first personal computer: it was a huge machine. It had two hard drives, and each hard drive had a 20-megabyte capacity.

But I still learned a lot on that machine. During my first 10 years as a GP, I also worked for our National Institute for Public Health, which is now Sciensano in Belgium, and I also had experience in public health. The introduction of laptops, which we could take with us to patients’ homes, and to the homes for the elderly, was important.

But I remember the first day that I worked as a GP. There were no mobile phones. Can you imagine that? When we had an emergency, people had to try to call from the practice to the patient where we were. Otherwise, they had to call the next patient to tell us that there was an emergency call. Communication is the first thing that changed with mobile phones and the introduction of laptops.

Then, the Internet was very important for patient empowerment, health literacy, and so on. But the Internet also changed our way of working. Now we are prescribing medication via the Internet, we are getting money from health insurance via the Internet, we are working paperlessly, and payments are paperless. Normally, I do not print out anything during my consultations. The Internet has played an important role.

Very recently, in my timeline anyway, we have seen the growth of mobile health, and now I see artificial intelligence (AI) here, in my University Hospital. It is used in almost every service, especially in radiology and diagnostic processes.

AI is also used by students writing their papers. I think this is one of the new challenges.

AI is really a challenge for the medical world, because people can find things on the Internet.

What will the limits of AI be? Things are just getting faster, and it is a pity that I am already 60 years old. I cannot imagine where we will be in the next 60 years. Sixty years ago, we would not have believed that we would communicate by a small screen, no matter where we are in the world. But this is very common now. Children who are 6 years old can do this. ●

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Ambiguous Effects of Obesity on Cancer Prognosis and Treatment Response: A Narrative Review Editor's Pick

This article explores the effects of obesity on cancer diagnosis through examining the possible immunological mechanisms behind the ‘obesity paradox'.

The authors shed light on conflicting findings through an extensive literature review, and highlight recent studies that have shown positive responses to certain types of immunotherapy as a treatment for patients with cancer and obesity. With obesity being an ever-growing global health risk, this pertinent review provides valuable insights into its implications in the oncological field.

Prof Lászlo Vécsei Head of Neuroscience Research Group, Department of Neurology, University of Szeged, Hungary Author:

*Swastik Pandita1 1. Shri Atal Bihari Vajpayee Medical College and Research Institute, Bengaluru, India *Correspondence to panditaswastik@gmail.com

Disclosure:

The author has declared no conflicts of interest.

Received:

17.05.23

Accepted:

04.09.23

Keywords:

BMI, immune checkpoint inhibitors, obesity, obesity paradox, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade.

Citation:

EMJ. 2023; DOI/10.33590/emj/10302656. https://doi.org/10.33590/emj/10302656.

Abstract Obesity is a lifestyle disease that is a proven predisposing factor for many illnesses and is often associated with a poor prognosis. Here, the author tries to associate the relationship between the incidence of obesity in patients with cancer and the prognosis of the same.

The present medical literature suggests an ambiguous and conflicting relationship.

This study presents an extensive literature review of the mechanisms that may govern the survival outcomes of patients with cancer presenting with obesity. Medical literature databases, namely PubMed, Google Scholar, and BioMed Central databases, were searched.

Out of 335 relevant results, 75 met the inclusion criteria. The results were varying in nature, with some papers showing poor prognosis due to the association of obesity with metabolic and endocrine abnormalities, which promote tumour growth, while others suggest that excess adiposity may promote a greater expression of programmed cell death protein-1 in effector CD8+ T lymphocytes, promoting a better response to immune checkpoint blockade therapies. Some even argue against the existence of the so-called ‘obesity paradox’, considering it a by-product of statistical misinterpretation and biases. In conclusion, the phenomenon is definitely intriguing but needs further investigation and research regarding other processes that may all in all affect cancer prognosis.

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Key Points 1. Obesity is a known negative prognostic factor for many diseases and is associated with higher risk of all-cause mortality. However, few recent large scale meta-analyses state that some patients with cancer with a high BMI may have better prognosis and survival outcomes than patients with a normal BMI. 2. This review article explores various explanations for the existence of the so-called ‘obesity paradox’ and the arguments given against the existence of the same focusing on the immunological aspects of the observation.

3. Although the positive linkage between obesity and prognosis of specific cancers is statistically significant and has strong mechanistic explanations backed by many studies, the bigger picture is that obesity should still be viewed as an overall negative marker for cancer-specific prognosis. The positive linkage may only be of clinical significance in the treatment response of immune checkpoint inhibitor therapy.

INTRODUCTION Obesity, defined as a BMI greater than or equal to 30 kg/m2, is a condition with rising incidence around the world that contributes to other health issues.1 Body fat is a negative prognosis factor for many illnesses. Large-scale studies have evaluated the relationship between obesity and mortality. A meta-analysis of more than 200 studies found that obesity was associated with a higher risk of overall mortality.2 An increased BMI is associated with an increased risk of various types of malignancies.3 Furthermore, obesity may increase cancer specific mortality.4 The pathophysiological mechanisms that contribute to higher cancer incidence may include variations in sex corticoid metabolism, insulin levels, and adipokine pathways.1 However, some studies state that patients with cancer with a high BMI (≥30 kg/ m2) may have better prognosis and survival outcomes than patients with a normal BMI (20–25 kg/m2). This finding, known as the ‘obesity paradox’, pre-exists in the cardiac literature but less so in oncology.5 The recurrent observation of the ‘obesity paradox’ has led to an increasing amount of research being conducted to find a suitable explanation. Explanations range from observations that contradict causality owing to confounding, to clinical explanations, such as seeking explanations for obesity being protective in varied circumstances.6

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However, one particular clinical explanation has gained significant attention from the scientific community, namely the association of obesity with increased efficiency of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) checkpoint blockade.6 This greatly increases the T cell response to cancer.

Checkpoint blockers are becoming a highly promising therapeutic approach yielding remarkable antitumour responses.7 However, despite the success of PD-(L)1 blockade in various malignancies, it fails to generate sustained beneficial outcome in the majority of patients.6 In this review, the author tries to demonstrate the marked effects of obesity on different types and forms of cancer, with particular emphasis on therapeutic outcomes in patients with cancer treated with PD-L1 checkpoint blockade categorised by body mass. This review highlights expected as well as contrasting effects of obesity on cancer prognosis, primarily focusing on, but not limited to, immunotherapy.

MATERIALS AND METHODS This paper provides an overview of the various proposed mechanisms by which obesity can have varying effects on cancer prognosis. An elaborate literature search was performed in the PubMed, Google Scholar, and BioMed Central databases. The keywords used for the search were “obesity paradox,” “immune checkpoint inhibitors,” “PD-1/PD-L1 blockade,” “BMI,”

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“obesity,” and various combinations of these words. A total of 75 articles were reviewed.

Obesity and Cancer: The Link

The publications were selected as per the following inclusion criteria: the objective of the research should be related to the effects of obesity on cancer prognosis; the literature showcasing immunotherapeutic mechanisms was preferred; and papers showing contrary results by the same mechanisms and methods were given due diligence. Exclusion criteria primarily included research papers in which the effect of obesity was not a specific aim or other comorbidities were present in the participants.

Clinical evidence establishes the proof of a significant association, backed by data, between obesity and various cancers.8 The pooled risk ratios of a particular study are shown in Table 1.

RESULTS The author’s literature search yielded 335 articles, of which 75 (22.3%) met the inclusion criteria for the overall literature review of obesity and its link with cancer outcomes with regard to overall survival, cancer-specific survival, and progression-free survival.

Evidence for increased risk of cancers

A particular reason can be that obesity is linked with endocrine abnormalities, such as changes in sex corticoid metabolism, insulin levels, and inflammatory pathways, all of which have been shown to stimulate tumour growth.9 Adipokines also contribute to Type 2 diabetes, causing higher insulin and insulin-like growth factor-1 levels, which in turn promote tumour growth.10 Sex corticoid metabolism and chronic inflammation mediate the relationship between obesity and cancer, while the evidence for a role of insulin and insulin-like growth factor signalling is, as such, moderate.9 Aromatase, which converts androgens to oestrogens, is found in adipose tissue and is increased in obesity, thus increasing blood oestrogen levels.11 7β-oestradiol can induce neoplastic growth in human breast, as proven by the proliferation of neoplastic cells in mice with severe combined immunodeficiency disease.12

Table 1: Link between obesity and various types of cancers.

Types of cancers

Inference from pooled risk ratios

Colon cancer

Males with obesity had an increased risk of colon cancer compared with males of normal weight (RR: 1.57; 95% CI: 1.48–1.65).8

Endometrial cancer

Females with obesity had an increased risk of endometrial cancer compared with females of normal weight (RR: 1.85; 95% CI: 1.3–2.65).8

Oesophageal adenocarcinoma

Among females with obesity, the pooled RR indicated an increased risk of oesophageal adenocarcinoma compared to females of normal weight (RR: 2.04; 95% CI: 1.18–3.55).8 Similar effects were not seen in males.

Leukaemia

Males with obesity had no increased risk of leukaemia compared with males of normal weight (RR: 1.16; 95% CI: 0.88–1.52).

For females with obesity, the pooled RR illustrated an increased risk of leukaemia compared with females of normal weight (RR: 1.32; 95% CI: 1.08–1.60).8

Pancreatic cancer

Males with obesity had an increased risk of pancreatic cancer compared with males of normal weight (RR: 1.36; 95% CI: 1.07–1.73).8

Postmenopausal breast cancer

Females with obesity had an increased risk of postmenopausal breast cancer compared with females of normal weight (RR: 1.25; 95% CI: 1.07–1.46).8

CI: confidence interval; RR: risk ratio.

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Additionally, there is strong conviction that weight loss positively affects the mechanisms mentioned above. Data on body weight loss have suggested that intentional weight loss, including surgical procedures, may reduce cancer risk.13,14 However, a particular contrasting study states that while bariatric surgery does reduce cancer risk in females, no such effect was seen in males undergoing bariatric surgery.10 Lifestyle change to affect intentional weight loss in patients with obesity normalises circulating cancer risk factors, including oestrogens, Insulin-like growth factor 1, and inflammatory cytokines.10 Additionally, the use of pharmacological approaches to tackle the problem of obesity has not resulted in obesity control at either individual or population levels.15 Considering animal models, collective data have shown that obesity in rodents promotes tumourigenesis and increases the incidence of many types of cancer.16

obesity and colorectal cancer. It further stated that significant heterogeneity is observed, which is attributed to the timing of BMI assessment.23 The link between obesity and a worse prognosis was cemented when BMI was calculated before diagnosis. This particular observation is strengthened by other literature that claims the ‘obesity paradox’ is not a paradox at all; rather, the studies in favour of paradoxical effects of obesity represent misclassification bias caused by the use of BMI as a measure of obesity, reverse causation, or collider stratification bias.24 A particular study argues that the obesity paradox is caused by the presence of statistical biases.

Although these biases are present in most studies, they are exaggerated when populations affected by a disease state are considered.25 In the upcoming section, the author will explain the abovementioned biases with respect to the paradox (Figure 1).

Another study reported observations showing that high-fat diets and obesity cause colon epithelial cells in mouse models to remodel their enhancer landscape analogously to the remodelling of the enhancer landscape seen in colorectal cancer.17

I) Misclassification bias

The obesity paradox: does it exist?

Clinical research pursued in recent years has reported lower mortality in subjects who are overweight (BMI of 25–30 kg/m2) affected by different types of cancer,18,19 although statistical significance varies and is questionable. In a particular meta-analysis, risk reduction of death by 3.6% was seen for every 1 kg/m2 increase in BMI.20 Obesity was found to be linked with higher efficacy of PD-1/PD-L1 blockade in both tumour-bearing mice and clinical patients with cancer.6 Additionally, the immunosuppressive microenvironment induced by obesity can make immune checkpoint inhibitors more sensitive.21 Although the literature also states that obesity is an increased risk factor for other types of cancer, a particularly interesting case is the curious scenario of the relation of obesity with colorectal cancer. With conflicting results observed in different studies, one particular meta-analysis, which investigated the relationship between postdiagnostic BMI and colorectal cancer, concluded that there was lower mortality among patients with obesity.22 Another meta-analysis of 29 studies concluded that there is increased mortality in patients with

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BMI, as a measure of adiposity, is controversial.

It is, by definition, an established fact that BMI can barely differentiate the ratio of fat to lean mass (LM).26 In any scenario, as the percentage of fat rose, so did BMI. On this basis, BMI seems sufficient at measuring adiposity, but there are other factors as well. As an example, BMI is not independent of height during infancy and puberty.

Additionally, during these periods, body weight is proportional to the third power of height. Another instance is that, both in the normal weight range and among those with obesity, individuals can have different body compositions even if they have similar BMI.6

II) Reverse causation

It refers either to a cause-and-effect relationship to a common pre-disposing factor or to a twoway causal relationship with each other. This term explains the confounding by weight loss that in turn elevates mortality risk.27 This means that since causative agents of low body weight cause increased mortality risk, it may seem as if high body weight lowers relative mortality, which is nothing but a statistical misinterpretation.

III) Collider stratification bias

This refers to the change in the relationship between two variables when viewed in the narrow context of a disease state. It is also known as ‘event index bias’.

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Figure 1: Statistical biases causing the formation of the so-called 'obesity paradox’.

Statistical biases causing the formation of the so-called 'obesity paradox'

I) Misclassification Bias: The utility of BMI as an index of adiposity is controversial. It is, by definition, an established fact that BMI is poor at discriminating the ratio of fat to lean tissue within body weight.26Individuals can differ in their body composition can differ in their body composition even if they have the same BMI value.6

II) Reverse Causation: Reverse causation refers either to a cause-and-effect contrary to a common presumption or to a two-way causal relationship with each other. This term includes confounding by weight loss or other determinants of low body weight that in turn elevate mortality risk.27

The relations between two different exposures (such as alcoholism and obesity) and their relation to mortality are dependent on the effect of being affected by another disease, such as diabetes.6 This effect can change the relationship between the two exposures relative to their relationship in the source population. The effect of this bias caused due to a pre-existing disease state is unpredictable without further information. In different cases, the usual correlation can be reversed or exaggerated due to the pre-existing condition. When reversed, it is referred to as reverse causation bias, as stated above.

As an example, the relation of smoking and obesity among those having diabetes as a comorbidity strengthens the negative association between smoking and obesity.25 The increased incidence of smoking among patients with diabetes will increase the incidence of weight loss relative to the source population.25 Due to the above processes, the lesser mortality of persons who are not obese in the source population can be muted or even reversed in the subpopulation consisting of people with diabetes.25 Among people with diabetes who never smoked, the relationship of higher mortality among those with obesity is sustained. Among non-smokers, there is no collision between obesity and smoking, thus the sources of bias associated with smoking are removed.25

III) Collider Stratification Bias: The relations between two different exposures (like alcoholism and obesity) and their relation to mortality are dependent on the effect of being affected by another disease, say diabetes.

Ambiguous Effects of Obesity on Programmed Cell Death 1 Checkpoint Blockade and Functioning of T Cells

First, T cell exhaustion is higher in patients with obesity across various different species.6 Mice with obesity show an increase in exhausted T cells in the blood, spleen, and liver. They also show a higher number of PD-1 positive T cells in the liver, which causes decreased cytokine production and cell proliferation. Similar results were observed in humans and non-human primates. Second, obesity promotes tumour growth.6 T cells originating from mice with obesity having malignant transformations present a transcriptomic profile that is varied from that of T cells from tumour-bearing control mice, findings which suggest increased exhaustion of T cells.6 Third, leptin levels are linked with PD-1 expression.6 The results indicated a role for leptin signalling in increasing PD-1 in tumour-bearing mice, which affects antitumour immunity.6 Signal transducer and activator of transcription 3, a downstream transcription factor of the leptin receptor, has known binding sites in the promoter region of PD-1 and has been implicated in driving expression of PD-1 in human and murine cancers, causing increased expression and better treatment response.6 Fourth, efficacy of PD-1/ PD-L1 checkpoint blockade is improved in mice with obesity.6 The excess adiposity may promote increased expression of PD-1 in CD8+ T cells, causing a better response to immune checkpoint

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blockade therapy.28 Human patients treated with PD-L1 checkpoint blockade showed a significant improvement in progression-free survival and overall survival in patients with obesity. This finding can be explained as follows: in obesity, PD-1 mediated immune suppression may be a naturally evolved mechanism to protect against possible autoreactive T cell responses induced by chronic inflammation.6 So, this increased expression of PD-1 receptor in patients with obesity may account for the higher efficacy of PD-1/PD-L1 checkpoint blockade therapy used for various cancers.

Finally, a new study concluded that patients with obesity are also linked with a higher possibility of experiencing immune-related adverse effects to various degrees, including but not limited to endocrine, gastrointestinal, and liver adverse events, among others, especially rheumatic and pulmonary events.29

DISCUSSION Understanding the ‘Obesity Paradox’ A BMI of 22.5 kg/m2 is accepted as a midreference point for normal weight.30

The so-called ‘obesity paradox’ occurs when the risk of mortality is decreased for BMI values above this value, when an increased risk is expected.

When the BMI value is very high, risk either returns to unity or increases.5 Here, BMI fails to contrast whether the excess weight is the result of increased fat mass or LM; thus, it is suggested that the ‘obesity paradox’ in the context of cardiovascular diseases is based on the inability of BMI to differentiate between LM and fat mass.

A particular study conducted in India concluded that total LM and regional LM were higher in the obese category than in the normal weight category.31 Research suggests that the positive impact of increased BMI results from the positive effects of lean tissue, which overcomes the negative effects of excess body fat.32

Immunological basis of the obesity paradox: a plausible explanation

To help readers understand the immunological basis of the obesity paradox, the immunological basis of cancer will be explained (Figure 2).

Immune checkpoint inhibitors

These have emerged as a first step treatment for various malignancies.33 The immune system is instrumental in the management of tumours, as

Figure 2: Mechanisms associated with the ‘paradox’ observed causing better treatment response with regard to immune checkpoint blockade therapy.

Leptin, an adipokine present in adipose cells (increased in obesity)

• Associated with low grade chronic inflammation

Increased immunosuppressive environment causing tumour progression

• Increased pro-inflammatory molecules like TNF-α and IL-6

Causing paradoxical favourable effects in treatment response when subjects were treated with anti-PD-1/ PD-L1 checkpoint inhibitors

PD-L1: programmed cell death ligand 1; PD-1: programmed cell death 1.

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well as in the techniques employed by tumour cells to escape the policing of immune cells, leading to the acceptance of immunotherapy as a new but encouraging approach to tackle this complex interaction between cancer and immunity.33 To protect the body against various pathogens, the immune system has developed various mechanisms and pathways over the course of biological evolution. However, it must do so while recognising and sparing the body’s own cells. This task is accomplished by the presence of multiple checkpoint pathways that regulate immune responses.

Among other negative regulatory receptors that mediate these inhibitory feedbacks, PD-1 has been one of the most intensively studied regulators due to its role in maintaining T cell function and immune system homeostasis. It is a chemokine receptor and is expressed on the T cell membrane. It recognises the body’s own cells by binding to the PD-L1 ligand expressed on those cells. Tumour cells take its advantage to evade T-cells by expressing PD-L1 ligand, which binds to the PD-1 receptor on cytotoxic T-cells, thus rendering the immune response ineffective.33 Thus, a mechanism was proposed, which was essentially the blockade of this checkpoint, and anti PD-1 checkpoint blockers were conceptualised to induce antitumour immune responses.33 PD-1/PD-L1 checkpoint blockade therapy has become one of the mainstream therapies for various malignancies. However, some patients do not show complete remission, and adverse events have been seen, which suggests that

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Aune D et al. BMI and all-cause mortality: systematic review and non-linear dose-response metaanalysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. BMJ. 2016;353:i2156.

Guh DP et al. The incidence of comorbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88.

a better understanding of immunosuppression mediated by this pathway is needed to predict prognosis and improve treatment.34 Examples include nivolumab and pembrolizumab.

Another study showed that patients with melanoma and a high BMI treated with ipilimumab had a greater response.28

CONCLUSION In the present review, the author showed different perspectives of academia on the existence of obesity, and logical explanations and deductions following them. Furthermore, emphasis was placed on the most weighted counterargument against the paradox that it is a product of statistical biases, namely, misclassification bias, reverse causation bias, and collider bias. Additionally, different explanations were cited, and particular focus was placed on the immunological aspect of the obesity paradox, that is, its ambiguous effect on the PD-1/PD-L1 immune blockade mechanism, mainly consisting of increased T cell exhaustion but increased efficacy of the blockade system.

Drugs such as ipilimumab, pembrolizumab, nivolumab, and atezolizumab have been used in cancer immunotherapy with considerable success.

The phenomenon is definitely intriguing but needs further investigation and characterisation regarding other processes that may all in all affect cancer prognosis.

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Wang Z et al. Paradoxical effects of obesity on T cell function during tumour progression and PD-1 checkpoint blockade. Nat Med. 2018;25(1):141-51.

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clinical outcome. Front Pharmacol.

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Dobbins M, Decorby K. The association between obesity and cancer risk: a meta-analysis of observational studies from 1985 to 2011. ISRN Prev Med. 2013;2013:680536.

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Lauby-Secretan B et al. Body fat and cancer--viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794-8.

10. Bruno DS, Berger NA. Impact of bariatric surgery on cancer risk reduction. Ann Transl Med. 2020;8(Suppl 1):S13.

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11. Kirschner MA et al. Obesity, androgens, oestrogens, and cancer risk. Cancer Res. 1982;42(Suppl 8):3281s-5s.

12. Russo J, Russo IH. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol.

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13. Aminian A et al. Association of bariatric surgery with cancer risk and mortality in adults with obesity.

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14. Luo J et al. Intentional weight loss and obesity-related cancer risk. JNCI Cancer Spectr.

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19. Hakimi AA et al. An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma. J Natl Cancer Inst.

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20. Xu H et al. The prognostic role of obesity is independent of sex in cancer patients treated with immune checkpoint inhibitors: a pooled analysis of 4090 cancer patients. Int Immunopharmacol.

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21. Smith LK et al. Obesity and the impact on cutaneous melanoma: friend or foe? Cancers (Basel).

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15. Saunders KH et al. Pharmacologic approaches to weight management: recent gains and shortfalls in combating obesity. Curr Atheroscler Rep. 2016;18(7):36.

22. Schlesinger S et al. Postdiagnosis body mass index and risk of mortality in colorectal cancer survivors: a prospective study and meta-analysis. Cancer Causes Control. 2014;25(10):1407-18.

16. Cleary MP. Impact of obesity on development and progression of mammary tumors in preclinical models of breast cancer.

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23. Wu S et al. Association of obesity and overweight with overall survival in colorectal cancer patients: a meta-analysis of 29 studies.

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17. Li R et al. Obesity, rather than diet, drives epigenomic alterations in the colonic epithelium resembling cancer progression. Cell Metab.

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24. Banack HR, Stokes A. The ‘obesity paradox’ may not be a paradox at all. Int J Obes. 2017;41(8):1162-3.

18. Li S et al. Systematic review of prognostic roles of body mass index for patients undergoing lung cancer surgery: does the ‘obesity paradox’ really exist?

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26. Wells JC. Commentary: the paradox of body mass index in obesity assessment: not a good index of adiposity, but not a bad index of cardio-metabolic risk.

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27. Tobias DK. Addressing reverse causation bias in the obesity paradox is not "one size fits all".

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28. Pasquarelli-do-Nascimento G et al. Obesity and adipose tissue impact the T-cell response and cancer immune checkpoint blockade therapy. Immunother Adv. 2022;2(1):ltac015.

29. Gülave B et al. High body mass index and pre-existing autoimmune disease are associated with an increased risk of immune-related adverse events in cancer patients treated with PD-(L)1 inhibitors across different solid tumours.

ESMO Open. 2021;6(3):100107.

30. Arnold M et al. Obesity and cancer: an update on the global impact.

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31. Garg MK et al. Relationship of lean mass and obesity in Indian urban children and adolescents.

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32. Szabó T et al. Differentiating between body fat and lean mass: how should we measure obesity?

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An Observational Evaluation of Primary Care Online Resources Authors:

*Pablo Millares Martin,1 Jorge Millares-Bobet1 1. Whitehall Surgery, Leeds, UK *Correspondence to pablo.martin@nhs.net

Disclosure:

The authors have declared no conflicts of interest.

Received:

27.03.22

Accepted:

13.03.23

Keywords:

Communication, general practice, information services, internet, patient portals.

Citation:

EMJ. 2023; DOI/10.33590/emj/10305829. https://doi.org/10.33590/emj/10305829.

Abstract Background: General practice websites are getting more relevant as more interaction with patients is occurring digitally; however, there are no regulations governing them, nor much research about their benefit or quality.

Objectives: To understand the online presence of general practices through time, using a tool developed for this purpose and assessing practices’ websites at two separate times.

Methods: A form was developed to assess websites on base of their performance against 17 parameters, including information about the practice (logo, interactive address, area covered, telephone, opening times, details about staff, and quality rate), website parameters (number of pages and links on the site, level of link errors, loading speed, and search engine), and online services provided (social media, interactions like messaging, booking appointments, ordering prescriptions, accessing medical records, and allowing video consultations). Possible scores ranged from 17–66 points, with two to four points per factor analysed. A lower score was a mark of quality.

Results: Practices were scored twice over the last 5 years; however, the sample average, although improving from 36.5 to 31.6, still puts practices websites midway in the quality range of the tool used. Looking at individual parameters, the homepage’s average loading time deteriorated, as well as maps showing the practice location. However, other details improved.

Conclusions: Websites are taking a more relevant role in healthcare interactions, but their quality has improved little in the last 5 years. There is a need for stricter regulations if the digital presence of primary care is expected to play a safe role in primary care provision.

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Key Points 1. Patients access more and more primary care websites looking for information for their health needs, and to interact with their practices; however, the websites for primary care physicians are quite variable in content and quality.

2. An instrument was created to assess and compare practices' websites quality through time. When the tool was used in the practices in Leeds, UK, in 2016 and 2021, improvements were found, but not consistently.

3. Guidelines and regulations are needed to improve further the standards of practices’ websites, so the digital presence of general practitioners provides good quality and safe advice and interactions with their patients.

INTRODUCTION General practices in the UK are under immense pressure due to numerous factors and the role of health informatics. Research has been conducted on subjects such as the complexity of current consultations1 ​and the use of electronic consultations.2,3 Unfortunately, their websites and the quality of their digital presence (the way the organisation appears and interacts on the internet) has not received the same attention; studies are more limited4 or simply old.5 It seems that when the digitalisation of primary care was taking place, some interest in the matter was present; however, this is no longer the case. Even the latest long-term plan from the National Health Service (NHS) fails to mention any requirements regarding practices’ websites when exploring digital solutions use.6​There are no current guidelines or regulations on health information on websites, and practices simply subcontract to website developers offering their solutions. With the COVID-19 pandemic and an accelerated shift towards digital working, the quality of this important portal of health information becomes even more relevant.

It is not possible to reduce primary care physicians’ workload without educating patients to look after themselves, providing them with reliable sources of information, and signposting them to other services that could be more convenient for their needs. For this purpose, the practice website could provide invaluable information. Equally, practices must share information about themselves, the services they offer, their team, and the quality of service

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provided, as per regulators assessment. Patients interacting with the website and searching for answers to their needs should receive an appropriate level of quality information.

The ability to assess a single primary care website against a set of parameters can facilitate an understanding of their quality of service. An easy to use but comprehensive assessment tool for primary care websites could facilitate the process and allow for comparisons among organisations. Furthermore, its use at different times could provide light on their quality trend.

METHODS This project consisted of two steps: the creation of an easy-to-use scoring instrument and its implementation on a sample of practices.

Short Website Assessment Tool in Primary Care

For the assessment tool, the parameters used were ones that had been previously considered for evaluation of general practice websites; one based in the UK with the STaRNet Website Assessment Tool (SWAT)5 and the other in the USA.4 Unfortunately, it seems that this subject has been absent in the medical literature for quite some time, and no relevant references were found when a literature search was conducted looking for “website” and “primary care.” The parameters from these papers were evaluated, and some were added from current English recommendations. Some were numeric (such

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as the number of links on the site), some were not (such as the presence of opening hours).

Eventually, 17 features contributed to the score.

The better the performance, the lower the score in each of the factors assessed. The SWAT in primary care tool responses followed a strict protocol, with “yes;” “no;” and some “partial” answer options, as the information could be present in a different format, or location than the ideal. The numeric values obtained were later added into well-defined categories to facilitate scoring.

The assessment was divided into three sections, and the parameters and reasoning are as follows.

Information about the practice

One basic role of a practices’ website is to be a virtual brochure of the primary care organisation,7 and practices in England are expected to have an “informative online presence.”8 It is also relevant to consider there are additional mandatory requirements, including delivering patient online services,9 and their quality rating according to the Care Quality Commission (CQC)​.10

Logo

Organisations are expected to have a unique name and logo​​.11 General practitioners should have their own identity that is clearly shown and not just the NHS logo.

Address with interactive map

map or textual explanation should be considered the minimum.

Telephone number (on the homepage)

It is common to use the Internet to find contact numbers and, ideally, the contact details should be visible on the homepage, without the need to navigate to find it. Furthermore, its digital presence is a minimum requirement​.7

Opening hours (on the homepage)

If the website has been used to find how to communicate with the practice, it would be expected that contact would follow and, for that purpose, an idea of when the premises are open for business is paramount. It is also a minimum requirement​.7

Doctors’ names, qualifications, and pictures Clinician names and their qualifications are mandatory on practice leaflets​.7 For transparency, clinicians’ portraits also should be present. With staff changes, it could be that not all details are present, but at least half of the clinicians’ details should be present in full to consider a level of quality and commitment to keep the site up to date.

Nurses and non-clinical staff names and pictures

All members of staff should be identifiable on the website.

Practice addresses are important to consumers12​and are part of the minimum information requirements about practices.7 Furthermore, an interactive map, a powerful tool to facilitate locating the place and getting directions, is paramount. As a minimum, some sort of map should be present to facilitate locating the physical location of the practice.

Practice rating (on the homepage)

Practice area with interactive map

Looking into the more technical detail of the websites, a free online tool called Dead Link Checker (Petersfield, UK) was used to assess how many links were present, and how many were not functional.13 A well-maintained practice website should have many links with a little number of rotten ones.

It is mandatory in the UK for practices to indicate the area from which patients are allowed to register​.7 This information should be easily available on the website for patients to consult. However, as above, it should consist of a responsive tool that facilitates finding out if a patient can or cannot register within that particular practice, considering the personal address of the potential patient related to the practice address. Any other form of a

Ratings are a way to assess the likelihood that the organisation will provide the services intended at a certain standard. In the UK, practices must be registered under the CQC and show their rating​.10 Ideally, it should be on the homepage and quite visible.

Website parameters

Number of homepage links of >100

It is difficult to determine how many pages a medical practice website should contain. It is clear that it should not recreate information

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elsewhere, but to signpost patients to good quality sources. As a consequence, the assessment was based on links, including on the homepage. Links to pages within the site as well as external sites were included; however, they were also considered to be elements of the page.

Finally, a 4 given to websites where the average page took >1.2 seconds.

Number of website links of >500

Online services

As with the above, it is difficult to quantify what number of links makes a primary care website one that is of a good quality. In the past links, to medical websites, medical journals, support groups, and more were considered​​.4,5 For the purpose of this tool, the assumption is that a reasonable number of links would be required for the basic signposting role of the website, and it is stated the need to have over 500 links.

Percentage of link errors

Search engine

They significantly increase a website’s usability, and they are expected to be present nowadays on any website.

Websites are not just a portal for customers to get information from, but a point of interaction and business. In healthcare, this could be through associated social media pages, messaging capabilities, and signposting to online lifestyle and health management sources; however, these should be via specific online services such as the already mentioned requisites of appointments, prescriptions, and electronic records access​​.7

The internet is not static and ‘link rot’ is common, affecting not only electronic citations14 in the literature but everything. Organisations should keep links up to date. A quality site should not have more than a handful of broken links. As the sites can be quite different in the number of links available, it is more reliable to have the percentage of link errors related to the number of links present on the site. Having <1% of ‘rotten’ links was considered a sign of excellent quality.

Social media presence

Loading speed

Websites need to provide this functionality, whether by email or non-clinical website forms, so that communication between patient and practice can take place digitally.

Information should be provided without a long wait, and the homepage should load quickly. For this assessment, load times were calculated using an automation tool, Selenium (Thoughtworks, Chicago, Illinois, USA),15 which loaded the websites’ unique uniform resource locators in a headless browser. The resulting time would be the difference between ‘navigationStart’ and ‘domComplete’, which should be recorded 5 times per website to obtain an average.

All recordings need to be taken with the browser running in ‘no cache’ mode, ensuring that no requests were cached, as this could potentially affect the loading times between retries. The practices were scored between 1 (best) and 4 (worst). Websites that used caching and took <500 ms to load on average were given a score of 1. Meanwhile, websites that took 500–800 ms per page were given a score of 2, and a score of 3 given to those taking 801–1,200 ms.

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It is clear that social media can facilitate health promotion, although it is also behind health misinformation​.16 Primary care should contribute to sharing reliable information on these platforms, and to balance the information available from less reputable sources that can undermine the health of the patients. Practices should be actively using social media.

Messaging capabilities

Core online services (appointments, prescriptions, and records)

All practices are expected to allow these services7​through their clinical software.

The website should provide a link to access the patient’s electronic health record (EHR). Additional clinical website forms or e-consultations could be offered.

Use of video consultations

According to the agreed framework between NHS England and the British medical Association (BMA): “All patients will have the right to online and video consultations by April 2021.”8 In consequence, practices are expected to promote the service on their websites, and to indicate how to access this type of consultation.

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Scoring

Although there are clear changes in the landscape of primary care in Leeds. The three clinical commissioning groups had merged into one and there were other mergers and closures of some health centres, as well as changes in website portal names. The cohort of the organisation/websites for the follow up were identified, and it had been reduced to 81 sites.

Finally, there was the question of whether there was a risk of variability to scoring. Data to qualify for each particular score was quite clear, so that inter-rater reliability and repeatability testing should not be required. The best possible score would be 17 and the worst possible would be 66 (Table 1).

Practices Websites Identification

RESULTS

General practitioners and their websites in the city of Leeds, which was divided into 94 primary care organisations in 2016, were chosen, as they were local and known to authors. The authors also considered that the size of the sample should be sufficient to come to relevant conclusions. They were identified using data available from the then three Leeds clinical commissioning groups.

Several issues can be defined when analysing the data obtained, such as the overall scores and the parameter changes between the two years in which the data was collected. A summary of findings is presented in Figure 1 and Table 2.

Table 1: Tool scoring card.

Parameter

Score to be assigned 1

2

3

4

Yes

NS

NS

No

Address with interactive map

Interactive map present

Another map

NS

No map

Practice area with interactive map

Interactive map

Another map

Text description

No description

Telephone number (on homepage)

Yes

Another page

NS

No

Opening hours (on homepage)

Yes

Another page

NS

No

All doctors' names, qualifications, and pictures

Full details

Partial (at least half)

NS

None

All nurses and nonclinical staff names and pictures

Full details

Partial (at least half)

NS

None

Practice CQC rating (on homepage)

Yes

Another page

Another page with external link

No details

Number of homepage links of >100

>100

50–100

<50

NS

Number of website links of >500

>500

100–500

<100

NS

Practice logo

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Table 1 continued.

Parameter

Score to be assigned 1

2

3

4

Percentage of broken links of <1%

<1%

1–5%

5.1–9.9%

Over 10%

Loading speed of <500 ms

Best: <500 ms

Good: 500–800 ms

Poor: 801–1,200 ms

Worst: >1,200 ms

Search engine present

Yes

NS

NS

No

Social media

Yes

NS

NS

No

Messaging capabilities

Yes

NS

NS

No

Link to online services (e.g., appointments, px, notes)

EHR+ other

Only EHR

NS

None

Video consultation

Yes

NS

NS

No

CQC: Care Quality Commission; EHR: electronic health record; NS: no score; px: prescriptions.

General Scores

In 2016, among the 94 organisations, the average score was 36.5, with a minimum of 27.0 and a maximum of 49.0 (standard deviation: 3.8). In 2021, the average score was 31.6 among the remaining 81 enterprises, with a minimum of 21.0 and a maximum of 40.0 (standard deviation: 3.8).

No statistical analysis is present, as there have been changes in the number of organisations and only descriptive statistics were used as the number of names and names of organisations changes in the 5-year period of the study. The aim was to present a general picture of the evolving and current presence in a location that could be extrapolated to understand primary care presence in the UK.

Particular Parameters

Considering the number of organisations in each sample is different, data are presented as percentages. Statistical differences among practices are not presented, as it is not the aim of this study, and the sample was small.

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Logo

Logos were used by 37.2% of organisations in 2016, increasing to 43.2% in 2021.

Address with interactive map

An address with an interactive map was present in 85.1% in 2016; however, it had declined to 78.7% in 2021. Some practices were simply putting a picture of a map or free text rather than a helpful interactive map to locate their premises.

Practice area with interactive map

Catchment area was not so commonly linked to an interactive map, used on only 20.2% of practices’ website in 2016; however, its use increased considerably to 40.4% in 2021.

Telephone number (within the homepage) The presence of a telephone number on the homepage was almost unanimous in 2016 (95.7%), with the only 4 organisations having it on a different page on the website; however, it declined in 2021 to 87.7%, with 10 practices offering the details elsewhere.

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Figure 1: Cumulative scores in 2016 (A) and 2021 (B) among the practices for the 17 parameters assessed.

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Figure 1 continued.

CQC: Care Quality Commission; px: prescriptions.

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Opening hours (within on the homepage)

Opening hours was present on the homepages in 26.6% of websites and absent in 1.1% in 2016. in contrast, its occurrence in the homepages increased considerably to 59.3% in 2021, and if not, it was present on another page.

more than 500 links in 2016 and that percentage was 88.9% in 2021.

Percentage of link errors

Link errors in 2016 ranged from 2–822, with a median of 16. In 2021, it ranged between 0–953, with a median of 26. The authors considered that Doctors’ names, qualifications, and pictures the ideal is to have <1% of links broken. This was Doctors’ names, qualifications, and portraits were the case in 9.6% of websites in 2016, while it was present in 73.4% of websites in 2016 and absent 11.1% in 2021. in only 3.2% of practices websites. However, a decline was noted in 2021, with 58.0% of Loading speed websites adequately recording this data and Websites were typically not optimised for 6.2% not having it available to patients. speed; not utilising content delivery networks effectively; and, in some cases, downloaded Nurses and non-clinical staff names excessively large content. It was found that most and pictures of the websites utilised caching effectively, with In 2016, in 53.2% of website sites had an most sites having cascading style sheets/images appropriate number of details about nurses and cached to reduce load time in subsequent non-clinical staff members; however, these were uploads. This typically reduced loading times absent in 6.4% of websites. In 2021, it was similar between 50–70%. Page loading speed in 2016 as 56.8% of practices included these details was best (<500 ms) in 4.3% of cases, while it while they were absent in in 13.6% of websites. was worst (>1.2 secs) in 9.6% of websites. In contrast, there was a general deterioration in Practice rating (on the homepage) 2021, even though 6.2% scored best as there A CQC rating was present on the homepages of was an increase in the number of websites that 28.7% of websites in 2016 and absent in 61.7%; were classed as worst (an increase of 55.6%). however, it was very different in 2021, where the When considering this aspect, one outlier should CQC rating was present on the homepages of be mentioned: a homepage that took over 80.2% of website and elsewhere on the website 8 secs to download as there was a video in the other cases.. embedded within it, a 42.3 MB file. The direct result was that the website was non-operational, Number of homepage links of >100 with no links accessible, until the download The median value for the number of homepage was complete. links in 2016 was 96. It varied between one and 500. The maximum was determined by the link Search engine checker used, affecting the score in nine website A search engine was present in 84% of sites portals in 2016 and none in the second group. analysed in 2016, and in 92.6% in 2021.

In 2021, it varied between three and 237, with a median of 158 and an average of 143 links per Social media presence site. For scoring, three groups were created, Social media presence was uncommon in 2016; it depending on the number of links being higher was found in 14.9% of practices’ websites, and it than 100, between 50–100, and below 50. In is still only in 25.9% in 2021.

2016, 43.6% of practices sites had >100 links, and in 2021 that increased to 77.8%.

Messaging capabilities Messaging capabilities (email address and forms Number of website links of >500 on website to communicate non-clinical issues) The median number of links in 2016 was 780, was provided by 76.6% of practices in 2016, and ranging from 10–2,000. This was limited by the it improved in 2021 to 79.0%. link checker used, and affecting eight websites in 2016 and three websites 5 years later. In 2021, Core online services (appointments, the median was 966, ranging from 3–2000. When prescriptions, and records) considered in groups (more than 500, between Core online services, such as access to hers and 100–500, and <100 links), 79.8% of sites had additional services in the way of e-consultations,

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Table 2: Average values per parameter and total.

Parameter

Average 2016

Average 2021

Practice logo

2.9

2.7

Address with interactive map

1.2

1.1

Practice area with interactive map

2.7

2.0

Telephone number (within homepage)

1.0

1.1

Opening hours (within homepage)

1.8

1.4

All doctors’ names, qualifications, and pictures

1.4

1.5

All nurses and non-clinical staff names and pictures

1.7

1.8

Practice CQC rating (on homepage)

3.0

1.3

Number of homepage links of >50

1.6

1.2

Number of website links of >100

1.2

1.1

Percentage of broken links of <1%

2.1

2.2

Loading speed of <500 ms

2.9

3.3

Search engine present

1.5

1.2

Social media

3.6

3.2

Messaging

1.7

1.6

Online services

2.4

1.4

Video consultation

3.9

3.4

Total score

36.5

31.6

CQC: Care Quality Commission.

were present in 51.1% of practices in 2016.

However, there were no links to EHR in 43.6% of cases. In contrast, all practices offered online access to her in 2021, and also provided access to additional services in 64.2% of websites.

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Use of video consultation

Video consultations were only advertised by 3.2% of practices in 2016; however, the percentage increased to 19.8% in 2021.

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DISCUSSION New regulations have been implemented in Europe regarding medical devices, defined as “products or equipment intended for a medical purpose.”17 Medical websites and social media, where there is an interaction among patients and clinicians through software, is not yet considered one. No regulation applies to this digital platform, even though its importance as a communication tool is increasing. Furthermore, advice can be given for symptoms without direct clinician involvement, whether for the triage of urgency for appointments or to self-management, for example. Therefore, it is important to start assessing the quality of the internet presence of general practice and its interaction with the patients, and how can it potentially affect outcomes. This paper has presented the variability in some basic quality markers among different organisations and has suggested some standards. The situation is further complicated the more the website responds automatically to patients’ input.

A website from a primary care physician can be quite limited in its content but still can have a considerable impact on a patient looking for health information. There is a need to regulate them, improve standards, and improve their safety as more and more patients use them, particularly since the recent COVID-19 pandemic.

The assessment completed among these organisations showed that there is fluctuation in the current unregulated landscape, and not necessarily improvement when data 5 years apart are compared.

The descriptive statistics used help to highlight that this is an area in urgent need of attention, as currently there are no regulations or standards to comply with. In consequence, primary care online resources are not necessarily safe.

Summary

The tool created was simple to use, and it allowed easy comparisons among different primary care websites on some minimum standards. The maximum score was 66 and the minimum was 17, with 49 points to play, and the higher values indicated poorer quality. A site could be classed as with very good quality if it

scored less than 70% of the available points.The smaller the score, the better the resource. So, sites could be classified into three groups based on their scores: very good (<32 points), good (between 32–51 points), and poor (a score above 51 points). This assumption would mean that 12.8% of websites in Leeds were good quality in 2016, while 87.2% were good quality in 2021.

No website was classed as poor. The scores varied between 27.0 and 49.0, with an average score of 36.5. When the practices’ websites were reassessed in 2021, 43.2% had very good quality and 56.8% had good standards.

Looking in more detail, some parameters improved while others deteriorated (such the time it took the homepage to load and the location of the practice’s telephone number).

There was a limited effect on the overall score.

However, the scores provide some insight on areas where practices should consider focusing when aiming to improve the quality of their services.

Strengths and Limitations

Websites analysis is a new subject, and it goes without the attention it requires as the flow of health information moves towards the internet. Practices’ websites need to deliver high standards to attract viewers; however, without clear guidance and probably regulations, service providers are free to offer packages of limited value. There is no recent literature on the matter, and, in consequence, this novel study highlights some of the areas that should be considered, as well as ways of comparing websites.

The tool is limited by its focus, and by the data collected. It has been a study of primary care physicians’ institutions in Leeds. It means some modifications will be required to be used in assessing other healthcare establishments in the UK or other countries. Analysing particular questionnaires and algorithms should require further in-depth studies. However, this tool is nonetheless a starting point to view and compare healthcare centres.

Implications for Research and/or Practice

There is a need to improve websites in primary care and equally a need for clear guidelines,

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as well as regulations on what should be the minimum requirements for practices, so providers can follow them and improve the current standards of websites, such as the ones assessed in this paper, which below the ideal.

Further research could be required on patients’ views on what they would like to see when accessing their practices’ websites, influencing their requirements, and ultimately improving the patient experience. Once the basics have been regulated, further research on the additional risks and benefits of automatic responses from websites triaging or guiding patients will need further research.

References 1.

2.

3.

4.

7.

Salisbury C et al. Measuring the complexity of general practice consultations: a Delphi and crosssectional study in English primary care. British Journal of General Practice. 2021;71(707):e423-31.

Edwards HB et al. Use of a primary care online consultation system, by whom, when and why: evaluation of a pilot observational study in 36 general practices in South West England. BMJ. 2017;7(11):e016901.

Leyton C et al. Evaluation of the effects of the COVID-19 pandemic on electronic consultation use in primary care. Telemed J E Health.

2022;28(1):66-72.

Alpert JM. Evaluating the content of family physician websites in the United States. J Healthc Qual.

2015;37(5)311-8.

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Howitt A et al. An evaluation of general practice websites in the UK. Fam Pract. 2002;19(5):547-56.

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National Health Service (NHS).

The NHS long term plan. 2019.

Available at: https://www. longtermplan.nhs.uk/wp-content/ uploads/2019/08/nhs-longterm-plan-version-1.2.pdf. Last accessed: 23 February 2023.

8.

9.

CONCLUSIONS There has been little improvement in the quality of websites over the period of 5 years, with most individual parameters improving while others had deteriorated. Stricter regulations are needed on what is expected from websites if the digital presence of primary care is going to play a relevant role in primary care provision, and if it aims to provide safe advice to patients.

National Health Service (NHS).

NHS England standard general medical services contract 2015/16.

2015. Available at: https://www. england.nhs.uk/commissioning/ wp-content/uploads/ sites/12/2015/06/gms-2015-16.pdf.

Last accessed: 23 February 2023.

British Medical Association (BMA); National Health Service (NHS).

Investment and evolution: a fiveyear framework for GP contract reform to implement the NHS long term plan. 2019. Available at: https://www.england.nhs.uk/ wp-content/uploads/2019/01/gpcontract-2019.pdf. Last accessed: 23 February 2023.

National Health Service (NHS) Commissioning Board. Enhanced service specification. Improving patient online access. 2013.

Available at: https://www. england.nhs.uk/wp-content/ uploads/2013/03/ess-patientonline.pdf. Last accessed: 23 February 2023.

10. Care Quality Commission (CQC).

Display your ratings. 2022.

Available at: http://www.cqc.org. uk/content/display-ratings. Last accessed: 23 February 2023.

11. Elrod JK, Fortenberry JL. Integrated marketing

communications: a strategic priority in health and medicine.

BMC Health Serv Res. 2020;20(Suppl 1): 825.

12. Sanchez MH, Sanchez PM. Evidence on the content of physician websites. J Bus Res. 2011;5(3):93-100.

13. Dead link checker. Site checker: free broken link tool. Available at: https://www.deadlinkchecker.com/ website-dead-link-checker.asp.

Last accessed: 23 February 2023.

14. D Vinay Kumar et al. URLs link rot: implications for electronic publishing. WDL. 2015;8(1):59-66.

15. Selenium. Getting started.

Available at: https://www.selenium. dev/. Last accessed: 23 February 2023.

16. Stellefson M et al. Evolving role of social media in health promotion: updated responsibilities for health education specialists. Int J Environ Res Public Health. 2020;17(4):1153.

17. European Medicines Agency (EMA). Medical devices. 2023.

Available at: https://www. ema.europa.eu/en/humanregulatory/overview/medicaldevices#medical-deviceslegislation-section. Last accessed: 23 February 2023.

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Hansen’s Disease with Pure Nerve Involvement and Perineural Abscess Mistaken for Peripheral Nerve Sheath Tumour Authors:

Moinuddin Sultan,1 Mitali Choudhary,1 Mazain Siddique,1 Nihal Lavhale,1 Padma Vikram Badhe2 1. Department of Radiology, Vedantaa Institute of Medical Sciences, Dahanu, India 2. Department of Radiology, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, India *Correspondence to choudharymitali16@gmail.com

Disclosure:

The authors have declared no conflicts of interest.

Received:

22.05.23

Accepted:

12.07.23

Keywords:

Case report, Hansen’s disease, hypoechoic cystic lesion, leprosy, ulnar nerve abscess.

Citation:

EMJ. 2023; DOI/10.33590/emj/10306433. https://doi.org/10.33590/emj/10306433.

Abstract Nerve abscess is an infrequently reported complication of leprosy. It is also an uncommon first manifestation of leprosy. In this case, due to the absence of classic signs and symptoms, such as skin lesions, hypoesthesia, and loss of sensation, the swelling was clinically diagnosed as a peripheral nerve sheath tumour on initial presentation. The authors have described an unusual presentation of pure neuritic leprosy that showcased nerve abscess. Clinical presentation was swelling over the medial aspect of the right arm and ulnar aspect of the right forearm, and clawing of the fourth and fifth digits of the right hand, with no signs of inflammation present on the skin surrounding the swelling. Hansen’s disease with pure nerve involvement could not be considered as a differential diagnosis solely based on clinical examination, therefore posing a diagnostic challenge. On ultrasonography, the right ulnar nerve showed diffuse intermittent thickening and a heterogeneously hypoechoic fusiform area with internal echoes at the site of swelling indicating a nerve abscess. These led the authors to the diagnosis of leprosy with perineuronal abscess. Histopathology confirmed the diagnosis by revealing granulomas and acidfast Hansen’s bacilli. The patient showed dramatic response to surgery, multidrug therapy, and systemic corticosteroids.

Key Points 1. Nerve abscess should always be kept in the list of differentials before clinically labelling the lesions along the course of a nerve as peripheral nerve sheath tumours.

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2. Ultrasound has a key role in prompt imaging diagnosis of nerve abscess in a pure neuritic case of Hansen's disease and its final confirmation through ultrasound-guided fine needle aspiration cytology.

3. A prime role is played by ultrasound in distinguishing nerve abscess from peripheral nerve sheath tumour, and hence clearing out the dilemma.

INTRODUCTION Leprosy, also known as Hansen's disease, is a chronic granulomatous infection. It is nonfatal and slowly progressive. Its causative organism is Mycobacterium leprae.1-11 There is skin involvement in the form of hypopigmented patches and loss of sensation over the affected areas, which commonly include the skin, peripheral nerves, mucosa of the upper respiratory tract, and eyes.2,4-9,11-13 It also involves the peripheral nervous system, mostly in the form of nerve thickening.2-6,8-15 The eyes and testes are highly susceptible to the disease, as they have a lower temperature than the core body temperature.3,4,16 The ability of the organism to invade the nerve sheath and cause immunemediated reactions gives rise to devitalisation and mutilation promoting coherent psychosocial disruption.2,4,9,11,13,14,17 Based on an individual’s immune status, leprosy presents as a spectrum of diseases, extending from polar tuberculoid in patients with higher immunity to polar lepromatous in patients with the least immunity.1-5,10,14 A characteristic feature of leprosy is the bacterial parasitisation of peripheral nerves.3,9-11,13,17,18 In most cases, a granuloma that is formed may soften to form an abscess. This nerve abscess may rupture through the skin, or may cause persistent pressure on the nerve fibres. Hence, it needs to be incised and drained.19 Patients with leprosy develop nerve abscesses in all forms of the disease, but those with the borderline tuberculoid form are known to commonly develop nerve abscess of the ulnar nerve.1,3,5,12,16,20 In literature, other words used as synonyms for pure neuritic leprosy include neural, neuritic, pure neural, primary neural, primary neuritic, simply neural, and polyneuritic leprosy.5,19,21

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This report elucidates the necessity of ultrasonography (USG) in a patient with purely neuritic leprosy. Uniqueness of this report lies in the way ultrasound changed the thought process from the clinical diagnosis of schwannoma to the actual diagnosis of nerve abscess in Hansen’s disease. In addition, ultrasound was also used to confirm the final diagnosis using ultrasoundguided fine needle aspiration cytology.

PATIENT INFORMATION A 12-year-old, female child came to the paediatric department for a gradually progressive, painless swelling that had developed over the medial aspect of the right arm and ulnar aspect of the right forearm in the past year. There was no history of fever, hypoesthesia, or loss of sensation. There was no past history or family history of any chronic medical, psychiatric, or surgical illnesses, and there was no relevant past medical or surgical intervention.

CLINICAL FINDINGS On clinical examination, no active lesions or skin nodules were seen at the sites of swelling, or anywhere on the body. The swelling over the medial aspect of the right arm was 3x3 cm, nodular-fusiform, soft, mobile, non-fluctuant, and non-tender. There was no local rise in temperature. The transillumination test was negative and the slip sign was positive. The swelling over the ulnar aspect of the right forearm measured 2x3 cm with similar clinical signs. It was fixed on active wrist flexion. Ulnar claw hand deformity in the fourth and fifth fingers of the right hand with wasting of the thenar and hypothenar muscles, and 'guttering' of first web space was observed (Figure 1).

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Figure 1: Clawing of the patient's fourth and fifth fingers.

Clinical image of the patient demonstrating ulnar claw hand with extension at the fourth and fifth metacarpophalangeal joint and flexion at the interphalangeal joint of the fourth and fifth digit, indicating the involvement of the ulnar nerve.

A clinical differential diagnosis of a nerve sheath tumour was made. The patient was advised to perform USG and USG-guided fine needle aspiration cytology of right arm and forearm masses.

DIAGNOSTIC ASSESSMENT USG with the high-frequency probe revealed multiple intermittent areas of right ulnar nerve thickening with a well-defined fusiform heterogeneously hypoechoic cystic area measuring approximately 3x1 cm at the site of the swelling. It showed internal debris and focal calcification within. There was no internal vascularity within the lesion (Figure 2). The diagnosis of nerve abscess was made.

USG-guided fine needle aspiration cytology was performed from the swelling (Figure 3).

The smears were reported to show neutrophils, lymphocytes, and histiocytes, including foamy histiocytes and epithelioid histiocytes forming an occasional aggregate with the background showing necrosis. On Ziehl–Neelson staining, acid fast tubercle bacilli were not seen. On Fite–Faraco staining, acid fast lepra bacilli

were seen. The impression indicated acute on chronic inflammation with focal epithelioid granulomas. They further advised a Mycobacterium tuberculosis workup and slit skin smear examination.

The patient was then referred to the Department of Dermatology and Venereal Diseases in view of Hansen's disease. On examination, thickening was present in bilateral ulnar, radial, and common peroneal nerves without any tenderness. In addition to this, Froment's test was positive in the right hand, and Card's test was positive in the right hand's fourth and fifth fingers. There was no evidence of ankylosis at the interphalangeal joints, and no signs of inflammation at the site of the lesion. The absence of skin lesions was also confirmed.

THERAPEUTIC INTERVENTION No skin lesions suggestive of leprosy were noted on complete skin examination. The peripheral nerves were thickened and showed nodular swellings along the course of the right ulnar nerve proximal to the medial epicondyle. There was no reduction in sensations to touch or temperature.

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Figure 2: Ultrasound image, and calcific foci in nerve abscess.

A

B A) Longitudinal ultrasound image shows a well-defined heterogeneously hypoechoic fusiform area (marked by arrows) with internal echoes at the site of swelling suggesting of nerve abscess.

1) represents the hyperechoic component within the abscess denoting debris within; and 2) denotes the liquefied component of the abscess.

B) Longitudinal ultrasound image shows a well-defined hypoechoic fusiform area (1) within the ulnar nerve with a focal calcification (within the circle).

A motor deficit was present, and no sensory manifestation was noted. Slit skin smear examination was negative. Based on all the radiological and clinicopathological findings, surgical exploration of the ulnar nerve aiming for pus drainage, debridement, external neurolysis, and decompression was performed by the Department of Surgery. The patient was started on 6 months of paucibacillary multidrug treatment, including dapsone 100 mg daily and rifampicin 600 mg monthly (supervised) for pure neuritic leprosy. Additionally, systemic corticosteroids (prednisolone) were administered.

FOLLOW-UP AND OUTCOME The patient did not show any neurological impairment or further progression of the disease.

They did not have any adverse effects from the drugs that were administered, and had a full recovery. A timeline of the case is represented in Figure 4.

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DISCUSSION Leprosy, a disease of bacterial origin, shows haematogenous dissemination or contiguous spread through the skin.3,20 The organism mainly resides in the peripheral myelin forming cells of the nerves, preferably at a site with lower temperature than the core body temperature, sites of injury, or at the site of nerve entrapment in the superficial soft tissue plane, but it can occasionally invade the ensheathed axons.3,18,20 These acid-fast Hansen’s bacilli in the affected nerves undergo restricted multiplication.3,9,10,18 The host immunity recognises the exposed bacterial antigen, thus initiating a granulomatous reaction.3,9 The Schwann cells assume phagocytic function and transform into macrophages or epithelioid cells of the granulomas.3,4,8-10,13,17,18,20,22 These granulomas may become caseous and show areas of necrosis leading to the formation of an abscess. The ulnar nerve is the most common nerve affected in a case of leprotic nerve abscess.5,23 Although nerve abscesses have been accounted in all types of

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Figure 3: Ultrasound image of ulnar nerve, and ultrasound-guided fine needle aspiration cytology.

A

B A) Thickened ulnar nerve indicated by arrows.

B) Needle tip (1) inside the nerve abscess (2) for FNAC. The hypoechoic area (3) within it denotes the liquefied component of the abscess.

FNAC: fine needle aspiration cytology.

leprosy, their highest occurrence has been noted in borderline tuberculoid leprosy.5,8,14,24-28 Leprotic nerve abscess is an extremely rare manifestation of leprosy, but should always be considered in endemic areas, as in the authors’ case.1,8,14,16,19 In leprosy, nerve abscesses are generally cold abscesses’, as seen in patients with tuberculosis, and are not painful.21 These are ‘silent abscesses’ with no indication of inflammation, and they are easily misdiagnosed as soft tissue mass lesions, neuroma, or lymphadenitis, especially if they appear at an unusual site.21,29-32 The magnitude of subsequent nerve function impairment is not reflected by the size of abscess. Depending on its placement in the nerve, even a tiny intraneural abscess can be linked with severe nerve function impairment.3,21 In the authors’ case, the patient had pure motor symptoms in the form of ulnar claw hand.

Peripheral nerve involvement without any skin lesion, presenting mainly as sensory and motor impairment affecting single or multiple nerves, is characteristic of pure neuritic leprosy.2,3,5,8-10,13,18,23,33-36 Its occurrence is more

common in the Indian subcontinent, frequently involving the upper limb nerves, of which the ulnar nerve shows the most common involvement.1,5,14,17,18,21,32 Swelling due to nerve abscess is an uncommon initial presenting symptom of leprosy. To make the correct diagnosis for nerve abscess, a high index of suspicion is required.23,34,37 In cases of leprosy, clinical examination is not always reliable since nerves may not be compliant to palpate.10,11,17,18,23,38 Therefore, amongst all radiological modalities, USG seems to be a more useful and feasible choice for its diagnosis as compared to MRI.2,3,8,11,12,17,18,20,22,32,34,36,39-43 A more useful method for diagnosis is high resolution ultrasound, which enables objective visualisation of nerve enlargement and evaluation of underlying soft tissue, and hence should be the preferred choice in suspected cases of pure neuritic leprosy.2-4,8,10-12,16-18,20,22,23,32-36,38,40-42,44-46 The most important findings of leprosy on high-resolution ultrasound include thickening of the nerves with loss of normal fibrillary pattern.3,4,8,10-12,17,18,20,22,23,32-36,40-43,45,46,48

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Figure 4: Timeline.

Patient came to the OPD with complaints.

Clinical examination was performed.

Clinical differential diagnosis of a nerve sheath tumour was made.

Further evaluation, including USG and USG-guided FNAC, was advised to confirm diagnosis.

Final diagnosis of ulnar nerve abscess was made.

Surgical exploration of the ulnar nerve aiming for pus drainage, debridement, external neurolysis, and decompression was performed.

Patient was started on 6 months of paucibacillary multidrug treatment.

No neurological impairment or further progression of the disease was seen.

Patient had a full recovery.

FNAC: fine needle aspiration cytology; OPD: outpatient department; USG: ultrasonography.

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Increased vascularity on Doppler can be seen.2,3,11,12,18,22,23,34,35,43,44 Sometimes, intermittent thickening of the nerve can be noted.2-4,8,10-12,16-18,20,22,23,32,34-36,38,40,41,44-49 Rarely, perineural and nerve abscesses can be seen, as in the authors’ case. In case of nerve abscesses, USG Doppler can be used to access the absence of vascularity within the lesion to differentiate it from peripheral nerve sheath lesions, which are generally hypervascular.2,3,12,18,22,23,34,38,44 This case emphasises the role of common non-invasive radiological modalities like ultrasound in pinpointing the diagnosis of Hansen's disease in endemic areas. At the same time, this case presents a learning point that not all nerve lesions are peripheral nerve sheath tumours.

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Vengalil S et al. Appropriately selected nerve in suspected leprous neuropathy yields high positive results for Mycobacterium leprae DNA by polymerase chain reaction method. Am J Trop Med Hyg. 2020;103(1):209-13.

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A mindful clinical and radiological approach with USG-guided intervention played a huge role in the diagnosis of this rare case, which is a great learning point.

PATIENT PERSPECTIVE The patient and patient’s parents/guardians chose not to make a statement.

METHODS The authors’ Institutional Review Board granted exemption for this case report. Written informed consent was obtained from the patient’s parents/ guardians as the patient was below 18 years of age. CARE reporting guidelines were used to draft the manuscript of this case report.50

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Ooi WW, Srinivasan J. Leprosy and the peripheral nervous system: basic and clinical aspects. Muscle Nerve. 2004;30(4):393-409.

10. Chen X et al. Coexistence of nerve enlargement and neuratrophy detected by ultrasonography in leprosy patients. Sci Rep. 2018;8(1):7812.

11. Rao PN, Jain S. Newer management options in leprosy.

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12. Suneetha SK, Rao PN. Highresolution ultrasonography in leprosy: value and applications.

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13. Sandhu S et al. Cytomorphological patterns of nerve aspirates in pure neuritic leprosy-a single centre cross-sectional observational study. J Cytol. 2021;38(1):14-20.

14. Rai D et al. Nerve abscess in primary neuritic leprosy. Lepr Rev. 2013;84(2):136-40.

15. Sasaki S et al. Mycobacterium leprae and leprosy: a compendium. Microbiol Immunol.

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16. Sen D et al. Ultrasonography and magnetic resonance imaging of ulnar nerve abscess in leprosy.

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17. Lugão HB et al. Asymmetric nerve enlargement: a characteristic of leprosy neuropathy demonstrated by ultrasonography. PLoS Negl Trop Dis. 2015;9(12):e0004276.

18. Aswani Y, Saifi S. Atraumatic main-en-griffe due to ulnar nerve leprosy. Pol J Radiol. 2016;81:1-4.

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20. Arun P. Analytical cross sectional study of peripheral nerve damage in leprosy by high resolution ultrasonography. 2020. Available at: http://repository-tnmgrmu. ac.in/13862/1/202000220arun.pdf.

Last accessed: 20 May 2023.

21. Rao PN, Suneetha S. Pure neuritic leprosy: current status and relevance. Indian J Dermatol Venereol Leprol. 2016;82:252-61.

22. Akita J et al. Comparison between nerve conduction study and high-resolution ultrasonography with color doppler in type 1 and type 2 leprosy reactions. Clin Neurophysiol Pract. 2021;6:97-102.

23. Reddy YM et al. Sonographic characteristics of median nerve neuropathy in Hansen’s disease: a case-control study. Lepr Rev. 2021;92(3):207-17.

24. Mahajan PM et al. A study of pure neuritic leprosy: clinical experience. Indian J Lepr.

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44. Elias J Jr et al. Role of ulnar nerve sonography in leprosy neuropathy with electrophysiologic correlation. J Ultrasound Med. 2009;28(9):1201-9.

27. Chauhan SL et al. Calcification of peripheral nerves in leprosy. Acta Leprol. 1996;10(1):51-6.

28. Siddalingaswamy MK, Rao KS. Nerve abscess in leprosy: a retrospective study. Lepr Rev. 1993;64(4):357-61.

29. Omar AE, Hussein MR. Clinically unsuspected neuritic leprosy with caseation necrosis. Ultrastruct Pathol. 2012;36(6):377-80.

30. Siddaraju N et al. Pure neuritic leprosy with nerve abscess presenting as a cystic, soft tissue mass: report of a case diagnosed by fine needle aspiration cytology.

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31. Chugh S et al. Leprosy nerve abscess in Indian male, misdiagnosed as tuberculous lymphadenitis and neuroma. Lepr Rev. 2013;84(2):158-60.

32. Afsal M et al. Evaluation of peripheral nerve lesions with high-resolution ultrasonography and color Doppler. Neurol India.

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33. Ashwini B et al. Ultrasound as a diagnostic modality for the involvement of peripheral nerves in leprosy. Indian J Lepr.

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36. Bathala L et al. Extensive sonographic ulnar nerve enlargement above the medial epicondyle is a characteristic sign in Hansen’s neuropathy. PLoS Negl Trop Dis. 2017;11(7):e0005766.

37. Lugão HB et al. Leprosy with ulnar nerve abscess: ultrasound findings in a child. Skeletal Radiol.

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38. Lawande AD et al. Role of ultrasound in evaluation of peripheral nerves. Indian J Radiol Imaging. 2014;24(3):254-8.

39. Pistoia F et al., "Imaging in leprosy," Nunzi et al. (eds.) Leprosy and Buruli Ulcer: A Practical Guide (2022), Cham: Springer International Publishing: pp.21322.

40. Wheat SW et al. A hand‐held ultrasound device for the assessment of peripheral nerves in leprosy. J Neuroimaging.

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41. Khadilkar SV et al. Neuropathies of leprosy. J Neurol Sci. 2021;420:117288.

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46. Zakrzewski J et al. Ultrasound elastography in the evaluation of peripheral neuropathies: a systematic review of the literature.

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47. Chaduvula MV et al. Highresolution sonography as an additional diagnostic and prognostic tool to monitor disease activity in leprosy: a two-year prospective study. Ultraschall Med. 2018;39(1):80-9.

48. Gupta S et al. High resolution sonographic examination: a newer technique to study ulnar nerve neuropathy in leprosy. Lepr Rev. 2016;87(4):464-75.

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Case Report

Spontaneous Subcapsular Hepatic Haematoma: A Rare Case Report Authors:

*Roisin Burrows-O’Donoghue,1 Rowena Donnison,1 Emmanuel D’Almeida1,2 1. Lake Macquarie Private Hospital, Gateshead, Australia 2. John Hunter Hospital, Newcastle, Australia *Correspondence to roisin1318@googlemail.com

Disclosure:

The authors have declared no conflicts of interest.

Received:

17.07.23

Accepted:

22.09.23

Keywords:

Conservative, haemorrhage, liver, spontaneous, subcapsular hepatic haematoma (SHH).

Citation:

EMJ. 2023; DOI/10.33590/emj/10300184. https://doi.org/10.33590/emj/10300184.

Abstract A spontaneous subscapular hepatic haematoma is a rare condition that has not widely been reported in literature. Subscapular hepatic haematoma has a high mortality rate, especially if the haematoma ruptures, so early diagnosis is imperative. In this case report, the authors present an unusual case of subscapular hepatic haematoma of a female in her 70s, who, in her first few days of admission for the management of acute calculus cholecystitis, developed acute onset right upper quadrant and epigastric pain radiating to her back. Her haemoglobin dropped from 112 g/L to 54 g/L, and her liver function tests and coagulation studies became deranged.

Abdominal and pelvic CT and angiography showed a subscapular liver haematoma without active bleeding. The patient received a blood transfusion and was managed conservatively, with no obvious cause being identified.

Key Points 1. This manuscript describes the presentation of a rare disease process that is not well understood, but has the potential to be fatal.

2. The authors discuss the aetiology, presentation, investigation, and management of a patient who developed a spontaneous subcapsular haematoma, as well as the importance of early recognition.

3. Consider spontaneous subcapsular haematoma when assessing a patient with right upper quadrant pain, nausea/vomiting, and hypovolaemic shock, especially in the presence of risk factors such as pregnancy or liver lesions.

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INTRODUCTION A spontaneous subcapsular hepatic haematoma (SHH) is both a rare and potentially lifethreatening condition. Although the pathogenesis of SHH is not well understood, it is most primarily attributed to complications of liver lesions or pregnancy.1-3 Presenting clinical signs are not specific, but can include right upper quadrant (RUQ) or epigastric pain, severe shoulder pain, nausea, vomiting, shortness of breath, abdominal distention, and hypovolaemic shock.3,4 Diagnosis can be delayed due to rarity and variability of presentation but is made by imaging, ultrasound, CT, or MRI. Management is either conservative or surgical.3,5

CASE PRESENTATION A 79-year-old female (patient A) presented to the emergency department with RUQ, back, and flank pain. She denied any history of trauma, including trivial, to the area. Her past medical history included ischaemic heart disease, with a previous coronary artery bypass surgery; congestive cardiac failure; atrial fibrillation; Type 2 diabetes, managed with insulin; gallstones; obesity; osteoarthritis; and osteoporosis. It is important to note that she was not taking an oral anticoagulant despite her diagnosis of atrial fibrillation. This was the result of a risk/benefit decision due to her risk of falls combined with her age and already being on aspirin. On physical examination, she had a tender RUQ, no guarding or peritonism, and present bowel sounds. She was haemodynamically stable: respiratory rate: 18; O2 saturations: 97% on room air; heart rate: 82 bpm; blood pressure: 160/90 mmHg; and a low grade temperature of 37.5–38.0 °C. Her blood sugar level was 10.4 mmol/L. Her blood tests on admission, including haemoglobin and liver function tests, were largely within normal ranges, and in line with patient A’s baseline (Table 1). Coagulation studies were not completed; this is notable and cannot be explained specifically. It is potentially attributable to an assumption that there was no initial concern of coagulopathy, and that she would likely not be a surgical candidate having been deemed not fit for a cholecystectomy previously in view of her extensive co-morbid state.

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Initial blood cultures yielded no growth, and urine culture grew Escherichia coli.

A CT abdomen/pelvis with contrast showed a 17.0 mm calculus impacted in the gallbladder neck, with associated distended gallbladder, but without definite evidence of cholecystitis, pericholecystic fluid, or extrahepatic bile duct dilation. The pancreas was severely atrophic and the spleen unremarkable. There were no urinary tract calculi or obstruction, and marked pelvic floor prolapse shown. A targeted ultrasound of the abdomen showed a 28.0 mm nonmobile gallstone seen at the gallbladder neck.

The gallbladder was distended, with diffuse thickening of the gallbladder wall to 5.5 mm.

There was no pericholecystic fluid. Features were compatible with acute calculus cholecystitis.

Following surgical review, patient A was admitted under the joint care of the general medical and general surgical teams in view of her complex medical background, and managed conservatively for acute calculus cholecystitis. She was commenced on a lowfat diet, and treated with intravenous (IV) antibiotics as per local guidelines (ceftriaxone and metronidazole), with consideration of a percutaneous cholecystostomy if she were to acutely deteriorate. Subsequently, her RUQ pain and tenderness started to improve, so it was assumed that the antibiotics were working, and the cholecystitis improving.

Three days into her admission, patient A developed acute worsening of the pain in her back and RUQ, which was not responsive to opiates; she had no nausea or vomiting, and her bowels were opening regularly. She described the pain as similar in character to her presenting pain, but with increased intensity. She was tender generally in her abdomen, but particularly in the RUQ. Bowel sounds were present, and her observations were stable. Patient A was reviewed by the surgical team, but it was decided further imaging was not needed at this stage, as there were no signs of peritonitis, and pancreatitis was unlikely as the gallstone was impacted and not obstructed. Instead, it was decided to monitor her blood results and treat symptomatically.

Patient A became progressively more hypotensive over the next 24–48 hours and her

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Case Report

Table 1: The sequence of haematologic, biochemical, and coagulation tests performed prior, at the onset of clinical deterioration, and following recovery.

Blood test

Units

Admission

SHH diagnosed

Discharge

Normal range

Hb

g/L

112

54

96

110–160

Haematocrit

N/A

0.36

0.18

0.31

0.30–0.46

RCC

×1012 /L

4.2

2.1

3.2

3.6–5.5

WCC

×109 /L

9.20

14.00

5.70

4.00–11.00

Neutrophils

×109 /L

7.81

7.56

3.59

2.00–7.50

Monocytes

×109 /L

0.78

1.26

0.73

0.00–1.00

NRBC

/100 WBC

<1.0

2.0

<1.0

<1.0

Platelets

×109 /L

195.00

196.00

214.00

150.00–450.00

Urea

mmol/L

5.7

15.0

5.9

3.5–9.5

Creatinine

μmol/L

60

115

55

45–95

eGFR

mL/min/1.73 m2

83

40

84

>59

ALP

U/L

81

139

151

30–115

GGT

U/L

20

87

79

5–35

AST

U/L

26

260

32

10–35

ALT

U/L

12

331

25

5–30

Albumin

g/L

41

27

27

36–47

CRP

mg/L

31.1

191.9

120.3

0.0–5.0

PT

seconds

N/A

17

N/A

9–13

INR

N/A

N/A

1.5

N/A

0.9–1.2

APTT

seconds

N/A

28

N/A

20–32

Thrombin time

seconds

N/A

15

N/A

15–22

Fibrinogen

g/L

N/A

4.1

N/A

1.5–4.2

2.2

8.4

N/A

<1.5

Lactate (venous) mmol/L

ALP: alkaline phosphatase; ALT: alanine transaminase; APTT: activated partial thromboplastin time; AST: aspartate transferase; CRP: c-reactive protein; eGFR: estimated glomerular filtration rate; GGT: γ-glutamyltransferase; Hb: haemoglobin; INR: international normalised ratio; N/A: not applicable; NRBC: nucleated red blood cells; PT: prothrombin time; RCC: red cell count; SHH: subcapsular hepatic haematoma; WBC: white blood cell; WCC: white cell count.

pain continued to worsen. Her IV antibiotics were escalated to piperacillin/tazobactam. She initially appeared responsive to IV fluids; however, she became notably pale, with cool peripheries and weak distal pulses. Her full blood count and renal and liver function tests became deranged (Table 1), with her haemoglobin dropping to 54 g/L, and blood film showing rouleaux++, anisocytosis++, polychromasia+, elliptocytes+, and nucleated red blood cell+. Coagulation

studies showed an international normalised ratio of 1.5, with a prothrombin time of 17 seconds.

The source of blood loss was unclear at first.

Patient A was taking no oral anticoagulant, there was no external blood loss, and she denied a history of trauma. She was taking regular aspirin lifelong following her coronary artery bypass surgery, and was prescribed enoxaparin 40 mg subcutaneously once daily since admission for

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Figure 1: CT angiogram of the abdomen/pelvis.

A

B

Axial (A) and coronal (B) views, showing a large subcapsular haematoma.

venous thromboembolism (VTE) prophylaxis, having been deemed to be at increased risk of VTE in part due to her age, large body habitus, and significantly reduced mobility associated with hospital admission. A rectal examination was normal.

A CT of the abdomen and pelvis was repeated, and a CT angiogram performed (Figure 1), which confirmed new changes of haemoperitoneum and a large subcapsular haematoma. Mildly hyperdense fluid could be seen extending from the inferior liver border into the pelvis via the right paracolic gutter. No active bleeding site was identified on the arterial, portal venous, or delayed phase imaging.

Patient A was managed acutely with 3 units of red blood cells, and both enoxaparin and aspirin were ceased. She responded well, with her haemoglobin rising to 96 g/L pre-discharge (Table 1). She remained stable, and her liver function tests and coagulation began to improve along with her symptoms clinically.

In view of there being no active bleed on imaging, along with weighing up her cardiac risk factors, she was managed conservatively.

She was prescribed morphine through a patient controlled analgesia pump for pain, and she slowly improved. Following family discussions,

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her ceiling of care was adjusted to ward based.

She had an extended stay due to slow recovery and poor mobility, but was eventually discharged around 1 month after admission.

No cause for patient A’s SHH was found, despite extensive testing. COVID-19 PCR was negative, and viral screening was negative for HIV. Cytomegalovirus and Epstein–Barr virus testing were found to be positive only for past infection, hepatitis A IgG was suggestive of previous exposure, and hepatitis B and C screening showed no evidence of infection. Changes in serum free light chains were consistent with ageing/renal impairment, and rheumatoid factor and serum protein electrophoresis were unremarkable. No paraprotein was detected, and antinuclear antibody, glomerular basement membrane antibodies, and Igs yielded no results.

An atypical anti-neutrophil cytoplasmic antibody was considered of no significance, and thyroid function was unremarkable. There was no indication of malignancy or any hepatic lesions on imaging.

DISCUSSION First described in 1844, SHH involves the spontaneous collection of blood between the capsule of Glisson and the liver parenchyma.1,3,4

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The pathogenesis is not well described, due to the rare nature of the condition, and there are very few cases available in literature. It commonly affects the right lobe of the liver, and is attributed mostly to complications of pre-eclampsia, eclampsia, and/or haemolysis, elevated liver enzymes, and low platelet count syndrome.1,6 In SHH related to pregnancy and haemolysis, elevated liver enzymes, and low platelet syndrome, it is thought that the deposition of fibrin triggers platelet activation, resulting in thrombi that can occlude capillaries and evolve into hepatic necrosis and haemorrhage.2,3,7 Other causes include malignancy (such as angiosarcoma, haemangioendothelioma, hepatoblastoma, and rhabdoid sarcoma), underlying benign liver lesions (including haemangioma, adenoma, focal nodular hyperplasia, nodular regenerative hyperplasia, biliary cystadenoma, and angiomyolipoma), coagulopathies and vasculitides, and liver trauma and iatrogenic injuries (such as endoscopic retrograde cholangiopancreatography, liver biopsy, biliary surgery). It can also be associated with connective tissue disease, peliosis hepatis, amyloid, systemic lupus erythematosus, and polyarteritis nodosa.1-3,5,6 A diagnosis of SHH is often the result of clinical suspicion in patients with a known underlying condition, such as those discussed above. However, it is not always as simple. Patients often present with nonspecific symptoms, commonly acute onset RUQ, epigastric, or shoulder pain. Nausea and vomiting can also occur due to hepatic parenchyma distension.3,4,7 It can, therefore, be misinterpreted to be an alternative intra-abdominal pathology, which present similarly, such as cholecystitis, or in pregnancy, the RUQ pain seen in pre-eclampsia.7 In the case of patient A, the potential delay in diagnosis was the result of the radiologically confirmed presence of cholecystitis. Patients with SHH can become haemodynamically unstable, presenting in hypovolaemic shock.3,4 This can be symptomatic of a ruptured haematoma, most commonly in the setting of trauma, and has a 75% mortality rate.2 Close monitoring is, therefore, needed.7 Prior to developing SHH, Patient A was prescribed both aspirin and a prophylactic dose

of enoxaparin. This was in keeping with the regional VTE guidelines for the prescription of prophylactic dose anticoagulation. The use of an antiplatelet, such as aspirin in the case of patient A, is deemed only a relative contraindication to prophylactic enoxaparin with risk/benefits to be considered.

Following VTE risk assessment, patient A was deemed as moderate- to high-risk for developing an inpatient VTE, with risk factors including an expected inpatient for more than 2 days, along with risk factors including obesity, age over 60, and significantly reduced mobility associated with hospital admission.8 It was deemed appropriate to continue both antiplatelet and anticoagulant therapy.

SHH is not an expected complication of either aspirin or prophylactic enoxaparin. The overwhelming available literature regarding bleeding as a complication involves therapeutic dose enoxaparin. Moreover, major haematoma remains an uncommon side effect, and related bleeding is usually minor, with only an estimated 0.5–4.0% of patients prescribed therapeutic enoxaparin found to experience major bleeding.9 There have been some reports of rectus sheath, retroperitoneal, and pelvic haematomas from therapeutic enoxaparin.10,11 To the authors’ knowledge, there have been no spontaneous subcapsular haematomas attributed to prophylactic dose enoxaparin. There have been cases of spontaneous haematoma reported in literature involving patients taking dual antiplatelet therapy (aspirin and clopidogrel).12,13 One case report was found describing a spontaneous perirenal haematoma found following low dose aspirin.14 The risk of clinically relevant bleeding is, however, higher when receiving both and should be highlighted.

In regard to the diagnoses of SHH, blood laboratory results can show anaemia and deranged hepatic and coagulation profiles, but final diagnosis is through imaging (ultrasound, CT, or MRI).5 Depending on the setting, a bedside ultrasound is often the most rapid investigation, with focused abdominal ultrasound for trauma examination undertaken in those who are haemodynamically unstable. CT and MRI are both highly sensitive for SHH; however, CT is

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often more easily accessible and, therefore, more appropriate in a deteriorating patient, as was the case with patient A.7 The high protein levels present in acute haematomas will appear hyperdense on imaging.1 Liver injuries can be graded by the American Association for the Surgery of Trauma (AAST) liver injury scale classifying hepatic injuries into categories I–VI.15 Two-thirds of liver injuries are between Grades I–III as was the case with patient A.7 Although there is no set protocol for the management of SHH, and each patient is managed on a case-by-case basis, the AAST acts as guidance.15 In haemodynamically stable patients, unless the haemorrhage is ongoing, conservative management is often favoured (including fluids and blood products), as in the case we have reported. However, in unstable patients, a hepatic haematoma is considered an acute surgical emergency. Surgical options to achieve homeostasis can be a challenge, and include hepatic artery embolisation, packing, drainage, hepatic artery ligation, hepatic resection of affected areas, or even transplantation.

Hepatectomy may be needed for bleeding due to neoplasms.1,3,5,7,15-18

Although complete resolution of a SHH can take a significant length of time, as was the case with patient A, if the patient’s condition and the haematoma remain stable, discharge and outpatient monitoring can be appropriate.7

CONCLUSION In conclusion, SHH is an uncommon diagnosis, especially in the absence of risk factors such as pregnancy. Presentation can be variable, and patients can deteriorate rapidly. SHH can be considered when assessing any patient presenting with RUQ pain, nausea, vomiting, or hypovolaemic shock. Management options vary, and involvement of both physicians and surgeons is important. As the authors report above, treating conservatively can yield a positive result, and the authors hope that this case report will raise awareness of the diagnosis, which has the potential to be fatal. Use of low dose anticoagulants being attributed to major lifethreatening bleeding is not well reported and was not considered to be a cause in this presentation, although it is noteworthy to mention as more research may be conducted regarding this in the future.

References

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1.

Tamimi AA, Alawad AA. Large spontaneous subcapsular hematoma of the liver: a rare case report. Pan Afr Med J. 2019;32:16.

Ndzengue A et al. An obscure case of hepatic subcapsular hematoma.

Case Rep Gastroenterol.

2011;5(1):223-6.

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Rosen S et al. Spontaneous subcapsular liver hematoma associated with pregnancy.

Arch Pathol Lab Med 2003;127(12):1639-40.

Bradke D et al. Grade III subcapsular liver hematoma secondary to HELLP syndrome: A case report of conservative management. Case Rep Womens Health. 2019;25:e00169.

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Marinaş MC et al. Postpartum spontaneous subcapsular hepatic hematoma (SSHH)- conservative management. Case report and review of literature. Curr Health Sci J. 2018;44(4):387-91.

8.

NSW Health. Venous thromboemolism (VTE) risk assessment tool. Available at: https://www.cec.health. nsw.gov.au/__data/assets/ pdf_file/0010/458821/VenousThromboembolism-VTE-RiskAssessment-Tool.pdf. Last accessed: 16 August 2023

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Anyfantakis D et al. Postpartum spontaneous subcapsular hepatic hematoma related to preeclampsia. Case Rep Emerg Med. 2014;2014:417406.

Badea R et al. Spontaneous retroperitoneal and subcapsular liver hematoma. The diagnostic contribution of CT, US and CEUS. Case report. Med Ultrason.

2013;15(2):157-60.

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Ellis MH et al. Hemorrhagic complications in patients treated with anticoagulant doses of a low molecular weight heparin (enoxaparin) in routine hospital practice. Clin Appl Thromb Hemost. 2006;12(2):199-204.

10. Chung KT. Intra-abdominal

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hematoma following enoxaparin injection. Clinical Medicine Insights: Case Reports. 2016;9:358.

11. Besir FH et al. Enoxaparinassociated giant retroperitoneal hematoma in pulmonary embolism treatment. N Am J Med Sci. 2011;3(11):524-6.

12. Darwish OS, Iqbal E. Dual antiplatelet agent-induced spontaneous liver hematoma. Ann Pharmacother. 2012;46(11):e33.

13. Ibrahim W et al. Antiplatelet therapy and spontaneous retroperitoneal hematoma: A case report and literature review. Am J Case Rep. 2017;18:85-9.

14. Yamamoto K, Yasunaga Y. Antiplatelet therapy and spontaneous perirenal hematoma.

Int J Urol. 2005;12(4):398-400.

15. Radiopedia. AAST liver injury scale.

Available at: https://radiopaedia. org/articles/aast-liver-injury-scale.

Last accessed: 17 August 2023.

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16. Srinivasa S et al. Spontaneous hepatic haemorrhage: a review of pathogenesis, aetiology and treatment. HPB (Oxford).

2015;17(10):872-80.

17. Bagus et al. Segment V

spontaneous hepatic haemorrhage from hepatic cirrhosis: an emergency abdominal surgery case report. Int Surg J. 2019;6(3):1013-5

management of intraoperatively diagnosed ruptured spontaneous sub-capsular liver hematoma in a woman with preeclampsia. Int J Womens Health. 2021;13:1175-9.

18. Tegene D et al. Successful

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An Atypical Case of Hepatitis B-Associated Vasculitis Authors:

Zhihong Ren,1 Georges El Hasbani,2 Christopher S. Jenkins,3 Mohamad R. Chehab,4 *Jyotsna Gummadi4 1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 2. Department of Medicine, Hartford Healthcare, St. Vincent's Medical Center, Bridgeport, Connecticut, USA 3. MedStar Georgetown University Hospital, Washington, D.C., USA 4. Department of Medicine, MedStar Franklin Square Medical Center, Baltimore, Maryland, USA *Correspondence to jyotsna.gummadi@medstar.net

Disclosure:

The authors have declared no conflicts of interest. Ren and El Hasbani contributed equally to this paper. Written consent was obtained from the patient.

Received:

23.07.23

Accepted:

13.09.23

Keywords:

Gangrene, hepatitis B virus (HBV), vasculitis, proteinase-3 (PR3) antibody.

Citation:

EMJ. 2023; DOI/10.33590/emj/10300609. https://doi.org/10.33590/emj/10300609.

Abstract One of the many extra-hepatic manifestations of hepatitis B virus (HBV) infections is vasculitis. While the classic HBV-associated vasculitis is polyarteritis nodosa, other vasculitides have been reported. The authors present an atypical case of acute HBV-associated vasculitis in a 57-year-old male with tobacco use disorder, characterised by extremity ischaemia, gangrene, splenic infarction, and positive proteinase-3 antibodies without sinopulmonary, gastrointestinal, or renal disease. The aggressiveness of the patient’s disease necessitated pulse-dose corticosteroids, cyclophosphamide, and two courses of plasmapheresis, and ultimately required multiple amputations of fingers and toes.

Key Points 1. Hepatitis B (HBV) is a chronic viral infection that has several extra-hepatic manifestations, one of which is vasculitis. HBV is classically associated with polyarteritis nodosa. Cryoglobulinemic vasculitis and antineutrophilic cytoplasmic antibody-associated vasculitis have also been reported in patients with HBV. 2. The authors present an atypical case of HBV-associated vasculitis, characterised by digital ischaemia, splenic infarction, complete occlusion of the bilateral ulnar arteries, and a strongly positive proteinase-3 antibody. Skin biopsy revealed perivascular inflammation with fibrinoid vessel wall necrosis but intact internal elastic lamina, as well as a fibrin-rich thrombus.

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3. Based on features of polyarteritis nodosa, antineutrophilic cytoplasmic antibody-associated vasculitis, and thromboangiitis obliterans, the patient was treated broadly with pulse dose glucocorticoids, cyclophosphamide, plasmapheresis, therapeutic anticoagulation, and systemic vasodilation. The authors propose that HBV-associated vasculitis exists on a spectrum, requiring individualised treatment. Their case highlights the importance of reviewing biopsy results with a pathologist when there is clinical uncertainty.

INTRODUCTION Although the exact pathophysiological mechanisms are still unclear, the association between viral infections and the development of autoimmune-mediated vasculitis has been well documented, especially with hepatitis B virus (HBV). HBV has been classically associated with polyarteritis nodosa (PAN), and to a lesser extent cryoglobulinemic vasculitis, with case reports of HBV-associated antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV).1-3 The causal relationship between HBV and vasculitis has been supported by the fact that antiviral treatments exert significant therapeutic benefits for concomitant vasculitis.4 Broadly, vasculitis is classified by the calibre of the main vessels involved: small, medium, and large. AAV, including microscopic polyangiitis, granulomatosis with polyangiitis (GPA), and eosinophilic GPA, can involve small or medium vessels. PAN mainly involves medium vessels.

Thromboangiitis obliterans (TAO), or Buerger disease, also classically affects small-to-medium sized vessels, though it is almost exclusively limited to vessels in the extremities.

AAV is a spectrum of diseases that classically manifest with a pulmonary-renal syndrome, plus or minus sinus involvement. As the name suggests, most cases have positive ANCA antibodies, with proteinase-3 (PR3) antibodies corresponding with GPA, and myeloperoxidase antibodies corresponding with microscopic polyangiitis. Eosinophilic GPA has been variably associated with both antibodies, and is distinguished by the presence of eosinophilia and symptoms of atopy. PAN typically presents with purpura, tender erythematous nodules reminiscent of erythema nodosum, renal insufficiency from renal arteritis, mononeuritis multiplex, and mesenteric arteritis. Orchitis, coronary arterial obstruction, splenic infarctions,

and ischaemic retinopathy also occur in variable rates.5 TAO is strongly associated with tobacco product use, and is characterised by Raynaud’s phenomenon; superficial thrombophlebitis; and digital ischaemia, with infrequent effects on arteries supplying the brain, heart, kidneys, or intestines.6 In this case presentation, the authors will discuss a 57-year-old male with tobacco use disorder, who presented with acute peripheralpredominant ischaemia in the setting of acute hepatitis B infection. The patient was subsequently found to have strongly positive PR3 antibodies, splenic infarctions, and complete occlusion of bilateral ulnar arteries, and then rapidly evolved into dry gangrene of multiple digits, requiring amputation.

CASE PRESENTATION A 57-year-old White male, with a past medical history of Roux-en-Y gastric bypass surgery eight years prior, renal cell carcinoma status post-partial nephrectomy 8 years prior, provoked subsegmental pulmonary embolism with lower left extremity deep vein thrombosis 4 years prior, and a 12.5 pack-year history of tobacco use, initially presented with 2 weeks of worsening pain and swelling in their bilateral hands and feet, Raynaud's phenomenon, blistering of the skin on bilateral lower extremities to an external hospital. Initial workup revealed moderately elevated liver enzymes, and the patient was subsequently found to have a newly diagnosed HBV, with a viral DNA load of over 145 million copies/mL. The patient denied recent blood transfusions, new sexual partners, or abdominal pain. The patient was started on entecavir, given symptomatic management, and discharged with close follow-up.

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Five weeks later, the patient presented to the authors' hospital with 1 week of coldness in their fingers and toes, with parasthesias and ischaemic changes extending to the proximal interphalangeal joints. Other than the pain in their hands and feet, the patient denied inflammatory arthralgias, myalgias, joint stiffness, sicca symptoms, gastrointestinal upset, changes in urination, epistaxis, focal weakness, shortness of breath, or systemic symptoms. The physical exam was notable for cool hands and feet, with duskiness and purpura of multiple fingers and toes (Figure 1), livedo reticularis of bilateral lower extremities, and weak radial and dorsal pedal pulses. The patient’s laboratory results were significant for markedly elevated inflammatory markers, normocytic anaemia, persistently elevated HBV viral DNA, strongly positive PR3 antibody (measured at 259 AU/mL on Day 2 and 276 AU/mL on Day 3, with a reference range of 0–19 AU/mL), and low positive anticardiolipin IgG and IgM antibodies. The patient’s renal function remained stable throughout their hospitalisation. Their cryoglobulins were negative on admission and 2 weeks later, with an unremarkable workup for systemic connective tissue diseases, including antinuclear antibody, Scl-70, complements, myeloperoxidase, rheumatoid factor, cyclic citrullinated peptide,

Sjögren's syndrome A, Sjögren's syndrome B, β2 glycoprotein, and lupus anticoagulant.

CT of the abdomen and pelvis with intravenous contrast revealed evidence of splenic infarctions that were not present on imaging 2 weeks prior (Figure 2A), which was confirmed with MRI imaging. CT angiography of the abdomen, pelvis, and lower extremities were negative for significant vascular abnormalities. Angiography of the bilateral upper and lower extremities showed complete obliteration of the patient’s ulnar arteries bilaterally beyond the wrist, with extraordinarily sluggish flow down both legs (Figure 2B and C).

Skin biopsy of the left thigh revealed superficial perivascular neutrophilic infiltration, fibrinoid necrosis in vessel walls, and fibrin thrombus involving one medium size artery in the deep dermis with an intact internal lamina (Figure 3).

Immunofluorescence was negative for IgG, IgM, C3, or fibrin immune deposits.

The patient was initiated on pulse dose glucocorticoids, therapeutic dose heparin, and vasodilation with nicardipine. Cyclophosphamide was started 5 days after admission at 600 mg/m2 every 2 weeks for a total of six doses.

Figure 1: Dry gangrene on the tip of the digits (A) and toes (B), with purpura and livedo reticularis findings of the right lower extremity (C).

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Figure 2: CT scans of the abdomen and pelvis, as well as the arms.

A

B

C

An axial cut of a CT scan of the abdomen and pelvis with intravenous contrast demonstrating numerous focal low-density areas in the spleen predominantly in the periphery (A; arrowheads), and an upper extremity angiogram, suggestive of distal occlusive disease (arrows) in the left arm (B) and right arm (C).

Figure 3: Skin biopsy.

A

B

C

D

A) 20x magnification (low power) of skin biopsy. The black arrow points to group of vessels of the most interest in the deep dermis/border of subcutaneous fat. B) 100x magnification of deep dermal vessels, showing a fibrin thrombus in a medium size vessel and a group of necrotic smaller vessels. C) 400x (high power) imaging of small necrotic vessels showing necrosis in the small vessels, with presence of fibrin (arrowhead). D) 400x magnification of the medium size vessel containing a thrombus (arrow), and showing some acute inflammation with nuclear debris in the vessel wall.

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The patient also began plasmapheresis, with three sessions at the beginning of their hospitalisation. The patient eventually underwent amputation of second through fifth fingers bilaterally at the proximal interphalangeal joints, requiring revision amputation to the metacarpophalangeal joints, as well as transmetatarsal amputation of the left foot. The patient’s course was complicated by gastric bypass anastomotic bleed, felt to be secondary to high dose steroids that, in combination with worsening skin changes, prompted their second course of plasma exchange for 5 days.

The patient was informed explicitly about the potential use of their anonymised medical data and photographs for the sole purpose of medical research, teaching, and publication, and written consent from the patient was obtained.

always the case in patients without HBV, and a review article indicates that PAN exists on a spectrum, including adenosine deaminase 2 deficiency, as well as aberrant activation of the innate and adaptive immune systems.14 PAN can present with purpura, livedo reticularis, painful nodules similar to erythema nodosum, renal dysfunction from renal arteritis, abdominal pain from mesenteric arteritis, mononeuritis multiplex, and orchitis.15 Digital ischaemia, with or without necrosis, was reported in around 12% of patients with PAN.5 Splenic infarction is extremely rare in PAN, with only a handful of reported cases in the literature.16 In fact, the French Vasculitis Study Group (FVSG) did not report any cases with splenic involvement in their PAN database reviews.1,5 Since splenic infarction is typically silent, this finding could be under-reported, as discussed below.

DISCUSSION

The treatment of PAN depends on severity and HBV status. In mild cases of HBV-associated PAN, treatment is antiviral monotherapy.

Entecavir is one of the most commonly prescribed antiviral agents for HBV. Common side effects include elevated liver function testing, headache, mild skin rashes, and haematuria; however, to date, it has not been implicated in the development of vasculitis. Those with severe HBV-associated PAN should also receive glucocorticoids and plasma exchange.17 Induction therapy for patients with mild systemic idiopathic PAN is glucocorticoids plus either methotrexate or azathioprine. Severe idiopathic disease should be managed with high-dose glucocorticoids plus cyclophosphamide.18

HBV has several extra-hepatic manifestations, including vasculitis, among which the most common subtype is PAN. One large cohort study found 33.7% of cases of PAN were due to HBV, though more recent estimates put the frequency closer to 7% due to HBV vaccination efforts.1 Conversely, 1–5% of patients with HBV will develop PAN.7 Most cases of PAN develop within the first 6 months of HBV infection.

Cryoglobulinemic vasculitis has also been reported in HBV, and occurs at a rate of 0.5–4.0% of patients who are infected with the disease.8-10 Multiple pathological mechanisms leading to endothelial damage of blood vessels have been suggested in HBV-associated vasculitis, including direct viral invasion, autoimmune antibodies formation, and immune complex deposition, and which may contribute to the complexity of its clinical manifestations.11,12 The authors’ patient had features of multiple vasculitides, including TAO, PAN, and AAV. Because of the overlap of characteristics, the authors’ therapeutic strategy was a combination of treatments directed at each distinct pathophysiology.

The vasculitis most classically associated with HBV infection is PAN. While the rate of PAN has decreased similarly with HBV, severe disease remains devastating, with up to 40% mortality at 5 years.13 The pathophysiology of HBV-associated PAN has been attributed to immune complex deposition.7 This is not

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AAV is a necrotising vasculitis with a preponderance for small-to-medium vessels.

The exact pathophysiology of AAV remains unclear, but ANCA have been shown to damage endothelium in vitro by activating both neutrophils and the alternative complement pathway.19-21 Patients can present with a wide variety of manifestations, including ocular inflammation, petechiae, purpura, respiratory distress from pulmonary infiltrates or diffuse alveolar haemorrhage, sinus disease (epistaxis, polyps, necrosis), renal dysfunction, and proteinuria or haematuria from glomerulonephritis. Digital ischaemia is very rare in AAV, with incidence of less than 1%, but is considered a severe disease manifestation in the American College of Rheumatology (ACR)

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management guidelines.22 Splenic infarction is likely underreported in AAV since the majority of patients are asymptomatic.23 The association between HBV and AAV is less clear. One study reported that 31% of patients with chronic HBV tested positive for ANCA, though the rate in the control group was 26%.24 They also demonstrated a higher rate of cytoplasmic ANCA and PR3 positivity as compared with perinuclear ANCA and myeloperoxidase in these patients with chronic HBV. Conversely, in a different cohort of patients with chronic HBV, only one out of 67 tested positive for ANCA.25 Association of HBV with AAV is even more limited, as the authors’ group was only able to find a single published case.3 In contrast, the risk of developing GPA or experiencing relapse has been correlated with chronic nasal carriage of Staphylococcus aureus.26,27 Management of AAV is separated into induction and maintenance phases. Induction therapy in mild cases without life or organ-threatening manifestations includes steroids with or without methotrexate, which is recommended over all other steroid-sparing agents.22 Those with severe disease, defined as having diffuse alveolar haemorrhage, glomerulonephritis, mononeuritis multiplex, cardiac involvement, mesenteric ischaemia, central nervous system disease, or limb/digit ischaemia, should be treated with high-dose steroids plus either rituximab or cyclophosphamide. The most recent ACR guidelines favour rituximab over cyclophosphamide based on demonstrated non-inferiority and better tolerability of rituximab.28 Plasma exchange should only be added for patients at high risk of progression to end-stage renal disease, concomitant antiglomerular basement membrane disease, or as salvage therapy in refractory cases.22,29 After remission has been achieved, maintenance therapy should be initiated or continued.

Those who had severe disease should receive rituximab for maintenance. Rituximab is favoured over methotrexate or azathioprine as rituximab was shown to have a lower relapse rate than azathioprine, and methotrexate and azathioprine have similar efficacy for remission maintenance.30,31 Patients who had mild disease are recommended to continue their same induction therapeutic agent.

Duration of maintenance therapy is unclear, but guidelines typically recommend a minimum of 18 months, with individualised decision making thereafter.

TAO does not seem to be associated with HBV, though its incidence has been correlated with periodontal infection.32 It is a segmental, inflammatory, non-atherosclerotic, occlusive vasculopathy. Tobacco product use is nearly ubiquitous in patients with TAO. Patients typically present with cold sensitivity of the fingers or toes, digital ischaemia, and superficial thrombophlebitis. TAO is an overwhelmingly peripheral disease, with very infrequent rates of cerebral, coronary, internal thoracic, renal, and mesenteric arteritis.6 Splenic infarction in TAO has only been described in three case reports.33-35 Histopathology reveals a highly cellular, inflammatory intraluminal thrombus with sparing of the vessel wall, and an intact internal elastic lamina.36 The cornerstone of treatment for TAO is smoking cessation, with emphasis on abstinence from both tobacco and cannabis. Since TAO is a vasculopathy, immunomodulatory therapy has not been shown to be efficacious in management, and the remainder of care is symptomatic, with some evidence supporting the use of vasodilators and intermittent pneumatic compression.37,38 The author’s case is unique, given that the patient had characteristics of all three vascular diseases. In one of the largest cohort trials of HBV-associated PAN, all patients (72 in total) who were tested for ANCA had negative results.1 In fact, ANCA positivity was an exclusion criterion in prior classification criteria for PAN.1 Since the aetiology of the patient’s condition was unclear, the authors implemented therapeutics that would work for all differentials considered. High dose steroids are central to the management of both PAN and AAV. Cyclophosphamide has also been shown to be effective in both diseases. Given the patient’s severe and refractory disease, plasma exchange was also an appropriate treatment modality. Smoking cessation and vasodilation were also implemented. Following the authors’ in-depth review of the case while preparing this manuscript, including discovery of an intact elastic lamina in the medium-sized cutaneous blood vessel weeks after discharge, the aetiology

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of this patient’s disease may well have been exclusively TAO. In the moment, it would have been difficult to justify withholding potentially limb-saving therapy given the patient’s HBV and PR3 positivity. Ultimately, this case serves as a reminder that treatment must be individualised, and based on a patient’s clinical status.

CONCLUSION The authors present an uncertain and protracted case of HBV-associated medium vessel

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vasculitis with features of PAN, AAV, and TAO that required treatment with a combination of pulse-dose steroids, cyclophosphamide, and plasma exchange. The patient ultimately required amputation of multiple fingers and toes after demarcation and stabilisation of the vasculitic process. Given the lack of clarity surrounding the patient’s case, the authors propose that HBV-associated vasculitis is a heterogeneous disease that warrants an individualised therapeutic strategy, based on disease manifestations and severity.

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14. Ozen S. The changing face of polyarteritis nodosa and necrotizing vasculitis. Nat Rev Rheumatol.

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16. Singh RK et al. A rarest of rare cause of acute abdominal pain: splenic infarction in polyarteritis nodosa. Am J Gastroenterol.

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17. Guillevin L et al. Short-term corticosteroids then lamivudine and plasma exchanges to treat hepatitis B virus-related polyarteritis nodosa.

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19. Pendergraft WF et al. Proteinase 3 sidesteps caspases and cleaves p21(Waf1/Cip1/Sdi1) to induce endothelial cell apoptosis. Kidney Int. 2004;65(1):75-84.

20. Schreiber A et al. Membrane proteinase 3 expression and ANCAinduced neutrophil activation.

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21. Kallenberg CG, Heeringa P. Complement system activation in ANCA vasculitis: a translational success story? Mol Immunol.

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23. Ghinoi A et al. Wegener granulomatosis with spleen infarction: case report and review of the literature. Semin Arthritis Rheum. 2008;37(5):328-33.

24. Calhan T et al. Antineutrophil cytoplasmic antibody frequency in chronic hepatitis B patients. Dis Markers. 2014;2014:982150.

25. Acay A et al. Assessment of the frequency of autoantibodies in chronic viral hepatitis. Pak J Med Sci. 2015;31(1):150-4.

26. Stegeman CA et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. 1994;120(1):12-7.

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27. Kallenberg CG, Tadema H. Vasculitis and infections: contribution to the issue of autoimmunity reviews devoted to "autoimmunity and infection".

Autoimmun Rev. 2008;8(1):29-32.

28. Stone JH et al. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med. 2010;363(3):221-32.

29. Walsh M et al. The effects of plasma exchange in patients with ANCA-associated vasculitis: an updated systematic review and meta-analysis. BMJ. 2022;376:e064604.

30. Guillevin L et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771-80.

31. Pagnoux C et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359(26):2790-803.

32. Iwai T et al. Oral bacteria in the occluded arteries of patients with Buerger disease. J Vasc Surg.

2005;42(1):107-15.

33. Sobel RA, Ruebner BH. Buerger's disease involving the celiac artery.

Hum Pathol. 1979;10(1):112-5.

34. Korsgaard N et al. A case of thromboangiitis obliterans affecting coronary, pulmonary, and splenic vessels. Is thromboangiitis obliterans a generalized vascular disease? Am J Cardiovasc Pathol.

1988;2(3):263-7.

35. Harten P et al. Multiple organ manifestations in thromboangiitis obliterans (Buerger's disease).

A case report. Angiology.

1996;47(4):419-25.

36. Lie JT. Diagnostic histopathology of major systemic and pulmonary vasculitic syndromes. Rheum Dis Clin North Am. 1990;16(2):269-92.

37. Montori VM et al. Intermittent compression pump for nonhealing wounds in patients with limb ischemia. The Mayo Clinic experience (1998-2000). Int Angiol.

2002;21(4):360-6.

38. Cacione DG et al. Pharmacological treatment for Buerger's disease.

Cochrane Database Syst Rev. 2016;3(3):Cd011033.

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Post-operative Dressing for Paediatric Hypospadias Repair Authors:

Cem Kaya,1 Sibel Eryılmaz,1 Alparslan Kapisiz,1 *Ramazan Karabulut,1 Zafer Turkyilmaz,1 Ali Atan,1 Kaan Sonmez1 1. Faculty of Medicine, Departments of Pediatric Surgery and Urology, Gazi University, Ankara, Türkiye *Correspondence to karabulutr@yahoo.com

Disclosure:

The authors have declared no conflicts of interest.

Received:

17.05.23

Accepted:

17.10.23

Keywords:

Children, dressing, hypospadias, paediatric.

Citation:

EMJ. 2023; DOI/10.33590/emj/10300906. https://doi.org/10.33590/emj/10300906.

Abstract The optimal dressing is still unclear, despite hypospadias being one of the most prevalent surgical operations. Children's dressing for hypospadias surgery was searched on PubMed as "dressing for hypospadias," "postoperative dressing for pediatric hypospadias," and "dressing AND hypospadias." Experimental studies, animal studies, reviews, letters, and repetitive publications were excluded from the study. By evaluating these reviewed publications, factors affecting hypospadias dressing, such as surgeon, country, dressing type, characteristics, and why it is preferred, will be revealed. As a result, 17 articles were examined, and the advantages of each were established by examining the results. The type of hypospadias, the surgeon's choice, and its ease of removal stand out as the crucial factors in treating hypospadias in children, along with the degree of development of the nation.

Key Points 1. There are thousands of retrospective, randomised, prospective case reports and systematic reviews in the literature comparing hypospadias surgery types, suture use, anaesthesia types, and complications. However, there are very few publications on dressing after hypospadias surgery in the post-operative period. Wrapping the penis with sterile gauze with antibiotic cream and fixing it with a plaster is the most used conventional method, and it is not often mentioned in the publications.

2. The optimal dressing is still unclear, despite hypospadias being one of the most prevalent surgical operations. Which factors affect hypospadias dressing, such as surgeon, country, dressing type, characteristics, and why it is preferred will be revealed in this study.

3. It is clear that, despite the fact that the removal of the dressing following a hypospadias surgery is quick and painless, it is still not the optimum dressing type that will satisfy the demands of both children and surgeons. The type of the dressing following a hypospadias surgery, the surgeon's choice, and its ease of removal stand out as the crucial factors in treating hypospadias in children, along with the degree of development of the nation.

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INTRODUCTION

RESULTS

One of the most typical congenital abnormalities found in males is hypospadias.1 Between 150– 300 live babies are known to have hypospadias.

The typical trio of a hooded prepuce, a ventrally advanced urethral meatus, and a ventral penile curvature indicating a stop in penile development serves as the diagnosis. Primary hypospadias repair aims to rectify penile curvature, advance the urethral meatus to allow adequate urine and sperm flow through the glans, and create an aesthetically beautiful penis. Local skin flaps, preputial and extragenital tissue grafts/ flaps, and urethral tubularisation are three general categories for the repair approaches.

Hypospadias repair is one of the most common surgeries performed by paediatric urologists, with over 300 types of surgery described.1,2 There are thousands of retrospective, randomised, prospective case reports and systematic reviews in the literature comparing hypospadias surgery types, suture use, anaesthesia types, and complications. However, there are very few publications on dressing after hypospadias surgery in the post-operative period. Wrapping the penis with sterile gauze with antibiotic cream, and fixing it with a plaster is the most used conventional method, and it is not often mentioned in the publications.3-8

Seventeen studies meeting the above criteria were reviewed.3-19 By examining these studies, dressing types, their properties, and why they were preferred was revealed. In general, it has been seen that these publications are mostly made from developed or developing countries, and plastic surgeons and urologists mostly use commercialised dressing materials for dressing after hypospadias surgery. It is presented as an advantage that the dressing can disappear, or be easily removed, especially by itself. However, in underdeveloped countries, or in rural areas of developing countries, the simplest and cheapest sterile gauze with antibiotic cream is used. Recently, it has become popular to add substances that increase wound healing to dressing materials. In published articles about dressing after hypospadias surgery, the advantages of the preferred dressing, the reason for preference, country, and characteristics of the surgeon are shown in Table 1.

The aim of this study is to reveal the factors affecting the hypospadias dressing in the accompaniment of the evaluated articles.

MATERIALS AND METHODS The number of papers published on this subject was relatively low before 2000; their number is, however, gradually increasing today. Children’s dressing for hypospadias surgery was searched on PubMed as “dressing for hypospadias,” “postoperative dressing for pediatric hypospadias,” and “dressing AND hypospadias.”

Experimental studies, animal studies, reviews, letters, and repetitive publications were excluded from the study. By evaluating these reviewed publications, factors affecting hypospadias dressing, such as surgeon, country, dressing type, characteristics, and why it is preferred will be revealed.

DISCUSSION Although one of the most performed operations by paediatric surgeons and urologists, the scarcity of reports on wound dressing in hypospadias could be related to the surgeons’ consideration on the sufficiency of conventional dressing methods. Furthermore, studies on appropriate wound dressing for these cases are either controversial or absent. Multiple dressing types and materials have been defined.

These materials include silastic foam, elastic bandage, glove finger, Tegaderm™ (3M™, Saint Paul, Minnesota, USA), Opsite (Smith+Nephew, Watford, Hertfordshire, UK), Cavi-care (Smith+Nephew), silicon foam sheet, topical ozone, and superglue. Related reports have focused on ease of removal or biodegradable, self-eliminating materials in paediatric patients.3,5,6,12-14 The ideal dressing should be flexible and adaptable to the penis during a child’s movements, while also being rigid to stabilise the penis during the dynamic changes occurring in physiological erections. It should also be affordable, straightforward, dependable, stable, snug-fitting, transparent, waterproof, nonadherent, and nonallergenic. Additionally, it

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Table 1: Dressing type and characteristics for hypospadias surgery.

Type

Name of dressing Speciality

Authors' Comment

Surgeon

Country

Authors

Wet dressing

Biopolymer pellicle made of sugarcane

Spontaneous loss and detached

Better and more tolerable dressing made from polyurethane (Tegaderm™, 3M™, Saint Paul, Minnesota, USA).

Paediatric Surgery

Brazil

Martints et al.3

Glove finger

Glove finger

Easy and cheap

Penis was dressed General with gauze inside, and surgery wrapped with a latex glove finger outside.

Provides uniform pressure, prevents infection, and allows inspection.

India

Singh et al.4

Soluble adhesive

Cavilon (3M™)

Dries quickly, breathable, transparent, easy to remove.

Prospective randomised trial, easier to remove than Elastoplast (Beiersdorf, Hamburg, Germany).

Paediatric urology

England

Sanders et al.5

Elastic and Velcro bandage

Elastic and Velcro No technical difficulties

Cheap, noncumbersome, painless, the elastic and Velcro dressing yields itself to erect and flaccid state of the penis, providing uniform compression without tourniquet effect.

General surgeon

India

Singh et al.6

Non-adherent tri-laminate

Alleyvn (Smith+Nephew, Watford, Hertfordshire, UK)

Nonadherent, simply apply

Inner non-adherent, central absorbent and outer water and microbial proof layers.

Not dislodged, remove with minimal stress.

Paediatric surgery

England

Fathi et al.7

Non-adherent tri-laminate

Alleyvn (Smith+Nephew)

Nonadherent, simply apply

Allevyn is cut as a dove and the tail lies over the scrotum, the wings and body of the protective dove are pulled around the penis. The wings are stabilised to thigh/ abdomen.

Plastic surgeon

England

Morris8

No need to remove

Dressing came out Paediatric spontaneously, no Surgery need to change, was not stuck to the wound, lesser pain compared the conventional dressing.

Iran

Hosseini et al.9

alcohol-free liquid barrier film

Cyanoacrylate Cyanoacrylate Glue Glue

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Table 1 continued.

Type

Name of dressing Speciality

Authors' Comment

Surgeon

Country

Authors

Octyl cyanoacrylate

Octyl cyanoacrylate

Easy to apply

It binds to the Paediatric epithelium and acts as surgery a pliable, waterproof, transparent dressing.

It is used as stent fixator.

Malaysia

Tan et al.10

Malleable, rigid, durable dressing

Cock-up splint bandage

Easy to apply, Zero graft loss, cheap the rigidity of the construct splints to graft, reducing secondary contracture and minimising downstream chordee deformity.

Plastic surgery

Singapore Hsieh et al.11

OxygenOxygen-enriched enriched oil oil based gel based gel with dressing conventional dressing

Promoting faster wound healing

Prospective randomised trial, better post-operative outcome compared to the control group.

Paediatric surgery and paediatric urology

Italy

Esposito et al.12

Tubular oxygenenriched oil inside-coated dressing

The device was polyurethane and poyester, whereas the inner part was coated in oxygenenriched olive oil.

Effective, easy to manage, cheaper.

Prospective randomised trial, better post-operative outcome compared to the control group.

Paediatric surgery and paediatric urology

Italy

Esposito et al.13

Slicone foam dressing

Mepilex border Easy, no foam sheet secondary (Molnlycke, dressing Milton Keynes, Buckinghamshire, UK)

The application is very simple, with no need for previous skills, and nonadherent, easily removed.

Paediatric surgery and urology

Spain

MendezGallart et al.14

Dressing or not dressing

Conventional dressing with Coban™ (3M™) bandage

-

Prospective randomised trial, minimal bleeding was observed in three patients in the non-dressing group but stopped sponteneously. Other results were similar.

Paediatric surgery

Türkiye

Karakaya et al.15

Tubular elastic Silcone gel mesh net bandage and tubular elastic net bandage

This bandage is gently compressive, comfortable, not inclined to slip off.

The elastic dressing did not disturb the voiding, lesser dislodgement.

Plastic surgery

China

Wang et al.16

Sandwich tip dressing to the abdomen

Glans and urethral catheter fixed to abdomen.

the pressure on the anastomotic line is reduced by this fixation; thus, wound healing is better, glans dehiscence is reduced.

Urology

Türkiye

Atan et al.17

Glans fixed to abdomen, sandwich tip dressing to the abdomen.

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Table 1 continued.

Type

Name of dressing Speciality

Authors' Comment

Surgeon

Country

Authors

Non-adherent tri-laminate

Alleyvn (Smith+Nephew)

Nonadherent, simple to apply, cheap.

Simple to remove, no maceration, protects infection.

Paediatric surgery

Türkiye

Narci et al.18

2-Octyl cyanoacrylate

2-Octyl cyanoacrylate

Easy to apply

Low rate complication rate, safe option.

Urology

USA

Brockway et al.19

should avoid faecal and urine contamination of the penis, which continually happens in infants under the age of 2–3 years old who wear diapers. The dressing should also guard against external wounds caused by children’s frequent scratching of the penis throughout the healing process. Even more care is required in the dressing of patients undergoing preputioplasty and urethroplasty surgery. It should also allow for simple maintenance examination, accommodate both the erect and flaccid phases of the penis, and provide modest compression throughout. In addition to preventing haematoma development, leaking, or infection, it should improve tissue adhesion, oedema resolution, and wound healing.

It should not contain any adhesives, sutures, casts, or allergic materials, and it should not restrict the patient’s mobility, or create ischaemia or a tourniquet effect. Finally, the optimal dressing should be simple to apply and remove without any pain.3-19 There is no hypospadias surgery dressing closure technique that satisfies all ideal requirements, according to a review of 17 papers. Applications that are self-disappearing, transparent, and unclothed have been found to be more effective, particularly in cases of distal hypospadias.3,5,9,10,15,19 For example, applying octyl cyanoacrylate to challenging hypospadias shapes is simple. It is a powerful urethral stent fixator and the best dressing for hypospadias surgery, because it forms a strong, watertight adhesive bond that separates from epithelial surfaces in 7–10 days.8 Due to their low cost and accessibility, gloves with fingers, elastic and velcro, tubular net elastic bandages, and Alleyvn (Smith+Nephew) bandages are utilised in several developed and developing nations.4,6-8,16,18

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With its inner non-adherent, central absorbent, and outside water- and microbial-proof layers, Alleyvn, a hydrocellular foam, has a distinctive tri-laminate structure. In 83 children, most of whom underwent hypospaias surgery, and were dressed with Alleyyn, premature dressing removal was not observed in any patient. On the ward, all dressings were removed with little discomfort to the patients. No early wound infection occurred. This tri-laminate dressing is non-adherent, easy to use, and suitable for hospital early discharge.The authors have used Alleyvn dressing following hypospadias surgery “in the shape of a dove,” the tail lying over the scrotum, and the wings lying on either side of the penis.7,8 The traditional dressing used following hyposdias surgery may not offer homogeneous compression, and a watertight barrier against outside infection-contamination.

Due to its instability over the sensitive organ, the dressing may potentially come off following surgery. When dressing a child’s penis, which has a smaller penile girth and length, it is simple to use a gloved finger because it is inexpensive, widely accessible, easy to use, uniformly presses the penis, and makes it possible to inspect the wet dressing with ease. While the authors do not recommend glove finger dressing for scrotal and perineal hypospadias surgery, they state that removing this dressing is easy and painless (Figure 1).4 Due to its elasticity, the tubular elastic net bandage is able to create a little compression and perfectly fits the penis shaft. The wound could be examined through the dressing since the tubular net bandage is a network. The authors stated that dressing gauze is not suitable for the erect and flaccid phases of the penis, and that the dressings slip off in nearly half of cases, and do not provide uniform

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Figure 1: Photographed form of glove finger dressing for hypospadias surgery.4

The patient’s consent was obtained from his parents for this image to be used in publications.

compression. They stated that this tubular elastic net bandage was well tolerated in children, while providing comfortable and gentle compression, and did not affect normal voiding, even after removal of the urethral catheter.16 It is debatable whether pressure should be used during the dressing after hypospadias correction. Lack of pressure can result in haematoma, oedema, and infection, which increases the likelihood of problems, while excessive pressure can impair the flap and skin’s blood supply, and cause tissue necrosis. According to the authors, a dressing is necessary to manage post-operative oedema, avoid haematoma development, which increases the risk of infection, and act as a barrier from the environment, particularly in developing nations, where ward cleanliness and hygiene may not be the best. To avoid problems, and provide appropriate compression, particularly in cases of severe hypospadias, several authors have employed specialised dressing materials or dressings.11,14,17 Hypospadias surgery significantly benefits from the use of a self-adherent, gentle silicone-foam dressing that reduces unpleasant removal.The Mepilex Border foam sheet (Molnlycke, Milton Keynes, Buckinghamshire, UK) is cut to match the length and circumference

of the penis. The dressing’s lower border is divided into three flaps, allowing self-adhesion to the pubic and scrotal region. To cover the penis, the foam dressing must be rolled into a cylinder, wrapped around it, and sealed on the dorsal side with an adhesive lateral border. In order to observe the colour of the glans and pass the urine catheter through the dressing during the post-operative period, the top of the dressing must be left open. No further dressings are required. This dressing is simple to apply, does not prolong operating time, and removal does not cause anxiety for the child or family.

It is easily removed without any analgesics.14 For wound healing and infection, some authors employed dressing materials containing ozone and comparable substances.7,12,13 Because it was stable and maintained the penis straight, while having a lower incidence and shorter duration of post-operative swelling than the conventional dressing, as described in Esposito et al.’s study,13 this innovative device seemed to satisfy all the requirements of an ideal hypospadias dressing. They used a tubular finger oxygen enriched oil inside coated dressing device for wound closure after distal hypospadias surgery. This device was a mechanical barrier

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that was effective through two mechanisms: firstly, the device’s exterior, which was not impregnated, was moderately water-repellent and protected the penis from contamination by urine and faeces, as well as traumatic injuries brought on by the child scratching the area where the wound had been, as in their experience. Secondly, a microenvironment that was adverse to the growth of the pathogens usually seen on skin lesions was established by the interior half of the device, which was coated with oxygen-enriched greasy gel. This allowed the microcirculation to be activated. The reduction of microbial infection, the debridement effect, the control of the inflammatory phase, the stimulation of angiogenesis, as well as biological and biochemical processes that favour oxygen metabolism increasing wound healing are all associated with the favourable effects of ozone on wound healing. It serves as an insulator, generating heat that speeds up the healing process by increasing local peripheral vasodilation, blood flow, oxygenation, and cellular metabolism. They also stated that this device is cheap, easy to apply, and has fewer skin

and urethral complications compared to other applications13 (Table 1).

In light of the information previously provided, it is clear that, despite the fact that the removal of the dressing following a hypospadias surgery is quick and painless, it is still not the optimum dressing type that will satisfy the demands of both children and surgeons. While dressing after hypospadias surgery in developing countries is generally done in the cheapest and simplest way with sterile gauze with antibiotic cream (Figure 2), dressing materials are becoming more commercialised, even if the surgeon is a plastic surgeon. In fact, depending on whether the centre where the hospital is located is metropolitan, and in developing or underdeveloped countries, more expensive or commercial products may be preferred.

The type of dressing used following a hypospadias surgery, the surgeon’s choice, and its ease of removal, stand out as the crucial factors in treating hypospadias in children, along with the degree of development of the nation.

Figure 2: Standard closure technique with sterile gauze with antibiotic cream.

The patient’s consent was obtained from his parents for this image to be used in publications.

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References 1.

2.

Borkar N et al. The comparison of interrupted and continuous suturing technique in Snodgrass urethroplasty in patients with primary hypospadias: a systematic review and meta-analysis. Urol Ann. 2023;15(1):74-81.

Cook A et al. A multicenter evaluation of technical preferences for primary hypospadias repair. J Urol. 2005;174(6):2354-7.

3.

Martins AG et al. A wet dressing for hypospadias surgery. Int Braz J Urol. 2013;39(3):408-13.

4.

Singh RB et al. Glove-finger dressing in paediatric hypospadias.

Pediatr Surg Int. 2002;18(2-3):2189.

5.

6.

7.

Sanders C et al. A prospective randomized trial of the effect of a soluble adhesive on the ease of dressing removal following hypospadias repair. J Pediatr Urol.

2007;3(3):209-13.

Singh RB, Pavithran NM. Elastic and Velcro dressing for penis.

Pediatr Surg Int. 2004; 20(5):38990.

Fathi K, Tsang T. A technique for applying a non-adherent, trilaminate dressing for hypospadias

repair. Ann R Coll Surg Engl.

2009;91(2):164-5.

8.

9.

Morris PN, Sassoon EM. Alleyvn: a quick, effective hypospadias dressing. Br J Plast Surg.

2005;58(2):277-8.

Hosseini SM et al. Cyanoacrylate glue dressing for hypospadias surgery. N Am J Med Sci. 2012;4(7):320-2.

10. Tan HL et al. The use of octyl cyanoacrylate (superglue) in hypospadias repair including its use as a fixator for urethral stents.

J Pediatr Surg. 2012;47(12):22947.

11. Hsieh MKH et al. The cock-up splint: a novel malleable, rigid, and durable dressing construct for the post-hypospadias repair.

Plast Reconstr Surg Glob Open.

2019;7(8):e2369.

12. Esposito C et al. Evaluation of efficacy of oxygen-enriched oil-based gel dressing in patients who underwent surgical repair of distal hypospadias: a prospective randomised clinical trial. World J Urol. 2021;39(6):2205-15.

13. Esposito C et al. Evaluation of a new tubular finger oxygenenriched oil ınside-coated dressing device in pediatric patients

undergoing distal hypospadias repair: a prospective randomized clinical trial part II. Front Pediatr.

2021;9:638406.

14. Méndez-Gallart R et al. A simple dressing for hypospadias surgery in children. Can Urol Assoc J. 2017;11(1-2):E58-9.

15. Karakaya AE et al. Dressing or not after tubularized ıncised plate urethroplasty. Urol Int. 2021;105(11-12):1029-33.

16. Wang Y, Li S. The tubular elastic net bandage: a useful penile dressing in pediatric hypospadias.

Indian J Surg. 2015;77(Suppl 3):1425-7.

17. Atan A et al. Fixation of the glans penis and urethral catheter to the abdominal skin to avoid wound dehiscence after a hypospadias surgery: a comparative study. Turk J Urol. 2019;45(Suppl 1):S104-7.

18. Narci A et al. A practical offer for hypospadias dressing: Allevyn®.

Afr J Paediatr Surg. 2011;8(3):2724.

19. Brockway WJ et al. 2-octyl cyanoacrylate hypospadias repair dressing: a retrospective, controlled comparison. Can J Urol.

2019;26(1):9675-9.

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Redefining Renal Cell Carcinoma: A Molecular Perspective on Classification and Clinical Implications Authors:

Arjun Athreya Raghavan,1 Ian W. Gibson,2 Robert Wightman,2 Piotr Czaykowski,1,3 *Jeffrey Graham1,3 1. Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada 2. Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada 3. CancerCare Manitoba, Winnipeg, Canada *Correspondence to jgraham9@cancercare.mb.ca

Disclosure:

The authors have declared no conflicts of interest.

Received:

06.10.23

Accepted:

13.11.23

Keywords:

Carcinoma, clear-cell, clinical, renal cell.

Citation:

EMJ. 2023;8[4]:116-123. DOI/10.33590/emj/10301071. https://doi.org/10.33590/emj/10301071.

Abstract Renal cell carcinoma (RCC) is the most common primary tumour of the kidney.

RCC is a clinically and pathologically heterogenous entity, which has traditionally been classified under two broad categories: clear-cell and non-clear cell. With improved molecular diagnostic methodologies and genetic testing, the classification of RCC has shifted from a morphological basis to a molecular/genetic focus, and has been systematically updated to reflect these advancements. The new 2022 World Health Organization (WHO) classification of RCC is the most recent of these updates, and contains significant changes, as compared to the previous 2016 classification. The most substantial of these changes is the establishment of a new category of molecularly-defined RCC, including TFE3-rearranged RCC, TFEBaltered RCC, ELOC-mutated RCC, fumarate hydratase-deficient RCC, succinate dehydrogenase-deficient RCC, ALK-rearranged RCC, and SMARCB1-deficient renal medullary carcinoma. In this narrative review, the authors briefly summarise the histopathological characteristics, clinical course, current treatment standards, and future treatment directions of each of these molecularly-defined RCC subtypes.

Key Points 1. This article summarises the key pathologic and clinical characteristics of the molecularly-defined renal cell carcinoma (RCC) subtypes incorporated within the new 2022 World Health Organization (WHO) classification system. This change signifies a broader trend in oncology, emphasising the role of molecular and genomic tumour descriptions.

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2. Molecularly-defined RCC subtypes may pose diagnostic challenges, due to morphological variability.

Ancillary techniques, including fluorescence in situ hybridisation, immunohistochemistry, and nextgeneration sequencing, are essential for accurate identification, requiring pathologists to adapt to this molecular-focused approach.

3. The clinical impact of molecularly-defined RCC subtypes remains uncertain. Interdisciplinary collaboration is emphasised for integrated diagnosis and treatment. Future research should focus on elucidating molecular pathways, exploring targeted therapies, and conducting prospective trials for personalised treatment approaches.

INTRODUCTION Renal cell carcinoma (RCC) is the most common primary tumour originating from the kidney, and accounts for more than 90% of all renal malignancies.1 RCC is a clinically and pathologically heterogenous entity, which can arise from various cell types within the nephron.

RCC has been traditionally classified into two broad pathologic categories: clear cell RCC (ccRCC) and non-clear cell RCC. Under the non-clear cell umbrella, the two most common histologic subtypes are papillary RCC (PRCC) and chromophobe cell RCC. Historically, RCC classification has been primarily morphologically focused, but has more recently incorporated a molecular/genetic basis.2 In 2016, the World Health Organization (WHO) classified RCC according to the latest knowledge about genetics, pathology, and epidemiology.3 Subtypes were named largely on the basis of cytologic features (e.g., chromophobe RCC), cell of origin within the nephron (e.g., collecting duct RCC), architectural features (e.g., papillary RCC), pathognomonic molecular/genetic alterations and mutations (e.g., succinate dehydrogenase [SDH]deficient RCC), and association with specific renal diseases (e.g., acquired cystic diseaseassociated RCC).3 With the advancement and widespread adoption of genomic sequencing, diagnostic methodology has shifted further from morphology to molecular descriptions.4 In 2022, the WHO introduced a new classification system consistent with this paradigm shift.4 This new system focuses more on a molecularly-driven tumour classification, and introduces several new molecularly-defined renal tumours (Table 1). The 2022 classification represents the first comprehensive molecular classification of renal tumours.4,5 The new

subtypes include: TFE3-rearranged RCC, TFEBaltered RCC, ELOC-mutated RCC, fumarate hydratase (FH)-deficient RCC, SDH-deficient RCC, ALK-rearranged RCC, and SMARCB1deficient renal medullary carcinoma (RMC).6 Molecularly-defined RCC may demonstrate heterogeneous morphology or architecture, and cannot necessarily be diagnosed by morphology alone.4 Accurate pathologic diagnosis requires a high degree of suspicion based on subtle morphologic features. Hence, these tumours require the use of ancillary techniques, such as fluorescence in situ hybridisation (FISH), immunohistochemistry (IHC), and nextgeneration sequencing, for their identification and diagnosis.6 It is important to note that some of the aforementioned molecularly-defined RCC, such as FH-deficient RCC, are derived from the previous classification of Type 2 PRCC, which has since been removed in the 2022 classification.7 Due to their morphological variability, these subtypes have been segregated from this previous morphologic label, and what was known formerly as Type 1 PRCC is now referred to as classical PRCC.7 From a clinical perspective, it is yet to be determined how these molecularly-defined renal tumours will impact clinical management. The molecular classification of other tumour types, such as lung cancer, breast cancer, and melanoma, has made a significant impact on the treatment and therapeutic landscape of these tumours, including the development of targeted therapy specific to certain molecular alterations.7-10 This narrative review aims to describe the characteristics of each of the new molecularlydefined subtypes of RCC, as well as to discuss

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Table 1: Summary of molecularly-defined renal cell carcinoma subtypes.

MolecularlyDefined RCC Subtype

Histological Findings

Clinical Characteristics

Ancillary Diagnostic Tests

Treatment

TFE3-rearranged RCC

Mixed papillary and nested pattern, with clear and/or eosinophilic cells, psammoma bodies

Variable, ranging from indolent to aggressive; patients may develop metastases 20–30 years after diagnosis

IHC/FISH for nuclear TFE3

No standard treatment: ICIs have activity, as do TKIs, such as cabozantinib

TFEB-altered RCC

Biphasic growth pattern, large clear and/or eosinophilic cells, smaller cells, hyaline stromal nodules

Typically more aggressive compared to TFE3rearranged tumours

FISH and/or IHC; for nuclear TFEB, cathepsin K, melan-A, HMB45

No standard treatment; potential treatments include use of ICIs and TKIs

ELOC-mutated RCC

Clear cellular morphology with tubulopapillary architecture, fibromuscular bands/septation

Usually indolent, with surgical removal often curative

IHC expression of CK7, CAIX, CD10.

Requires molecular detection of a mutation of the ELOC gene

Current treatment consistent with that of ccRCC

FH-deficient RCC

Papillary architecture, including eosinophilic cells, macronucleoli with perinucleolar clearing

Typically aggressive with high metastatic potential; most common sites of metastasis include lymph nodes in the chest and abdomen, bone, and liver

IHC to reveal absence of FH staining, positive for 2SC; confirmed by genetic detection of mutations in FH

Options include erlotinib+bevacizumab, ICI+/-TKI

SDH-deficient RCC

Eosinophilic cells, cytoplasmic vacuoles or flocculent inclusions

Most present as low grade, and have a low risk of metastasis

CD117 negative, requires staining negative for SDHB via IHC

Most cured via surgical removal; TKIs may be beneficial

ALK-rearranged RCC

Morphologically heterogeneous; mucinous intracellular component; rhabdoid cytology

Vary based on the specific fusion genes involved, and can range from indolent to more aggressive

IHC or FISH for ALK required for diagnosis; nuclear INI-1 retained

ALK inhibitors (crizotinib, alectinib)

SMARCB1-deficient RMC

Infiltrative reticular or cribriform pattern, rhabdoid cytology

Aggressive and associated with poor overall prognosis with a median survival of approximately 13 months

Negative staining Platinum-based of SMARCB1 (INI-1) chemotherapy; potential via IHC role for proteasome inhibitors

ccRCC: clear cell renal cell carcinoma; FH: fumarate hydratase; FISH: fluorescence in situ hybridisation; IHC: immunohistochemistry; RCC: renal cell carcinoma; RMC: renal medullary carcinoma; SCH: succinate dehydrogenase; TKI: tyrosine kinase inhibitor; 2SC: 2-succinocysteine.

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Article the potential therapeutic implications of this reclassification.

TFE3-REARRANGED RENAL CELL CARCINOMAS TFE3-rearranged RCC is most commonly discovered during childhood, and is found in up to 75% of childhood RCC.6 A history of previous chemotherapy is present in up to 15% of cases.9 In previous classifications, TFE3-rearranged RCC was organised under microphthalmia transcription (MiT) family translocation carcinomas, along with TFEB-rearranged RCC.10 As its name indicates, TFE3-rearranged RCC is characterised by a translocation of TFE3, which is derived from the MiT subfamily of transcription factor genes.10 The Xp11 translocation is pathognomonic for TFE3-rearranged RCC.6 Further, TFE3 is notably able to rearrange with more than 20 gene partners to create fusion subtypes, with variable tumour morphology and clinical behaviour.11 Histologically, most cases reveal a mixed papillary, solid, and nested pattern, with large voluminous clear and eosinophilic cells, and psammoma body calcifications may be present.10,12 IHC expression of melanocytic markers (HMB45, Melan-A) is present in up to 40% of cases.10 Due to its heterogeneity, and resemblance to other types of RCC, however, IHC for nuclear expression of TFE3 and FISH assay for TFE3 rearrangement are required for accurate diagnosis.6,12 The clinical behaviour of TFE3-rearranged RCC can be variable, ranging from indolent to highly aggressive.6 Additionally, some patients may develop metastases 20–30 years after diagnosis.12 There are no standard treatment recommendations for advanced/metastatic TFE3-rearranged RCC, and most treatment regimens are consistent with those used in ccRCC.13 A retrospective study has suggested that immune checkpoint inhibition is effective in the treatment of advanced TFE3 RCC, as well as specific tyrosine kinase inhibitors (TKI), such as cabozantinib.6,12

TFEB-ALTERED RENAL CELL CARCINOMA TFEB-altered RCC is similarly predominantly found in children, but is less common than TFE3-rearranged RCC.6 There are two primary types of TFEB-altered RCC: TFEB-rearranged RCC and TFEB-amplified RCC.12 The TFEB gene is located on chromosome six and, in TFEBrearranged RCC, is most commonly translocated to chromosome 11, where it fuses with the MALAT1 gene.10 As mentioned previously, TFEBrearranged RCC was also previously organised under the MiT family translocation carcinomas.10 In TFEB-amplified RCC, the elevated expression of the TFEB gene often coexists with the amplification of other oncogenic genes, such as vascular endothelial growth factor A.12 The histologic appearance of TFEB-altered RCC is variable, with solid and papillary architecture.12 The most important morphologic clues are a biphasic growth pattern of large, clear, and eosinophilic cells with high nuclear grade, and compact collections of smaller tumour cells clustered around nodules of hyaline basement membrane-type stromal material.12 Melanocytic markers and cathepsin K are positive in up to 90% of cases.10 Definitive diagnosis of TFEBaltered RCC requires the use of IHC for nuclear TFEB expression, and FISH assay for TFEBrearrangement versus amplification.12 Clinically, TFEB-amplified RCC is thought to be more aggressive compared to TFE3-rearranged tumours, with a 5-year survival rate of 48%.12 Given its rarity, there are a lack of current treatment recommendations for TFEB-altered RCC.6,12 TFEB-altered RCC can be misdiagnosed as conventional ccRCC; hence, prescribed treatment is often that of ccRCC.12 Some studies indicate that TFEB may evade the immune system via programmed cell death ligand 1 expression; hence, immune checkpoint inhibitors (ICI) may be a therapeutic option.6 Similarly, targeted therapies against vascular endothelial growth factor receptors may be effective in the treatment of TFEB-amplified RCC.6

ELOC (FORMALLY TCEB1)MUTATED RENAL CELL CARCINOMA ELOC-mutated RCC is an uncommon malignancy that predominantly affects older age groups, as

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compared to the translocation RCC subtypes.12 The ELOC gene codes for the protein elongin C, an important component of the von Hippel– Lindau protein complex, and is responsible for the ubiquitination and degradation of HIF1α.14 With an ELOC mutation, this degradation is inhibited, leading to HIF1α accumulation, and activation of various oncogenes with subsequent tumourigenesis.14 Morphologically, ELOC-mutated RCC resembles ccRCC with predominant voluminous clear cell cytology, acinar or tubulopapillary architecture, and smooth muscle-rich fibromuscular bands/ septation.12 The tumour is, in most cases, diffusely positive for CD10, CK7, and CAIX, and needs therefore to be distinguished from the clinically indolent clear cell papillary renal cell tumour.12 The staining for CAIX is a box-like pattern, rather than the cup-shaped pattern seen in clear cell papillary renal cell tumour.15 This entity has, in the past, been described as ‘RCC with fibromuscular stroma’.7 It is important to note, however, that this morphological presentation is not pathognomonic, as there exists some RCC with fibromuscular stroma caused by mTOR pathway mutations, and these are histologically indistinguishable from ELOCmutated RCC.7 Therefore, ELOC-mutated RCC requires molecular characterisation of a mutation of the ELOC gene for definitive diagnosis.6,13,14 The current treatment of ELOC-mutated RCC is consistent with that of ccRCC, as ELOC-mutated RCC was previously considered to be one type of ccRCC.12 Clinically, ELOC-mutated RCC tends to be more indolent, and surgical removal in localised disease is often curative.6

FUMARATE HYDRATASE-DEFICIENT RENAL CELL CARCINOMA FH-deficient RCC is a rare form of RCC that predominantly affects adults; it was previously classified as hereditary leiomyomatosis and RCC syndrome-associated RCC.6,12 FH is an enzyme in the tricarboxylic acid cycle that is involved in the production of cellular energy through oxidative phosphorylation.12,16 Autosomal dominant germline mutations in the gene encoding FH can cause accumulation of fumarate, which has oncogenic properties, and can drive tumourigenesis.16 The primary rationale for the

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reclassification of hereditary leiomyomatosis and RCC-syndrome associated RCC is the discovery of somatic biallelic alterations causing sporadic cases of FH-deficient RCC, in addition to the more common hereditary form.6 Positive family history, and multiple cutaneous and (in females) uterine leiomyomas are not always present.17 Genetic testing of family members for FH mutation is necessary, due to up to a 30% lifetime risk of RCC in affected individuals.17 Prior to the discovery of FH-deficient RCC, these tumours were generally classified as high grade RCC (not otherwise specified), Type 2 papillary RCC, or collecting duct carcinoma. FH-deficient RCC may display a variety of histologic growth patterns, the most common being papillary, with other patterns being solid, tubulocystic, and cribriform or sieve-like.12 Tumour cells generally have granular eosinophilic, rather than clear, cytoplasm.12 A characteristic cytologic feature that is an important clue to raise suspicion of the diagnosis, and pursue appropriate confirmatory IHC testing, is the presence, at least focally, of very large ‘cherry red’ inclusionlike macronucleoli, sometimes with perinuclear clearing.12 IHC shows loss of cytoplasmic reactivity for FH, and strong nuclear and cytoplasmic staining for 2-succino-cysteine, due to the enzyme blockade in the tricarboxylic acid cycle.6,12 Clinically, FH-deficient RCC is often aggressive, with high metastatic potential.6 The most common sites of metastasis include lymph nodes in the chest and abdomen, bone, and liver.12 There is no clear standard of therapy for FHdeficient RCC, and current treatment is largely consistent with that of ccRCC.12 Several drugs have been explored in recent years, including ICIs (e.g., nivolumab and ipilimumab), and TKIs (e.g., sunitinib and pazopanib). Some data suggest that treatment with ICIs in combination with TKIs may be superior to monotherapy.18 Furthermore, a recent trial evaluating the combination of erlotinib and bevacizumab has shown favourable results, with a response rate of 51%.19

SUCCINATE DEHYDROGENASEDEFICIENT RENAL CELL CARCINOMA SDH-deficient RCC is predominantly found in male patients, and can affect individuals of all

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Article ages.12 SDH is a mitochondrial enzyme complex composed of four subunits (SDHA, SDHB, SDHC, and SDHD), which plays an important role in energy metabolism.20 The pathogenesis of SDH-deficient RCC involves germline mutations of the genes that encode these SDH subunits, most commonly in SDHB.12,20 These germline mutations result in the development of adrenal phaeochromocytomas, extra-adrenal paragangliomas, gastrointestinal stromal tumours, and pituitary adenomas, in addition to RCC.20 SDH-deficient RCC can be solid or cystic, and up to 30% can be multifocal and bilateral.20 Histologically, tumour cells have a uniform granular eosinophilic cytoplasm, and if the nuclear grade is low, a serious misdiagnosis of benign renal oncocytoma is possible.12,20 The growth pattern is generally sheet-like or papillary.20 High grade nuclei, necrosis, and sarcomatoid transformation are described.20 The most characteristic pathologic feature of SDHdeficient RCC is the presence of cytoplasmic vacuoles or flocculent inclusions, representing enlarged mitochondria.6,12 IHC is generally negative in tumour cells for CD117 (in contrast to oncocytoma); intratumoural CD117-positive mast cells may be prominent.20 Diagnosis of SDH-deficient RCC requires an absence of cytoplasmic staining in tumour cells for SDHB, using IHC.12 Clinically, most cases of SDH-deficient RCC present as low-grade, and have a low risk of metastasis.12 In these cases, most cases of localised disease can be cured via surgical resection.6 Those tumours that present as high grade have a higher risk of metastasis (up to 70%), and, in these cases, studies have shown that using TKIs may be beneficial.6,12

ALK-REARRANGED RENAL CELL CARCINOMA ALK-rearranged RCC is a rare tumour, with incidence estimated to be between 0.1–0.6%.12 The ALK gene functions to regulate cell proliferation and promote cell motility; hence, when gene rearrangement occurs, it can lead to tumourigenesis.12 Similar to TFE3-rearranged RCC, ALK-rearranged RCC may form fusion genes with various partner genes.21 Underlying sickle cell trait is seen with the VCL-ALK gene fusion.22

ALK-rearranged RCC can be very morphologically heterogeneous, with the majority expressing various growth patterns, including tubulopapillary, cribriform, solid, and sarcomatoid.4 There can even be a metanephric adenoma-like morphology.21 High-grade pleomorphic nuclei are typically present, as well as large cells with eosinophilic cytoplasmic inclusions (rhabdoid morphology).21 Cytoplasmic vacuolation with a signet ring cell mucinous intracellular component and myxoid stroma are also typical features, giving morphologic overlap with mucinous tubular and spindle cell carcinoma.21 Prominent tumour-infiltrating inflammatory cells are seen with the TPM3ALK gene fusion. IHC shows tumour cells are generally positive for PAX8, CK7, and AMACR (racemase), and there is retained nuclear INI1 in contrast to SMARCB1-deficient RCC.12,21,23 Positive ALK staining by IHC, or FISH for ALK rearrangement, is required for definitive diagnosis.21,23 Clinically, the behaviour of ALK-rearranged RCC can vary, based on the specific fusion genes involved, and can range from indolent to more aggressive.12 Given the rarity of this subtype, there is no standard therapy for advanced disease.6,12 Extrapolating from the treatment of ALK-rearranged lung cancer, there is interest in the use of targeted inhibition of ALK, and there are case reports showing effectiveness of ALK inhibition in ALK-rearranged RCC.22,24

SMARCB1-DEFICIENT RENAL MEDULLARY CARCINOMA SMARCB1-deficient RMC, previously classified simply as RMC, is an aggressive cancer that is found almost exclusively in adolescents and young adults with sickle cell trait, sickle cell disease, or other haemoglobinopathies.25 Increased sickling of red blood cells causes regional ischaemia in the renal medulla, which is thought to be key to its pathogenesis.25 The disease is characterised by the loss of tumour suppressor gene SMARCB1 on chromosome 22.12 Morphologically, SMARCB1-deficient RMC can be quite heterogeneous, but most commonly exhibits a highly infiltrative reticular, microcystic, or cribriform pattern, with spaces of variable sizes.6 Rhabdoid cytology with prominent eosinophilic cytoplasmic inclusions, and high-

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grade nuclei are typical histologic features.12,26 In addition to this morphology, and its characteristic clinical course, the absence of nuclear staining for SMARCB1 (INI1 protein) via IHC is utilised for diagnosis.12 It should be noted that there is pathologic and clinical overlap with collecting duct carcinoma, as both entities arise within the renal medulla.27 In contrast to SMARCB1deficient RMC, collecting duct carcinomas typically retain SMARCB1 expression.27 Clinically, SMARCB1-deficient RMC is highly aggressive, and is associated with a poor overall prognosis, with a median survival of approximately 13 months.6 The current standard therapy for advanced SMARCB1-deficient RMC is systemic chemotherapy, including platinumbased regimens.6 Recent studies have explored targeted therapies, such as proteasome inhibitors.6,12 A clinical trial of the proteasome inhibitor ixazomib, in combination with gemcitabine and doxorubicin, in patients with RMC, is currently enrolling patients.28

DISCUSSION The revised pathologic classification of RCC represents a significant shift in oncology, prioritising molecular characteristics over traditional tumour morphology, and is a departure from the more simplified clear cell versus nonclear cell RCC classification. This is reflective of a broader trend in oncology, as molecularlytargeted therapies are increasingly showing promise. Current treatments for these newlydefined RCC subtypes are still, for the most part, extrapolated from treatments for ccRCC. Still, the hope is that a deeper understanding of these tumours at the molecular level will lead to more targeted and effective therapies. This classification is an important step forward in understanding the genetic and molecular basis of rare kidney cancer subtypes, as it recognises the biologic heterogeneity of RCC, and provides a more precise characterisation of these tumours.

This molecular classification emphasises the importance of ancillary diagnostic techniques, such as specialized IHC, FISH, and nextgeneration sequencing for diagnosis, as these molecularly-defined RCC subtypes may not exhibit distinct morphological features. Surgical pathologists need to have a high index of

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suspicion for ordering these additional diagnostic tests, in order to catch the rare positive cases that would be expected in routine practice. Any tumour showing morphology that would have in the past been classified as Type 2 papillary RCC, collecting duct carcinoma, or RCC not otherwise specified, should be considered for additional ancillary molecular and IHC testing. If rhabdoid tumour cell cytology is encountered, ALK and INI1 IHC stains are mandatory to investigate possibility of ALK-rearranged RCC and SMARCB1-deficient RMC, respectively.

The implications of this reclassification for clinical practice remain uncertain. Beyond improved diagnostic precision, it could pave the way for the development of biomarkerselected targeted therapies, akin to those seen with other cancers, such as breast, lung, and melanoma. In addition, accurate pathologic categorisation can have important implications on prognosis (e.g., SMARCB1-deficient RMC, which is associated with a particularly aggressive phenotype, and poor prognosis). It is also likely that interdisciplinary collaboration between pathologists, geneticists, and oncologists will become more critical, as diagnosis and treatment become more intertwined with molecular findings.

Future research should focus on further elucidating the molecular pathways of these RCC subtypes, and determining whether specific targeted therapies can be selected based on molecular classification. Although challenging due to the rarity of these conditions, prospective clinical trials designed to enrol patients based on their molecular subtype would help to generate more robust data on the benefit of novel therapeutics. Clinical trials in other rare subtypes of RCC have been performed, including RMC and papillary RCC, showing that it is possible to conduct trials in less common diseases.29 As we move forward in RCC classification, it is becoming more evident that the simple distinction between ccRCC and nccRCC may not adequately capture the true biologic and pathologic complexity of this condition, and that future treatments may become more tailored to the underlying tumour biology.

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Rizzo M et al. Clinico-pathological implications of the 2022 WHO Renal Cell carcinoma classification. Cancer Treat Rev. 2023;116:102558.

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Argani P. MiT family translocation renal cell carcinoma. Semin Diagn Pathol. 2015;32(2):103-13.

10. Caliò A et al. TFE3 and TFEBrearranged renal cell carcinomas: an immunohistochemical panel to differentiate from common renal cell neoplasms. Virchows Arch.

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13. Bakouny Z et al. Integrative clinical and molecular characterization of translocation renal cell carcinoma.

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14. Wang Y et al. Analysis of clinicopathological and molecular features of ELOC(TCEB1)-mutant renal cell carcinoma. Pathol Res Pract. 2022;235:153960.

23. Hang JF et al. ALK-rearranged renal cell carcinoma with a novel PLEKHA7-ALK translocation and metanephric adenoma-like morphology. Virchows Arch.

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15. Aldera AP, Govender D. Carbonic anhydrase IX: a regulator of pH and participant in carcinogenesis.

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16. Bezwada D, Brugarolas J. Reporting on FH-deficient renal cell carcinoma using circulating succinylated metabolites. 2023.

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Effect of Liraglutide on Weight Loss and BMI Among Patients Who Are Overweight and Obese with Type 2 Diabetes: A Systematic Review and Meta-analysis Authors:

C. Zorampari,1 Rachna Gupta,2 *Lalit K. Gupta1 1. Department of Pharmacology, Lady Hardinge Medical College and Smt. Sucheta Kriplani Hospital, New Delhi, India 2. Department of Pharmacology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India *Correspondence to lkg71@rediffmail.com

Disclosure:

The authors have declared no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Gupta conceived the study. Zorampari and Gupta captured data. All authors analysed the data, prepared results, and interpreted the results.

All authors contributed to the first draft and have approved the final manuscript.

Received:

26.09.23

Accepted:

27.10.23

Keywords:

Diabetes, glucagon-like peptide-1 (GLP-1), liraglutide, obesity, overweight.

Citation:

EMJ. 2023;8[4]:124-134. DOI/10.33590/emj/10306493. https://doi.org/10.33590/emj/10306493.

Abstract Objectives: This study assessed the effect of liraglutide as a monotherapy and add-on to metformin on weight loss and BMI, among patients with Type 2 diabetes (T2D) who are overweight or obese.

Methods: The following databases were assessed to identify relevant papers published until July 2023: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), clinicaltrial.gov, and Web of Science. All clinical trials evaluating the effect of liraglutide on weight loss and BMI in patients with T2D who are obese or overweight, treated for at least 2 months, were included in the review. All analysis and risk of bias assessment was done using Cochrane Review Manager software, version 5.4.1 (Cochrane, London, UK). A random-effects model with inverse variance was used to synthesise the results.

Results: In total, 10 randomised controlled trials involving 945 participants were included in the meta-analysis. Treatment with liraglutide with or without metformin for more than 2 months led to a significant weight loss (mean difference: -4.75 kg; 95% confidence interval: -7.02–-2.48; p<0.01). Liraglutide supplementation also led to a significant decrease in BMI (mean difference: -2.07; 95% confidence interval: -2.75–-1.39; p<0.01). However, the decrease in weight and BMI was not statistically significant as compared to treatment with other oral hypoglycaemic drugs or placebo.

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Conclusion: Liraglutide used alone or as adjunctive therapy to metformin produces reduction in weight and BMI when administered in adult patients with T2D who are obese or overweight.

Key Points 1. Liraglutide, when used as a monotherapy or in combination with metformin, can lead to a significant reduction in weight and BMI in patients with Type 2 diabetes who are overweight or obese.

2. The study found that liraglutide's effect on weight loss and BMI was statistically significant compared to baseline measurements, but it was not significantly better than other oral hypoglycaemic drugs or placebo.

3. The GRADE recommendation for the evidence in this study varies from moderate certainty of evidence for BMI reduction to very low certainty evidence for weight reduction, indicating the need for further studies.

INTRODUCTION Obesity is a major risk factor for the development of Type 2 diabetes (T2D), with the prevalence of both increasing in a parallel manner. The appearance of the term ‘diabesity’ across different articles and literature shows that many patients with diabetes are obese.1 In this subgroup of patients, the therapeutic goal is to achieve adequate blood sugar control and weight loss. Among the available pharmacotherapies for T2D, metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors are shown to help with weight reduction.2 Glucagon-like peptide-1 (GLP-1) receptor agonists are recommended as initial therapies by the American Diabetes Association (ADA) based on glycaemic needs, and for individuals at high risk for atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease.3 Liraglutide is a long acting GLP-1 analogue available in the market as Victoza® (1.8 mg subcutaneous injection; Novo Nordisk, Bagsværd, Denmark) and Saxenda® (3.0 mg subcutaneous injection; Novo Nordisk).4,5 Liraglutide 1.8 mg was approved by the U.S. Food and Drug Administration (FDA) for the management of T2D in adults and paediatric patients aged 10 years and older, as an adjunct therapy to diet and exercise.6 A metaanalysis comparing GLP-1 agonists (exenatide, liraglutide, albiglutide, semaglutide, lixisenatide) with placebo shows weight reduction of

approximately 3% at 6 months in the GLP-1 agonists group.7 Subsequently, liraglutide 3.0 mg was approved for chronic weight management in adult patients (2014) and in patients aged 12 years or older (2020) with an initial BMI of ≥30 kg/m2 (obese) or ≥27 kg/m2 (overweight) in the presence of one or more weightrelated conditions (e.g., hypertension, T2D, or dyslipidaemia).8 Another meta-analysis of adults without T2D who are obese reported significant weight loss in the group treated with GLP-1 receptor agonists (semaglutide, liraglutide).9 GLP-1 is a hormone secreted by enteroendocrine cells in response to food intake, stimulating postprandial glucose-induced insulin secretion and suppressing glucagon secretion. Besides glucose homeostasis, it delays gastric emptying and promotes satiety.10 Peripheral and central administration of GLP-1 not only inhibits food intake through its central action in the hypothalamus, but also reduces leptin-induced activation of GLP-1 in the brain. Conversely, GLP-1 antagonists have been shown to stimulate feeding in rats.11 Weight loss achieved with GLP-1 agonists appears to be related to this mechanism. GLP-1 produced in the intestine is rapidly cleaved by DPP-4 and therefore has a very short half-life (<2 minutes) in the bloodstream.12 Sitagliptin, a DPP-4 inhibitor that acts to prolong GLP-1 circulation time, has also been reported to cause weight loss in patients with T2D.13 Liraglutide, a human GLP-1 analogue with 97% homology to endogenous GLP-1, has

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a half-life of 13 hours and is suitable for once a day dosing.14 A meta-analysis comparing the effects of sitagliptin and liraglutide on patients with T2D who are overweight/obese shows a greater reduction in haemoglobin A1c, fasting plasma glucose, postprandial plasma glucose, and weight in the liraglutide-treated group.15

Science. The search syntax contained related keywords as follows: (((“Type 2 diabetes”) AND (Weight OR Obesity OR BMI OR Body Mass OR Quetelet) AND (Liraglutide OR Victoza OR Saxenda))).

The present systematic review and meta-analysis assessed the effect of liraglutide treatment as monotherapy and add-on therapy to metformin on reduction of weight and/or BMI in adult patients with T2D who are obese or overweight.

Titles and abstracts were scanned by two reviewers independently to identify eligible studies for further assessment. Selected abstracts were screened to remove studies that did not meet the inclusion criteria. The rest were further assessed for eligibility by reviewing the full text. Final papers were selected and reviewed.

METHODS

Data Collection

Eligibility Criteria Inclusion criteria

Eligible randomised controlled trials (RCT; published in English) involving human subjects were included in the analysis if they met the following framework: patients with T2D who were overweight or obese receiving monotherapy with liraglutide/Victoza/Saxenda, or combined treatment of liraglutide with metformin for at least 2 months, providing weight and/or BMI values.

Exclusion criteria

Exclusion criteria included Type 1 diabetes; prediabetes; patients who were not overweight or obese; use of other glucose lowering therapies; mixed treatment with liraglutide; non-randomised controlled trials; reported use of weight loss agent/surgery in the intervention group; studies with treatment duration less than 2 months; and treatment with any other oral antidiabetic drugs (except for short-term treatment with insulin at the discretion of the investigator).

Outcomes

The primary outcome was post-treatment weight (at last follow-up) and secondary outcome was post-treatment BMI.

Literature Search/Information Sources

The following electronic databases were searched for related publications until July 2023: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), and Web of

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The following data were collected for each included study: study design, title, author’s name, year of publication, sample size, study duration, patients’ age, weight and/or BMI at baseline, and study end. All the data were extracted by one reviewer and validated by a second reviewer.

Risk of Bias and Study Quality

Two authors independently assessed the risk of bias of selected articles using version 2 of the Cochrane Risk of Bias tool (Cochrane, London, UK). Disagreements were resolved by discussion or consultation with a third author.

Risk of bias for included studies was assessed using the Cochrane Review Manager 5.4.1 risk of bias assessment (Cochrane). All the articles were evaluated based on the following domains: random sequence generation, allocation concealment, participant and staff blinding, outcome assessment blinding, incomplete outcome data, and selective reporting. Articles were classified as having low, unclear, and high risks of bias in each domain. Funnel plots were made to ascertain publication bias and they had minimal asymmetry on visual inspection. The authors did not exclude any studies due to risk of bias. They also assessed GRADE-pro evidence using the validated tool.16 This review has not been registered and the review protocol has not been published.

Statistical Analysis

The analysis was performed using RevMan 5.4.1 (Cochrane). An inverse variance random effects

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model was used to solve for mean differences (MD) in body weight and BMI between the treatment groups. Also, 95% confidence interval (CI) and χ2 values were calculated. The I2 statistic was used to assess the within-group heterogeneity to measure the degree of variation between studies. All the statistical tests were two-tailed and p<0.05 was statistically significant for all the tests.

RESULTS Studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.17 A total of 645 citations were retrieved from the initial literature search of the aforementioned database.

Of these, 211 were multiples, leaving 434 unique study titles or abstracts. After an initial review of abstracts and titles, 107 papers were excluded, resulting in 327 potentially relevant titles. Further evaluation resulted in removal of 317 titles, leaving 10 articles to be analysed.18-27 However, quantitative analysis could be done only for eight studies for BMI and nine for body weight studies.

The characteristics of the included studies and the pooled results of the meta-analysis are summarised in Table 1. Weekly dose titration of liraglutide was performed and patients were administered the maximum tolerated dose ranging from 1.2–1.9 mg subcutaneous once daily in the included studies. Five studies used liraglutide as monotherapy, four RCTs added liraglutide to a stable dose of metformin, and participants in one RCT received metformin plus a statin. The comparator groups received placebo or other oral hypoglycaemic agents (metformin, pioglitazone, glimepiride, and insulin glargine) alone or in combination, with or without lifestyle modification in the form of exercise.

Effect Of Liraglutide Versus Control Treatment on Body Weight

In this meta-analysis of nine RCTs with n=850, patients treated with liraglutide alone (n=131) or as an adjunct to metformin (n=298) weighed more than the control group (pioglitazone 30 mg once daily [n=30], metformin 1,000 mg twice daily [n=59], placebo±metformin [n=63], insulin glargine at starting dose 0.2 IU/kg/ day+metformin [n=24], glimepiride 8 mg once

daily [n=245]) after ≥2 months of treatment (MD: -1.35 kg; 95% CI: -5.75–3.04; p=0.55; Figure 1A).

Effects of Liraglutide on Body Weight (Pre- Versus Post-treatment)

Nine RCTs involving 429 participants found significant weight loss with liraglutide alone (n=131) or as an adjunct to metformin (n=298) for ≥2 months (MD: -4.75 kg; 95% CI: -7.02–-2.48; p<0.01; Figure 1B).

Effects of Control Antidiabetic Drugs on Body Weight (Pre- Versus Posttreatment)

Analysis of nine RCTs involving 421 participants indicated that control regimens (antidiabetic drugs pioglitazone 30 mg once daily, metformin 1,000 mg twice daily, placebo±metformin, insulin glargine at starting dose 0.2 IU/kg/day, glimepiride 8 mg once daily) also resulted in weight loss (MD: -0.99 kg; 95% CI: -3.59–1.62; p=0.46; Figure 1C).

Effect of Liraglutide Versus Control Treatment on BMI

This analysis of eight RCTs involving 437 participants shows that patients treated with control antidiabetic drugs (n=207) have a lower BMI as compared to patients treated with liraglutide alone (n=120) or with metformin (n=110) after ≥2 months of treatment (MD: -0.30; 95% CI: -1.82–1.22; p=0.70); however, this is not statistically significant (Figure 2A).

Effects of Liraglutide on BMI (PreVersus Post-treatment)

An analysis of eight RCTs involving 230 participants found that treatment with liraglutide for ≥2 months resulted in a significant reduction in BMI (MD: -2.07; 95% CI: -2.75–-1.39; p<0.01; Figure 2B).

Effects of Control Antidiabetic Drugs on BMI (Pre- Versus Post-treatment)

Analysis of eight RCTs with n=207 participants found that control antidiabetic drugs (pioglitazone 30 mg once daily [n=30], metformin 1,000 mg twice daily [n=102], placebo±metformin [n=55], insulin glargine starting dose 0.2 IU/kg/

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Guo et al.22

Iacobellis et al.21

Feng et al.20

Lambadiari et al.19

Zhang et al.18

Authors (Year)

30

31

41

54

29

29

30

30

30

30

Sample size (n)

26 weeks

6 months

24 weeks

6 months

24 weeks

Treatment duration*

52.6±3.9

53.1±6.3

52.0±10.0

50.0±10.0

46.3±2.3

46.8±1.8

50.0±12.0

51.0±10.0

51.5±12.1

50.2±11.5

Age† (years)

Table 1: Characteristics of included studies.

Placebo

Liraglutide 1.8 mg

Metformin 1,000 mg BD

Liraglutide 1.8 mg+metformin (dose not specified)

Metformin 1,000 mg BD

Liraglutide 1.8 mg

Metformin 1,000 mg BD

Liraglutide 1.8 mg

Pioglitazone 30 mg

Liraglutide 1.2 mg

Intervention

28.4±3.5

27.1±4.6

29.0±4.7

33.0±5.0

25.5±0.7

26.2±0.5

26.9±3.0

30.9±5

27.8±4.3

24.2±2.7

‡

‡

‡

‡

‡

‡

‡

‡

‡

BMI† (end of Mean† treatment, kg/ difference m2) in BMI (kg/m2)

81.6±12.1

79.4±9.3

Not reported

Not reported

71.2 (2.55)

75.5 (2.0)

77.0±14.0

92.0±6.0

79.1±9.7

69.2±10.1

Weight† (end of treatment, kg)

‡

‡

‡

‡

‡

‡

‡

‡

‡

Mean† difference in weight (kg)

Randomised, open label placebocontrolled, parallel group clinical study

Randomised, open-label, activecontrolled, parallel group clinical study

Randomised, open-label, active comparator study

Randomised, activecontrolled, parallel group clinical study

Randomised, open-label, activecontrolled, parallel group clinical study

Description

China

USA

China

Greece

China

Study location

Article

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245

242

16

17

24

24

10

11

7

15

52 weeks

16 weeks

26 weeks

14 weeks

16 weeks

53.3±10.9

52.2±10.8

55.6±12.0

56.5±9.0

45.6±7.6

43.1±9.7

55.4 (6.7)

58.6 (10.3)

63.0±2.0

62.0±2.0

Glimepiride 8 mg+metformin

Liraglutide 1.8 mg+metformin

Placebo+exercise± metformin

Liraglutide 1.8 mg+exercise±metformin

Insulin glargine 0.2 IU/kg/ day+metformin ≥1,500 mg/day

Liraglutide 1.8 mg+metformin ≥1,500 mg/day

Placebo

Liraglutide 1.9 mg

Placebo+metformin (any dose)+statin

129

BD: twice daily.

‡Not calculated due to non-availability of data.

†Expressed as mean±standard deviation or mean (standard error) with (%) change.

Not reported

Not reported

31.8±5.1

31.3±3.4

‡

‡

-0.5±1.0

-1.1±1.1

-0.4±1.5

-1.1±1.2

28.9±2.9

29.1±3.8

‡

‡

-0.7±1.2 (-2.2%)

-0.8±0.8 (-2.5%)

Not reported

Not reported

32.3±4.1

Liraglutide 1.8 31.0±3.7 mg+metformin (any dose/ stable dose)+statin (stable dose)

*Minimum treatment duration was 2 months for inclusion.

Bode et al.27

Mensberg et al.26

Yan et al.24

Vilsbøll et al.24

Matikainen et al.23

Table 1 continued.

94.4±1.23

90.5±1.31

95.2±17.7

97.6±4.9

84.4±14.6

82.9±11.1

80.5±15.7

90.3±17.8

89.8±6.3

96.1±11.2

Randomised, open label, activecontrolled, parallel group clinical study

Randomised, double-blind, placebocontrolled, parallel group clinical study

Randomised, single blind, placebocontrolled, parallel group clinical study

1.12 (0.27)

-2.45 (0.28)

Randomised, double-blind, activecontrolled, parallel group clinical

-3.40±2.90 Randomised, double blind, placebo -1.60±3.20 controlled, parallel group clinical study

-1.20±4.20

-3.60±4.90

-4.00±4.80

-2.80±2.70

-2.10±3.00 (-2.2%)

-2.40±2.50 (-2.5%)

USA

Denmark

China

Denmark

Finland

Article

Article

Figure 1: Forest plot for effect of A) liraglutide versus control; B) pre- versus post-liraglutide; and C) pre-versus post-control medicines on weight, following administration for at least 2 months.

A

B

C

CI: confidence interval; IV: inverse variance; SD: standard deviation.

day+metformin [n=24]) resulted in a significant reduction in BMI (MD: -0.98; 95% CI: -1.65–-0.35; p<0.01; Figure 2C).

GRADE Recommendations for the Evidence

Following treatment with liraglutide, the GRADE recommendation for BMI was rated as moderate certainty of evidence, and very low certainty of evidence for weight reduction as the I2 statistic was higher. When comparing the effect of liraglutide versus control, GRADE evidence was very low for both weight and BMI reduction.

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DISCUSSION The main finding of this meta-analysis, which included 10 RCTs and compared data from 945 participants, was that liraglutide at doses of 1.2– 1.9 mg once daily, produced reduction in weight and BMI when administered in adult patients with T2D who were obese or overweight.

In these patients, liraglutide was used as a monotherapy or as an adjunct therapy to other oral glucose-lowering drugs. However, there was no significant effect of liraglutide when it was compared to the control treatment, and in effect

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Figure 2: Forest plot for effect of A) liraglutide versus control; B) pre- versus post-liraglutide; and C) pre-versus post-control medicines on BMI, following administration for at least ­­ 2 months.

A

B

C

CI: confidence interval; IV: inverse variance; SD: standard deviation.

it appeared less effective in causing weight loss (Figure 1A).

schizophrenia spectrum disorder being treated with atypical antipsychotics.28-33

Beneficial effects of liraglutide on glycaemic control parameters, including glycated haemoglobin, fasting glucose, and fasting insulin levels, are well documented. Several studies using varying doses of liraglutide (0.6–3.0 mg) as monotherapy or added to other antidiabetic therapy, showed reduced body weight, improved glycaemic and metabolic control, reduced fat mass and fat percentage, and alteration in central nervous system response to food, in a wide variety of patients regardless of body weight or T2D status, including patients with

Thus, the authors’ results are consistent with those of the aforementioned study, but the patient population in the authors’ meta-analysis was different, i.e., they had T2D and the treatment period was much shorter.

Mechanistic studies were conducted to investigate whether GLP-1-related weight loss in humans was associated with changes in hormone levels important in energy homeostasis using the maximum daily dose (1.8 mg) of liraglutide. An earlier study found that liraglutide

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treatment did not affect 24-hour energy expenditure (12.6 kJ/h) in comparison to placebo (13.7 kJ/h; p=0.799).34 GLP-1 has also been suggested to suppress energy intake in humans.35 It is estimated that 80% of people with T2D are obese, and losing weight is beneficial as even more people may be overweight due to accumulation of abdominal fat.

It would be desirable if peripherally administered GLP-1 induced weight loss by reducing energy intake. A major drawback is that native GLP-1 has a very short plasma half-life due to rapid degradation by intravenous dipeptidyl-peptidase (t0.5=1.5 minutes after intravenous injection).

Liraglutide has a prolonged action (t0.5=13 hours) and is suitable for once-daily dosing.

These results appear similar to the authors’ analysis. It is understood that reductions in visceral and abdominal subcutaneous adipose tissue are associated with improvements in fasting glucose levels, glucose tolerance, and lipid profiles, and would be especially valuable.36 GLP-1 agonists improve glycaemic control by stimulating insulin release, and are approved for T2D. Due to their delayed gastric emptying and promoting satiety effects, they also have roles in decreasing body weight. Based on evidences from RCTs showing reduced body weight and improved metabolic control, liraglutide 3 mg daily subcutaneous was approved for adult patients with obesity in 2014, which was then extended for adolescents aged 12–17 years in 2020.28 Semaglutide (2.4 mg once weekly) was then approved in 2021 for weight control in adults who are obese or overweight with weight-related complications.37 Semaglutide and liraglutide 1.8 mg doses have also been shown to reduce the risks of serious cardiovascular events in patients with T2D.38,39 There are no data on the effect of liraglutide 3 mg on cardiovascular outcomes.40 Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic peptide agonist, received fasttracked designation from the FDA in 2022.41 In the SURMOUNT-1 study, tirzepatide 5 mg, 10 mg, and 15 mg resulted in a weight loss of 5% or more in 85%, 89%, and 91%, respectively, over the 72 weeks study period. The most common side effect was gastrointestinal disturbance.42 Metformin used as a first-line treatment for patients with T2D, has not been approved as a

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treatment for obesity, but metformin used for the treatment of T2D can cause weight loss.43 The ADA recommends metformin for patients who are obese and are at high risk of developing T2D.44 As compared to anti-obesity drugs approved by the FDA, it has a relatively milder side effects profile, the most common being gastrointestinal reaction, which usually decreases with long-term use. It also has added advantages of decreasing low-density lipoprotein cholesterol level by improving lipid metabolism and alleviating symptoms of hyperandrogenism in females suffering from polycystic ovary syndrome.45,46 A meta-analysis of metformin treatment in different populations concluded that metformin treatment leads to approximately one unit reduction in BMI after 3–32 months of treatment, making it a good option for patients who are overweight or obese and at high risk for diabetes.47 Pioglitazone has been reported to cause increase in body weight and BMI in several studies and meta-analyses.

However, due to its favourable effects on major adverse cardiovascular events and lipid profile, it is still being prescribed by many clinicians.48,49 When combined with metformin, the slight increase in weight is accompanied by improved glycaemic control.50 Glimepiride is a second generation sulfonylurea, usually prescribed as a second line agent for T2D. Although increase in weight is reported when compared with DPP-4 inhibitors, it is unlikely to be clinically relevant.51 Conversely, a decrease in weight was reported when glimepiride was combined with metformin in another trial.52 Use of metformin by a large number of patients in the control group (n=146 of 421 for weight and 181 of 211 for BMI) might explain why there was no statistically significant reduction in weight and BMI in the liraglutidetreated group as compared to the control group.

This meta-analysis has several limitations, the first being lack of sufficient studies, which limits the overall sample size. Second limitation is the short duration of study period. Although the authors kept a minimum of 2 months duration as an inclusion criterion, this also may be insufficient to make clinically meaningful conclusions for conditions like obesity and overweight. Substantial heterogeneity in the included studies, as well as mostly unclear risk of bias, are other limitations. For these reasons, the GRADE recommendation is moderate to very low for most outcomes.

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To conclude, results of this meta-analysis suggest that liraglutide alone or as add-on treatment to metformin produces reduction in weight and BMI when administered in adult

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