Xenofon Baraliakos and Jette Primdahl discuss the future of rheumatology
Telerheumatology: What Should We Be Thinking About Now? Feature:
Editorial Board 07 Welcome
Foreword
Congress Review
10 Review of the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress, 12th-15th June 2024
Congress Features
23 Chimeric Antigen Receptor T Cell Therapy in Autoimmune Disease
Helena Bradbury
26 Understanding Sjögren's Syndrome
Victoria Antoniou
Abstract Reviews
30 Effects of High-Intensity Resistance Training for Patients with Myositis: 1-Year Follow-Up on a Randomised Controlled Intervention Trial
Jensen et al.
33 Comparison of Lung Ultrasound B-Lines and Pleural Line Alterations with Automated Quantitative CT: is it Possible to Overcome the Limitations of the Ultrasound Method?
Beigi et al.
36 Abstract Highlights
Congress Interviews
43 Xenofon Baraliakos
45 Jette Primdahl
48 Daniel Aletaha, Andrew Cope, and Mwidimi Ndosi
Interviews
53 Qasim Akram
57 Rizwan Rajak
Infographic
60 Biosimilars in Bone Health Treatment
Features
63 Ageing Population and Landscape of Rheumatoid Arthritis Treatment in Japan
Kubo and Tanaka
69 Telerheumatology: What Should We Be Thinking About Now?
Peoples and Taylor Articles
74 Successful Screening of Undiagnosed Psoriatic Arthritis in Primary Care Utilising Digital Interventions Within a Quality Improvement Programme
Chan et al.
83 Eosinophilia in Rheumatology: A Management Challenge
Alsharkawy et al.
93 Atypical Presentation of Gouty Arthritis That Mimics Hand Soft Tissue Infection: Case Report
"This year’s Congress aimed to unite medical professionals, people living with RMDs, health professionals in rheumatology..."
Editorial Board
Editor-in-Chief
Prof Ian C. Chikanza
Catholic University of Zimbabwe and University of Zimbabwe, Harare, Zimbabwe
Consultant in Adult and Paediatric Rheumatology and Director of the Arthritis Care Centre, and Chairman Board of Trustees, Arthritis Care Africa Foundation.
Dr Richard Conway
St James Hospital and Trinity College, Ireland
Dr Lucía Silva-Fernández
Complexo Hospitalario Universitario de A Coruña (CHUAC), Spain
Dr Christakis Christodoulou
University of Nicosia Medical School, Cyprus
Prof Elaine Dennison
Southampton General Hospital, UK
Prof Dr Hendrik Schulze-Koops
Ludwig Maximilian University of Munich, Germany
Dr Ajesh Maharaj
Prince Mshiyeni Memorial Hospital, Nelson R Mandela School of Medicine, South Africa
Mike Backhouse University of Warwick, UK
Aysen Akıncı
Hacettepe University, Türkiye
Pankaj Bansal
Mayo Clinic School of Medicine and Science, USA
Özgür Kasapçopur
Istanbul University, Türkiye
Prof Prodromos Sidiropoulos
University of Crete Medical School, Greece
Gyorgy Nagy
Semmelweis University, Hungary
Aims and Scope
EMJ Rheumatology is an open access, peer-reviewed eJournal committed to publishing the highest quality medical research concerning all aspects rheumatic function and disease to help advance the development of this field.
The journal is published annually, six weeks after the European Alliance of Associations for Rheumatology (EULAR) Congress, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. Additionally, this journal covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.
EMJ Rheumatology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests.
EMJ Rheumatology is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.
EMJ Rheumatology endeavours to increase knowledge, stimulate discussion, and contribute to a better understanding of rheumatic diseases. Our focus is on research that is relevant to all healthcare professionals in the field. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance research and inform of coming trends affecting clinical practice in rheumatology.
Further details on coverage can be found here: 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 who are recognised authorities in their respective fields.
• Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on 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.
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.
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.
Editorial staff have final discretion over any proposed amendments.
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.
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
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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
Staff members attend medical congresses as reporters when required.
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. EMJ is completely independent of the review event (EULAR 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Vienna, Austria, the location of EULAR 2024.
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adult patients who are candidates for systemic therapy, and severe psoriatic arthritis in adults; mild to moderate Crohn’s disease either alone or in combination with corticosteroids in adult patients refractory or intolerant to thiopurines. Posology and method of administration: Should only be prescribed by physicians who are familiar with the various characteristics of the medicinal product and its mode of action. Patients must be educated to use the proper injection technique. The first injection of Metoject PEN should be performed under direct medical supervision. Adults, rheumatoid arthritis: The recommended initial dose is 7.5 mg of Metoject once weekly, administered subcutaneously. Depending on the individual activity of the disease and tolerability, the dose may be increased gradually by 2.5 mg per week. A weekly dose of 25 mg should in general not be exceeded. Polyarthritic forms of juvenile idiopathic arthritis: The recommended dose is 1015 mg/m2 body surface area (BSA)/once weekly, administered subcutaneously. In therapy-refractory cases the weekly dosage may be increased up to 20 mg/m2 BSA/once weekly. Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is available for this population. Psoriasis vulgaris, psoriatic arthritis: Test dose of 5 – 10 mg should be administered parenterally, one week prior to therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously. The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Crohn’s disease: Induction treatment: 25 mg/ week administered subcutaneously. Response to treatment can be expected after approximately 8 -12 weeks. Maintenance treatment: 15 mg/week. Elderly: Dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves. If changing the oral to parenteral administration a reduction of dose may be required due to the variable bioavailability. Contraindications: Hypersensitivity to methotrexate or any of the excipients; severe liver impairment; alcohol abuse; severe renal impairment (creatinine clearance < 30 ml/min); pre-existing blood dyscrasias (bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anaemia); serious, acute or chronic infections such as tuberculosis, HIV, other immunodeficiency syndromes; ulcers of the oral cavity and known active gastrointestinal ulcer disease; pregnancy, breastfeeding; concurrent vaccination with live vaccines. Special warnings and precautions for use: In the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and psoriatic arthritis, and Crohn’s disease, Metoject PEN (methotrexate) must only be used once a week. Dosage errors in the use can result in serious adverse reactions, including death. Undesirable effects: Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and StevensJohnson syndrome. Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal disorders e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite and abnormal liver function tests e.g. increased ALAT, ASAT, bilirubin, alkaline phosphatase. Other frequently (common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus. Effects: Pharyngitis, infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis. Lymphoma. Leukopenia, anaemia, thrombopenia, pancytopenia, agranulocytosis, severe courses of bone marrow depression, lymphoproliferative disorders, eosinophilia. Allergic reactions, anaphylactic shock, hypogammaglobulinaemia. Precipitation of diabetes mellitus. Depression, confusion, mood alterations. Headache, tiredness, drowsiness, dizziness, pain, muscular asthenia or paraesthesia/ hypoaesthesia, changes in sense of taste (metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis, encephalopathy/ leukoencephalopathy. Visual disturbances, impaired vision, retinopathy. Pericarditis, pericardial effusion, pericardial tamponade. Hypotension, thromboembolic events. Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of breath and fever, pulmonary fibrosis, Pneumocystis jirovecii pneumonia, shortness of breath and bronchial asthma, pleural effusion, epistaxis, pulmonary alveolar haemorrhage. Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain, oral ulcers, diarrhoea, gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis, gingivitis, haematemesis, haematorrhea, toxic megacolon. Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and bilirubin), cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin, acute hepatitis, hepatic failure. Exanthema, erythema, pruritus, photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticarial, increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia, skin exfoliation/ dermatitis exfoliative. Arthralgia, myalgia, osteoporosis, stress fracture, osteonecrosis of jaw (secondary to lymphoproliferative disorders). Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition, renal failure, oliguria, anuria, electrolyte disturbances, proteinuria. Inflammation and ulceration of the vagina, loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge. Fever, wound-healing impairment, asthenia, injection site necrosis, oedema. Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions (such as burning sensations, erythema, swelling, discolouration, pruritus, severe itching, pain) were observed, decreasing during therapy. Overdose: Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate. Legal classification: POM Marketing authorisation holder: medac medac GmbH, Theaterstr. 6, 22880 Wedel, Germany. Date of revision of text: 20.09.2023
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Welcome
Dear Readers,
I’m excited to welcome you to the 2024 issue of EMJ Rheumatology, bringing you all the latest updates from the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress, which took place in Vienna, Austria from the 12th–15th June.
In this issue, you will find key highlights from the event, including a study demonstrating the elevated risk of fracture in post-menopausal women when osteoporosis treatment is withdrawn, and an exciting study investigating predictive tools for life-threatening complications in Still’s Disease. We are delighted to feature interviews with experts who discuss a wide range of themes, from vasculitis and rheumatic diseases in pregnancy, to global collaboration and education in rheumatology.
Make sure not to miss a feature article discussing key aspects of the management of rheumatologic diseases and the role that telemedicine and AI play in the future of the field. Other peerreviewed content includes a compelling article discussing the successful screening of undiagnosed psoriatic arthritis utilising digital interventions, demonstrating that small changes made within quality improvement cycles can bring positive clinical impact.
In closing, I would like to take the opportunity to thank our Editorial Board, peer reviewers, and contributors for bringing this great issue together and helping us ensure a high level of quality. We look forward to receiving your manuscripts for next year’s issue. I hope you enjoy reading through this journal!
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Evgenia Koutsouki Editor
Foreword
Welcome to the latest issue of EMJ Rheumatology, featuring a range of peer-reviewed articles, interviews with key rheumatology experts, and features highlighting the latest advancements in the field. This issue also contains a review of the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress, held in Vienna, Austria, from the 12th–15th June, spotlighting the most significant advances presented at the Congress.
EMJ had the pleasure of speaking with several field experts, namely Rizwan Rajak and Qasim Akram, who share insights into their fascinating careers. Furthermore, key leaders from the EULAR Congress, Daniel Aletaha, Xenofon Baraliakos, and Jette Primdahl, discuss the expansion of research areas in rheumatology to include polymyalgia rheumatica, vasculitis, and rheumatic diseases in pregnancy, as well as the latest developments in clinical and translational research.
The articles in this issue cover a plethora of topics. Chan et al. review successful screening techniques of undiagnosed psoriatic arthritis in primary care, utilising
digital interventions within a quality improvement programme. In an insightful case report, AlSinan et al. discuss the atypical presentation of gouty arthritis that mimics hand soft tissue infection. Such lesions may, however, become secondarily infected. Dubey et al. review the recurring challenges posed by eosinophilia in rheumatology.
AlSinan et al. discuss the atypical presentation of gouty arthritis that mimics hand soft tissue infection
As Editor-in-Chief, I would like to thank all authors, peer-reviewers, and Editorial Board members who contributed to the success of this 2024 issue. I hope this journal will continue to expand your knowledge of the field, and elevate the quality of your daily clinical practice.
Ian C Chikanza
Medical Director, International Arthritis & Hypermobility Centre, Harley Street Clinic, London, UK; Professor & Consultant in Adult and Paediatric Rheumatology, Barts and The London School of Medicine, UK; Catholic University of Zimbabwe, Harare, Zimbabwe
EULAR 2024
This year’s Congress aimed to unite medical professionals, people living with RMDs, health professionals in rheumatology...
Congress Review
Review of the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress
THE European Alliance of Associations for Rheumatology (EULAR) 2024 Congress took place in Vienna, Austria, from June 12th–15th, with 14,000 rheumatologists attending. The event featured oral presentations, abstract and poster talks, and meet-the-expert sessions.
EULAR is a leading non-profit organisation dedicated to reducing the impact of rheumatic and musculoskeletal diseases (RMD) across Europe, representing patients, health professionals, rheumatologists, researchers, and scientific societies.
The Congress is renowned for its high scientific standards, serving as a platform for sharing advancements in rheumatology and fostering collaboration among experts.
This year’s Congress aimed to unite medical professionals, people living with RMDs, health professionals in rheumatology, paediatric rheumatologists, and industry partners. This alliance strives to improve the lives of those affected through innovation, education, and collaboration.
EULAR President David Aletaha conducted the opening ceremony, showcasing the organisation's core values of patientcentredness, innovation, responsibility, flexibility, inclusivity, and dedication. In an exciting announcement, Aletaha and EULAR President-Elect Xenofon Baraliakos introduced the new 2024–2029 EULAR manifesto focusing on improving care quality, advocating for better social policies, and advancing RMD research and innovation. Key goals include better
prevention, timely specialist access, and the integration of digital health technologies.
Loreto Carmona, Past-Chair of the EULAR Advocacy Committee, started with explaining the patient-centredness objective of the manifesto. She explained that one in five Europeans are affected by RMDs, and called for greater awareness and action from policymakers and the public. RMDs are a significant reason for patients to seek out medical consultations; however, their impact on health systems and economies remains under recognised. The manifesto calls for collective efforts from rheumatologists, healthcare professionals, and patients with RMD to address these issues. Other key focus areas in the manifesto are improving quality of care, social policies, and research and innovation. Uta Kiltz, Chair of the EULAR Quality of Care Committee, highlighted the importance of prioritising RMDs in the European Union (EU) non-communicable diseases initiative, placing an emphasis on the importance of early diagnosis, prevention, and cost-effective patientcentric treatment models. Elsa Mateus, EULAR PARE Vice President, called for the recognition of RMDs as a leading cause of
disability, urging policymakers to enhance social care and mental health services, and create more inclusive work environments and education. Roland van Vollenhoven, Chair of the EULAR Research Committee, highlighted the importance and necessity of research and innovation to better understand and treat RMDs, calling for a collaboration between the EU, member states, medical societies, and patient associations to drive advancements in rheumatological care.
In recognition of special achievements in the field of rheumatic and musculoskeletal diseases, Aletaha hosted the annual awards ceremony. The EULAR Meritorious Service award went to Julia Rautenstrauch, University Medical Center, Johannes Gutenberg University of Mainz, Germany, for her outstanding service to rheumatology. Thea Vliet Vlieland, Universiteit Leiden, the Netherlands, received the EULAR HPR Lifetime Achievement Award, and Emma O’Carroll received 1st place for the EULAR Edgar Stene Prize, awarded to a person with an RMD submitting the best essay describing their experience.
Laure Gossec, EULAR Council Treasurer, followed by sharing her insights on exiting projects such as RheumaFacts, which provides essential data on rheumatic diseases to support advocacy, identify
underserved care areas, and highlight the needs and challenges of patients with RMDs. Gossec also introduced the ENTRI network, aimed at enhancing clinical trial collaboration across Europe to accelerate new treatments. Additionally, she discussed the EULAR Impact of RMDs survey, a large patient-led initiative to gather firsthand information on how RMDs affect patients, informing future policies and care strategies.
The ceremony concluded with the EULAR abstract awards, the undergraduate abstract award was received by Maria Hanif, University of Liverpool, UK, and Yuan Zhao, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. The EULAR Abstract Award PARE (People with Arthritis/Rheumatism in Europe) was received by Zoë Clark, National Axial Spondyloarthritis Society, London, UK. The EULAR Abstract Award FOREUM was received by Edoardo Cipolletta, Polytechnic University of Marche, Ancona, Italy, for Clinical Science and Stefania Croci, IRCCS of Reggio Emilia, Italy, for Basic Science.
EMJ was thrilled to be part of the 2024 Congress, and look forward to attending the EULAR 2025 Congress, which will be held in Barcelona, Spain.
Other key focus areas in the manifesto are improving quality of care, social policies, and research and innovation
Withdrawing Osteoporosis Treatment in PostMenopausal Women Increases Fracture Risk
BISPHOSPHONATES and denosumab are recommended first-line and second-line treatments for post-menopausal women with osteoporosis, helping to reduce the risk of fractures by maintaining bone density.
These drugs are usually prescribed for the length of 3–5 years or longer for high-risk patients, based on the length of clinical trials. Recent recommendations suggest long-term use should be discontinued. However, recent data from the USA suggests that stopping these medications can increase fracture risks, these data are now supported by a new study from France, presented at the EULAR 2024 Congress.
The case-control cohort study collected data from the French National Claim Database (SNDS). It aimed to analyse the impact of long-term discontinuation of osteoporosis treatments (either oral or intravenous) on fragility fractures, and compare the risk with women continuing treatment. The study involved over 128,000 women with post-menopausal osteoporosis, focusing on those who discontinued bisphosphonates or denosumab.
Results showed that 55.1% of women prescribed oral bisphosphonates, 68.9% of those prescribed intravenous bisphosphonates, and 42.5% of those prescribed denosumab had at least one discontinuation. Discontinuations occurred in women in their mid-to-late 70s after 3.6–4.8 years of treatment. Results also showed an upward trend in the incidence of longterm discontinuations, rising from 1.6–17.6% in 2015 and 12.1–29.5% in 2020.
Women who discontinued treatment faced a significantly higher risk of fragility fractures compared to those who continued treatment. Discontinuation of bisphosphonates increased fracture risk by 12.4%, while stopping denosumab nearly doubled the risk (92.3%). The most significant increase was observed in hip fractures, with a 19% increase for bisphosphonates discontinuation and a 108.3% increase for denosumab discontinuation. However, no significant differences were seen with the discontinuation of intravenous bisphosphonates.
Discontinuations occurred in women in their mid-to-late 70s after 3.6–4.8 years of treatment
The study’s findings highlight that discontinuation of denosumab is not recommended, with 42.5% of women who discontinued this treatment for at least a year presented with doubled fracture risk. Furthermore, increased fracture risks after treatment discontinuation varied in oral verses intravenous bisphosphonates, which warrants further research and clarification in treatment guidelines to mitigate risks associated with the discontinuation of osteoporosis medications.
VEXAS: Towards Molecular and Phenotypic Characterisation
NEW findings on VEXAS syndrome were presented at the EULAR 2024 Congress, shedding light on the molecular and phenotypic characteristics of this rare and life-threatening autoinflammatory disease.
VEXAS, an adult-onset condition caused by a somatic mutation in the UBA1 gene, involves severe rheumatic and haematologic symptoms, complicating its diagnosis due to symptom overlap with other inflammatory diseases. Since its discovery in 2020, the medical community has struggled to fully understand VEXAS syndrome.
Researchers at the IRCCS San Raffaele Hospital in Milan, Italy, focused on the haematopoietic stem/progenitor cells (HSPC) in six patients with VEXAS, using multiparametric immunophenotypic analysis and single-cell RNA sequencing of peripheral blood and bone marrow. Their findings were compared with healthy ageand sex-matched controls.
The study revealed a myeloid skewing in the mutant HSPC of patients with VEXAS. This was evidenced by a two- to threefold reduction in primitive stem cells, multipotent, and lymphoid progenitors in the bone marrow, coupled with a two-fold increase in myeloid progenitors compared to healthy individuals. Additionally, there was a three- to four-fold increase in circulating HSPC, myeloid-biased HSPC, and immature myeloid cells. Gene expression analysis showed upregulated inflammatory pathways and metabolic changes, including hyperactivation of the glycolytic pathway and alterations in lipid metabolism.
A notable discovery from the single-cell RNA sequencing of bone marrow mononuclear cells was a specific subpopulation of CD34+ cells unique to patients with VEXAS, marked by upregulated stress response and immune activation pathways.
There was a three- to fourfold increase in circulating HSPC, myeloid-biased HSPC, and immature myeloid cells
Furthermore, the research team developed VEXAS models using gene-editing technologies on healthy human HSPC. When these gene-edited HSPC were transplanted into immunodeficient mice, there was a striking 100-fold reduction in circulating B cells, while the natural killer cell and myeloid compartments remained preserved.
These findings underscore the role of UBA1 mutations in driving the expansion of HSPC and enhancing myelopoiesis, leading to the accumulation of myeloid precursors. The success of the gene-editing models offers hope for preclinical testing and validation of novel therapeutics for VEXAS syndrome, paving the way for potential new treatments for this rare disease.
Revealing Joint-Specific Responses in Psoriatic Arthritis Treatments
NOVEL results presented at the EULAR 2024 Congress shed new light on treating psoriatic arthritis (PsA), highlighting the importance of considering joint-specific responses to therapy.
EULAR advocates for a progressive management approach tailored to specific manifestations and disease activity in PsA. Traditionally, treatment outcomes have been measured by the overall reduction in the number of affected joints, often overlooking the specific locations of these joints. However, new research suggests that the location of the joint may significantly influence treatment effectiveness. Arthritis manifests differently across various joints despite being driven by systemic inflammatory cues. Previous studies in rheumatoid arthritis have shown that transcriptomic differences in synovial fibroblasts from different joints can lead to joint-specific phenotypes, each with unique characteristics and cytokine responses.
The clinical response to TNFi in PsA is influenced by joint location, at least in the time to first resolution of joint swelling
Adrian Cieurea, University Hospital Zurich, Switzerland, and colleagues investigated whether different anatomical locations in patients with PsA might respond variably to tumour necrosis factor inhibitor (TNFi) treatment. The study analysed real-life data from over 1,700 patients with PsA across several European registries within the EuroSpA network. The primary outcome measured was the time to the first resolution
of joint swelling, assessed on an individual joint level using the 28-joint count at baseline and various intervals over two years. At baseline, the average number of swollen and tender joints was 4.8 and 7.4, respectively, with a mean disease activity score using C-reactive protein (DAS28-CRP) 4.7.
The study found significant variations in the resolution of joint swelling depending on the joint location. Specifically, joints in the upper limb, such as the elbow and shoulder, showed a higher swelling resolution rate than the proximal interphalangeal joint of the third digit (PIP3). Conversely, the wrist demonstrated a lower rate of resolution relative to the PIP3 joint. No significant difference was observed in the resolution of swelling in the knee compared to the elbow.
These findings suggest that the clinical response to TNFi in PsA is influenced by joint location, at least in the time to first resolution of joint swelling. The study indirectly identified joints less likely to respond to TNFi treatment, implying that local factors, such as mechanical influences or specific synovial fibroblast phenotypes, may impact treatment effectiveness. This research underscores the necessity for future studies to explore joint-specific responses in PsA and their associations with distinct therapeutic mechanisms, potentially leading to more targeted and effective treatment strategies.
Biological Treatments Reduce Psoriatic Arthritis Risk in Patients with Psoriasis
RESEARCH presented at the EULAR 2024 Congress suggested that early intervention with biologic treatments may prevent the progression from psoriasis to psoriatic arthritis (PsA).
The prevalence of PsA is estimated to be between 6% and 42%
PsA affects about one-third of individuals with psoriasis, a chronic inflammatory skin condition. The prevalence of PsA is estimated to be between 6–42%. However, in most cases symptoms precede PsA, making skin psoriasis a model for pre-PsA.
The retrospective study utilised electronic history data from a global network of electronic health records, encompassing over one million patients. Researchers compared the incidence rates of new-onset PsA among patients receiving first or second line biologic treatments for psoriasis. The studied biologics included tumour necrosis factor inhibitors (TNFi) and biologics targeting interleukins (IL-12i, -23i, -17i, and -12/23i). The incidence rates of PsA were tracked over 5 years, for first-line treatments, and for 3 years for second line treatments, using the first-line TNFi population as a reference group.
Results showed that patients with psoriasis undergoing first-line treatment with IL-12/23i had a 37% lower risk of developing PsA, and those on IL-23i had a 39% lower risk compared to those on TNFi, at 5 years. For second-line treatments, the risk of developing PsA was 32% lower with IL-12/23i and 31% lower with IL-23i at 3 years, compared to first-line TNFi. Additionally, IL-23i showed a 47% lower probability of PsA development compared to IL-17i in both first and second line treatments over 3 and 5 years.
The findings of the study indicate that biologic treatments, particularly IL-12/23i and IL-23i, may significantly reduce the risk of PsA in patients with psoriasis, in both newly exposed patients and those who have been previously exposed to biologics. The findings underscore the potential of biologics in early intervention and altering the disease course, offering a promising strategy for preventing progression to PsA.
Predicting Response in Treatment-Naïve Rheumatoid Arthritis
A RECENT study presented at the EULAR 2024 Congress assessed the power of multi-modal analysis of synovial tissue inflammation in treatment-naïve patients with rheumatoid arthritis (RA), with the aim of identifying predictive biomarkers for treatment response.
Researchers examined 373 treatment-naïve patients with RA, who were given an ultrasoundguided synovial tissue biopsy
Researchers examined 373 treatmentnaïve patients with RA, who were given an ultrasound-guided synovial tissue biopsy. The synovitis degree and synovial pathotype was then determined for each individual. A subset of 45 samples was used for synovial tissue macrophage phenotyping and profiling in order to measure the abundance of distinct macrophage populations. The transcriptomic profile of CD68ᵖºˢ cells in distinct regions of interest within the synovial tissue was also determined using spatial technology. After study entry, patients were managed with a treat-to-target strategy.
The findings showed that those patients who reached disease remission at 6 months had a lower Krenn Synovitis Score (KSS) at baseline compared to people who did not achieve this outcome. People who had been stratified based on synovial pathotype as lympho-myeloid or diffusemyeloid pathotype had a lower response to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) compared
to people with a pauci-immune pathotype. Further analysis suggested, however, that at an individual level, baseline KSS has limited capacity to distinguish between responders and non-responders, which highlights the need for multi-modal tissue deconvolution.
Flow cytometry analysis revealed that those with lympho-myeloid or diffusemyeloid pathotypes showed comparable enrichment of two distinct synovial tissue macrophage populations (MerTKposCD206pos and MerTKnegCD206neg), while patients with the pauci-immune pathotype showed a predominance of MerTKposCD206pos The enrichment of MerTKposCD206pos synovial tissue macrophages was also higher in people who achieved remission at 6 months. Notably, enrichment of these MerTKpos synovial tissue macrophages greater than 44.3% from baseline was shown to be an independent factor associated with achieving remission at 6 months.
This research has revealed that a multimodal analysis of synovitis could enable differentiation of treatment-naïve patients with RA at their first medical evaluation. This data strongly supports the predictive value as a patient-based decision test tool.
Predictive Tools for Life-Threatening Complications in Still’s Disease
A SIGNIFICANT advancement for rheumatology; a multi-centre, observational, prospective study presented at the EULAR 2024 Congress has underscored the clinical value of the systemic score in predicting lifethreatening complications in Still's disease.
This inflammatory disorder, characterised by fever, arthritis, and skin rash, affects both children and adults. Formerly known as systemic juvenile idiopathic arthritis in children and adultonset Still's disease in adults, the condition can lead to severe complications, including macrophage activation syndrome and increased mortality.
This study gathered data from 597 patients across two major research groups: the Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) AOSD-study group and the AutoInflammatory Disease Alliance (AIDA) Still’s disease registry.
Patients were assessed using the systemic score, which assigns one point to each of 12 clinical manifestations, including fever, rash, pleuritis, pneumonia, pericarditis, hepatomegaly or abnormal liver function tests, splenomegaly, lymphadenopathy, leucocytosis >15,000/mm3, sore throat, myalgia, and abdominal pain. Notably, 100% of the study's patients exhibited fever, 87.9% had joint involvement, and 66.1% presented with skin rash. Additionally, liver involvement was noted in 43.5% of patients, macrophage activation syndrome in 13.1%, and lung disease in 6.9%, with a mortality rate of 3.4% due to Still’s disease.
The study revealed that a systemic score of seven or higher is a significant predictor of life-threatening evolution. Further riskprofile assessments and a multivariate logistic regression model adjusted for age and sex identified liver involvement and lung disease as independent predictors of severe outcomes. Specifically, patients with liver involvement frequently experienced lymphadenopathy, splenomegaly, pericarditis, and pleuritis, while those with lung disease showed higher rates of sore throat, lymphadenopathy, splenomegaly, liver involvement, pericarditis, pleuritis, and abdominal pain.
A systemic score of seven or higher is a significant predictor of life-threatening evolution
These findings suggest that the systemic score is a valuable prognostic tool in clinical practice. Moreover, liver involvement and lung disease should be recognised as key multi-organ manifestations and major predictors of life-threatening evolution in Still’s disease. This study represents a crucial step forward in understanding and managing this complex condition.
New Threshold Recommendation for Spondyloarthritis Treatment
DECISIONS
for treatment intensification for patients with axial spondyloarthritis (axSpA) is associated with a higher disease activity score cut-off than what is recommended, according to a study by Weber and colleagues presented at the EULAR 2024 Congress.
For patients with axSpA, persistent disease activity necessitates adapting treatment. EULAR, in collaboration with the Assessment of SpondyloArthritis International Society (ASAS), recommends using the Ankylosing Spondylitis Disease Activity Score (ASDAS) with a cut-off ≥2.1 to identify high disease activity and therefore consider treatment intensification. However, this recommendation is not always implemented in clinical practice, possibly because the ASDAS was initially developed for research purposes. This study aims to investigate whether the cut-off values align with treatment intensification decisions in everyday clinical practice.
ASDAS cut-off varied from 2.3–2.8, consistently higher than the recommended 2.1
For the study, treatment intensification was defined as an increase in the dose or frequency of the same drug, switching to another drug, or adding a new drug due to inefficacy. Data were sourced from a prospective multi-centre registry for SpA, including 350 patients with 2,265 ASDAS measurements. Analyses included all observations, and were repeated with only the first observation per patient per calendar year to balance the number of observations per patient by follow-up duration. Approximately two-thirds received a biologic or targeted synthetic diseasemodifying antirheumatic drug at some point during follow-up.
Researchers found that treatment intensification followed 10.4% of ASDAS measurements. Patients were often already on anti-inflammatory treatment at the time of intensification. Intensification typically involved switching to another drug within the same class or adding a drug, while the use of conventional synthetic disease-modifying antirheumatic drugs and corticosteroids was limited. The mean ASDAS and the proportion of patients with ASDAS ≥2.1 were higher at intensification time points than at non-intensification time points. The optimal ASDAS cut-off related to treatment intensification was 2.7 when all measurements were included, and similar when only one measurement per patient and calendar year was used. Over the years, the optimal ASDAS cut-off varied from 2.3–2.8, consistently higher than the recommended 2.1.
The study concluded that, in daily practice, treatment intensification in axSpA is associated with a higher ASDAS cut-off value than the recommended 2.1. This discrepancy suggests that rheumatologists may find the current cut-off too stringent, or that they consider additional factors beyond disease activity in their treatment decisions. EULAR and ASAS emphasise the need for individualised treatment considering axial, peripheral, and extramusculoskeletal manifestations, along with each patient's comorbidities and psychosocial factors.
Achieving Drug-Free Remission in Early AxSpA: Challenges and Successes
EARLY therapeutic interventions in inflammatory rheumatic diseases have been effective in achieving drug-free remission, as recommended by EULAR.
These interventions, particularly using conventional synthetic disease-modifying antirheumatic drugs (csDMARD), have slowed disease progression in conditions like rheumatoid and psoriatic arthritis. However, axial spondyloarthritis (axSpA) poses unique challenges for early intervention studies due to its insidious onset and often delayed diagnosis.
Of the 55 patients who completed the trial, 61.8% achieved sustained clinical remission, and 21.8% had low disease activity at Week 52
At the EULAR 2024 Congress, Łukasik and colleagues presented a prospective study on a tight control, treat-to-target approach for newly diagnosed, treatment-naïve patients with axSpA, following Assessment of SpondyloArthritis international Society (ASAS)-EULAR recommendations. Patients initially received optimal doses of two different non-steroidal anti-inflammatory drugs (NSAID) for at least 4 weeks. If no clinically significant improvement was observed, monotherapy with golimumab was initiated. Patients were monitored until achieving sustained clinical remission, defined as inactive disease state at two consecutive visits spaced at least 12 weeks
apart, or until the end of the trial. Postremission, patients were observed in routine clinical practice to assess the feasibility of maintaining drug-free remission.
Of the 55 patients who completed the trial, 61.8% achieved sustained clinical remission, and 21.8% had low disease activity at Week 52. This marked the first clinical trial in early axSpA where over 60% of patients achieved sustained inactive disease. Univariate analysis indicated that sex and baseline BASDAI score significantly differed between those who did and did not achieve remission. Multivariate analysis further identified male sex, smoking abstinence, and lower BASDAI score as remission predictors.
Despite achieving remission, 84.8% of patients experienced a disease relapse within a year after stopping treatment, especially those who achieved remission with NSAID treatment. The median time to relapse was 61 days for NSAID-treated patients and 155 days for golimumabtreated patients, with 18.2% of the latter maintaining drug-free remission for over 3 years. Thus, while a treat-to-target approach can induce high rates of inactive disease in early axSpA, maintaining drugfree remission remains challenging.
Reassessing Glucocorticoid Withdraw in Lupus Management
RECENT findings presented at the EULAR 2024 Congress offered new insights into the optimal management of glucocorticoid therapy for systemic lupus erythematosus (SLE).
The session comprised two abstracts tackling the debate about the safest and most effective dosing strategies. Glucocorticoids are a cornerstone in treating SLE, yet their long-term adverse effects have made dose reduction a critical objective in the treatto-target management approach. EULAR guidelines recommend a glucocorticoid dose of no more than 5 mg/day, while the lupus low disease activity state (LLDAS) definition allows for up to 7.5 mg/day. However, a significant challenge is whether it is safe and feasible to discontinue glucocorticoids after achieving remission.
Filippo Vesentini, University of Padua, Italy, presented data on the risk of flare associated with glucocorticoid discontinuation versus low-dose maintenance. Based on prospectively collected data, the retrospective analysis evaluated flare-free remission in patients with SLE who had either discontinued glucocorticoids or maintained a dose of 5 mg/day or less. During the followup, 484 patients achieved remission, with 360 discontinuing glucocorticoids and 124 remaining on a low dose. Over an average of 87 months, 85 flares were recorded, of which 48 discontinued and 37 remained on a low dose. This equated to an annual flare rate of 8.5 flares per 100 patients/year for the
discontinuation group and 1.65 for the lowdose group. Factors influencing flare-free remission included disease duration and antiU1RNP status. Vesentini's team concluded that glucocorticoid discontinuation is safe and associated with a low risk of flare when correctly tapered.
In a separate presentation, Eric Morand, Monash University, Australia, examined the impact of lowering the glucocorticoid ceiling in the LLDAS definition to align with the 5 mg/day EULAR recommendation (LLDAS-5).
The study analysed data from a longitudinal cohort of 2,213 patients with SLE. Results showed that 2.1% of patients died, 29% accrued organ damage, and 67% experienced flares. LLDAS-7.5 was achieved by 87% of patients in 47% of visits, while 83% attained LLDAS-5 in 42% of visits. Both thresholds provided similar protection against mortality, organ damage, and flare rates.
These findings underscore the importance of glucocorticoid dose reduction in SLE management. However, no evidence supported a revision of the current LLDAS dose threshold, indicating that the validated LLDAS definition should continue to guide clinical practice and research.
Vesentini's team concluded that glucocorticoid discontinuation is safe and associated with a low risk of flare when correctly tapered
Barriers and Facilitators for Physical Activity in Rheumatic Diseases
A SYSTEMATIC review and qualitative study presented at the EULAR 2024 Congress explored the barriers and facilitators affecting adherence to EULAR’s physical activity recommendations.
Challenges in real-world clinical settings persist, despite the well-established benefits for patients with rheumatic and musculoskeletal diseases (RMD). EULAR has long promoted health-enhancing physical activity, but significant gaps remain between research findings and their practical application.
A systematic review of 68 articles, identifying 29 themes across social, environmental, and systematic factors was conducted. Concurrently, a qualitative research study was conducted in Denmark, observing clinical practices and conducting interviews with healthcare professionals to understand their perspectives on integrating physical activity guidance into routine care.
Results of the systematic review showed that the five most significant facilitators for physical activity adherence were family and friends, a supportive health professional, costs, and access to adapted and supervised programs. At the same time, the results of the qualitative study identified barriers related to healthcare professionals’ skills, competencies, and professional identity. The study on facilitators and barriers collected data from four
rheumatology outpatient clinics in Denmark. Other major barriers identified in the study were environmental context and resources, particularly the lack of physical and clinical resources needed to provide appropriate guidance. However, informants shared beliefs about the potential benefits of incorporating physical activity guidance into rheumatology care. The Theoretical Domains Framework and template analysis were used in the data work-up and interpretation.
Significant gaps remain between research findings and their practical application
The findings of the two studies underscore the need to improve the abilities of healthcare professionals to guide their patients in physical activity. Additionally, addressing the environmental and systemic barriers, such as costs and access to resources is also crucial. Further research, including a planned questionnaire in four European countries, aims to tailor strategies to enhance the adoption and adherence to EULAR’s physical activity recommendations. These continued efforts will ultimately benefit people with RMDs.
Chimeric Antigen Receptor T Cell Therapy in Autoimmune Disease
HOT off the press from the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress was a session spotlighting the latest advancements in immunotherapy for rheumatological diseases. The session was led by Georg Schett, Friedrich-Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Germany, and chaired by Anastasia Madenidou, University of Manchester, UK, and Christophe Richez, Centre Hospitalier Universitaire de Bordeaux Groupe hospitalier Pellegrin, France.
BACKGROUND OF CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY
Schett opened his talk by detailing the structure and precise mechanism of chimeric antigen receptor T (CAR-T) cell therapy. These antigens possess the extraordinary ability to recognise and destroy antigen-expressing cells. “They are serial killers,” Schett stated. Structurally chimeric antigen receptors comprise a targeting element, a transmembrane domain, and an intracellular signalling domain. Extending out from the T cell, the targeting domain acts as a bridge between the immune system and the pathogenic cell, whilst the transmembrane and intracellular domains drive proliferation and cytokine secretion, following activation of the T cell.
Schett subsequently explained the variability in the transduction method, and type of procedure, and explored the latest innovations in this field. Traditionally, lenti- or retro-viruses are the common vectors; however, increasingly liposome nanoparticle and CRISPR-CAS9 gene editing systems are used. Regarding cell infusion, this can either be autologous, where the cells are taken from the patient, or allogenic, where the cells are taken from a healthy donor and gene-edited to reduce
antigenicity. Alternatively, transduction can also occur in vivo within the patient. The cellular source can also vary between T cells or natural killer cells.
CASE STUDY: CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOSUS
Schett shared an insightful case study of a 20-year-old female patient. Diagnosed with severe and refractory systemic lupus erythematosus (SLE), the patient additionally presented with active lupus nephritis, nephrotic syndrome, pericarditis, pleurisy, rash, arthritis, and a history of Libman-Sacks endocarditis. Previous treatments included hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, and tacrolimus, as well as the B cell-targeting therapies belimumab and rituximab, with none driving significant improvement. Her anti-dsDNA levels, for instance, were 8,000-12,000 units/mL (normal <4 units/mL) and proteinuria of 4–6 g/day (normal <0.15 g/day). After the infusion of 50 million CAR-T cells, the patient showed no major toxicity and massive expansion of the CAR-T cells during the first 10 days.
Notably, results revealed a rapid loss of circulating B cells, after CAR-T exposure, and a fast decrease of anti-dsDNA antibodies and seroconversion later on. Additionally, normalisation of complement factor C3 and C4 levels and regression of proteinuria were observed. Schett was elated to share that now, over 3 years later, the patient is completely free of all immunosuppressive treatments, and is living a healthy, normal life.
EXPLORER STUDY: POTENTIAL OF RITUXIMAB
Schett provided developments on the EXPLORER trial.1 Conducted in 2010, this trial investigated the use of rituximab for the treatment of SLE. Rituximab is a monoclonal antibody targeting CD20, a protein found on the surface of B cells, which are implicated in the pathogenesis of autoimmune diseases like SLE. Overall, 257 patients enrolled, with individuals entering with a ≥1 British Isles Lupus Assessment Group (BILAG) A score or ≥2 BILAG B scores, despite background immunosuppressant therapy. The BILAG scoring system is a tool used to determine the disease activity in patients with SLE,
Over 3 years later, the patient is completely free of all immunosuppressive treatments
ranging from ‘A’ (severe activity requiring significant treatment) to D (previous activity but currently inactive).1 Unfortunately, the EXPLORER trial concluded that rituximab did not demonstrate a statistically significant improvement in the treatment of SLE compared to the placebo. However, it did provide valuable insights into the disease and helped guide further research into the treatment of SLE and the use of B cell-targeted therapies. In fact, Rituximab has shown to be an effective form of treatment for rheumatoid arthritis. For instance, a 2007 clinical trial by Vos et al,2 studied the effects of rituximab treatment on the synovium in patients with rheumatoid arthritis early after initiation of treatment. Seventeen patients with rheumatoid arthritis underwent an arthroscopic synovial biopsy procedure directly before and 1 month after receiving chimeric anti-CD20 monoclonal antibody rituximab, and showed considerable reductions in synovial B cell count.2
DEEP NARROW VALLEY
Schett described the depletion pattern of B cells following CAR-T therapy as a ‘deep narrow valley’; short in length and deep in effect. Following depletion of the autoreactive B cells, a ‘reconstitution’ phase ensues in which new CD19 negative B cells are generated. As explained by Schett, this new population of B cells largely comprises naive cells, with low levels of memory B cells and complete eradication of plasmablasts and activated B cells, the latter of which is associated with lupus activity.3 Supporting evidence of this includes the CASTLE study,4 which reported a short-term peak of CAR-T cells after 8 days, and reconstitution of B cells 30–90 days following treatment administration.
Touching on the deep effects of CAR-T cell therapy in autoimmune disease, Schett noted interstitual lung disease and a partial reconstruction of papillary structures in the skin, a phenomenon not observed post rituximab treatment. Additionally, there is a significant downregulation of Type 1
References
1. Merrill JT et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus. Arthritis Rheum. 2010;62(1):222-33.
interferon genes in T cells, disrupting this immune response. Importantly, Schett also shed light on the potential adverse effects of CAR-T cell therapy including elevated body temperature, typically in the first days following infusion, and cytokinerelease syndrome Grade 1. Furthermore, mild infections can occur, namely upper respiratory tract infection, SARS-CoV-2, and herpes zoster virus.
FINAL TAKEAWAYS
Overall, this EULAR 2024 Congress session showcased the promising results of CAR-T cell therapy in treating refractory cases of systemic lupus erythematosus, offering hope for patients with limited options. The discussions also delved into the mechanisms, innovations, and potential adverse effects associated with these treatments. As the field continues to evolve, these insights pave the way for further research and development, aiming to improve outcomes for patients with autoimmune diseases.
2. Vos K et al. Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis. 2007;56(3):772-8.
3. Müller F et al. CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up. N Eng J Med. 2024;390(8):687-700.
4. Schett G et al. POS0030 safety and preliminary efficacy of CD19 CAR-T cell treatment in rheumatic diseasedate from the first part of the phase I/II CASTLE BASKET study. Annuals of the Rheumatic Diseases. 2024;83:327.
THIS year’s European Alliance of Associations for Rheumatology (EULAR)
Congress took Vienna, Austria by storm, with a multitude of fascinating sessions taking place between 12th–15th June. Not least among them was the insightful ‘Bench to Bedside’ session on Sjögren's syndrome, expertly chaired by Hendrika Bootsma, University of Groningen, the Netherlands; and Fai Ng, Newcastle University, UK. This session addressed new developments and hypotheses on the pathogenesis of Sjögren's syndrome, along with novel methods for assessing disease activity and future treatments based on new pathogenic mechanisms.
PATHOPHYSIOLOGY OF SJÖGREN’S SYNDROME
Frans Kroese, University Medical Centre Groningen, the Netherlands, introduced Sjögren’s syndrome as the second most common rheumatic systemic autoimmune disease, affecting approximately ten times more women than men. Sjögren’s syndrome is typically characterised by the presence of sicca symptoms, caused by a dysfunction in the lacrimal and salivary glands. Extraglandular manifestations are also present in many patients, of which fatigue is the most common. The pathogenesis of this disease is not fully understood, however, and there is no approved treatment as of today.
As explained by Kroese, some vital aspects of the pathogenesis of Sjögren’s syndrome are understood. The presence of lymphocytic infiltrates in salivary and lacrimal glands, for example, is known, and studies have highlighted the importance of antigen presentation and B cells in this pathogenesis. Kroese went on to describe how lymphocytic infiltrates are frequently considered responsible for the dysfunction in the glands, and therefore the reduced saliva and tear production in patients: a hypothesis that he challenged. “There is an extremely poor, if (there is one) at all, association between the number of infiltrates and the saliva production,” Kroese
emphatically pointed out, highlighting research that demonstrated the lack of correlation between the focus score in the labial gland and the amount of saliva production stimulated.1 However, the number of infiltrates in the parotid glands does indeed show a correlation to saliva production.1 It is for these reasons that Kroese emphasised the need for analysis of salivary glands without infiltrates in patients with Sjögren’s disease. In doing so, he hopes to be able to better understand the early stages of pathogenesis of this syndrome.
This analysis has shed light on a new model for considering the factors contributing to the disease
He went on to describe an as of yet unpublished study which assessed the cells of patients with Sjögren’s disease without lymphocytic infiltrates. The expression of genes was shown to be dysregulated in the acinar cells of these patients. Further research additionally demonstrated that the mitochondria were also affected in patients with Sjögren’s disease.2 Kroese discussed his research analysing the activation of fibroblasts, whose trigger is unknown, but which then produce CXCL chemokines and extracellular matrix components, activating T cells. This process then transforms functional acinar cells into dysfunctional
acinar cells, leading to impaired saliva production, he explained, as well as damage to the mitochondria. This then leads to the formation of lymphocytic infiltrates, which contribute to impaired saliva production; however, this research shows that they may not be the initiating factor.
Kroese and colleagues’ research plays a vital role in understanding the pathogenesis of Sjögren’s syndrome, which until recently has not been well understood. Though the full story is not yet revealed, this analysis has shed light on a new model for considering the factors contributing to the disease.
ASSESSING TREATMENT EFFICACY OF SJÖGREN’S SYNDROME
Raphaèle Seror, Université Paris-Saclay, France, took to the stage to discuss the treatment of Sjögren’s syndrome, and the various considerations when assessing treatment efficacy. She introduced the key points that must be taken into account when assessing drug efficacy, namely key inclusion criteria, key noninclusion criteria, and primary outcome. Seror then provided a comprehensive
overview of how to define the target population and how inclusion criteria might be challenged, ensuring patients can be included despite restrictions of inclusion criteria. Seror additionally discussed the main challenges of choosing a primary endpoint; in particular, capturing all disease features while remaining sensitive to change and ensuring it is suitable for all patients. One of the most crucial aspects of assessing treatment efficacy and designing a study is listening to patients’ needs. Whilst understanding the expectations and unmet needs of patients during clinical trials can often be difficult, it is, however, absolutely necessary when examining drug efficacy, ensuring no patients feel neglected.
CURRENT AND FUTURE TREATMENT
With the first two talks in mind, Thomas Dörner, Charité Universitätsmedizin Berlin, Germany, looked to the current treatment landscape of Sjögren’s syndrome and how it may continue to develop in the future, addressing the various guidelines that are provided to clinicians for treatment.
The treatment of sicca symptoms is well established, with options such as tear drops or artificial tears for dry eyes, and H2O supplements or artificial saliva for dry mouth, being commonly understood and available.3 Treatment of systemic manifestations, such as fatigue or arthralgia, is less understood, pointed out Dörner, and clinicians often must turn to their knowledge of other rheumatic diseases, using nonsteroidal anti-inflammatory drugs (NSAID), glucocorticosteroids, immunosuppressives, or hydroxychloroquine, to name a few. There are now certain recommendations, provided by EULAR, that assist treatment, based on individual organ manifestations, which then must be further tailored to each patient.
Many trials to treat Sjögren’s disease have failed, often due to a lack of appropriate outcome measures. As a result, Dörner elaborated, the future of trials in Sjögren’s syndrome must be altered. He explained that the three main challenges in disease treatment are sicca symptoms, extraglandular manifestations, and constitutional symptoms, particularly fatigue. The first potential future mechanism for treatment of Sjögren’s disease discussed by Dörner is none other than dual anti-B cell therapy. By depleting B cells in this therapy, the impairment of saliva production was reduced.4 The clinical response was positive when this technique was trialled, with treated patients showing a significant change in baseline compared to the placebo group.4 Similar results were shown with other therapies that do not deplete B cells but block their intracellular signalling pathway; over 24 weeks, the EULAR Sjögren’s syndrome disease activity index (ESSDAI) separated well from baseline, and treated
References
1. Mossel E et al. Histopathology, salivary flow and ultrasonography of the parotid gland: three complementary measurements in primary Sjögren's syndrome. Rheumatology. 2022;61(6):2472-82.
2. Katsiougiannis S et al. Salivary gland epithelial cell in Sjögren's syndrome: metabolic shift and altered
patients showed significantly increased levels of unstimulated salivary flow.5
Dörner went on to describe other novel therapies for treating Sjögren’s; for example, therapies which block CD40 or CD40L (CD154). He analysed the efficacy and safety of these methods, emphasising the effect on ESSDAI, and highlighting the potential for future treatments to address extraglandular symptoms as well as sicca. At the moment, the medical need for patients with Sjögren’s remains high, but with all the innovative treatments being developed, Dörner was hopeful that this would not be the case in the future.
FINAL TAKEAWAYS
The eye-opening session that had taken a captive audience through the pathophysiology of the disease, how to design a study to effectively analyse new treatments for Sjögren’s, and what the future may hold for patients, not only in terms of treating sicca symptoms, but also extraglandular symptoms, came to a close with a final presentation from Pierre-Marie Duret, Hôpitaux Civils de Colmar, France, who briefly described his research on lymphoproliferative disorders complicating Sjögren’s disease. His talk completed this extensive look at Sjögren’s, its complications, origins, and how to treat it.
This session presented at EULAR provided a detailed analysis of Sjögren’s, shining light on many factors, perhaps most importantly highlighting the future treatments from which patients might one day benefit, as a result of our deeper understanding of the disease.
5. Dörner T et al. Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, doubleblind, placebo-controlled phase 2 trial. Ann Rheum Dis. 2024;83(3):360-71.
Abstract Reviews
Explore the latest developments in rheumatology with novel abstracts presented by experts in the field at the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress. Read on for their fascinating insights.
Effects of High-Intensity Resistance
Training
for
Patients
with Myositis: 1-Year Follow-Up on a Randomised Controlled Intervention Trial
Authors: *Kasper Yde Jensen,1 Per Aagaard,2
Charlotte Suetta,3,4 Casper Simonsen,5
Jakob Lindberg Nielsen,2 Jan Christensen,6
Henrik Daa Schrøder,7 Rune Dueholm Bech,8
Louise Pyndt Diederichsen,1,4,9
1. Rigshospitalet, Copenhagen Research Center for Autoimmune Connective Tissue Diseases (COPEACT), Center for Rheumatology and Spine Diseases, Denmark
2. Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
3. Geriatric Research Unit, Department of Geriatric and Palliative Medicine, Bispebjerg and Frederiksberg Hospital, Denmark
4. Department of Clinical Medicine, Faculty of Health and Health Sciences, University of Copenhagen, Denmark
5. Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
6. Department of Occupational Therapy and Physiotherapy, Rigshospitalet, Copenhagen, Denmark
7. Department of Pathology, Odense University Hospital, Denmark
8. Department of Orthopaedics and Traumatology, Zealand University Hospital, Koege, Denmark
9. Department of Rheumatology, Odense University Hospital, Denmark
*Correspondence to kasper.yde.jensen@regionh.dk
Disclosure: The authors have declared no conflict of interest.
Acknowledgements: Physiotherapist and PhD student Charlotte Grønset performed all physical function tests, and her help was indispensable for the completion of the current study.
Keywords: Functional capacity, muscle strength, non-pharmacological interventions, quality of life (QoL).
Reduced muscle endurance and strength are cardinal traits in patients with myositis.1 These traits are associated with reduced quality of life (QoL),2 thus an increase in endurance and strength could potentially lead to improved QoL. The authors’ randomised controlled trial3 investigated the effects of 16 weeks of progressively adjusted high-intensity resistance training on the QoL in patients with myositis.
Increases in QoL, muscle strength, and muscle endurance were observed immediately following the 16-week intervention period for participants allocated to high-intensity resistance exercise compared to non-exercising controls. However, it is unknown to which extent these positive changes are sustained over time.
OBJECTIVE
To investigate if the effects of 16 weeks of high-intensity resistance exercise persist at the 1-year follow-up in patients with myositis.
METHODS
In the randomised controlled trial, 32 patients with myositis were allocated to either 16 weeks of high-intensity resistance training (n=15) or 16 weeks of care-asusual (control, n=17). The present follow-up study compared outcomes from baseline (Week 0) to 1-year follow-up (Week 52). Following the 16-week intervention, both groups were given training programmes and encouraged to exercise. Twenty-seven patients completed follow-up (training, n=13; control, n=14) and were included in the per-protocol analysis.
The primary outcome was QoL (36-Item Short Form Survey, physical component summary). Secondary outcomes included functional capacity (including Functional Index 3, 30-Second Sit-to-Stand test, Timed up and Go test, 2-minute walk test, and handgrip strength), body composition by dual-energy X-ray absorptiometry (heightadjusted appendicular muscle and fat mass), self-reported levels of physical activity, and measures of disease activity and damage (including health assessment questionnaire, Manual Muscle Testing 8 [MMT8], physician and patient global activity, and physician and patient global damage).
Paired t-testing was used to perform withingroup comparisons between baseline and 1-year follow-up. Further, a linear model was used to evaluate differences in between-group over time.
RESULTS
The training group demonstrated increases in physical component summary (p=0.005), Functional Index 3 (p=0.004), 30-Second Sit-to-Stand (p=0.008), Timed up and Go (p<0.001), and handgrip strength (p=0.023) at 1-year follow-up compared to baseline; while 30-Second Sit-to-Stand (p<0.001) and 2-minute walk test (p<0.001) were improved in the control group (Table 1). Reduced levels of physical activity were observed in the training group (p<0.001).
In disease activity and damage measures, only MMT8 increased for the training group (p=0.020). In the control group, MMT8 (p=0.020), physician (p=0.003), and patient global damage (p=0.020) were improved at 1-year follow-up.
With the exception of the height-adjusted appendicular fat mass (p=0.049), no differences were observed in the betweengroup over time.
Table 1: Changes in quality of life, functional capacity, body composition, subjective physical activity levels and IMACS core sets from pre to 1-year follow-up in the training group and the control group.
Quality of Life
Table 1: Continued.
Body composition
Physical activity
Disease activity
Extra muscular activity (0–100)
Creatine kinase (U/L)
Disease damage
Data are presented as group means and standard deviation. Between-group difference is presented with 95% CI in parentheses.
*Data is significant
HA app: height adjusted appendicular; IMACS: International Myositis Assessment & Clinical Studies Group disease activity; IPAQ: International Physical Activity Questionnaire; MCS: mental component summary; MMT8: Manual Muscle Testing 8; PCS: physical component summary; PhGA: physician global activity; PhGD: physician global damage; PtGA: patient global activity; PtGD: patient global damage; SD: standard deviation.
CONCLUSION
Patients with myositis allocated to 16 weeks of high-intensity resistance training showed sustained within-group improvements in physical QoL, functional capacity, and muscle strength at 1-year follow-up. However, these sustained improvements were not superior to care-as-usual, as the group also improved in some functional parameters and muscle strength at 1-year follow-up. No signs of increased disease activity or damage were observed at 1-year follow-up.
2. Poulsen KB et al. Quality of life correlates with muscle strength in patients with dermato- or polymyositis. Clin Rheumatol. 2017;36(10):2289-95.
3. Rigshospitalet. High-intensity Strength Training in Myositis (HI-STIM). NCT04486261. https:// clinicaltrials.gov/study/NCT04486261.
Comparison of Lung Ultrasound B-Lines and Pleural Line Alterations with Automated Quantitative CT: Is it Possible to Overcome the Limitations of the Ultrasound Method?
Authors: *Davide Mohammad Reza Beigi,1,5 Greta Pellegrino,1,4 Nicholas Landini,2 Monica Mattone,2 Chiara De Nardo,2 Gregorino Paone,3 Ilaria
B-lines (BL) and pleural line alterations (PLA) are the typical lung ultrasound (LUS) findings for the detection and severity assessment of systemic sclerosis-associated interstitial lung disease (SSc-ILD).1-3 Recently, LUS scores have been shown to correlate with the extent of interstitial lung disease (ILD) and radiological abnormalities assessed by automated quantitative CT (qCT).⁴ Nevertheless, one of the limitations of LUS remains the ability to explore only the superficial areas of the lung parenchyma.
The aim of the study is to compare quantitative LUS scores with three-level qCT analysis (apices, midfields, and lung bases), and to evaluate their possible association with ILD extension of lung surface and core.
MATERIAL AND METHODS
During the period 2021–2023, patients with consecutive systemic sclerosis (SSc) underwent CT and LUS on the same day, performed by two blinded certified operators using the 14 intercostal space assessment technique.5 The total number of
Table 1: A) Characteristics of study population and descriptive analysis of lung ultrasound and automated quantitative computed tomography assessment. B) Spearman's correlation of the three-level qCT abnormalities extent (cm3) with the number of B-lines and with the pleural line alteration score of the same sites.
A)is of lung ultr
Characteristics
DLCO: diffusing capacity for carbon monoxide; FVC: forced vital capacity; ILD: interstial lung disease; N: number; ns: not significant; PLA: pleural line alteration; r: Spearman's correlation coefficient.
Automated
BLs was collected, and the quantitative PLA score proposed by the authors’ centre was applied, dividing each lung into three levels. CT images were assessed by two thoracic radiologists for ILD definition and then analysed via automated texture analysis software, quantifying the volumes of total ILD, ground-glass (GG), and reticulations (RET), also differentiating ILD volume of the lung surface and core.
RESULTS
Eighty-two patients were enrolled, with 59 (72%) presenting ILD on CT (Table 1A and 1B). The median number of BLs was one (0;4) for apices, 6.5 (1;16) for mid-fields, and 11 (3;26) for lung bases. Median PLA score of the apical, middle, and basal lung fields was one (0;2), five (2;8), and six (2;11), respectively. Detailed qCT analysis is reported in Table 1A
Both BL number and PLA score of midbasal lung fields correlated with the extent of GG, RET, and ILD of the same level at qCT (p<0.005). The PLA score of lung apices correlated with the extent of GG and reticulations of the same site on qCT, whereas the number of BLs correlated only with RET (p<0.05). The extent of ILD, GG, and RET of the lung surface on qCT was significantly higher than the equivalent of the lung core (p<0.05). The basal lung BLs number was found to correlate with superficial and core ILD extent (p<0.005). The PLA score of the apices, mid-fields, and bases correlated with surface lung ILD, GG, and RET (p<0.05), and the mid-basal PLA score also correlated with deep lung alterations on qCT (p<0.02) (Table 1B).
CONCLUSION
The study confirms and expands on the recently emerged findings on the correlation of LUS with ILD extent at qCT, suggesting the ability of LUS to reflect lung morpho-structural changes, especially at basal lung, most affected by SSc-ILD. For the first time, LUS (particularly the PLA score proposed by the authors’ centre) was found to be associated with ILD volume of the lung core. This is probably because structural changes in the lung core would be reflected in the lung surface, where SScILD is prevalent. These results may suggest the possibility of overcoming the traditional LUS limitation of investigating only the superficial lung parenchyma.
References
1. Gutierrez M et al. Ultrasound as a potential tool for the assessment of interstitial lung disease in rheumatic patients. Where are we now? Radiol Med. 2019;124(10):989-99.
2. Radić M et al. Pulmonary ultrasonography in systemic slerosis-induced interstitial lung disease-a systematic review and meta-analysis. Diagnostics (Basel). 2023;13(8):1429.
3. Bruni C et al. Lung ultrasound B-Lines in the evaluation of the extent of interstitial lung disease in systemic sclerosis. Diagnostics (Basel). 2022;12(7):1696.
4. Mohammad R B D et al. Lung ultrasound compared to computed tomography detection and automated quantification of systemic sclerosisassociated interstitial lung disease: preliminary study. Rheumatology (Oxford). 2024;63(5):1240-5.
5. Xie HQ et al. A simplified lung ultrasound for the diagnosis of interstitial lung disease in connective tissue disease: a meta-analysis. Arthritis Res Ther. 2019;21(1):93.
The following highlights spotlight the latest research in rheumatology, featuring studies presented at this year’s annual European Alliance of Associations for Rheumatology (EULAR) 2024 Congress. Ranging from predicting persistent inflammatory arthritis in patients with palindromic rheumatism to the identification of inflammatory phenotypes and systemic sclerosis, these highlights showcase the latest cutting-edge developments and most talked-about topics in the field today.
Axial Involvement in Psoriatic Arthritis and Spondyloarthritis
RESEARCH on axial involvement in psoriatic arthritis (PsA) and spondyloarthritis (SpA) presented at the annual EULAR 2024 Congress, determined the proportion of axial psoriatic arthritis (axPsA) among patients with PsA, as well as how it is diagnosed in clinical practice and the clinical and demographic characteristics associated with axPsA.
Researchers used data from the Rheumatic Diseases Portuguese Registry (Rheuma. pt) on adult patients diagnosed with PsA or axSpA, with psoriasis, who met the CASPAR criteria. Axial involvement was defined as either physician-reported spondylitis or imaging findings such as radiographic sacroiliitis (SI), SI on MRI, or syndesmophytes in axial radiography. Bivariate and multivariate analyses were performed to identify characteristics associated with axPsA.
Results showed that out of 2,304 patients, 854 (35.1%) had axPsA, with 21.8% having exclusive axPsA and 78.2% having concomitant peripheral involvement. The diagnosis of axPsA was based on suggestive imaging findings in 30.1% of the cases, with radiographic SI being the most common (75.9%). The remaining 69.9% were diagnosed based on physician reports. axPsA was associated with the male sex, positive HLA-B27, younger age at diagnosis and symptom onset, higher incidence of enthesitis, uveitis, psoriasis, inflammatory bowel disease, and a lower incidence of dactylitis and nail dystrophy, in extra-articular manifestations. Lifestyle factors such as current or previous tobacco exposure and alcohol consumption were also linked to axPsA. Patients with axPsA
started biological disease-modifying antirheumatic drug (bDMARD) therapy at a younger age but had a longer time from symptom onset to the start of treatment (7 years versus 6 years; p=0.003).
Lifestyle factors such as current or previous tobacco exposure and alcohol consumption were also linked to axPsA
The prevalence of exclusive axPsA among patients with PsA was 8.1%, increasing to 37.1% when including those with concomitant peripheral involvement. Radiographic sacroiliitis was the most common imaging finding in diagnosing axPsA. Patients with axPsA showed distinct clinical profiles, including higher rates of HLA-B27 positivity and enthesitis, and lower rates of dactylitis. The findings underscore the importance of thorough diagnostic evaluations to prevent underdiagnosis, particularly in subclinical cases, and highlight the need for targeted treatment strategies in managing axPsA.
New Insights into Interstitial Lung Disease Risk and Incidence in Systemic Sclerosis
RECENT research presented at EULAR 2024 has shed light on the incidence and risk factors associated with the onset of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) who initially test negative for the condition.
Although the prevalence of ILD in SSc is well-documented, little was known about the incidence of new-onset ILD following a negative high-resolution computed tomography (HRCT) at baseline. The study aimed to estimate the annual incidence of new ILD cases in patients with SSc who initially tested negative, and identify key risk factors associated with the disease's onset.
Researchers analysed data from the European Scleroderma Trials and Research group (EUSTAR) database, including patients with SSc who met the 2013 American College of Rheumatology (ACR)/EULAR criteria, had no ILD on their baseline HRCT, and had at least a 1-year follow-up visit. Patients with pulmonary hypertension, diagnosed by right heart catheterisation, were excluded from the study. Follow-up HRCT was performed, and based on the results, patients were divided into two groups: patients with new onset of ILD (incident group) and patients who remained ILD negative (negative group).
Out of 5,331 baseline ILD-negative patients, new-onset ILD was detected in 1,075 cases over a median follow-up of 3.8 years, resulting in an incidence rate of 3.7 cases per 100
person-years. The incidence rate remained stable for up to 10 years from baseline. Among patients with at least three visits within 5 years from baseline, 18.8% developed ILD, with an incidence rate of 3.6 per 100 person-years. For patients with a disease duration of 5 years or less, 21.5% developed ILD, with an incidence rate of 4.4 per 100 person-years.
Key risk factors for developing new-onset ILD included dyspnoea (New York Heart Association [NYHA] stage ≥2), male sex, older age, elevated inflammatory markers, anti-topoisomerase I antibody, and a history of digital ulcers. Protective factors included higher DLCO/SB% (single-breath carbon monoxide diffusing capacity) levels, higher haemoglobin levels, and the presence of anti-centromere antibodies.
The study highlights the importance of continued screening for ILD in patients with SSc, regardless of disease duration. Identifying these risk factors is crucial for early diagnosis and prompt treatment initiation, potentially improving patient outcomes. The findings emphasise that ILD can develop at any stage after SSc diagnosis, underscoring the need for vigilant monitoring over time.
The incidence rate remained stable for up to 10 years from baseline
Predicting Persistent Inflammatory Arthritis in Patients with Palindromic Rheumatism
PALINDROMIC rheumatism (PR) is a precursor to rheumatoid arthritis (RA), with up to 50% of patients with PR progressing to persistent inflammatory arthritis (PIA), predominantly RA.
Identifying and studying PR longitudinally is challenging, and the risk factors for progression are not well understood. This study aimed to develop the first risk stratification tool for predicting PIA progression in patients with PR, using data from a large UK prospective PR cohort. Results of this study were presented at EULAR 2024.
The Leeds PR cohort included patients recruited from primary and secondary care, defined by episodic joint pain and swelling with no alternative diagnosis. Baseline assessments of clinical, serological, and immunogenetic parameters were conducted, followed by regular evaluations. PIA progression was identified by clinical synovitis persisting for over 3 weeks.
The study followed 161 patients with PR from July 2008–January 2023, with 90% DMARD-naÏve at baseline. Of these, 33% (53/161) developed PIA, and 91% met RA
criteria. Key predictive factors identified through LASSO and Cox regression analysis included female gender, anti-cyclic citrullinated peptide positivity, rheumatoid factor positivity, age over 40 years, smoking history, and flare intervals of less than 1 month. Significant associations were found for female gender (hazard ratio: 2.2) and high anti-CCP levels (hazard ratio: 5.9).
The study developed 'Ever' and 'Two-year' prediction models, stratifying patients into low-, moderate-, and high-risk groups. High-risk patients had progression rates of 53% and 37% for the 'Ever' and 'Two-year' models, respectively, while no low-risk patients progressed. The findings suggest that combining these predictive factors allows effective risk stratification, enabling better monitoring and potential intervention for high- and moderate-risk groups in clinical practice.
The study followed 161 patients with PR from July 2008–January 2023, with 90% DMARD-naÏve at baseline
Assessing Infections in Patients with Rheumatoid Arthritis
NEW research presented at EULAR 2024 aimed to address the safety profile of JAK inhibitors (JAKi), particularly with regard to infection risk.
The safety profile of JAKi remains a critical concern amongst patients with rheumatoid arthritis (RA), as real-world data on the incidence and severity of opportunistic infections and herpes zoster (HZ) remains an area of active study.
In order to shed more light on the topic, lead author Romain Aymon, Geneva University Hospital, Switzerland, and colleagues studied patients from 14 RA registries across Europe and Québec, that were starting JAKi, TNF-inhibitors (TNFi), or bDMARDs with other modes of action (OMA). The outcomes being measured included all infections, serious infections (requiring hospitalisation, intravenous treatment, or resulting in death), all infections excluding HZ, and HZ. Infections were linked to treatments within 3 months of cessation (1 year after initiation for rituximab) or until follow-up loss, death, or study end. Incidence rates (IR) per 100 patient-years (PY) with 95% CI were computed. Poisson regressions with propensity score weighting (including country, disease, patient characteristics, and comorbidities) were performed within each individual register and combined using random-effect meta-analysis to obtain adjusted incidence rate ratios (aIRR) with 95% CI.
Overall, 54,905 treatment initiations were considered in 36,838 patients with a mean patient follow-up of 2.8 years. Amongst these patients, 7,070 incident infections were reported, of which 1,379 were considered as serious, and 352 were HZ. Crude incidence of any infection was lower for TNFi (7.0/100 PY) than for JAKi (9.0/100 PY) and OMA (10.6/100 PY). The adjusted Poisson regression found no significant difference in the incidence of any infections (aIRR: 1.13; 95% CI: 0.91; 1.40) or serious infections (aIRR: 0.99; 95% CI: 0.71; 1.39) between JAKi versus TNFi. However, the incidence of any infection was higher for OMA versus TNFi (aIRR: 1.20; 95% CI: 1.09; 1.32). Compared to TNFi, the incidence of HZ was significantly higher for JAKi (aIRR: 2.27; 95% CI: 1.71; 3.02), but not for OMA (aIRR: 1.07; 95% CI: 0.74; 1.55).
The team found that there was no significantly higher risk of infections, either any or serious, in patients with RA treated with JAKi compared to TNFi. However, they reported that there was a higher risk of any infections with OMA. Compared to TNFi, the incidence of HZ was significantly higher in patients receiving JAKi. The authors elaborated, explaining that future planned subgroup analyses will focus on at-risk populations, specific medications, and infection types to guide treatment choices.
Risk of Mortality in Patients with Tophaceous Versus Non-tophaceous Gout
PATIENTS with tophaceous gout face significantly higher risks of mortality, acute myocardial infarction (MI), and end-stage renal disease (ESRD) compared to those with non-tophaceous gout, according to recent research presented at EULAR 2024.
The study, which analysed data from a cohort of 213 million patients using the TriNetX Diamond network, included 284,241 individuals with tophaceous gout and 73,569 with non-tophaceous gout. Through rigorous propensity score matching, the researchers balanced the baseline characteristics of 73,495 patients in each group, ensuring a robust comparison.
Results highlighted that after 1 year, 5.0% of patients with tophaceous gout had died, compared to 4.2% of those with non-tophaceous gout, reflecting a 20% higher risk (hazard ratio [HR]: 1.20; 95% CI: 1.15–1.26). The disparity widened over 5 years, with mortality rates at 14.1% for tophaceous gout patients versus 11.4% for those with non-tophaceous gout (HR: 1.24; 95% CI: 1.20–1.27).
The risks of acute MI and ESRD also increased significantly in the tophaceous gout group. At 1 year, the incidence of acute MI was 1.7% in tophaceous gout group, compared to 1.4% in the non-tophaceous group (HR: 1.20; 95% CI: 1.10–1.31). Over 5 years, these rates escalated to 4.4%
and 3.7%, respectively (HR: 1.21; 95% CI: 1.15–1.28). Similarly, ESRD risk was 1.2% at 1 year for patients with tophaceous gout versus 1.1% for the others (HR: 1.12; 95% CI: 1.02–1.24), and 3.2% at 5 years compared to 2.8% (HR: 1.16; 95% CI: 1.09–1.23).
These findings confirm that tophaceous gout is associated with an increased risk of mortality, acute MI, and ESRD. The authors highlight that these risks may relate to increased total urate burden, inflammation, and cumulative cardio-renal adverse effects of non-steroidal anti-inflammatory drugs or glucocorticoid use. They call for further investigation into intensive urate-lowering therapies, such as uricase, to mitigate these critical health risks.
These findings confirm that tophaceous gout is associated with an increased risk of mortality, acute MI, and ESRD
Identification of Inflammatory Phenotypes and Prognoses in Systemic Sclerosis
C-REACTIVE protein (CRP)-associated inflammatory phenotypes in systemic sclerosis (SSc) have been identified by researchers, in addition to their association with increased risk of all-cause mortality and interstitial lung disease, according to research presented at EULAR 2024.
SSc has a complex pathology consisting of immune system dysregulation, tissue fibrosis, and vascular dysfunction, which results in inflammatory, fibrotic, and vascular alterations in patients. Previously in the field, a link between elevated CRP levels and inflammation in early disease onset has been established, but there is a lack of data to elucidate this association. Researchers from the Department of Rheumatology, León University Hospital Complex, Spain, aimed to identify CRP-associated inflammatory phenotypes and prognostic implications in patients with SSc.
SSc has a complex pathology consisting of immune system dysregulation, tissue fibrosis, and vascular dysfunction
The research identified 133 patients with SSc, according to the 2013 American College of Rheumatology (ACR)/EULAR criteria. With CRP levels above 5 mg/L at their first clinic visit, patients were classified as having an inflammatory phenotype. Compared to patients with a noninflammatory phenotype (CRP <5mg/L), patients with inflammation at SSc onset demonstrated higher serum levels of KL-6 (p=0.002) and IL-18 (p=0.040) at baseline.
Assessment of clinical parameters revealed that diffuse-cutaneous disease (p=0.020), anti-Scl-70 autoantibodies (p=0.020), interstitial lung disease (p=0.020), lower diffusing capacity for carbon monoxide (p=0.010), and myositis (p=0.040), were more frequently associated with an inflammatory phenotype. Additionally, logistic regression analysis revealed that
inflammation at SSc onset was linked to mortality (β: 0.65, p=0.004), interstitial lung disease (β: 0.45, p=0.007), arthritis (β: 0.40, p=0.040), myositis (β: 0.23, p=0.040), IL-18 levels (β: 0.32, p=0.002), and anti-Scl70 positivity (β: 0.21, p=0.040).
In 53 (39%) patients, elevated CRP levels continued for over 80% of visits (classed as a persistent inflammatory phenotype). Analysis with Cox regression models revealed that persistent inflammation was associated with a 4.6 times higher risk of all-cause mortality (hazard ratio: 4.61; 95% CI 1.2–15.2; p=0.04) and 5.6 times higher risk of interstitial lung disease (hazard ratio: 5.41; 95% CI: 2.4–16.4; p=0.02).
The results of the study demonstrate that CRP-associated inflammation at disease onset is linked to specific clinical and immunological features in patients with SSc, which may aid in diagnosis. Additionally, the finding that persistent inflammation increases the risk of all-cause mortality and interstitial lung disease highlights the need for personalised treatment strategies focused on CRP-associated inflammation.
Congress Interviews
Xenofon Baraliakos, Jette Primdahl, Daniel Aletaha, Andrew Cope, and Mwidimi Ndosi spoke with EMJ, sharing their insights from this year’s EULAR Congress. The experts discussed the expansion of research areas to include polymyalgia rheumatica, vasculitis, and rheumatic diseases in pregnancy. As well as the importance of quality care and patient safety in rheumatology and enhancing global collaboration and education.
Xenofon Baraliakos
Head of Rheumatology, Rheumazentrum Ruhrgebiet, Herne, Germany; Professor for Internal Medicine and Rheumatology, RuhrUniversität Bochum, Germany; and European Alliance of Associations for Rheumatology (EULAR) President-Elect.
Since our last interview, how has your journey in rheumatology evolved, particularly in your role as a professor and researcher at RuhrUniversität Bochum?
Thank you, it has been and still is an interesting journey. We have grown as a department, have broadened our fields of research to other diseases beyond spondyloarthritis and psoriatic arthritis, and now want to help the field develop in areas such as polymyalgia rheumatica, vasculitis, pregnancy and rheumatic diseases, vaccination, etc. Rheumatology and immunology are an extremely dynamic field and my whole team is happy to be part of and lead these developments.
piece of fundamental knowledge reaching the clinical field. This is inspiring and motivating.
Q3 Your research has significantly impacted the field of axial spondyloarthritis and psoriatic arthritis. What do you consider the most groundbreaking aspect of your work?
The most groundbreaking aspects have been in the development of knowledge and understanding of the imaging aspects of the disease, including inflammatory as well as radiographic aspects. I have been blessed to work with people who have supported me and also been fundamental in brainstorming and developing ideas, bringing them to life in the form of results and publications.
Rheumatology and immunology are an extremely dynamic field and my whole team is happy to be part of and lead these developments
Q2 What continues to inspire you in the field of rheumatology, and have there been any pivotal moments or influences in your career recently?
A big inspiration is that rheumatology as a discipline does not stop developing at a very fast speed. For more than 20 years we have seen at least one new
Q4
With an h-index of 82, your work has a substantial impact on the scientific community. What strategies do you employ to ensure your research remains relevant and influential?
This is the work of many, not just of a single person. The strategy is
simple: be creative, yourself, and open to ideas from the outside; try to think one step ahead of the current times; and of course, share the ideas with others. This means either benefiting from brainstorming or helping others to develop themselves, since this always comes back to you in a positive way.
Q5
Are there any gaps in the literature or unmet needs in the field of rheumatology that you aim to address through your future research?
I believe we are now at the moment of being able to speak about the role of translational research and its implications for clinical research. Both have been there for decades; however, I believe that we now can close the gap to connect them and truly aim for personalised treatments for our patients.
Q6 As the President-Elect of EULAR, set to begin your presidency in 2025, what are your primary goals and vision for the organisation?
I have many goals and visions that are related to all the developments the field of rheumatology has made in recent years. These don’t have to be fancy changes, but I want to help, together with all other people at EULAR, past Presidents, and future ones, to establish EULAR and European rheumatology as the leading force in clinical, translational, and basic science in the world. Furthermore, I believe that we cannot reach all these goals without collaboration, this includes the opinions and ideas of patients and healthcare professionals.
Q7
How do you envision the future of rheumatology, particularly in terms of patient care and research advancements?
My vision is that we will be able to implement personalised medicine in our daily routine practice, getting the help of AI and specific tests that can maximise the effects of the available treatments for all our patients, independent of financial status or the healthcare system.
Q8
Can you discuss any recent technological innovations or methodologies in rheumatology that you find particularly promising?
At the moment, we are in the process of understanding what AI is capable of. Right now, I am not sure how fast this will go, and obviously (and luckily) this is a never-ending story since systems evolve with time. However, speaking about technological innovations and methodologies, we need to include the usage of current tools in a more optimised way. For example, the simple understanding of imaging procedures to avoid misdiagnoses or overtreatment. This is a really interesting part of medicine in general, where EULAR will also play a protagonist role in the near future. The strategy is simple: be creative, yourself, and open to ideas from the outside; try to think one step ahead of the current times
Jette Primdahl
Rheumatology Rehabilitation Professor, University of Southern Denmark (SDU) and the Danish Hospital for Rheumatic Diseases; European Alliance of Associations for Rheumatology (EULAR) VicePresident HPR.
I have always had a focus on developing quality of care; no matter what kind of position I've been in
Q1Can you talk us through what inspired you to pursue a career in rheumatology rehabilitation? And how has your journey led you to your current role at the University of Southern Denmark and the Danish Hospital for Rheumatic Diseases?
I started my career as a nurse, working for many years in cardiology, a speciality that I really liked. After further education, and working with quality development, I took up a position in quality and patient safety at a rheumatology hospital. This role was my entry into rheumatology, where I focused on quality development, patient safety issues, and accreditation of procedures. But I think that all kinds of specialties would be interesting for me if I were to dive into them, there are always patients who are challenged by the diseases they have. That’s what inspires me. I have always had a focus on developing quality of care; no matter what kind of position I've been in, that has always been my main interest. After many years in quality development and patient safety, I had the chance to become a PhD student and was offered to stay in a research position.
I enjoy doing clinical-based research, which is very close to the patient, allowing me to see the direct impact of our work. What drives and motivates me is improving patient outcomes. Although register-based studies might seem easier, I find clinical research, especially in rehabilitation, where we train people to do things differently and work together, to be more challenging but ultimately more
rewarding. I think this approach makes a significant difference for patients.
Additionally, I am undertaking cardiovascular screening consultations. For instance, people with inflammatory arthritis have double the risk of cardiovascular disease, similar to those with diabetes. General practitioners are very good at managing diabetes but often overlook cardiovascular risks in patients with inflammatory arthritis. After finishing my PhD, EULAR published recommendations for cardiovascular risk management, which we implemented locally. This area is also part of my research interest, and I find it rewarding to see the positive results in patients.
Q2How do you envision the future of rheumatology, particularly in terms of patient care and research advancements?
I think there will be a continuous development of new medications, and that's very important for our patients. But despite that, approximately 30% of patients either do not have effective medication options or cannot tolerate the side effects. Even those who achieve a low disease activity or remission still face significant challenges such as fatigue, pain, and depression. We need to focus not only on disease activity in patients with inflammatory arthritis but also on overall disease impact.
This is where non-pharmacological interventions and rehabilitation come in, involving multiple professionals working together to help patients manage their pain,
fatigue, and physical disabilities. We should also focus more on prevention by identifying those at risk of developing these conditions and intervening earlier in the disease pathway. This approach has shown promise in spondyloarthritis. Reducing the delay from the onset of symptoms to seeing a physician and then a rheumatologist is crucial for better patient outcomes.
Q3 Could you elaborate on your research in rheumatology and rehabilitation, and how it has evolved over the years?
In the beginning, my focus was on patient education. Now it's more focused on developing and testing new types of outpatient rehabilitation, particularly workrelated rehabilitation for those who feel challenged to maintain their jobs, self-management, support and management of fatigue. We aim to support those who have been vulnerable and challenged for many years by creating continuity and establishing strong relations to our patients based on a person-centred and biopsychosocial approach.
For instance, in one study, it was the nurse who was the primary point of contact for patients, but they also had the opportunity to refer to physical therapists, occupational therapists, and social workers. In another study on early rehabilitation for people suspected to have spondylarthritis, the primary point of contact is a physiotherapist, because physical activity is essential for these patients. In work-related rehabilitation, that central person is an occupational therapist because they hold specific competencies in relation to the interplay between activities, daily life, and
the patient’s work situation. It's important to involve the whole multidisciplinary or interdisciplinary team, as patients have different challenges that require access to different professionals.
Q4
Your work on nurseled care and the management of cardiovascular risk and fatigue has been significant. What are some of the key findings and implications of your research in these areas?
When I started, very few patients had regular access to a rheumatology nurse. We created evidence for nurse-led care, where nurses monitor disease activity, examine joints, administer medication, and refer to or get supervision from a rheumatologist if needed. The approach has shown that nurse-led care can achieve results comparable to traditional rheumatologist-led care. This model of care together with patient-initiated follow-up is now in clinical practice in many countries and allows for more frequent and accessible patient monitoring.
Q5
Focusing on your role at European Alliance of Associations for Rheumatology (EULAR), as Vice President of HPR. What are your main objectives and your vision for the organisation, especially thinking about health professionals in rheumatology?
My dream is for more patients to have access to the wider interdisciplinary team. In many countries, patients do not have access to professionals like nurses, physiotherapists, social workers, occupational therapists, and psychologists; it's really rare. This gap necessitates capacity building for health professionals and an awareness among
You cannot just cure a disease with medication; you need to see the person behind the illness
rheumatologists that medication is not the only thing to help our patients, and in fact, there are some issues it cannot resolve. We also need non-pharmacological interventions to help prevent comorbidities. Many of our patients struggle with anxiety and depression, and it’s essential to adopt a biopsychosocial approach. This means understanding the patient’s values, life situation, work, and family context. You cannot just cure a disease with medication; you need to see the person behind the illness.
Q6 Do you see this approach as being the future direction of rheumatology rehabilitation and nurse-led care?
I think there's still a long way to go. In many countries, there is a lack of clearly defined roles for healthcare professionals in rheumatology, and there is a significant need for more localised education. The resources available are often in English, which poses a barrier for many healthcare professionals. It’s crucial to provide education in local languages and to raise awareness among rheumatologists about the valuable contributions of healthcare professionals, such as nurses, physiotherapists, occupational therapists,
psychologists and social workers. There is still much progress to be made, but these steps are essential for moving forward. In addition, telehealth will be central in the future offering support outside the hospitals.
Q7 What aspects of your work do you find the most rewarding as a professor and researcher?
I think there are two main drivers for me. First, it's the ability to see the impact we can have on patients' lives and help improve their wellbeing. That is a major motivation. The other driver is seeing the growth and development of PhD students or other students under my guidance, like watching flowers bloom. It's incredibly rewarding to help them become better researchers.
Additionally, I am now focusing on spreading models of good practice. For example, we have started the Danish Centre for Expertise in Rheumatology at our hospital, and I believe we are just at the beginning. There is so much more we can do to disseminate evidence and effective practices to professionals in primary care, helping to improve patient outcomes across the patients’ pathway.
Q8 Can you tell us about any PhD projects or studies that you are particularly excited about?
Well, some of them were presented at this conference. One project on work-related rehabilitation is particularly important because it helps individuals maintain their paid work, which is crucial for their identity, economy, and overall society. We are moving this project into a randomised controlled trial, involving various stakeholders to test its efficacy on a larger scale.
Another study I'm proud of is a collaboration with a hospital in Copenhagen, focusing on people with inflammatory arthritis who still experience substantial disease impacts. We've found that a relatively small intervention, about 8 hours of support, can make a significant difference over 6 months. This isn't costly compared to medication, yet it has a profound impact.
Overall, my goal is to create evidence that nonpharmacological interventions can truly benefit our patients.
1. President of EULAR, Professor and Head of Department of Rheumatology at the Medical University of Vienna, Austria
2. Panel member for Basic and Translational Science at EULAR, Head of the Centre for Rheumatic Diseases and Associate Director of the King's Clinical Trials Unit at King's College London, UK
3. Chair of EULAR HPR Committee, Associate Professor in Rheumatology and Nursing at the University of the West of England Bristol, UK
Q1Can you talk us through your role at the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress? And what have been your key priorities within this role?
Aletaha: This is a difficult question, one I’ve been asked many times. It has been very difficult to choose an abstract for this conference, you can tell by my choice that I think understanding the impact of rheumatic diseases is important in quantifying and dealing with diseases that create a lot of impact. The rheumatic and musculoskeletal diseases (RMD) survey that I presented at the Congress is an example. Understanding the osteoarthritis onset is an example of addressing an unmet need of a highly prevalent disease that does create social and economic impact. I think that the future challenges lie in non-inflammatory diseases; inflammatory diseases are more exciting for scientists, and there are new processes and some strange things going on that you can treat. But in terms of the impact, I think the noninflammatory diseases are really the major challenges for the Congress.
Secondly, I am a speaker at the conference. I’ve given a couple of talks: one on a replication study that was published recently and another during a cancer session. Lastly, my role at the Congress is within European Union (EU) law as I’m a member of a group that comes up with initiatives as part of the United Research Centre. My focus is on the clinical research subcommittee. We are setting up the ENTRI Network of Clinical Trials Centres, our first initiative. Our subcommittee is currently encouraging applications and working on building this network.
I think the non-inflammatory diseases are really the major challenges for the Congress
Cope: I have three main roles at this year’s congress. Firstly, the fundamental one is attending as a delegate to listen to various sessions and learn new things. This can range from basic science to the latest research developments and treatment methods, particularly the ‘What’s New’ and ‘What’s HOT’ sessions, so that I can do a better job when I return to my clinics in London, UK.
Ndosi: For this congress, I am responsible for the programme, specifically for health professionals in rheumatology (HPR). The HPR programme caters for a broad audience of nonphysician health professionals that are involved in the care of people with RMDs. This includes a wide variety of professions such as nurses, physiotherapists, occupational therapists, psychologists, podiatrists, and nutritionists. To ensure that the programme meets the educational needs of these professions, we have to get up to speed with the direction of scientific research, clinical developments, and patient needs. My role also includes evaluating the quality of abstracts submitted for the Congress, prioritising those that provide strong evidence, as we aim to ensure that all our interventions are evidence-based. Part of this work also involves recognising and rewarding outstanding research contributions, further supporting advancements in care for people with RMDs.
Daniel Aletaha,1 Andrew Cope,2 and Mwidimi Ndosi3
Q2 What are some of the unique challenges associated with providing care in your field? And how do you think the Congress will help to tackle these?
Aletaha: Diseases affecting the musculoskeletal system significantly affect people’s lives, distinguishing them from other diseases. They prevent people from being able to care for themselves or others, go to work, or continue working until retirement age. Therefore, they create a lot of difficulty for those affected and for society as a whole, so we must find ways to manage patients and their situations effectively. Additionally, managing rheumatic diseases quickly and efficiently is not only a medical concern but also an economic one. Early recognition and intervention can reduce the long-term burden on the affected individuals and society. The Congress will feature many presentations and discussions aimed at early disease recognition, the impact of both inflammatory and non-inflammatory diseases, and effective patient monitoring.
Cope: For me, there are two main challenges. First is the lack of sufficient contact with primary care, to get people triaged and into the clinics in the first place. Second is the volume and waiting times, which are horrific, and the National Health Service (NHS), especially in London, is under immense strain. The expectations are high, and the demands within the health sector, not just among health professionals but also between general practitioners and patients, have grown exponentially. Managing this volume of workload has been extremely difficult. There are always specific areas I am keen to explore, particularly the ‘What's New’ and ‘What's HOT’ topics. My clinical interest is in rheumatoid arthritis, for which we have many treatments. However, as Aletaha mentioned earlier, we still struggle with conditions like osteoarthritis, pain, and fatigue, where effective treatments are lacking. Attending conferences like this helps get an idea of what’s new and how to do a better job.
Ndosi: My key area is selfmanagement and patient education. The main challenge is
that people today are bombarded with information constantly. By the time they consult healthcare professionals, they will have often already searched online and encountered information or misinformation. The real challenge is to identify their specific educational needs. It’s not just about giving information but understanding where patients are in their knowledge and providing the appropriate education. This means correcting misconceptions and ensuring that the information we provide is evidence-based, accurate, and applicable. That is the challenge we face in today's society.
Q3 What are the most impactful initiatives EULAR has implemented recently to advance patient care and research?
Aletaha: I think the EULAR Network of Trial centres (ENTRI) is helping the advancement of science dramatically, by facilitating quicker market access for new drugs and quicker access of knowledge to the broader community. One of the major limitations in clinical trials is
One of the key initiatives at EULAR is to broaden education, awareness, best clinical care, prevention, and research
recruitment, and ENTRI helps to expedite investigator-initiated studies, addressing this issue. The major scientific evidence comes from clinical science. When you put these efforts together, the impact of ENTRI becomes clear. The rheumatic and musculoskeletal disease impact survey is another initiative that’s important in understanding the disease impacts. Additionally, the RheumaFacts project collects global data on the prevalence of rheumatic diseases, creating a comprehensive database accessible to anyone across Europe to build understanding in the industry, and for policymakers and press, on differences and consistencies in the prevalence of the disease.
Cope: It’s still very early, but I think the response to joining the ENTRI network has been huge. Over the next 1–2 years, getting the network up and running and thoroughly testing will be crucial. We’ve touched a bit on RheumaFacts and other surveys, which aim to understand the quality of care across Europe. This is significant because it will likely reveal inequalities that need to be addressed by the governments and health sectors so that they can make improvements. For instance, even in the UK, there are variations in prescribing patterns, referral rates, and the speed at which patients achieve remission. These variations indicate that there are many irregularities in care pathways that need to be fixed; addressing this will be a major focus moving forward.
Ndosi: Our strategy aims to reduce the impact of RMDs on individuals and societies, which is the focus of the HPR community. One of the key initiatives at EULAR is to broaden education, awareness, best clinical care,
prevention, and research. Some people are not aware of our education offers. I would like to highlight that we provide online courses, webinars, and other free materials, depending on need. Providing these resources is crucial for the professional development of our communities. Additionally, research is fundamental to advancing our professions. We have a dedicated research grant programme for healthcare professionals, funding only high-quality proposals. This helps to build the evidence base needed for our field. These initiatives have a significant impact on our community, supporting both education and research to improve patient care and professional development.
Q4
What are your main goals and priorities for EU law over the coming years?
Aletaha: I think EULAR will continue to play an important role in global rheumatology. We’re trying to engage with our partner organisations across the world, because we’re all pulling on the same strings and we don’t want to do that in competition, but rather in partnership. EULAR has historically been built on certain pillars: healthcare professionals, patients, scientists, and rheumatologists. Bringing these groups together for the advancement of medicine and rheumatology is something I am really interested in. One of my goals is to strengthen the connection between national societies in Europe and EULAR. Although they are all members of EULAR, I want to enhance their contributions and ensure they fully benefit from what EULAR offers. By fostering closer collaboration and integration, we can advance the field of rheumatology more effectively.
Cope: I’d like to embed the Research Centre into the EULAR community so that people understand that there is a valuable resource that they can use to conduct research and get training and support for research. Those are our main goals. We also aim to identify young talent coming through that we can train and help to excel in these areas. The ENTRI network is our first initiative, and over the next few years we will explore additional ways to support the community, specifically in the area of research. Another area we’re hoping to work closely on is with the patient research partners, I think their role is fundamental. By creating a network of translators, we can identify which centres also have cohorts of patients who are willing to serve as patient experts, because they can provide huge insight into all sorts of things we do.
Ndosi: The coming years will be quite challenging. I’m very passionate about prevention when dealing with long-term conditions, we often focus only on single diseases without considering other related factors. If we think
about prevention and look at the patient holistically, we can address multiple areas simultaneously. For instance, interventions like physical activity and education do not only manage existing conditions but also prevent new ones from developing. My ambition is to prevent diseases from occurring in the first place. At EULAR, we share this ambition, and I believe we can achieve significant progress by focusing on comprehensive preventative strategies.
Q5 Are there any sessions that you’re particularly looking forward to?
Aletaha: I would really like to see the digital health session. When I attend a Congress without my different roles and committee responsibilities, I like to go to the plenary sessions where the top abstracts are presented and invited speakers share their insights. I also try to attend the highlight sessions. Additionally, we have a recommendation session and the digital health session I mentioned earlier. There are so many interesting sessions, not to
mention the escape room and the occasional coffee break that I'd like to squeeze in.
Cope: This conference is all about highlighting various clinical trials. Three of my colleagues are presenting the results of their trials, which is very exciting. Additionally, there was a talk on the history of reactive arthritis and an excellent session on osteoarthritis. There is a wealth of valuable information and many interesting presentations to look forward to.
Ndosi: The sessions that I always tell people not to miss are the abstract sessions. The abstracts present the latest evidence from studies that have recently been published or have not even been published yet. It's the best way to stay updated on current evidence. I always advise everyone to never miss the abstract sessions. Of course, there are many other interesting sessions beyond abstracts, it's like a vast menu of fascinating topics to choose from. Truly amazing!
Interviews
Qasim Akram and Rizwan Rajak spoke with EMJ, sharing details about their career and research. Akram shares why he chose to specialise in musculoskeletal ultrasound, and Rajak shares insights on challenges and successes he has encountered in treating early inflammatory arthritis.
Qasim Akram
Consultant Rheumatologist and General Physician, Stockport NHS Foundation Trust, UK
Q1 What sparked your initial interest in rheumatology, and has led you to pursue a career in this specialty?
I was lucky enough to work with some incredible people, who really inspired me.
I fell in love with rheumatology as a specialty during one of my first rotations as a foundation Year 1 doctor in 2007. I loved the multisystem nature of the disease presentations, and the problem solving and diagnostic challenges each of them presented. There was a nice mix of both acute and chronic cases, from inflammatory arthritis to vasculitis and systemic lupus erythematosus. I was lucky enough to work with some incredible people, who really inspired me. They loved their jobs, and I could see the fantastic relationship physicians had with their patients. Around this time, the anti-TNF biologic era was also starting to revolutionise treatment for many inflammatory musculoskeletal diseases, meaning better patient outcomes were possible, leading to great job satisfaction.
Q2 Having dual trained in general (internal) medicine, are there any benefits from this that you find filter into your practice?
Now, with the shape of training, everyone is mandated to dual train in internal medicine. However, whilst I was training, this was optional. I decided to take the hard road and dual train to have a Certificate of Completion of Training (CCT) in both general internal medicine and rheumatology. Rheumatic diseases are usually multisystem in nature, and I think this advanced grounding in general internal medicine gives you a wider knowledge and experience of managing patients in cardiology, respiratory, and gastroenterology.
I think it also creates better relationship with general physicians, meaning better links to the general medicine wards and acute medicine.
Q3
Why did you choose to specialise in musculoskeletal ultrasound, and why do you think every modern rheumatologist should train using ultrasound?
I am very hands-on as a clinician, and enjoyed cardiology and gastroenterology as specialties during my core medical training years. They had lots of procedural aspects, and I felt that rheumatology was missing something like this.
I saw how ultrasound was being used by radiologists to diagnose and manage rheumatic disease, through guided injections, and felt that it would be a very powerful tool in the hands of a clinician. Using ultrasound as a clinician is very widespread in Europe, and I am very envious of this.
Most medical specialties have excellent diagnostic capacity that they carry out themselves, and I think rheumatologists in the UK are trailing behind by not learning this skill. I really think it should be part of the curriculum, and more should
be done to develop ultrasound training centres across the country.
Q4
You currently co-lead an early inflammatory arthritis (EIA) ‘one-stop shop’ ultrasound Clinic, and a giant cell arteritis (GCA) ‘fast-track’ ultrasound clinic. Could you please outline some of the benefits to patients these initiatives are producing under your watchful eye?
The EIA one-stop shop means that anyone presenting with a suspected diagnosis of EIA is seen within a few weeks. Patients are seen by a clinician, and following initial assessment, have an ultrasound scan done by a Consultant on the same day, allowing them to get an early diagnosis. Treatment decisions are made there and then, meaning better disease outcomes, less disability and impairment of mobility, and normal life can resume. We see patients with EIA aged 18 years and above. It also means there are fewer appointments, leading to improved waiting lists and patient flow.
The EIA one-stop shop means that anyone presenting with a suspected diagnosis of EIA is seen within a few weeks.
The GCA fast-track ultrasound clinic means those presenting with GCA, an irreversible sight-losing vasculitis, are seen and assessed using ultrasound within a few days of presenting, meaning accurate treatment can be started very early. This model has been shown to reduce blindness and overall morbidity with the disease.
Q5
How has your book, entitled ‘Ultrasound in Rheumatology: A Practical Guide to Diagnosis’ been received since its publication in 2021?
Generally, the book has had an excellent response. It’s always difficult to produce a book like this in a short space of time, especially during the height of the COVID-19 pandemic, whilst being on the front lines.
The book was written with a busy clinician who is starting on their journey towards ultrasound in mind. It is very practical and hands-on, giving a brief overview of some basic anatomy, followed by the relevant sonoanatomy, and the correct probe position to produce these images.
From a sales point of view, the book has sold several hard copies, but mainly electronic versions, which makes sense, as people can scan whilst looking at their tablet device. We have received excellent feedback globally, and it has now been translated to Chinese.
Q6
What are the main lessons you learnt from the ultrasound fellowship in 2016, which you completed under the guidance of Esperanza Naredo?
This was an incredible experience, and one which I will never forget. I started learning to train in ultrasound in 2012, but
was finding training specific to rheumatology difficult in the UK; the lack of trainers and training centres meaning that opportunities were limited.
I decided to pursue a specialised ultrasound fellowship and trained under a global expert, Naredo. I was unique in being one of the first rheumatologists in the UK to do something like this. It enabled me to train with the best, fasttrack my advanced ultrasound competencies, and achieve international European Alliance of Associations for Rheumatology (EULAR) accreditation.
This fellowship allowed me to carry out a research project learning basic methodologies when carrying out research, especially in relation to ultrasound, and I presented my work at an international EULAR conference.
I was also able to compare healthcare in a country outside of the UK, and see how they utilised ultrasound in rheumatology, giving me some ideas of how to integrate it into my practice as a National Health Service (NHS) Consultant in the future.
Q7
As a lead of an Ultrasound Fellowship Programme for specialty trainees, what qualities do you attempt to instil, and believe are integral to the next generation of rheumatologists?
I am very passionate about teaching and training the next generation of physicians, as I believe that ultrasound is a fundamental requirement for all rheumatology trainees. I am a EULAR Level 2 Instructor, and have learned many lessons along the way with my great teachers, including Naredo.
Although there is limited time in my NHS job plan, I have created a structured ultrasound training programme for specialty trainees at Stepping Hill Hospital, Stockport, UK, who are usually on rotation for 1 year. Trainees learn to perform ultrasound in specialised clinics, such as the EIA one-stop, general ultrasound clinics, and the GCA fast-track clinic, and get lots of supervised, hands-on scanning experience. Throughout the year, I complement this practical learning with tutorials on the basics of ultrasound in rheumatology, and mentor them towards formal accreditation. Trainees will also do an audit, QIP or research, with a view to publication, relating to ultrasound under my supervision.
Q8 Have you found your experience with ultrasound has benefitted you in terms of career opportunities? Is this something you would recommend to young rheumatologists?
Absolutely; I think this experience makes you a better rheumatologist. It is an extension of clinical examination, and allows you to directly visualise and understand the patient’s disease process. There is also a better relationship with patient, as you can explain what is happening whilst performing ultrasound, increasing patient satisfaction with consultation.
I think having this skill makes you far more employable, especially if you can utilise onestop shop models in both EIA and GCA ultrasound clinics. There are also several exciting teaching and research opportunities. In the future, there may also be more applications in other aspects of rheumatology, such as lupus or scleroderma.
Q9
What has led you to set up your own Rheumatology Ultrasound Course in zManchester? Why do you think this is important? What feedback did you receive, and are there any plans for further courses?
There are several reasons why I set up the Rheumatology Ultrasound Course in Manchester. I feel there is a huge unmet need in this area. There is a huge interest in people wanting to learn to scan, from rheumatologists to allied healthcare professionals who value learning this invaluable skill for their day-to-day practice. There is also a real lack of highquality Consultant-led ultrasound training courses, especially in rheumatology, that involve learning to scan on real-life patients with real-life pathology. For many people, training is also becoming increasingly difficult in a stretched and demanding NHS environment.
We offer something very different on our course. We have a varied faculty, including very experienced radiologists who specialise in rheumatology, and rheumatologists who specialise in ultrasound. All of our tutors have completed a form of a fellowship in musculoskeletal ultrasound, and we ensure that the groups are small, so there is lots of time scanning, and lots of pathology to practice on.
Q10
Are there any innovations in the field of rheumatology that you are particularly excited to see translated into practice?
There are certainly a few innovations that I am really excited about. I believe these can really revolutionise the day-to-day care of patients with rheumatological diseases. First, I have a seen a few excellent smartphone apps, that allow patients to use carefully designed patient-reported outcome measures, which can be
used to communicate symptoms with the clinician. This can be very important in terms of triaging patients based on urgency, reduce number of outpatient visits, and, as a result, improve the burden on the healthcare system. This can also allow a better, productive clinical encounter. It allows patients better control of their illness through the app, with easy-to-access information based on their disease, treatment, any questions/queries, and what to do in the event of a specific issue. Within the app, a virtual assistant would be very helpful to reduce the healthcare burden.
I am also excited about the potential of artificial intelligence technology in rheumatology, which can be useful in imaging modalities, and can provide accurate and early detection of disease. Prediction of disease progression can help tailor and customise treatments, which can ultimately improve disease outcomes.
Rizwan Rajak
Clinical Lead for Osteoporosis & Metabolic Bone Health and Rheumatology Musculoskeletal Ultrasound, Croydon Health Services NHS Trust, UK
Q1 What motivated you to specialise in rheumatology, and how did your training at the University Hospital of Wales, Cardiff, UK, and the Royal National Hospital for Rheumatic Diseases, Bath, UK, shape your expertise?
Q2
When I joined the current trust, my first task was to develop the early arthritis service.
Ever since medical school, I was always interested in musculoskeletal medicine and found this one of the most compelling subjects. During training in general medicine, I undertook a clinical experience week in rheumatology, and felt this was the right specialty of interest for me. I completed my specialist training at the University Hospital of Wales, and subsequently became a consultant at the Royal National Hospital for Rheumatic Diseases. At both sites, I managed to develop my specialisation in osteoporosis as well as musculoskeletal ultrasonography. Furthermore, I had the opportunity to see many common, as well as rare conditions, which further consolidated my general rheumatology expertise. The multidisciplinary clinics, in particular, were especially helpful at these two training centres.
As the Clinical Lead for Osteoporosis & Metabolic Bone Health and Rheumatology Musculoskeletal Ultrasound at Croydon Health Service NHS Trust, UK, could you elaborate on the initiatives you've spearheaded in developing local integrated bone health services and diagnostic services?
In terms of the musculoskeletal ultrasound diagnostic service, I essentially set up a diagnostic service for early inflammatory arthritis (EIA) to complement and enhance the diagnostic capability of the EIA service. I established imaging protocols (including early rheumatoid screening, psoriatic arthritis screening, and giant cell arteritis), linking of images to the picture archiving and communication system, formal rheumatology-focused image reporting, and formal training of interested specialists.
With regard to the osteoporosis service, I started by identifying the multidisciplinary stakeholders, and formed a formal integrated bone health service within the trust (including geriatricians, fracture liaison service nurses,
dual-energy X-ray absorptiometry technicians, pharmacists, endocrinologists, orthopaedics, dietitians, gastroenterology, renal medicine, primary care, patient experts, and others). I then developed a term of reference for this service, and then went on to help build the actual clinic and bone health multidisciplinary team. Through the service stakeholders, I led the development of multiple osteoporosis care pathways, including treatment algorithms, monitoring pathways, and management of complications.
Through both specialist services, I have undertaken several research projects with a focus on ultrasonography in early arthritis and psoriatic arthritis, with the musculoskeletal ultrasonography service and osteoporosis risk factors, responses to treatment, and osteoporosis imaging diagnostics with the bone health service.
Q3 As the Course Director and Tutor for Rheumatology at South Wales University, what are your primary goals in shaping the curriculum, and guiding the next generation of rheumatologists?
In this role, which I have been doing since 2016, my aim has been to ensure a robust diploma and Master’s programme in rheumatology, encompassing the broad range of rheumatology conditions, scientific knowledge and understanding, and therapeutics. The objective of the qualification is to ensure that students are equipped to apply for rheumatology-based jobs, as well as use their knowledge to develop rheumatology specialist services. Given that students are from around the world, I have had to
ensure that the course is relevant on an international level. In 2022, working alongside the university’s administrative and management team, I led the revalidation process for the course, to ensure that the learning curriculum and objectives were closely aligned with the UK rheumatology specialist training programme. Some of the key elements and successes of the course format have been providing a range of teaching and assessment modalities that are befitting realworld clinical practice.
Q4 As a co-lead on the development of an Early Inflammatory Arthritis service, please share some insights into the challenges and successes you've encountered in diagnosing and treating inflammatory arthritis early?
When I joined the current trust, my first task was to develop the early arthritis service. I started this process by developing a streamlined EIA referral form for general practitioners to use, to ensure rapid access to the rheumatology services. I also developed a referral pathway and a 1-year rheumatoid arthritis management pathway as part of the development of this service. Furthermore, to enhance rapid diagnostics I developed the musculoskeletal ultrasound service, ensuring that patients with EIA had a swift diagnosis to ensure early therapeutics. I undertook several education sessions with primary care colleagues, as well as patients, in public forums to increase awareness of the service and to ensure that the appropriate patients were identified and referred.
Q5 What motivated you to pursue a Master’s in Medical Law, and how has this additional expertise enhanced your practice as a consultant rheumatologist?
I first took an interest in medical law following a lecture I attended as a registrar as part of our generic training. Following this, I discovered an unknown passion for legal interpretation and interrogation, and how this closely fitted with the practice of clinical interrogation in rheumatology. Subsequently, I undertook a Master of Laws at Cardiff Law School, UK. Using this qualification, I have worked as an expert witness in rheumatology litigation cases since 2018. I have also provided medical legal lectures to medical colleagues and lawyers, and helped develop
a diploma in medical law at the University of South Wales, UK.
Q6 Are there any innovations on the horizon in the field of rheumatology that are of particular interest to you?
Having seen the change in osteoporosis practice, where the focus has been on defining fracture risk in determining the most appropriate treatment has been refreshing, and I think it is a significant forward step in the management of osteoporosis. Furthermore, there have been developments in diagnostic possibilities in osteoporosis assessment, which has been very interesting, including CT densitometry, trabecular bone assessment, ultrasound densitometry, and biomarkers.
Using this qualification, I have worked as an expert witness in rheumatology litigation cases since 2018.
Another important innovation that has been of particular interest is the increased number of cytokine targets in the management of psoriatic arthritis. I have generally found this condition more challenging than managing patients with rheumatoid arthritis, and the increase in the number of therapeutic targets has been very encouraging to see.
BIOSIMILARS IN BONE HEALTH TREA
BONE HEALTH is a serious public health concern that is undertreated in both osteoporosis and metastatic bone disease. 1,2 Biosimilars can increase treatment options, and potentially lower costs through market competition. 3
OSTEOPOROSIS:
• Osteoporosis is underdiagnosed and undertreated 1
• Osteoporosis increases the risk of fractures, which are associated with pain, disability, and mortality4,5
• After a major osteoporotic fracture, the risk of a second fracture within one year is 2.7-fold higher than among the general population 6
• 60–85 % of females >50 years of age with osteoporosis did not receive treatment in 2018 7
BONE METASTASIS:
• Antiresorptive medications* are underused in patients with bone metastases 2
• It is estimated that more than half of cancers develop bone metastases 8
• Most (~68 % ) of patients with skeletal metastasis experience pain, and many sustain fractures, 8 leading to significant deterioration in quality of life and worsened survival 2
• Many (39 % ) of patients with mCRPC did not receive bone health agents during follow-up 2
TREATMENT OPTIONS
• Anti-resorptive medications are the firstline treatment to reduce fractures in adults with osteoporosis, 4,9 and the first-line nonsurgical treatment of bone metastases 8
• Treatment recommendations to reduce the risk of fractures in people with osteoporosis * (EU/USA):
• Bisphosphonates or another inhibitor of bone resorption, such as denosumab, are recommended in those at high risk of fracture 4,9-12
• Denosumab is particularly recommended for those who have contraindications to, or experience adverse effects of, bisphosphonates 4,11
• Denosumab is indicated for the treatment of adults with osteoporosis who are at high risk of fracture13,14
• HRT can be used in younger postmenopausal females (aged ≤60 years) at high risk of fractures, and with a low risk for adverse malignant and thromboembolic events 11
• Treatment recommendations to reduce the risk of fractures in people with bone metastases (EU/USA):
• Guidelines recommend the use of bisphosphonates or denosumab in metastatic bone disease15,16
*Anabolic drugs such as teriparatide and/or romosozumab, followed by a bisphosphonate, are recommended for use in postmenopausal females, and in males ≥50 years of age with osteoporosis at very high risk of fractures4,8,11
*Antiresorptive drugs include bisphosphonates, denosumab, oestrogens, calcitonin, and others.
TREATMEN T
The publication of this infographic was sponsored by Sandoz. This infographic is intended for healthcare professionals based in the USA, Canada, and Europe.
Timeline of approvals for bone health treatments for osteoporosis and bone metastasis (USA/EU):
First approved for bone metastasis:
• EMA 17
First approved for osteoporosis:
• EMA 17
• FDA 18
First approved for bone metastasis:
• FDA 19
First approved for osteoporosis:
• FDA 13
• EMA 14
First approved for bone metastasis:
• FDA 20
First approved for bone metastasis:
• EMA 21
First biosimilar approved for osteoporosis:
• FDA 22
• EMA 23
First biosimilar approved for bone metastasis:
• FDA 24
• EMA 25
Reference medicine
A biosimilar is a biological medicine that is highly similar to another biological medicine already approved (the ‘reference’ medicine) 3,32
Because they are made by living organisms, biologic medicines usually contain slight variations of a protein. This variability exists both between batches of a biologic medicine, and between a reference medicine and a biosimilar 3,32
These minor differences are not clinically meaningful; for example, there may be differences in glycosylation, but the amino acid sequence of the protein remains the same in all batches.
In order to be approved, biosimilars must demonstrate that they are highly similar to, and have comparable safety and efficacy to, the reference medicine 3,32
The availability of biosimilars can provide patients with more treatment options, increase access to lifesaving medications, and potentially lower healthcare costs through market competition 3
Biosimilar medicine
KEY LEARNINGS
Bone health is undertreated in both osteoporosis and metastatic bone disease. The recent approval of denosumab biosimilars could improve patient access to these medications, reducing the onset of pain, disability, and mortality associated with fractures once available on the market.
1. Delsmann MM et al. High prevalence and undertreatment of osteoporosis in elderly patients undergoing total hip arthroplasty. Osteoporos Int. 2021;32(8):1661-8.
2. Kuppen MCP et al. Symptomatic skeletal events and the use of bone health agents in a real-world treated metastatic castration resistant prostate cancer population: results from the CAPRI-Study in the Netherlands. Clin Genitourin Cancer. 2022;20(1):43-52.
3. U.S. Food & Drug Administration (FDA). Biosimilars: overview for health care professionals. https://www.fda.gov/ drugs/biosimilars/overview-health-careprofessionals. Last accessed: 18 March 2024.
4. Qaseem A et al. Pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults: a living clinical guideline from the American College of Physicians. Ann Intern Med. 2023;176(2):22438.
5. Tu KN et al. Osteoporosis: a review of treatment options. P T. 2018;43(2):92-104.
6. Johansson H et al. Imminent risk of fracture after fracture. Osteoporos Int. 2017;28(3):77580.
7. International Osteoporosis Foundation (IOF). Broken bones, broken lives: a roadmap to solve the fragility fracture crisis in Europe. 2019. https://www.osteoporosis.foundation/sites/ iofbonehealth/files/2019-06/1.%202018_EU6_ Report_BrokenBonesBrokenLives_English. pdf. Last accessed: 18 March 2024.
8. Ardakani AHG et al. Metastatic bone disease: early referral for multidisciplinary care. Cleve Clin J Med. 2022.89(7):393-9.
9. Gregson CL et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 2022;17(1):58.
10. National Institute for Health and Care Excellence (NICE). Osteoporosis –prevention of fragility fractures. Scenario: management. 2023. https://cks.nice.org.uk/ topics/osteoporosis-prevention-of-fragilityfractures/management/management/. Last accessed: 18 March 2024.
11. National Institute for Health and Care Excellence (NICE). Treatment summaries: osteoporosis. https://bnf.nice.org.uk/ treatment-summaries/osteoporosis/. Last accessed: 18 March 2024.
12. Kanis JA et al. Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures. Osteoporosis Int. 2020;31:1-12.
13. U.S. Food & Drug Administration (FDA). PROLIA (denosumab) prescribing information. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2024/125320s213lbl.pdf. Last accessed: 18 March 2024.
14. European Medicines Agency (EMA). PROLIA (denosumab) Summary of product characteristics. https://www.ema.europa. eu/en/documents/product-information/ prolia-epar-product-information_en.pdf. Last accessed: 18 March 2024.
15. Grávalos C et al. SEOM Clinical Guideline for bone metastases from solid tumours (2016). Clin Transl Oncol. 2016;18(12):1243-53.
16. Coleman R et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2020;31(12):1650-63.
17. European Medicines Agency (EMA). Questions and answers on the review of bisphosphonates and atypical stress fractures. https://www.ema.europa.eu/en/documents/ referral/questions-and-answers-reviewbisphosphonates-and-atypical-stressfractures_en.pdf. Last accessed: 18 March 2024.
18. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab. 2010;95(4):1555-65.
19. Von Moos R et al. Management of bone health in solid tumours: from bisphosphonates to a monoclonal antibody. Cancer Treat Rev. 2019;76:57-67.
20. U.S. Food & Drug Administration (FDA). XGEVA (denosumab) prescribing information. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2020/125320s203lbl.pdf. Last accessed: 18 March 2024.
21. European Medicines Agency (EMA). XGEVA (denosumab) Summary of product characteristics. https://www.ema.europa. eu/en/documents/product-information/ xgeva-epar-product-information_en.pdf. Last accessed: 18 March 2024.
22. U.S. Food & Drug Administration (FDA). JUBBONTI (denosumab-bbdz). Prescribing information. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2024/761362s000lbl. pdf. Last accessed: 18 March 2024.
23. European Medicines Agency (EMA). JUBBONTI (denosumab). Summary of product cha racteristics. Available at: https://www.ema.europa.eu/en/documents/ product-information/jubbonti-epar-productinformation_en.pdf. La s t accessed: 25 June 2024.
24. U.S. Food & Drug Administration (FDA). WYOST (denosumab-bbdz). Prescribing information. https://www. accessdata.fda.gov/drugsatfda_docs/ label/2024/761362s000WYOST.pdf. Last accessed: 18 March 2024.
25. European Medicines Agency (EMA). WYOST (denosumab). Summary of product characteristics. Available at: https:// www.ema.europa.eu/en/documents/ product-information/wyost-epar-productinformation_en.pdf. L ast ac cessed: 25 June 2024.
26. U.S. Food & Drug Administration (FDA). EVENITY (romosozumab). Prescribing information. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2019/761062s002lbl. pdf. Last accessed: 18 March 2024.
27. European Medicines Agency (EMA). EVENITY (romosozumab). Summary of product characteristics. https://www. ema.europa.eu/en/documents/productinformation/evenity-epar-productinformation_en.pdf. Last accessed: 18 March 2024.
28. U.S. Food & Drug Administration (FDA). FORTEO (teriparatide). Prescribing information. https://www. accessdata.fda.gov/drugsatfda_docs/ label/2021/021318Orig1s056lbl.pdf. Last accessed: 18 March 2024.
29. European Medicines Agency (EMA). FORSTEO (teriparatide). Summary of product characteristics. https://www.ema.europa.eu/ en/documents/product-information/forsteoepar-product-information_en.pdf. Last accessed: 18 March 2024.
30. European Medicines Agency (EMA). TERROSA (teriparatide). Summary of product characteristics. https://www.ema.europa.eu/ en/documents/product-information/terrosaepar-product-information_en.pdf. Last accessed: 18 March 2024.
31. U.S. Food & Drug Administration (FDA). Drugs@FDA: FDA-approved drugs. Teriparitide. TEVA PHARMS USA. https://www.accessdata.fda.gov/scripts/ cder/daf/index.cfm?event=overview. process&ApplNo=208569. Last accessed: 18 March 2024.
32. European Medicines Agency (EMA). Biosimilars in the EU. https://www. ema.europa.eu/en/documents/leaflet/ biosimilars-eu-information-guide-healthcareprofessionals_en.pdf. Last accessed: 18 March 2024.
Ageing Population and Landscape of Rheumatoid Arthritis Treatment in Japan
Authors: Satoshi Kubo,1,2 *Yoshiya Tanaka2
1. Department of Molecular Targeted Therapies, University of Occupational and Environmental Health, Kitakyushu, Japan
2. The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
*Correspondence to tanaka@med.uoeh-u.ac.jp
Disclosure: Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, BristolMyers, Abbvie, Eisai, Pfizer, and Astra-Zeneca; and research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas. Tanaka has received consulting fees, speaking fees, and/or honoraria from Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-Kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, and Santen; and research grants from MitsubishiTanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, and Bristol-Myers. Kubo contributed to the writing of the manuscript. Tanaka thoroughly reviewed the manuscript.
Acknowledgements: The authors would like to thank Hiroko Yoshida, Yoko Saito, Yuki Itose, and Machiko Mitsuiki of the FIRST registry for excellent data management. They would also like to thank Kazuyoshi Saito from Tobata General Hospital; Shunsuke Fukuyo from Wakamatsu Hospital at the University of Occupational and Environmental Health; Keisuke Nakatsuka from Fukuoka Yutaka Central Hospital; and all staff members of Kitakyushu General Hospital and Shimonoseki Saiseikai Hospital for their engagement in data collection from the FIRST registry.
An ageing society is characterised by the elderly population, classified as individuals aged 65 years or older, constituting ≥7% of the total population. Furthermore, when the ageing rate reaches 14%, the designation shifts to an aged society, and upon reaching 21%, it is termed a super-aged society. Japan achieved the status of an ageing society in 1970, transitioned to an aged society in 1994, and attained super-aged society status in 2007, marking it as the country with the world’s most elderly population. The speed of ageing is typically measured by the number
of years it takes for the proportion of elderly individuals to increase from 7% (ageing society) to 14% (aged society). Remarkably, Japan transitioned to an aged society within a brief period of 24 years. It took France 126 years, Sweden 85 years, the USA 72 years, the UK 46 years, and Germany 40 years to undergo a similar transition. As such, Japan’s ageing population is progressing at an unprecedented rate.1 As of 2020, the percentage of Japanese citizens aged ≥65 years has exceeded 29%, and it is anticipated to reach 35% in less than 20 years.
This has led to an ageing population, not only among healthy individuals, but also among patients with rheumatoid arthritis (RA). The ageing of the population is not exclusive to Japan, and there is a global increase in the number of elderly individuals with RA. This rise is attributed not only to the ageing of the overall population but also to an increase in carryover, as advancements in treatment enable adolescent and middle-aged-onset patients with RA to survive longer. The incidence of elderly onset RA is also on the rise, although a definitive explanation has not yet been provided.
Several therapeutic challenges have been recognised in the treatment of RA in elderly patients, with the most significant being the compromised ability to metabolise drugs due to diminished organ function.2,3 Specifically, methotrexate (MTX), located in Phase I of the European Alliance of Associations for Rheumatology (EULAR) treatment recommendation for RA, relies on kidney-dependent metabolism. The decline in renal function associated with ageing elevates MTX concentrations, thereby heightening the risk of concentrationdependent adverse events, such as myelosuppression. Additionally, a decline of cognitive function and depressive tendencies pose a risk of reduced medication adherence and overdose. Furthermore, musculoskeletal deterioration (sarcopenia), compounded by impairments in activities of daily living due to the disease activity of RA itself, heightens the risk of becoming bedridden.4 Consequently, choosing drugs solely based on efficacy in the elderly population may lead to lower continuation rates due to their elevated susceptibility to infections. The treatment of elderly patients with RA is one of the most important issues because achieving remission or low disease activity, as recommended by EULAR, remains the goal even in older patients.5 Addressing this concern is crucial for enhancing the healthy life expectancy of elderly individuals and can contribute to mitigating the decline in the labour force and escalating healthcare costs.
As mentioned earlier, the World Health Organization (WHO) defines the elderly as individuals aged 65 years or older. However, recent data on the physical and mental ageing phenomenon among the elderly in Japan indicate that the majority of individuals aged 65–74 years maintain good physical and mental health, enabling them to engage in active social activities. In other words, the conventional inclination to categorise individuals aged ≥65 years uniformly as elderly is no longer realistic given the current scenario, as those aged 65–74 years significantly differ from those aged ≥75. Consequently, the treatment of patients with RA ≥65 years old and those ≥75 years old should be considered separately.
ACCUMULATION OF REAL-WORLD CLINICAL EVIDENCE (FIRST REGISTRY)
Since the approval of biologics for RA treatment in Japan in 2003, patients initiating molecular targeted therapy from the University of Occupational and Environmental Health, Kitakyushu, Japan, and neighbouring hospitals, have been included in a registry (Figure 1A and B). Short-term hospitalisation, which includes risk assessment and self-injection instruction following a clinical path, was implemented, and a systematic database is being constructed with the support of five data management staff. Presently, the registry includes more than 5,000 patients with RA, and real clinical data have been reported utilising this dataset. For instance, in a study on the withdrawal of biologic drugs in patients with long disease duration, deep remission was identified as a factor contributing to successful withdrawal of TNF inhibitors.6 Additionally, as a strategy to minimise selection bias inherent in realworld clinical data, the team have pioneered the use of propensity score matching and propensity score-based inverse probability of treatment weighting in the field of rheumatology. These methods effectively mitigated bias, facilitating comparisons of efficacy among drugs that had not undergone clinical trials.7,8
Figure 1: A) Cumulative use of molecular targeted therapies over the years: total number of all molecular targeted therapies. B) Cumulative use of molecular targeted therapies over the years: cumulative usage of each molecular targeted therapy, including TNF inhibitors, anti-IL-6 receptor antibodies, cytotoxic T lymphocyte-associated antigen 4-Ig, and JAK inhibitors.
cytotoxic T lymphocyte-associated antigen 4-Ig; JAKi: JAK inhibitors; TNFi: TNF inhibitors.
Real-world clinical data exhibit a lower level of clinical evidence compared to clinical trials. This is attributed to the inherent bias present in real-world clinical settings and the inability to predetermine study designs. However, patients are sometimes excluded
from clinical trials due to age limitations or comorbidities. Specifically, elderly patients with RA frequently face exclusion from clinical trials based on these criteria, leading to a current lack of evidence regarding efficacy and safety for this group.
CTLA4-Ig:
Compared to Japan, where the population is ageing at an accelerated rate, the ageing of the population in Western countries is relatively mild. Nevertheless, addressing the treatment of RA in elderly patients aged >75 years is a challenge that Western countries also encounter. Japan, with its super-aged society, could offer valuable insights. Thus, the team investigated the persistence rates of molecular targeted therapies in the elderly demographic and conducted a detailed analysis of trends associated with specific drugs.9
OPTIMAL DRUG SELECTION FOR GERIATRIC PATIENTS WITH RHEUMATOID ARTHRITIS
Biologics theoretically selectively suppress signals related to their target molecules, and are generally unaffected by hepatic or renal dysfunction. Additionally, due to their favourable balances of efficacy and safety, it is considered an optimal treatment option for elderly patients. On the other hand, the findings from the ORAL Surveillance study on tofacitinib have raised concerns regarding the risk of malignancy and major adverse cardiovascular events.10 Consequently, both
the U.S Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued warnings regarding the use of JAK inhibitors, particularly in patients aged >65 years.11 Given this context, the medical care of the elderly should aim to optimise the benefits of molecular targeted therapies and employ them judiciously. Hence, the team conducted a comparison of the 3-year retention rates for four classes of molecular targeted therapies (TNF inhibitors, anti-IL-6R antibodies, CTLA-4Ig, and JAK inhibitors) across three age groups (<65 years, 65–75 years, and >75 years) to ascertain their suitable utilisation for each demographic.9
Before the commencement of molecular targeted therapy, numerous variables, including erythrocyte sedimentation rate and the presence of comorbid hypertension, exhibited variations across age groups. Among these variables, the rate or quantity of concomitant use of MTX exhibited considerable variability (Figure 2). Ageing is the most significant risk factor for the decline in renal function, as it results in a reduction in glomerular count. Approximately 40% of individuals >65 experience a decline in estimated glomerular filtration rate to 60 mL/min/1.73 m2 . The ageing process
Figure 2: Methotrexate dosage per week across generations.
is associated with a diminished immune response, heightening the risk of infections. Additionally, there is a decline in pulmonary and cardiac reserve, amplifying the severity of adverse events. Moreover, the presence of coexisting lung disease, posing a risk for bacterial pneumonia development, was observed in 39.2% of individuals >75 years of age, contrasting with a rate of only 19.4% in those under 65 years; a notable two-fold difference. Indeed, a Japanese survey examining MTX-related deaths in patients with RA unveiled that 64.6% of the 851 reported deaths occurred in individuals aged ≥70 years. This underscores the heightened susceptibility of elderly patients to adverse drug reactions, likely influenced by diverse factors. In this context, the challenge of being unable to use MTX in Phase I or to combine MTX with molecular targeted therapy in Phase II and subsequent phases may pose a significant obstacle in the treatment of elderly patients with RA.
When comparing the continuation rates of molecular targeted therapies, JAK inhibitors and anti-IL-6R antibodies exhibited the highest rates of continuation among younger patients.9 In this study, the incidence of infection and its associated discontinuation at a young age was <1.0 per 100 patient-years for all drugs, suggesting that all drugs are relatively safe to use. Generally, younger individuals tend to have higher social activity needs, necessitating more robust suppression of disease activity. Therefore, considering their efficacy, JAK inhibitors were deemed more suitable for younger patients. Meanwhile, the retention rates of JAK inhibitors and abatacept were higher in the early elderly population, aged 65–74 years. It is noteworthy that drugs with distinct characteristics, such as the highly effective JAK inhibitor and the safer abatacept, exhibited the highest continuation rates. In this generation, TNF inhibitors and cytotoxic T lymphocyteassociated antigen 4-Ig were the only ones with infections and associated discontinuations <1.0 per 100 patientyears, while JAK inhibitors and anti-IL-6R antibodies showed an increasing trend. The diverse treatment goals for 65–74-yearolds emphasise the importance of shared decision-making. The persistence rates in
the elderly (≥75 years) were highest for abatacept and anti-IL-6R antibodies. The incidence of infections and associated discontinuations in this generation was high for JAK inhibitors, exceeding 4.0 per 100 patient-years. This suggests that the use of JAK inhibitors in patients ≥75 years old should be considered with caution regarding the development of infections. On the other hand, the safety profile of abatacept was outstanding among molecular targeted drugs, with infections and associated discontinuations below 1.0 per 100 patient-years even among patients aged ≥75 years.
These findings highlight a crucial aspect: the reasons for discontinuation varied significantly across different age groups. In younger patients, discontinuations due to adverse events were less frequent, necessitating a more efficacy-based selection. Conversely, the incidence of discontinuations due to adverse events increased with older age. Particularly noteworthy are the variations of each molecular targeted drug in continuation rates observed among the early elderly, aged 65–74 years, as mentioned earlier. A unique follow-up study in Denmark has demonstrated that the younger a person appears cognitively (cognitive age), the more their physical function is retained, leading to an extension of life expectancy.12 Individuals aged 65–74 years exhibit diverse variations in physical function, encompassing factors such as heart and kidney function, and maintaining a youthful appearance may also play a crucial role. The observation that drugs with higher continuation rates differed between individuals aged 65–74 years and those aged ≥75 years is also significant for future clinical studies, and these two age groups should be considered separately.
However, the findings come with certain limitations. First, the evidence level is lower as the results were not based on a randomised prospective trial, posing potential challenges in generalising the results. Rituximab, known for its safety, was not included in the authors’ study, as it is not approved for RA in Japan. Additionally, the number of patients may be insufficient
to accurately detect the rate of adverse events, requiring more power for such assessments.
CONCLUSION
Biologics theoretically do not inhibit any molecules other than their intended targets. Their metabolism is predominantly taken up and degraded by cells of the reticular system, akin to gamma globulin. Hence, serum concentrations of biologics are
References
1. United Nations Department of Economic and Social Affairs (UN DESA). Revision of world population prospects. 2022. Available at: https:// population.un.org/wpp/publications/. Last accessed: 5 June 2024.
2. Boots AM et al. The influence of ageing on the development and management of rheumatoid arthritis. Nat Rev Rheumatol. 2013;9(10):60413.
3. van Onna M, Boonen A. Challenges in the management of older patients with inflammatory rheumatic diseases. Nat Rev Rheumatol. 2022;18(6):326-34.
4. Bennett JL et al. Rheumatoid sarcopenia: loss of skeletal muscle strength and mass in rheumatoid arthritis. Nat Rev Rheumatol. 2023;19(4):239-51.
5. Smolen JS et al. EULAR recommendations for the management
unaffected by renal or hepatic function. In this context, the successful utilisation of biologics, particularly in the elderly, is regarded as a crucial therapeutic strategy in the management of RA. The findings represent crucial evidence that enhances the basis for collaborative decision-making in clinical contexts. The team aspire for this research conducted in Japan, home to the world’s most aged population, to serve as a guiding framework for the global surge in ageing and the corresponding management of RA in the elderly.
of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18.
6. Tanaka Y et al. Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis. 2015;74(2):389-95.
7. Kubo S et al. Comparison of the efficacies of abatacept and tocilizumab in patients with rheumatoid arthritis by propensity score matching. Ann Rheum Dis. 2016;75(7):1321-7.
8. Kubo S et al. Comparison of efficacy of TNF inhibitors and abatacept in patients with rheumatoid arthritis; adjusted with propensity score matching. Clin Immunol. 2018;191:6774.
9. Kubo S et al. Generation-dependent retention rates and reasons for
discontinuation of molecular targeted therapies in patients with rheumatoid arthritis: from FIRST registry. Rheumatol Ther. 2023;10(6):1705-23.
10. Ytterberg SR et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-26.
11. U.S Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Available at: https://www.fda.gov/ drugs/drug-safety-and-availability/ fda-requires-warnings-aboutincreased-risk-serious-heart-relatedevents-cancer-blood-clots-and-death. Last accessed: 5 June 2024.
12. Christensen K et al. Perceived age as clinically useful biomarker of ageing: cohort study. BMJ. 2009;339:b5262.
Telerheumatology: What Should We Be Thinking About Now?
Authors: *Christine Peoples,1 Steven Taylor2
1. University of Pittsburgh Medical Center, Pennsylvania, USA
2. University of Colorado, Anschutz Medical Campus, Aurora, USA *Correspondence to peoplesc2@upmc.edu
Disclosure: The authors have declared no conflicts of interest.
Received: 09.04.24
Accepted: 25.06.24
Keywords: AI, eConsults, population health, telerheumatology.
The present era of rheumatology is unmatched in history in terms of disease understanding, disease treatment, and disease discovery; yet it is faced with new problems that may not readily yield to our scientific prowess. Considering disease discovery, two new diseases entered the field recently, VEXAS syndrome and Dedicator of Cytokinesis 11 (DOCK11), defined primarily by their genetics as opposed to their syndromic presentations. The arena of therapeutics has achieved previously inconceivable outcomes, particularly with the use of chimeric antigen receptor T cells (CAR-T), resulting in drug-free remission in otherwise treatment-refractory lupus.1 While time will ultimately tell, it is incredibly exciting to consider we might be on the verge of deeming a case of lupus ‘cured’. Each of these incredible advances depends on talented rheumatologists to bring them to the bedside of patients suffering from rheumatic diseases. Standing in seeming opposition to these advances is the rheumatology workforce shortage. To ensure the future of this vibrant speciality, we must implement creative volumebased solutions that look beyond the important work of numerically expanding the workforce. Telemedicine will be crucial to tying these new innovations together to
improve the care of our patients regardless of where they live.
Rheumatology Workforce Shortage: Is It Over Now?
To say that rheumatology is experiencing a workforce shortage is an understatement, mainly due to a supply of rheumatologists that cannot keep pace with the increasing demand. In fact, the scene from the ‘I Love Lucy’ show where Lucy and Ethel are working in a chocolate factory, trying to keep up with wrapping pieces of chocolate coming down the conveyor belt, comes to mind. An American College of Rheumatology (ACR) workforce projection predicts a shortage of about 2,500 rheumatologists by the year 2025.2 In 2007, when this article was published, 2025 seemed to be a distant horizon that is now rapidly approaching. The news about the rheumatology workforce is not all bad. The number of clinically active rheumatology providers in the USA grew more than 20% from 2009–2019, and the number of advanced practice providers has experienced tremendous growth.3 Despite these two positive trends, there are still not enough rheumatology providers to meet the projected demand.
Each workforce analysis highlights the disproportionate lack of rheumatology care in rural areas, with 95% of rheumatology
practices being in urban settings, and 93% of rural counties without any adult rheumatologists, in contrast to only 48% of urban counties.3 How can we try to keep up with the demand? Telemedicine provides a key piece of the solution. Telemedicine modalities allow for efficient use of a rheumatologist’s time and for the type of care to be to what is needed by each patient at that specific time point. The goal is telehealth access to any patient who needs it. There has been an increasing demand from patients and healthcare systems for access to rheumatologists through telemedicine for decades. The COVID-19 pandemic thrust telemedicine into the spotlight, resulting in most of us adapting quickly to providing virtual care. This is not to suggest that only telemedicine modalities will solve the problem. However, telerheumatology serves as an important cornerstone to address the increased demand for rheumatology care.
Telerheumatology: We Know it Works… How Do We Use it Strategically?
Providing virtual rheumatology care is not a new concept. Many patients with rheumatic disease need a rheumatologist and the rheumatologist is often far away. We were aware of the impending rheumatology workforce shortage well before the COVID-19 pandemic. The pandemic simply put our foot harder on the gas pedal in terms of providing rheumatology care using various virtual methods. Additional systematic reviews and published studies will always be needed; however, the question is not ‘can’ we provide rheumatology care virtually but ‘how’ can we provide the right care for the right patient at the right time in the best way. When we look at addressing the distribution of rheumatologists in the USA, there will not be a solution that involves spreading rheumatologists evenly throughout the country. But that is okay; we must use a shared decision-making approach when deciding how a patient’s follow-up care should be delivered. Many patients have access to the appropriate technology and broadband internet to participate in audio-visual visits from home. However, access to technology
and broadband internet must be improved for all rheumatology patients; otherwise, there is a risk of worsening healthcare disparities. Another strategy for patients in rural and underserved communities is to travel to a localised telehealth centre for care that involves the local primary care provider. It is crucial to consider both patient factors and rheumatologist factors when deciding the type of follow-up visits. Consideration should be given to pre-visit screening and/or a disease activity measure that can be used to help determine the most appropriate visit type. Additionally, it is important to train rheumatology fellows in telemedicine modalities. It goes without saying that the field continues to face challenges. Several articles have discussed the limitations with various telerheumatology modalities.4-6 Additional research is needed, which will guide best practice recommendations and allow for the development of practical and efficient guidelines, just as what is done for any other tool in medicine, from lab testing to imaging studies. While the COVID-19 pandemic caused us to ‘floor it’ when it came to providing virtual care, we should not ‘let up on the gas’, but find a navigation system to determine the potential routes and pick the best route for each situation.
FUTURE OF RHEUMATOLOGY AND TELEMEDICINE
Population Level Approaches
The modern paradigm for rheumatoid arthritis (RA) and other rheumatic disease treatment is early intervention with the goal of reducing accumulated endorgan damage. Active research in preclinical RA states challenges where the definition of early RA sits, and recent trials have explored the impact of diseasemodifying antirheumatic drugs on disease development in these early states.7-9 As a speciality, we should expand this line of inquiry to transition towards thinking more broadly about caring for whole populations: those at risk for disease (shared epitope etc.), those with pre-clinical disease, established early disease, and those on
maintenance medications. We cannot manage each of these individuals in our respective clinics, but as a speciality, we should be proactively defining how these populations are best cared for by the whole healthcare system. This will optimise our impact on the individuals as they move through these different disease stages. A chronic care model for common rheumatic diseases could provide a framework for organising the approach, and a useful case study would be the approach taken by the American Diabetes Association (ADA) for patients with diabetes.10 The most recent Standards of Care in Diabetes outlines screening protocols and diagnostic criteria. In RA, on the other hand, classification criteria for research appropriately emphasise that the disease is a clinical diagnosis. However, these classification criteria are being suggested as screening criteria outside of the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR), a role these criteria are not designed to play. This misapplication is resulting in an overemphasis on serologies, as opposed to a clinical diagnosis of inflammatory arthritis, contributing to over-testing and misaligned referrals. Future work of our speciality should focus on translating the ongoing research into guidelines with screening algorithms. A Chronic Care Model focuses on moving to a proactive healthcare delivery system, providing self-management support, creating patient registries, building decision support tools, developing community resources, and promoting quality-oriented healthcare systems. These same goals are likely shared by rheumatologists; however, they have not been broadly put to paper.11 We in rheumatology need to be proactive in developing these care models as we face the workforce crisis. We cannot define rheumatic care simply as care that occurs when a patient is in the rheumatology clinic, and much of this effort will rely on telemedicine.
eConsults
Thinking about providing virtual care to rheumatology patients, we tend to focus on synchronous methods. However, many
common rheumatology questions can be addressed more efficiently by using eConsults. Joint pain, back pain, and fatigue are extremely common reasons for any patient to see a doctor. However, a rheumatologist does not need to see most patients with joint pain, back pain, or fatigue. It can be challenging for the ordering provider, most often a primary care provider, to know when a rheumatology question would be most appropriate for an eConsult versus a traditional consult. As rheumatologists, we need to provide primary care providers with guidelines for which patient questions fit with which modality. eConsults can also be used as a triage method to determine which patients need to be seen more urgently and serve as a type of pre-visit preparation. For rheumatology eConsults to be successful, the ordering provider needs to prepare the necessary information that needs to be reviewed by the rheumatologist and review the eConsult recommendations with the patient.
The majority of eConsults focus on outpatient clinical questions. However, in-patient eConsults are part of our near future. As rural areas lose their hospital systems, there will be a dramatic shortage of rheumatologists to cover in-patient services. We should have a similar thought process as to a neurologist managing potential stroke patients in rural and underserved areas. It is important to consider those patients with serious rheumatology diagnoses, such as various forms of vasculitis and lupus nephritis. The hospitalist or intensivist can be guided to allow for proper and timely rheumatology care, especially when the alternative is no care at all.
Artificial Intelligence
Society is becoming increasingly technology-driven, with a growing interest in using AI to enhance rheumatology care. When we think about AI, a ‘glamourous’ topic is transformer models such as ChatGPT (OpenAI, Microsoft, Redmond, Washington, USA). Can an AI modality replace the job of a rheumatologist to diagnose and treat patients? While this is ‘trendy’ to discuss, AI
in rheumatology can best be used in other ways. For example, when a new patient is seen or when making a diagnosis of a chronic systemic rheumatic disease such as rheumatoid arthritis or lupus, there are many topics to address during that patient visit. This also arises during follow-up visits, with additional information regarding treatment, supportive care, physical therapy and occupational therapy, and other important parts of care such as updated vaccinations and age-appropriate malignancy screening. Can we use an AI modality to answer patient questions and provide patient education and counselling? This is an intriguing concept that could make patient visits more efficient and improve their satisfaction as all their questions are being answered fully.2 Rheumatologists certainly should employ the use of AI for documentation.12 Many of the reasons they face burnout is due to the increased requirements for documentation in the electronic medical record and increasing demands for administrative work. Can AI modalities be used to aid with rheumatology education for medical students, residents, fellows, nursing students, and physical therapy students?12 This seems like a good idea as it is known that providing education to primary care providers about common rheumatology issues is a goal that is worth achieving. To make that goal easier and more efficient, AI could be an ace in our pocket.
LOOKING FORWARD
The future of rheumatology is bright; we are facing challenging diseases armed with treatments with previously unfathomable results. But we also must begin revolutionising the provisions of these treatment advances. Healthcare in the USA is shifting from a volume-based system to a value-based system. Increasing the
References
1. Mackensen A et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124-32.
2. Deal CL et al. The United States rheumatology workforce: supply and
workforce on its own is a volume-based solution; value-based solutions should be searched for to complement ongoing efforts at expanding the workforce. A common reason for a rheumatology consult is an isolated positive antinuclear antibody (ANA), often ordered for non-specific and vague symptoms. Let’s look at an example of how this might be handled in the future drawing on volume-based, telemedicine supported, solutions.
Imagine a visit with a primary care provider; the patient is a 65-year-old female, she describes new fatigue, a little numbness, but is otherwise well. The provider begins entering an ANA order; the electronic ordering system shows the provider a message mentioning that the patient’s symptoms are non-specific and that non-clinically concerning ANAs are very common in this age group. The ANA is not ordered, and additional workup is performed by the provider identifying sleep apnea. This patient avoids both a face-to-face evaluation with a rheumatology provider and an eConsult through the implementation of decision support tools at the point of care.
Perhaps another patient; a 43-year-old female, was seen in a rheumatology clinic, which is 400 miles from her home, 2 years ago for an ANA with vague symptoms. During the visit, she was enrolled in a registry of patients with positive ANAs. When she sees her primary care provider for an annual wellness exam, the complete blood count reveals a low lymphocyte count and new proteinuria, and her chart is flagged in the registry. When proteinuria is persistent, the rheumatology clinic contacts the patient for re-evaluation via telemedicine. Careful history and lab testing results in an early lupus nephritis diagnosis and prompt initiation of treatment in her hometown.
3. Mannion ML et al. Changes in the workforce characteristics of providers who care for adult patients with rheumatologic and musculoskeletal disease in the United States. Arthritis Rheumatol. 2024;76(7):1153-61.
4. Ahmed S et al. APLAR recommendations on the practice of telemedicine in rheumatology. Int J Rheum Dis. 2022;25(3):247-58.
5. Jackson LE al. Telemedicine in rheumatology care: a systematic review. Semin Arthritis Rheum. 2022;56:152045.
6. Grainger R et al., “Telerheumatology during the COVID-19 pandemic and beyond.” Peoples C (ed.), Telerheumatology (2022), New York: Springer International Publishing, pp.263-80.
7. Rech J et al. Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, doubleblind, placebo-controlled trial. Lancet. 2024;403(10429):850-9.
8. Niemantsverdriet E et al. TREAT
early arthralgia to reverse or limit impending exacerbation to rheumatoid arthritis (TREAT EARLIER): a randomized, double-blind, placebocontrolled clinical trial protocol. Trials. 2020;21(1):862.
9. Gerlag DM et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study. Ann Rheum Dis. 2019;78(2):179-85.
10. Wagner EH. Chronic disease management: what will it take to improve care for chronic illness? Eff
Clin Pract ECP. 1998;1(1):2-4.
11. Russell-Westhead M et al. Mixed methods study of a new model of care for chronic disease: co-design and sustainable implementation of group consultations into clinical practice. Rheumatol Adv Pract. 2020;4(1):rkaa003.
12. Chandwar K, Misra DP. What does artificial intelligence mean in rheumatology? Arch Rheumatol. 2024;39(1):1-9.
Successful Screening of Undiagnosed Psoriatic Arthritis in Primary Care Utilising Digital Interventions Within a Quality Improvement Programme
Authors: *Antoni Chan,1 Matthew Pearce,2 Liz van Rossen3
1. University Department of Rheumatology, Royal Berkshire NHS Foundation Hospital, Reading, UK
2. Brookside Group Practice, Reading, UK,
3. East Kent Hospitals University NHS Foundation Trust, UK *Correspondence to antoni.chan@nhs.net
Disclosure: Chan has received honoraria for speakers’ bureau for Novartis, Abbvie, UCB, and Janssen; and advisory boards for Novartis, UCB, Lilly, Abbvie, and Janssen. Van Rossen works for AbbVie Medical as a Project Lead. Pearce has disclosed no conflicts of interest.
Acknowledgment: The authors would like to thank the members of the Rheumatology Academy and Collaborative Network (RheumACaN) for the joint working between primary, secondary, and community care. The authors would also like to thank Brookside Group Practice, Reading, UK, for their collaboration with the University Department of Rheumatology, Royal Berkshire NHS Foundation Hospital, Reading, UK, in this project.
Received: 12.01.24
Accepted: 20.03.24
Keywords: Digital, inflammatory arthritis, integrated care, primary care, psoriasis (PsO), psoriatic arthritis (PsA), quality improvement.
Background: Despite the advancements in the management of psoriasis (PsO) and psoriatic arthritis (PsA), there remains a significant delay to diagnosis of PsA. National guidelines recommend regular screening of patients with PsO for PsA. The aim of this study was to increase the screening of patients with PsO, and reduce the delay to diagnosis in PsA.
Methods: A retrospective baseline audit was conducted in patients with PsO attending a large general practice (Brookside Group Practice, Reading, UK) between November 2022–April 2023. In the follow-up stage between May–November 2023, a digital Egton Medical Information System (EMIS; Emis Health, Rawdon, Leeds, UK) web template, using the Psoriasis Epidemiology Screening Tool (PEST) questionnaire was implemented. The number of patients with PsO screened for PsA, and the number of newly diagnosed PsA cases, were recorded.
Results: At baseline, 15 patients with PsO were identified, and none had PsA screening done. In the follow-up phase, 28 patients coded for PsO were identified. There was an increase in the number of patients screened for PsO from 15 to 28, representing an increase of 87% from baseline.
From the follow-up group, 12 (43%) patients were screened for PsA. These patients were referred to the specialist clinic, and seven (58%) had confirmed PsA. This represented a population of patients with previously undiagnosed PsA within the general practitioner (GP) surgery.
Conclusions: The authors have successfully implemented an integrated and interactive digital screening tool for PsA within the GP system. This has led to an increase in the detection of patients with PsA. This practical and effective approach is in line with national guidelines for early detection, to prevent long-term damage and disability from PsA.
Key Points
1. Increasing screening for PsA in patients with psoriasis (PsO) at primary care level using digital interventions can improve identification and referral of potential psoriatic arthritis (PsA) at an early stage.
2. The screening tool optimised patient education opportunities for possible symptoms of PsA in patients presenting with PsO, so that they could return to the general practitioner if the relevant symptoms developed.
3. The concept of this paper is to show that small changes done within quality improvement cycles can bring positive clinical impact, that may be used in other areas as well.
INTRODUCTION
Psoriasis (PsO) is a chronic inflammatory skin condition that affects around 2% of the population in Europe.1 Psoriatic arthritis (PsA) can affect up to 30% of patients with PsO, and has a prevalence of around 0.37% in the UK.2 Despite the recent advancements in the management of PsA,3 there remains a delay to diagnosis, with a median time of 2.5 years.4 Reducing the delay to diagnosis of PsA is important, as joint damage can occur as early as 6 months from onset of symptoms.5 Half of people with PsA can develop irreversible joint damage within 2 years.6 Earlier treatment of patients with PsA using a treat-to-target approach aiming for remission or low-disease activity can result in better clinical outcomes.7
The majority of patients with PsA present with preceding PsO. When presenting with PsO in primary care, there is a lack of screening for underlying joint symptoms, contributing to the delay in diagnosis for PSA, where up to 85% of patients with PsO who are followed up in secondary care have undiagnosed PsA.8 To improve the earlier detection of PsA, there is a need to address the unmet need of enhancing clinicians’ awareness, through the use of a screening tool. The national guidance in the
UK recommends annual screening for PsA in patients with PsO.9 The use of the Psoriasis Epidemiology Screening Tool (PEST) has been recommended by the National Institute of Clinical Excellence (NICE) in the UK. The PEST questionnaire is a validated screening tool, and a score of 3 or more out of 5 indicates a referral to rheumatology should be considered.10 Other screening questionnaires have been used in primary care, and there are minimal differences in the sensitivity and specificity for the detection of PsA.11 The use of screening questionnaires in real-world primary care clinics are dependent on simplicity and easy access, for both patients and clinicians.
Rationale and Aims
The objective of the study was to increase screening for PsA in patients with PsO at primary care level, with the implication to identify potential PsA at an early stage. A secondary objective was to utilise patient education opportunities for possible symptoms of PsA in patients presenting with PsO, so that they could return to the general practitioner (GP) if any of the relevant symptoms developed. The authors evaluated the use of the PEST screening tool, which was integrated into the GP system in the follow-up audit. The earlier referral to the rheumatology clinic for these
patients would be in line with the PsO guidelines. The ultimate aim then would be for earlier referral for possible PsA in patients with PsO.
METHODS
The authors conducted this study within the collaboration set up between primary and secondary care, called the Rheumatology Academy and Collaborative Network (RheumACaN). This network provides training and mentoring of primary care clinicians through collaboration with secondary care rheumatology specialists.12 Using a quality improvement approach, which utilises the Plan, Do, Study, Act (PDSA) cycle, the authors evaluated the presence and effectiveness of PsA screening in patients with PsO (Table 1). This study was done within a service improvement framework, and had institutional approval. The authors
planned (P) the study by carrying out a baseline audit to evaluate the existing practice of screening for PsA in PsO, prior to any improvement interventions. An audit was carried out at baseline for a 6-month period between the start of November 2022 to the end of April 2023. A retrospective case note analysis of patients with any form of PsO in a large GP surgery (Brookside Group Practice, Reading, UK), who attended the clinic during this period, were analysed. The case notes were reviewed to ascertain if screening for PsA had been undertaken during the clinic consultation for patients with PsO.
Following the baseline audit, in the Do (D) stage, the authors implemented a new screening system in the GP system. Using the PEST questionnaire, which was integrated into the GP web-based system, Egton Medical Information System (EMIS; Emis Health, Rawdon, Leeds, UK), in a large urban GP surgery, patients with PsO
Table 1: The Plan, Do, Study, Act cycle used for the quality improvement programme to increase the screening and diagnosis of psoriatic arthritis in patients with psoriasis.
Stages in the PDSA cycle Activities and interventions carried out
Plan (P)
Do (D)
Study (S)
Act (A)
• Perform retrospective baseline study of patients with PsO who have been screened for PsA
• Develop a digital EMIS web template for future screening of PsO patients for PsA
• Complete the retrospective baseline study, and determine the number of patients screened for PsA
• Screen all patients coded for PsO in the GP practice
• Repeat the similar exercise for future cohorts of patients once the EMIS web template has been implemented
• Review the data collected at baseline and at each 6-month interval once the intervention (EMIS web template) has been used
• Report the findings from the study using the SQUIRE 2.0 guidelines
• Understand the strength and limitations of the programme, in order to refine and improve the EMIS web template
• Implement the use of the EMIS web template in patients with PsO Increase knowledge and use of the EMIS web template for all members of staff in the GP surgery
• Implement its use at IT induction
• Improve rapid referral to rheumatology for patients with suspected PsA
• Increase educational resources for patients
• Repeat the audit cycle to ensure the highest rate of detection and reduction in delays to diagnosis in PsA
EMIS: Egton Medical Information System; GP: general practitioner; PDSA: Plan, Do, Study, Act; PsA: psoriatic arthritis; PsO: psoriasis.
were screened for the possible presence of PsA. A total score of 3 or more out of 5 from PEST was positive, and indicated a review of the patient for possible PsA. There was an assessment of patients who had possible PsA, including examination of skin and joints. In addition to the five questions from PEST, the authors also added two additional questions on the type of PsO, namely nail and scalp involvement, as these were likely predictors of PsA. The screening questionnaire was available for all members of staff at the GP surgery to use (Figure 1). Patients with PsA already known to secondary (specialist) care were excluded from the study.
In the Study (S) phase, the authors evaluated the number of patients with possible PsA detected, and the effectiveness of the digital screening system for PsA. In the Act (A) phase, they refined the digital system, and added in induction and educational programmes to enhance the detection of PsA in patients with PsO. The authors used the Standards
for QUality Improvement Reporting Excellence 2.0 (SQUIRE 2.0) guidelines for reporting the key components of this systematic effort to improve the quality, value, and impact of their intervention.13
RESULTS
The GP surgery has around 30,000 patients registered, and had a good representation of the different age, sex, and ethnic groups represented. The GP database was screened for patients with PsO. At baseline, patients attending the surgery between November 2022–April 2023 were screened retrospectively for PsO. A cohort of 15 patients with PsO were identified. Of this group of patients with PsO, none (0%) were documented as having been screened for PsA (Figure 2a).
In the follow-up period, patients with PsO attending between May–November 2023 were screened for PsA following the implementation of the EMIS web template.
This was integrated into the GP practice EMIS web template used for screening for PsA in patients with PsO. EMIS: Egton Medical Information System; PsA: psoriatic arthritis; PsO: psoriasis.
Figure 1: The integrated screening tool for psoriatic arthritis in patients with psoriasis.
In this follow-up audit, a cohort of 28 patients with PsO were identified. From the 28 patients with PsO, 12 (43%) patients were screened for PsA. In eight of the 12 patients (67%), the EMIS web tool was used to screen patients with PsO for PsA (Figure 2b). All 12 patients were referred to rheumatology clinic, and from this, seven (58.3%) patients had a confirmed diagnosis of PsA.
Comparing the follow-up study using the screening tool with baseline, there was an increase in the number of patients screened for PsO from 15 to 28, representing an increase of 87% from baseline. The number of patients with PsO screened for PsA and referred had increased from zero to 12 patients at baseline and follow-up, respectively.
DISCUSSION
Patients with PsO often experience musculoskeletal (MSK) symptoms preceding the diagnosis of PsA. These MSK symptoms are often referred to
as the psoriatic march leading to the development of PsA. There is increased prevalence rates of MSK symptoms and burden experienced by patients newly diagnosed with PsO through 5 years of follow-up.14 This presents an opportunity for screening of patients with PsO for PsA, leading to earlier diagnosis, and preventing long-term joint damage and functional limitations. More recently, the European League Against Rheumatism (EULAR) have produced points to consider for definition of clinical and imaging features suspicious for the progression from PsO to PsA.15 In children, juvenile spondyloarthropathies are a heterogeneous group of diseases, and, based on the International League of Associations Rheumatology (ILAR) classification criteria, patients with juvenile spondyloarthropathies are mainly classified under enthesitis-related arthritis or psoriatic arthritis groups.16 MSK symptoms, such as arthralgia, joint, and entheseal pain in people with PsO should be considered as a risk factor for PsA development. These features should be assessed regularly, and, if present, referral to a rheumatologist should be considered. Imaging such as
Number of PsO patients
Baseline audit
Follow up audit
Figure 2a: The number of patients with psoriasis identified at baseline and at follow-up after implementation of the EMIS web template quality improvement programme.
EMIS: Egton Medical Information System; PsO: psoriasis.
2b: The number of patients with psoriasis screened for PsA, and the number of patients with the EMIS web template used for screening for PsA.
EMIS: Egton Medical Information System; PsA: psoriatic arthritis.
ultrasound and MRI in people with PsO can also be used to help identify those at risk for PsA; in particular to detect synovioentheseal involvement or abnormalities. These clinical and imaging features may help define patients with PsO suspicious of progression to PsA.
Different screening questionnaires for PsA in patients with PsO have been used in primary care. These include the PEST, the 8-item questionnaire CONTEST, and CONTEST with a minikin (CONTESTjt).17 Minimal differences in discriminative ability between these three screening questionnaires were found. The choice of which instrument to use will depend on other factors, such as simplicity and low patient burden.18 Other PsA screening questionnaires include Psoriatic Arthritis Screening and Evaluation (PASE),19 and the Toronto Psoriatic Arthritis Screen (ToPAS),20 which have been utilised in dermatology clinics.21 The Early Psoriatic Arthritis Screening Questionnaire (EARP) has also been used in clinics.22 There is also a need to develop screening questionnaires for diverse languages and cultures. One example is the Italian PsA screening tool,
the Screening Tool for Rheumatologic Investigations in Psoriatic Patients (STRIPP) questionnaire.23 Developed from PASE, the STRIPP questionnaire had a higher sensitivity (0.92) and specificity (0.93) compared to the Italian version of PASE, with a sensitivity and specificity of 0.73 and 0.76, respectively.
The presence of numerous screening questionnaires for PsA reflects the heterogeneity and the various different domains of the condition, which also requires a systematic and joined-up multidisciplinary approach in its implementation in clinics. Clinical assessment is particularly important, as there may be other conditions that mimic PsA when the screening questionnaires are applied. The most frequent PsA-alternative diagnoses were osteoarthritis and fibromyalgia.24
A meta-analysis of psoriatic arthritis screening25 showed that the pooled sensitivity and specificity for the most commonly reported questionnaire-based screening tools (ToPAS, PEST, PASE, and EARP) ranged between 0.65–0.85, and 0.68–0.85, respectively. EARP was the most
Figure
accurate screening tool, with the highest sensitivity and specificity (0.85 each), including when only high-quality studies were included. However, with further evidence and direct comparisons with other screening questionnaires, EARP’s accuracy was not comparably higher than that of the other questionnaire screening tools. The performance of the screening tools for PsA in primary care was evaluated in a cross-sectional study.26 Comparing the PEST, PASE, and EARP questionnaires for detecting PsA among patients with PsO in primary care, the PEST questionnaire has the most favourable trade-off between sensitivity (0.67) and specificity (0.71) to screen for PsA. EARP had a favourable sensitivity (0.87), but lower specificity (0.34). For this reason, the authors used the PEST in their study.
The implementation of the EMIS web template has been a beneficial intervention for increasing the number of patients with PsO who are screened for PsA. During the second 6-month period of the study, between May–November 2023, when the intervention took place, the number of patients with PsO who were screened had increased by 67% compared to baseline. The early identification of these patients with suspected PsA will allow for rapid referral to the early inflammatory arthritis clinic, which has a waiting time of less than 3 weeks. The case finding of seven previously undiagnosed patients with PsA is a significant achievement, as a result of the intervention put in place. In the authors’ model, this has improved the screening for PsA compared to baseline, where there was no documentation of this.
In a survey of clinical practice, 81% of dermatologists use PsA-specific screening instruments, while only 26.8% of rheumatologists use PsA screening tools to assess patients referred to them from all sources.27 In the authors’ study, 67% of patients with PsO who were screened for PsA had this done using the EMIS web template. This represents an improvement in detecting undiagnosed PsA compared to baseline, where none of the patients with PsO were screened for PsA.
The EMIS web template also served as a prompt for patient education. Increasing awareness and knowledge of PsA through patient education can help reduce delays to diagnosis, with patients with PsO reporting MSK symptoms to the clinicians earlier. The use of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)’s treatment recommendations and educational resources can be helpful in this regard.28 The EMIS web template can signpost clinicians to these educational resources. It increases the awareness of the need for PsA screening, as well as for comorbidities, including cardiovascular screening in patients with PsO.
The template helped both clinicians and patients with PsO to recognise the possible MSK features that may signify the presence of PsA. This served as a prompt for the early referral of patients with PsO meeting criteria within the PEST questionnaire to the rheumatologists. The re-audit demonstrated an improvement in opportunistic screening for PsA in patients presenting with PsO. The screening tool is used as a pop-up or reminder when patients present with PsO in the clinic. There is potential to increase the use of PsA screening in patients presenting with PsO, and interventions employed include repeat presentations at clinicians’ meetings to increase awareness. There is also now the inclusion of the new template in new clinician IT inductions.
Screening of patients for PsA has been shown to be cost-effective compared to no screening. A study in Canada has shown that implementing screening in patients with PsO was expected to represent a cost saving of 220 million CAD per year, and improve the quality of life.29 Implementing a screening strategy such as the authors’ will be important, as the incidence of PsA is likely to rise in the future. A recent study in Germany predicted higher numbers of PsA in the coming decades if preventive strategies are not implemented. In the long term, it is important to implement preventive strategies to identify predictors, and treat PsO symptoms early, in order to delay, or even prevent, the transition of psoriasis to PsA.30
The limitations of the study are that the authors only screened patients with PsO attending the GP surgery during two 6-month periods, from November 2022–November 2023, hence the small sample size. They plan to screen all patients with PsO for features of PsA from the GP database in future. This will increase the number of patients screened and diagnosed with PsA. Not all patients with PsO were screened for PsA following the implementation of the EMIS web template (16 out of 28 were not screened), showing that further clinician training, induction, and awareness that is planned will be required. This is part of the quality improvement programmes, with repeat PDSA cycles, to continually improve the detection of PsA in patients with PsO.
The strengths of the study are that this EMIS web template has been implemented in real-world GP surgeries, with improvement in the screening of PsA from baseline, and improved training for clinicians and education for patients. Within a year of commencing the programme, there was positive improvement. This programme was also carried out with a quality improvement set-up, ensuring the sustainability of the intervention long-term.
References
1. Parisi R et al. National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study. BMJ. 2020;369:m1590.
2. Druce KL et al. The epidemiology of psoriatic arthritis in the UK: a health intelligence analysis of UK Primary Care Electronic Health Records 1991-2020. Rheumatology (Oxford). 2023;kead586.
3. Tucker L et al. The 2022 British Society for Rheumatology guideline for the treatment of psoriatic arthritis with biologic and targeted synthetic DMARDs. Rheumatology (Oxford). 2022;61(9):e255-66.
4. Karmacharya P et al. Diagnostic delay in psoriatic arthritis: a population-based study. J Rheumatol. 2021;48(9):1410-6.
5. Haroon M et al. Diagnostic delay of more than 6 months contributes to
Summary
In the authors’ study, the implementation of the EMIS web template improved the screening of PsA in patients with PsO. There was a significant increase in the number of patients with undiagnosed PsA that were detected in the re-audit, once the digital intervention. This has also led to improved awareness of PsA in clinicians, and education for patients. With further repeat PDSA cycles, the opportunistic screening of patients with PsO will lead to earlier and higher detection of PsA in this group of patients.
CONCLUSION
The authors have shown in their study a practical and pragmatic real-world digital approach to improved time to diagnosis in PsA. This is in line with national and international guidelines, and best practice. With earlier diagnosis and screening, this will reduce the physical, functional, social, and financial burden of PsA, which is significant if left untreated. Interventions such as this are needed, as the incidence of PsA is likely to increase in the future. The integrated and interactive approach between all sectors in healthcare will be crucial to achieving the aim of improving outcomes for patients with PsA.
poor radiographic and functional outcome in psoriatic arthritis. Ann Rheum Dis. 2015;74(6):1045-50.
6. Kane D et al. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology (Oxford). 2003;42(12):1460-8.
7. Gossec L et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update. Ann Rheum Dis. 2020;79(6):700-12.
8. Reich K et al. Epidemiology and clinical pattern of psoriatic arthritis in Germany: a prospective interdisciplinary epidemiological study of 1511 patients with plaquetype psoriasis. Br J Dermatol. 2009;160(5):1040-7.
9. Psoriasis: assessment and management [Internet]. Available at: https://www. nice.org.uk/guidance/cg153. Last
accessed: 12 November 2023.
10. Ibrahim GH et al. Evaluation of an existing screening tool for psoriatic arthritis in people with psoriasis and the development of a new instrument: the Psoriasis Epidemiology Screening Tool (PEST) questionnaire. Clin Exp Rheumatol. 2009;27(3):469-74.
11. Helliwell PS et al. The comparative performance of three screening questionnaires for psoriatic arthritis in a primary care surveillance study. Rheumatology (Oxford). 2023;kead310.
12. Chan A et al. Pos1097 improved referrals from primary care and management of inflammatory arthritis through an integrated collaborative academy and network using blended learning, mentoring and action learning sets. Ann Rheum. 2023;82:873.
13. Ogrinc G et al. SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): revised publication
guidelines from a detailed consensus process. BMJ Qual Saf. 2016;(25):986-92.
14. Merola JF et al. Prevalence of musculoskeletal symptoms in patients with psoriasis and predictors associated with the development of psoriatic arthritis: retrospective analysis of a US claims database. Dermatol Ther (Heidelb). 2023;13(11):2635-48.
15. Zabotti A et al. EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis. Ann Rheum Dis. 2023;82(9):1162-70.
16. Yıldız M et al. Juvenile spondyloartropathies. Eur J Rheumatol. 2022;9(1):42-9.
17. Coates LC et al. Development and testing of new candidate psoriatic arthritis screening questionnaires combining optimal questions from existing tools. Arthritis Care Res (Hoboken). 2014;66(9):1410-6.
18. Coates LC et al. Comparison of screening questionnaires to identify psoriatic arthritis in a primary-care population: a cross-sectional study. Br J Dermatol. 2016;175(3):542-8.
19. Dominguez P et al. Psoriatic arthritis screening and evaluation (PASE)
questionnaire and the role of dermatologists: a report from the GRAPPA 2009 annual meeting. J Rheumatol. 2011;38(3):548-50.
20. Chandran V, Gladman DD. Toronto psoriatic arthritis screening (ToPAS) questionnaire: a report from the GRAPPA 2009 annual meeting. J Rheumatol. 2011;38(3):546-7.
21. Coates LC et al. Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study). Br J Dermatol. 2013;168(4):802-7.
22. Tinazzi I et al. The early psoriatic arthritis screening questionnaire: a simple and fast method for the identification of arthritis in patients with psoriasis. Rheumatology (Oxford). 2012;51(11):2058-63.
23. Burlando M et al. The STRIPP questionnaire (Screening Tool for Rheumatologic Investigation in Psoriatic Patients) as a new tool for the diagnosis of early psoriatic arthritis. G Ital Dermatol Venereol. 2020;155(3):294-8.
24. Floris A et al. The challenging differentiation of psoriatic arthritis from other arthropathies and nonspecific arthralgias in patients with psoriasis: results of a cross-sectional rheumatologic assessment of a large
25. Iragorri N et al. Psoriatic arthritis screening: a systematic review and meta-analysis. Rheumatology (Oxford). 2019;58(4):692-707.
26. Karreman MC et al. Performance of screening tools for psoriatic arthritis: a cross-sectional study in primary care. Rheumatology (Oxford). 2017;56(4):597-602.
27. Song K et al. Screening and referral strategies for the early recognition of psoriatic arthritis among patients with psoriasis: results of a GRAPPA survey. J Rheumatol. 2023;50(11):1439-45.
28. Coates L et al. Group for research and assessment of psoriasis and psoriatic arthritis (GRAPPA): updated treatment recommendations for psoriatic arthritis 2021. Nat Rev Rheumatol. 2022;18(8):465-79.
29. Iragorri N et al. Model to determine the cost-effectiveness of screening psoriasis patients for psoriatic arthritis. Arthritis Care Res (Hoboken). 2021;73(2):266-74.
30. Wang J et al. A population-based projection of psoriatic arthritis in Germany until 2050: analysis of national statutory health insurance data of 65 million German population. Rheumatol Int. 2023;43(11):2037-47.
Eosinophilia in Rheumatology: A Management Challenge
Authors: Michael Alsharkawy,1 Duncan Murray,2 *Shirish Dubey1,3
1. Department of Rheumatology, Oxford University Hospitals NHS Foundation Trust, UK
2. University Hospital Coventry and Warwickshire NHS Trust, UK
3. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK
*Correspondence to shirish.dubey@ouh.nhs.uk
Disclosure: The authors have declared no conflicts of interest.
Received: 07.05.24
Accepted: 05.07.24
Keywords: Drug, DRESS syndrome, eosinophilia, eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), hypereosinophilic syndrome, IgG4RD, Kimura's disease, reactions.
Eosinophils are an important and mediate several key functions; however, they can be associated with a number of different disorders and organ dysfunction. Eosinophilia is defined as counts above 0.5–1.5x109/L, and persistent counts above 1.5x109/L are classed as hypereosinophilia. Although several systemic diseases and single-organ diseases manifest with eosinophilia, it is not always pathological. In some, eosinophilia is a key marker of disease activity, and in others, it is a reaction to another immune trigger, making it crucial to making the right diagnosis. These include helminthic and parasitic infections; immunological disorders; haemato-oncological disorders, such as hypereosinophilic syndrome; rheumatological disorders, such as eosinophilic granulomatosis with polyangiitis; and organ-specific disorders, such as asthma (respiratory) and eosinophilic oesophagitis (gastrointestinal). A systematic approach to eosinophilia is essential to make a prompt diagnosis and institute appropriate management. This article discusses the approach to a patient presenting with eosinophilia, the diagnostic work up, and management considerations. The authors particularly focus on some of the rheumatological conditions that can give rise to significant eosinophilia, and how to differentiate between these.
Key Points
1. This article discusses the key homoeostatic role of eosinophils and the pathological pathways in eosinophilic disorders.
2. Included is a summary of haematological, rheumatological, and immunological causes of eosinophilia.
3. The article also discusses an approach to patients with eosinophilic disorders, in particular differentiating patients with haematological and rheumatological aetiologies.
INTRODUCTION
In clinical practice, cases presenting with eosinophilia can sometimes be challenging due to their heterogeneous nature and diversity.1 Eosinophilia can be seen across a wide range of conditions. Many of these conditions would be associated with an increased tissue eosinophil cell count and activation with the presentation based on organ dysfunction. But sometimes, the eosinophilic nature of the condition would only be demonstrated after a high clinical index of suspicion and subsequent specialised testing. Although better known for their immunological and anti-microbial role, eosinophils have critical roles in organ development and metabolism, and it is important to have a good understanding of these processes in health and under normal homeostatic conditions to understand the pathological roles of eosinophils. This narrative review was constructed in two separate parts, with the initial part focusing on eosinophils in health and disease and the second part on rheumatological diseases associated with eosinophilia. PubMed and subsequently Google Scholar searches with English language filter were performed using the terms “eosinophilia” or “hypereosinophilia” AND “rheumatology,” “arthritis,” “lupus,” and “vasculitis.” Abstracts of the PubMed results, and the title and the text of Google Scholar results, were reviewed to find any case reports, case series, or review articles, in which case eosinophilia and absolute eosinophil counts (AEC) were described in the manuscript. Additional manuscripts were identified through searches of cited articles or through personal contact.
EOSINOPHIL DEVELOPMENT AND DIFFERENTIATION
As with other blood cell lineages, eosinophil production is in the bone marrow and is led by common myeloid progenitors, which leads to an eosinophil lineage-committed progenitor (EoP).2 The EoP has a distinct surface expression phenotype and is cluster of differentiation 34 (CD34), CD38, and CD125 positive.3 These progenitor cells are seen in very small numbers in the peripheral
blood and umbilical cord blood. They are more commonly seen in the bone marrow, but still only make approximately 0.05% of lineage-negative CD34+ cells. EoPs then mature into eosinophils under the influence of GATA1 gene transcription factors.4,5 These are a large family of transcription proteins that highly regulate haematopoiesis. The differentiation of eosinophils requires several factors, including high GATA1 expression and various cytokines that share common β-chain receptors such as interleukin-5 (IL-5), IL-3, and granulocyte-macrophage colony-stimulating factor.6 The most specific of these is IL-5, which is associated with selective differentiation and mobilisation of eosinophils from the bone marrow and into the various tissues, and is a very important target for pharmacotherapy in nonhaemato-oncological eosinophilic disorders.7
Eosinophils released into the circulation from the bone marrow make up 1–5% of all circulating leukocytes.8 Eosinophil counts are performed by automated cell counters, which use flow cytometry to measure cell size and complexity to rapidly classify eosinophils. This can be verified on a blood film, where the cells have a distinctive appearance with granules staining bright red/pink with eosin. In the peripheral circulation, eosinophils are normally less than 0.5 x109/L.9,10 A count between 0.5–1.5 x109/L is considered as eosinophilia, and persistent counts above 1.5 x109/L as hypereosinophilia. Eosinophil migration to tissues is meditated by a family of chemokines called eotaxins. Stromal cells, including fibroblasts, smooth muscle cells, and endothelial cells, are the origin of eotaxins, although they can also be produced by epithelial cells.11,12 During inflammation, innate tissue lymphoid cells contribute to the migration of eosinophils via a complex interaction between IL-5, IL-3, and granulocyte-macrophage colonystimulating factor.13
Physiologically, eosinophils reside in the gastrointestinal tract in much larger numbers than in the blood (about 20–30% of the total number of resident leukocytes). In contrast, certain tissues, such as the adipose tissue and the lung eosinophils, constitute much smaller proportions at ≤4% of the stromal/
vascular fraction and ≤1% of total leukocytes, respectively.14 This means that the definition of excess eosinophils is dependent on the tissue and there are different values for each tissue. Typically, eosinophilic oesophagitis requires ≥15 eosinophils per high-power microscopy field (HPF) for confirmation of diagnosis.15 For eosinophilic colitis, the cut-offs are different for the different parts of the colon, with the right side harbouring much more (>50/HPF), compared to the transverse and left colon. Over 35/HPF in the transverse colon and >25/ HPF in the left colon are required for diagnosis. In the lungs, eosinophils are not seen very frequently and figures for pathological expression run at ≥2% of cells in sputum or ≥3% in bronchoalveolar lavage.14
EOSINOPHIL FUNCTION
The survival half-life of eosinophils in the peripheral blood is 3–18 hours. In tissues, such as the intestines, uterus, and lungs, they survive much longer with half-lives of approximately 6–7 days, 6 days, and 36 hours–6 days, respectively.4 Eosinophil survival can be prolonged by incubation with cytokines, and can survive for 14 days or longer in vitro. 16 Eosinophils take up various roles in tissues: interacting with the various immune system components, releasing stored proteins as an immune effector cell, or participating in metabolic functions.17 Eosinophils increase the survival of plasma cells in both the bone marrow and gut epithelium through the release of survival factor activation and proliferationinduced ligand, and also facilitate the development of IgA plasma cells that play a key role in mucosal defence.18,19 Several pattern recognition receptors are expressed by eosinophils, including Toll-like receptors (TLR) 1–5, 7, and 9; nucleotide oligomerisation domains 1 and 2; Dectin-1; and receptors for advanced glycation end products. These receptors have important physiological functions in recognising pathogens and are labelled pathogen-associated molecular patterns (PAMP) and danger-associated molecular patterns (DAMP).20
Eosinophils are granulocytes, and they exert a large part of their function through
the release of granules that include major basic proteins 1 and 2, eosinophil cationic protein, eosinophil peroxidase, eosinophilderived neurotoxin, cytokines, and cytosolic Charcot-Leyden crystal protein/ galectin-10.21 These granules not only have effector functions such as lysing microbe cell walls, but also activate basophils, mast cells, neutrophils, dendritic cells, and T2 immune responses.21,22 Whilst eosinophils have long been recognised to have a significant role in the immune responses against helminths and parasitic infections, it is now widely understood that they contribute to immunity against bacteria as well as viruses.1,23-26
Eosinophils are found to accumulate in the tumour microenvironment.27-29 Tumour cells can produce chemotactic factors such as eotaxin. Tumour-associated eosinophilia can be prognostically variable; for example, it has been linked to poor prognosis in Hodgkin’s lymphoma, or improved prognosis in tumours such as colorectal, breast, or prostate cancers.28,29 Eosinophils have been found to play roles in regulating fat deposition, glucose homeostasis, tissue remodelling and development, liver and muscle repair, neuronal regulation, and epithelial and microbiome regulation.30 Eosinophils also produce IL-4, and this results in the activation of muscle resident fibrocyte-adipocyte progenitors, thereby inducing regeneration of (injured) muscle and liver tissue.31 Vascular endothelial growth factor is a growth factor that can be produced by eosinophils and induces angiogenesis.
EOSINOPHIL ACTIVATION AND INFLAMMATION
In the inflamed site, eosinophils can have regulatory effects and proinflammatory and/or inhibitory effects.32 The driver for eosinophilic inflammation is T helper Type 2 (Th2) cells.33 Th2 cells produce several cytokines, including interleukin IL-5. Other cells such as Group 2 innate lymphoid cells are another potent source of IL-5 in inflammation.34 Initially described as eosinophil colony stimulating factor, IL-5 is a key factor in eosinophil maturation and
activation.35 Its role includes maturing EoPs into eosinophils, promoting eosinophils from the bone marrow into the circulation, and acting alongside chemotaxins to move eosinophils into peripheral tissues, extending their lifespan and inducing activation and degranulation.36 Eosinophils have a direct effect on several different mediators. These include Type 1 cytokines (IL-12 and interferon-gamma [IFN-γ]), Type 2 cytokines (IL-4, IL-5, IL-9, IL-13, and IL-25), acute proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), chemokines (regulated by activation, normal T cell expression and secretion, and eotaxin), and lipid mediators (platelet-activating factor and LTC4).37 Eosinophils also influence the function of several different enzymes that can lead to an anti-inflammatory effect. These include histaminase, acid phosphatase, collagenase, arylsulphatase B, phospholipase D, lysophospholipase, catalase, and nonspecific esterases.
EOSINOPHIL SUBTYPES
Two distinct eosinophil variants have been identified based on density when analysed by peripheral blood leukocyte centrifugation.38 These were classified as normodense (specific gravity >1.085 g/L) or hypodense (specific gravity <1.085 g/L). Patients with asthma demonstrated an increased number of hypodense eosinophils in the peripheral blood. Studies have suggested a correlation between this and the clinical severity of their disease.39 Inhaled corticosteroids significantly reduced hypodense eosinophils in these patients. Similar results were seen in bronchoalveolar lavage.40 More recently, eosinophils were shown to demonstrate two distinct subtypes based on other appearance features and cell markers, with IL-5 being a key differentiator. The first subgroup are resident eosinophils (rEos), which are Siglec-Fint, CD62L+, and CD101 low.14,30,41 These are IL-5 independent parenchymal cells with ring-shaped nuclei. The other subtype is inducible eosinophils (iEos), which are Siglec-Fhigh, CD62L–, and CD101 high. These cells have a segmented nucleus and are IL-5 dependent, typically found in the peribronchial area. Lung rEos were found to be in the parenchyma. In
previous studies, tissue eosinophilia in patients with asthma had demonstrated to be in the peribronchial area as opposed to the parenchyma.42 Kanda et al.41 demonstrated that rEos were normodense, while iEos were hypodense. Moreover, rEos expressed genes implicated in the downregulation of the immune system, while iEos expressed several proinflammatory genes such as Slc3a2, TLR4, C3ar1, IL13ra1, and IL6. In addition to their different surface proteins, tissue location, and effect on inflammation (pro-inflammatory or antiinflammatory), rEos and iEos were also found to differ in additional properties such as adhesion and survivability.43
SPECTRUM OF EOSINOPHILIA ASSOCIATED CONDITIONS
Eosinophilia can be the presenting feature of several different organ-based or systemic conditions. These can be dermatological, allergic, drug reactions, rheumatological, respiratory, gastrointestinal, immunological, and infections.9,44 Table 1 provides an overview of these.
EOSINOPHILS IN DISEASE: APPROACH TO EOSINOPHILIA
It is important to recognise that there can be tissue eosinophil recruitment and activation that does not result in peripheral eosinophilia. Peripheral eosinophilia can be reactive (i.e. secondary), even with very high levels, and so it is important to differentiate primary and secondary causes.45,46 Hypereosinophilia is defined as a persistent eosinophilia above 1.5 x109/L. Its definitions have evolved over time, and whilst previously a time frame of 3–6 months was necessary, this has now been amended by World Health Organization (WHO) to be simply ‘persistent’.47 Some patients with hypereosinophilic syndrome (HES) are at particular risk of organ damage, such as neurological and cardiac damage, and urgent investigations through CT or MRI head, electrocardiogram, 24-hour tape, echocardiogram, and serum troponin can be important in identifying patients requiring urgent treatment. Unprovoked
Table 1: Conditions associated with eosinophilia.
Haemato-oncological causes
HES
Rheumatological and autoimmune causes Other
EGPA
Myeloid neoplasms GPA
Lymphoid neoplasms and acute lymphoblastic leukaemia IgG4RD
Chronic eosinophilic leukaemia
Cocaine/Levamisole induced vasculitis
Lymphoproliferative HES Drug reaction
Systemic mastocytosis Drug induced vasculitis
Solid tumours
Heparin-induced thrombocytopenia
N/A
Systemic lupus erythematosus
Rheumatoid arthritis
Eosinophilic fasciitis
Polyarteritis nodosa
Sarcoidosis
Gleich syndrome (episodic angio-oedema with eosinophilia)
Allergic bronchopulmonary aspergillosis and other fungal infections
Helminth infections
Chronic pancreatitis
Primary GI disorders with eosinophilia such as eosinophilic oesophagitis
Inflammatory bowel disease
Coeliac disease
Asthma
Seasonal allergic disorders
Atopic dermatitis
Wells syndrome
Eosinophilia myalgia syndrome
Acute and chronic eosinophilic pneumonias
Cholesterol embolisation
N/A
EGPA: eosinophilic granulomatosis with polyangiitis; GI: gastrointestinal; GPA: granulomatosis with polyangiitis; HES: hypereosinophilic syndrome; IgG4RD: IgG4 related disease.
venous thromboembolism should also be considered secondary to the eosinophilia. End-organ damage can occur due to any aetiology of hypereosinophilia, and treatment should be started urgently (with high-dose corticosteroids if appropriate) if there is any concern.
Helminth infections are also an important cause and would usually be accompanied by gastrointestinal symptoms such as diarrhoea, although this is not always the case.48 Although sensitivity is low, there is still value in sending stool cultures. Strongyloides stercoralis and Toxocara can often be subclinical, and serology should also be considered, given their association with eosinophilia.48 More definitive treatment is usually given only when there is a high index of suspicion for this aetiology or confirmatory evidence has been obtained.
Eosinophilia is not a common presentation in rheumatology clinics. In one study from Türkiye, high eosinophil counts above 0.5 x109/L were seen in 3.900% of patients and more than 1.5 x109/L in 0.065%.49 It is often picked up incidentally on routine blood tests or with non-specific constitutional symptoms. A detailed history including travel history, infections, allergies, and drugs is essential. History of skin rashes, lymphadenopathy, and exposure to chronic infections such as HIV are also important, alongside direct questioning for constitutional symptoms such as fever, weight loss, drenching night sweats, pruritus, and musculoskeletal symptoms. This should be supported by physical examination of the systems including the skin and joints, which are sometimes forgotten. A blood film can be helpful as automated counters may misclassify hypogranular eosinophils, and the film can highlight other features of myeloproliferative neoplasms, such as left shift, monocytosis, and basophilia, as well as circulating blasts, mast cells, or abnormal lymphoid cells.9,44,49 The degree of eosinophilia can also provide some clues to the underlying aetiology. As an example, haematological disorders such as HES can result in very high eosinophil counts (above 10 x109/L), which is not often seen with other conditions. Shortness of breath and
cough are common respiratory symptoms in patients with allergic bronchopulmonary aspergillosis and this is associated with eosinophilia, and may mimic pulmonarypredominant EGPA.50 Serum testing such as for aspergillus fumigatus specific IgE and IgG, sputum testing (isolating aspergillus in sputum samples) or BAL showing aspergillus can be valuable in confirming the diagnosis of allergic bronchopulmonary aspergillosis. This, and other respiratory eosinophilic conditions can present similarly to EGPA, and differentiating them can be difficult.51,52 Several features including peripheral eosinophilia, asthma, and lung infiltrates are common to both. However, EGPA should usually involve other organs and antineutrophil cytoplasmic antibodies (ANCA), usually myeloperoxidase, can be positive in about 40% of cases.53 Asthma flare is often associated with a rise in eosinophil count that responds well to treatment. Gastrointestinal disorders often present with organ-specific symptoms such as refluxtype symptoms or diarrhoea and are usually diagnosed with biopsies of the relevant organs. In countries with a high prevalence of infections that can lead to eosinophilia, empirical treatment is often provided.
RHEUMATOLOGICAL CONDITIONS
Many rheumatological conditions can give rise to eosinophilia, most resulting in modest eosinophilia with counts usually less than 1.5 x109/L.49 Conditions associated with higher counts include vasculitides, drug reactions, DRESS syndrome, eosinophilic fasciitis, and IgG4 related disease. Drug reactions can cause eosinophilia that usually improves by stopping the offending drug. However, it is important to differentiate this from de novo vasculitis, which can also be caused by some drug reactions, such as cocaineinduced vasculitis.54 DRESS (drug reaction, eosinophilia and systemic symptoms) syndrome often presents with patients feeling quite unwell and often admitted to hospital.55 These patients usually have an extensive skin rash, organ involvement, fever, lymphadenopathy, lymphocytosis, and eosinophilia. Amongst the vasculitic conditions, the most common associations
are for granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA); however, there are some other less common associations such as Buerger’s disease. Eosinophilia can sometimes be seen in patients presenting as temporal arteritis, and some of these patients turn out to have EGPA. Eosinophilia can also be seen on temporal artery biopsy specimens, but there is no evidence yet that it has an impact on outcomes.56 Very rarely, EGPA and temporal arteritis can co-exist in the same patient.57 Low-grade eosinophilia can be associated with inflammatory arthritis and other rheumatological conditions such as systemic lupus erythematosus.58 Inflammatory arthritis can also be seen in GPA and EGPA, although rare and it is more common that they experience arthralgia. In very rare instances, EGPA can present similarly to rheumatoid arthritis, with destructive joint disease and nodules (with negative rheumatoid factor and cyclic citrullinated peptide antibodies); typically these nodules are eosinophilic on biopsy and associated with poor response to standard treatment.
GPA and EGPA tend to have rather different ear, nose, and throat, and lung involvement, which can help to differentiate between them. They also have different types of ANCA antibodies: the former usually has antibodies directed to proteinase 3. Patients with GPA do not usually have co-existent asthma, and nasal crusting and bleeding are the predominant ear, nose, and throat manifestations rather than nasal polyps (as is typical of EGPA). GPA is also characterised by cavitating pulmonary nodules, nasal crusting and bleeding, hearing loss, renal or other organ inflammation, and paranasal sinus erosions.59 Myeloperoxidase-ANCA antibodies, on the other hand, are typically associated with microscopic polyangiitis (MPA) and EGPA, although MPA is seldom a differential for patients with eosinophilia and does not tend to have upper respiratory tract involvement.60 Renal involvement is also quite common in MPA, whilst this is rare in EGPA. IgG4-related disease (IgG4RD) can also present with significant eosinophilia and has several different presentations. Patients with IgG4RD can have
manifestations of allergy, sinus disease, eosinophilia, and pulmonary infiltrates, hence this is an important differential to consider.61 Histological features for IgG4RD include storiform, obliterative phlebitis without features of vasculitis, or eosinophilic granulomas, allowing the differentiation from EGPA. High eosinophil counts in IgG4RD may suggest a poor prognosis and can be useful in stratifying patients.62 Similarly, in patients with RA, the presence of eosinophilia has been associated with a higher likelihood of systemic symptoms and worse outcomes.63 Kimura’s disease is a rare cause of eosinophilia typically presenting with eosinophilia and raised IgE levels in East Asian populations with symptoms of lymphadenopathy, subcutaneous nodules, and salivary gland hypertrophy.64
HAEMATO-ONCOLOGICAL CONDITIONS
Hypereosinophilia can occur in several haematological disorders (Table 1), but eosinophil counts tend to be higher in HES.45 Several haematological disorders can be associated with hypereosinophilia, and once investigations have ruled these out, idiopathic HES is considered. However, HES encompasses a heterogeneous range of disorders with organ involvement, and often there is no clear underlying cause.45,65 There are several different haemato-oncological etiologies based on their pathogenetic mechanisms, and this can include a number of different malignant processes such as myeloid and lymphoid neoplasms with eosinophilia. These are associated with genetic abnormalities of platelet-derived PDGFRA (e.g. FIP1L1-PDGFRA), PDGFRB, or FGFR1. Chronic eosinophilic leukaemia or other myeloid neoplastic disease with associated eosinophilia (lacking associated genetic abnormalities) and lymphoproliferative HES-variant (aberrant lymphocytic production of eosinophil haematopoietins [IL-3/5]) is also present with eosinophilia. Idiopathic HES is typically labelled when the patient does not have any specific characteristics that would allow another diagnostic label.47,65,66 Clinically, it can be quite difficult to differentiate between idiopathic HES (when there is
no cytogenetic abnormality) and EGPA, particularly given the non-specific nature of the associated symptoms, such as background of asthma, nasal polyposis, etc.67 Particularly, the ‘hypereosinophilic’ stage of EGPA with ANCA-negative status and no genetic abnormalities can be very similar to idiopathic HES. Idiopathic HES is not typically associated with nasal polyps or asthma; however, these are common co-morbidities in the general population. Idiopathic HES by definition does not have vasculitis and is typically ANCA-negative in contrast to EGPA, which requires evidence of vasculitis for accurate classification. Biopsies, however, are not always helpful in identifying granulomatous vasculitis and there remains a lack of clarity about which team should be leading the management of these patients. In fact, there do not appear to be differences in biomarkers in the two groups of patients, as evidenced by a study comparing serum biomarkers in patients with ANCA-negative EGPA and PDGFRA-negative HES.67 In fact, one patient with EGPA was found to have the genetic abnormality FIP1L1-PDGFRA fusion.52 This highlights the challenges in diagnosis and management, and this continues to remain a challenge for patients, clinicians, and academics. Eotaxin-3 has emerged as a potentially important biomarker for diagnosis, and further studies are needed to evaluate the role of this.68,69 It is important to note that joint involvement with inflammatory arthritis can occur in HES as well, but typically tends to be large joints from the author’s experience. The underlying genetic abnormalities in HES (e.g. FIP1L1-PDGFRA) cause constant
References
1. Lombardi C et al. The emerging roles of eosinophils: implications for the targeted treatment of eosinophilicassociated inflammatory conditions. Curr Res Immunol. 2022;(3):42-53.
2. Fulkerson PC. Transcription factors in eosinophil development and as therapeutic targets. Front Med (Lausanne). 2017;(4):115.
3. Mori Y et al. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common
activation of tyrosine kinase enzymes, suggesting that this might be a useful therapeutic target, and indeed this group of patients does respond well to imatinib (a tyrosine kinase inhibitor).70 However, response does not appear to be limited to patients with genetic abnormalities, although better response is seen in patients with these genetic rearrangements.52
CONCLUSION
Eosinophilia is associated with several different conditions some of which are rheumatological. It is important to explore the various differentials so that the right disease can be diagnosed, and appropriate management can be instituted. There are a few important rheumatological conditions to consider, and prompt diagnosis is essential as these patients can be at risk of organ damage or serious illness. The most serious rheumatological conditions causing hypereosinophilia include GPA and EGPA, whilst DRESS syndrome will also often cause significant morbidity and can be induced by rheumatological drugs such as sulfasalazine and allopurinol. In patients with hypereosinophilia that is not limited to a single organ and for which there is no clinically obvious diagnosis, genetic testing is helpful once parasitic and helminth infections have been ruled out. In some cases where there is an imminent risk of organ damage, empirical treatment is needed to ensure that hypereosinophilia is being controlled whilst the diagnostic work up continues.
4. Shah K et al. The emerging roles of eosinophils in mucosal homeostasis. Mucosal Immunol. 2020; 13(4):574-83.
5. Kim HJ, Jung Y. The emerging role of eosinophils as multifunctional leukocytes in health and disease. Immune Netw. 2020;20(4):e24.
6. Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147-74.
7. Sanderson CJ. Interleukin-5,
eosinophils and disease. Blood. 1992;79(12):3101-9.
8. Mould AW et al. Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J Clin Invest. 1997;995(5):1064-71.
9. Butt NM et al. Guideline for the investigation and management of eosinophilia. Br J Haematol. 2017;176(4):553-72.
10. Bochner BS. The eosinophil: for better or worse, in sickness and in health. Ann Allergy Asthma Immunol. 2018;121(12):150-5.
11. Rothenberg ME. Eotaxin. An essential mediator of eosinophil trafficking into mucosal tissues. Am J Respir Cell Mol Biol. 1999;21(3):291-5.
12. Ponath PD et al. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest. 1996;97(3):604-12.
13. Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016;17(7):765-74.
14. Mesnil C. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J Clin Invest. 2016;126(9):3279-95.
15. Marasco G et al. Current and novel therapies for eosinophilic gastrointestinal Diseases. Int J Mol Sci. 2023;24(20):15165.
16. Park YM, Bochner BS. Eosinophil survival and apoptosis in health and disease. Allergy Asthma Immunol Res. 2010;2(2):87-101.
17. Klion AD et al. Contributions of eosinophils to human health and disease. Annu Rev Pathol. 2020;15:179209.
18. Berek C. Eosinophils: important players in humoral immunity. Clin Exp Immunol. 2016;183(1):57-64.
19. Chu VT et al. Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity. 2014;40(4):582-93.
20. Jacobsen EA et al. The expanding role(s) of eosinophils in health and disease. Blood. 2012;120(19):33823890.
21. Acharya KR, Ackerman SJ. Eosinophil granule proteins: form and function. J Biol Chem. 2014;289(25):17406-15.
22. Persson EK et al. Protein crystallization promotes type 2 immunity and is reversible by antibody treatment. Science. 2019;364(6442):eaaw4295.
23. Simon HU et al. The cellular functions of eosinophils: Collegium Internationale Allergologicum (CIA) update 2020. Int Arch Allergy Immunol. 2020;181(1):1123.
24. Lee JJ et al. Eosinophils in health and disease: the LIAR hypothesis. Clin Exp Allergy. 2010;40(4):563-75.
25. Percopo CM et al. Activated mouse eosinophils protect against lethal respiratory virus infection. Blood. 2014;123(5):743-52.
26. Phipps S et al. Eosinophils contribute to innate antiviral immunity and promote
clearance of respiratory syncytial virus. Blood. 2007;110(5):1578-86.
27. Grisaru-Tal S et al. A new dawn for eosinophils in the tumour microenvironment. Nat Rev Cancer. 2020;20(10):594-607.
28. Davis BP, Rothenberg ME. Eosinophils and cancer. Cancer Immunol Res. 2014;2(1):1-8.
29. Varricchi G et al. Eosinophils: the unsung heroes in cancer? Oncoimmunology. 2017;7(2):e1393134.
31. Aoki A et al. Eosinophils: Cells known for over 140 years with broad and new functions. Allergol Int. 2021;70(1):3-8.
32. Jackson DJ et al. Eosinophils and eosinophilic immune dysfunction in health and disease. Eur Respir Rev. 2022;31(163):210150.
33. Gurram RK et al. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019;16(3):225-35.
34. Kim BS, Artis D. Group 2 innate lymphoid cells in health and disease. Cold Spring Harb Perspect Biol. 2015;7(5):a016337.
35. Lopez AF et al. Murine eosinophil differentiation factor. An eosinophilspecific colony-stimulating factor with activity for human cells. J Exp Med. 1986;163(5):1085-99.
36. Kouro T, et al. IL-5- and eosinophilmediated inflammation: from discovery to therapy. International Immunology. 2009;21(12):1303-9.
37. Kanda A et al. Multiple biological aspects of eosinophils in host defense, eosinophil-associated diseases, immunoregulation, and homeostasis: is their role beneficial, detrimental, regulator, or bystander? Biol Pharm Bull. 2020;43(1):20-30.
38. Prin L et al. Heterogeneity of human peripheral blood eosinophils: variability in cell density and cytotoxic ability in relation to the level and the origin of hypereosinophilia. Int Arch Allergy Appl Immunol. 1983;72(4):336-46.
39. Kuo HP et al. Hypodense eosinophil number relates to clinical severity, airway hyperresponsiveness and response to inhaled corticosteroids in asthmatic subjects. Eur Respir J. 1994;7(8):1452-9.
40. Kroegel C et al. Blood and bronchoalveolar eosinophils in allergic subjects after segmental antigen challenge: surface phenotype, density heterogeneity, and prostanoid production. J Allergy Clin Immunol. 1994;93(4):725-34.
41. Kanda A et al. The multiple functions and subpopulations of eosinophils in tissues under steady-state and pathological conditions. Allergol Int. 2021;70(2):227.
42. PJ, Barnes. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008;8(3):183-92.
43. Januskevicius A et al. Blood eosinophils subtypes and their survivability in asthma patients. Cells. 2020;9(5):1248.
44. Leru, PM. Eosinophilic disorders: evaluation of current classification and diagnostic criteria, proposal of a practical diagnostic algorithm. Clin Transl Allergy. 2019;9(36).
45. Valent P et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012;130(3):607-12.
46. Miyabe Y wt al. Eosinophil-mediated inflammation in the absence of eosinophilia. Asia Pac Allergy. 2021;11(3):e30.
47. Shomali W, Gotlib J. World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97(1):129-48.
48. O'Connell EM, Nutman TB. Eosinophilia in Infectious Diseases. Immunol Allergy Clin North Am. 2015;35(3):493-522.
49. D Cansu et al. Evaluation and differential diagnosis of hypereosinophilia in rheumatology practice. Int Arch Allergy Immunol. 2022;183(1):51-8.
50. Agarwal R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135(3):80526.
52. White J, Dubey S. Eosinophilic granulomatosis with polyangiitis: a review. Autoimmun Rev. 2023;22(1):103219.
53. Emmi G et al. Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis. Nat Rev Rheumatol. 2023;19(6):378-93.
54. Gill C et al. Cocaine-induced granulomatosis with polyangiitis-an under-recognized condition. Rheumatol Adv Pract. 2023;7(1):rkad027.
55. Choudhary S et al. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. J Clin Aesthet Dermatol. 2013;6(6):31-7.
56. Boiardi L et al. Eosinophilic giant cell arteritis: a different subset of disease? Semin Arthritis Rheum. 2024;65:152409.
57. Vidal E et al. Concurrent temporal arteritis and Churg-Strauss syndrome. J Rheumatol. 1992;19(8):1312-4.
59. Vaglio A et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): state of the art. Allergy: Allergy. 2013;68(3):261-73.
60. Vaglio A et al. Churg–Strauss syndrome. Kidney Int. 2009;76(9):1006-11.
61. Maritati F. IgG4-related disease: a clinical perspective. Rheumatology (Oxford). 2020;59(3):iii123-31.
62. Culver EL et al. Increases in IgE, eosinophils, and mast cells can be used in diagnosis and to predict
relapse of IgG4-related disease. Clin Gastroenterol Hepatol. 2017;15(9):1444-52.
63. Guellec D et al. Eosinophilia predicts poor clinical outcomes in recent-onset arthritis: results from the ESPOIR cohort. RMD Open. 2015;1(1):e000070.
64. Gupta A et al. Kimura's disease: a diagnostic and therapeutic challenge. Indian J Otolaryngol Head Neck Surg. 2019;71(Suppl 1):855-9.
65. Simon HU et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126(1):45-9.
66. Bain BJ et al. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1. Haematologica. 2010;95(5):696-8.
67. Khoury P et al. Serum biomarkers are similar in Churg-Strauss syndrome and hypereosinophilic syndrome. Allergy. 2012;67(9):1149-56.
68. Polzer K et al. Eotaxin-3 is involved in Churg-Strauss syndrome - a serum marker closely correlating with disease activity. Rheumatology (Oxford). 2008;47(6):804-8.
69. Zwerina J et al. Eotaxin-3 in ChurgStrauss syndrome: a clinical and immunogenetic study. Rheumatology (Oxford). 2011;50(10):1823-7.
70. Cools J. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-14.
Atypical Presentation of Gouty Arthritis That Mimics Hand Soft Tissue Infection: Case Report
Authors: *Fatima M AlSinan,1 Faisal Sabaa,1 May S. Alkhaldi,1 Sarah AlArafah,1 Hind A. Alshuqayfi,1 Fahad Almutairi1
1. Department of General Surgery, Dammam Medical Complex, Saudi Arabia *Correspondence to Fatima.m.alsinan@gmail.com
Disclosure: The authors have declared no conflicts of interest.
1. Gout is a common rheumatological disease mimicking a wide variety of inflammatory conditions.
2. Involvement of the hand is atypical requiring high index of suspicion to identify and investigate suspected patients.
3. Management should be tailored to individual patients by combining early surgical intervention with rheumatological assessment.
INTRODUCTION
Gouty arthritis, also called monosodium urate (MSU) crystal deposition disease, is an inflammatory disease where monosodium urate crystals build up in the joints and soft tissues, secondary to high uric acid levels in the blood.1 Due to its rarity, hand gouty arthritis is often excluded from the differential diagnosis. The authors report a unique instance of hand gouty arthritis manifesting as a soft tissue infection, which has been reported in line with the Surgical CAse REport (SCARE) 2023 criteria.2
CASE PRESENTATION
A 27-year-old male not previously known to have any medical illness presented to the emergency department complaining of right-hand soft tissue swelling and pain for 8 days. The swelling started in the right ring finger and extended proximally up to the elbow joint, associated with a limited range of motion. There was no history of hand trauma or a personal or family history of any rheumatological or autoimmune diseases. Ten days prior to his presentation, the patient underwent drainage of a right ring finger abscess. Upon examination, the right hand was oedematous with
A B C
(A) Preoperative picture of the right hand showing diffuse hand soft tissue swelling with erythema over the middle and ring finger. (B) Z-shaped incisions over the right, middle, and ring fingers with thick whitish discharge. (C) Post-operative picture with subsided swelling and erythema of the right hand and healed wounds.
induration, hotness, and severe tenderness on palpation, with fluctuation over the middle and ring finger (Figure 1A). There was a limited range of motion of the fingers, wrist, and elbow. His laboratory workup revealed a normal white blood count of 6.95x109. X-rays of the hand revealed soft tissue nodules on the middle and ring fingers. There were also lytic lesions on the second and third metacarpal bones and the proximal phalanx of the index finger (Figure 2). The targeted hand ultrasound did not reveal any localised collection. The patient was admitted to the regular ward with the impression of hand cellulitis and a possible abscess collection. The patient started on intravenous antibiotics with no improvement. The patient was taken for an incision and drainage. During the operation, the surgeon made two Z-shaped incisions over the plantar aspect of the middle and ring fingers, along with a counter incision on the dorsal part of the middle finger. There was a thick, whitish material discharge from the wound that was sent for acid fast bacilli; cytology; bacterial, fungal, and mycobacterial cultures (Figure 1B). After the operation, the patient was kept on IV antibiotics and started hand exercises through physiotherapy. There was
significant improvement in the oedema and pain, with slow improvement in his range of motion. An MRI scan of the right upper limb was used to determine if there was still a collection. The MRI showed synovitis in the metacarpophalangeal joint of the index, middle, ring, and little finger, but did not show any drainable collection during the scan. The results of all cultures and the cytology of the whitish discharge were negative for any growth. Subsequently, the patient was screened for rheumatological causes of inflammation. His serum urate measurement 5 weeks following the initial episode was 698 umol/L, and his erythrocyte sedimentation rate was 30 mm/hour. Gout was diagnosed based on his elevated serum urate, along with his clinical presentation. After discharge, the patient was followed in the outpatient clinic. He had significant improvement in his hand movement, and the wound healed with no remaining signs of inflammation (Figure 1C). He was able to resume his work with no limitation on his hand range of motion. The patient was referred to the rheumatology department for further management of gouty arthritis and initiating treatment with allopurinol and colchicine.
Figure 1: Pre- and post-operative pictures of the right hand.
Figure 2: Hand radiograph showing soft tissue nodules over the middle and ring finger with lytic lesions on the 2nd and 3rd metacarpal bones and the proximal phalanx of the index finger.
CLINICAL DISCUSSION
Gouty arthritis typically presents with pain, swelling, and erythema. It is sometimes associated with joint deformities in longstanding diseases. Doctors can easily recognise and diagnose it during an acute flare or in the presence of chronic tophi. Although gout commonly manifests as monoarticular disease, several cases have described patients presenting with polyarticular arthropathy. The first metatarsophalangeal joint is the most affected, especially during the first attack.3,4 Patients with no previous history of gout may not be aware of the unusual involvement of the hand in this condition, leading to potential missed diagnoses. These patients may present with entrapment neuropathy, tophaceous deposits infiltrating tendons, tenosynovitis or cellulitis, and abscesses, as seen in this case.4-6
There are three classifications of hand soft tissue infection: superficial, such as cellulitis; deep, such as abscess; and necrotising fasciitis. Swelling, erythema, hotness, and pain occur in patients due to the pressure within the confined space in the hand and digits. Untreated hand infections can progress to serious limb and life-threatening complications if not properly treated. Management involves
antibiotics with drainage and debridement of any underlying collection and necrotic tissue.7 Previously, the literature reported the initial presentation of a gout-imitating hand abscess. The patient presented with acute and diffuse involvement of the hand, simulating an infection. During exploration, no pus was observed, and a negative fluid culture was obtained. Subsequently, the medical team investigated the patient and diagnosed them with gouty arthritis.6
Differentiation between gouty arthritis in the hand and soft tissue infection can be challenging, especially with an atypical presentation and multi-joint involvement as seen in this patient. Identifying urate crystals in the joint aspirate makes a definitive diagnosis of gout. However, this is not always clinically applicable, especially in the small joints of the hand, where patients may present without joint effusion to allow aspiration. High serum uric acid increases the risk of gout, but is not reliable in an acute attack of gout as it is often normal. The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) established the new gout classification criteria in 2015 to aid in the clinical diagnosis of gout (Table 1).3,4,8 Both gouty arthritis and infections can cause non-specific elevations of inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein.4,9
Table 1: The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) gout classification criteria.8
to maximum pain <24 hours
Serum urate* (Measured without treatment, 4 weeks after an acute flare, or highest value recorded during flare)
Score ≥8 out of 23, sensitivity and specificity of 92% and 89%, respectively.
*Serum urate ≥4–<6 mg/dL is scored as 0
**DECT: dull energy computed tomography; MTP: metatarsophalangeal joint; US: ultrasound.
CONCLUSION
The first line of treatment for acute gout flare-ups mostly involves non-steroidal anti-inflammatory drugs, colchicine, or oral corticosteroids. Long-term therapy with allopurinol and lifestyle modification aims to lower serum urate levels and prevent further crystal deposition.10,11 Certain patients undergo surgical interventions to achieve symptomatic relief of pain through nerve decompression and the evacuation of any underlying collection or source of infection. Excision of gout tophi is another indication for surgery in patients with a limited range of motion due to infiltration of the tendons by tophi.4,6,12
Gout is known to mimic a wide variety of inflammatory conditions, including soft tissue infections. Diagnosis of gout of the hand with such a presentation can be challenging. This case adds valuable insight into the diagnostic challenges and considerations when gout manifests atypically. The misdiagnosis of gout as a soft tissue infection highlights the need for clinical awareness and broad differential diagnosis in cases of hand swelling and pain, particularly when initial treatments fail. Current clinical guidelines for gout primarily focus on its typical presentations. Documenting rare cases like this case can
stimulate further research into atypical presentations of common conditions and contribute to expanding the diagnostic guidelines to include rare presentations.
References
1. Lally EV et al. The clinical spectrum of gouty arthritis in women. Arch Intern Med. 1986;146(11):2221-5.
2. Sohrabi C et al. The SCARE 2023 guideline: updating consensus Surgical CAse REport (SCARE) guidelines. Int J Surg. 2023;109(5):1136-40.
3. Redmond CE et al. Erosive polyarticular tophaceous gout: an unusually deforming and destructive presentation. BMJ Case Rep. 2013;2013:bcr2013202335.
4. Chui CH, Lee JY. Diagnostic dilemmas in unusual presentations of gout. Aust Fam Physician. 2007;36(11):931-4.
5. Wakefield RJ et al. Gout related upper limb cellulitis: an ultrasound study. J Rheumatol. 2003;30(2):417-9.
This perspective can aid clinicians in avoiding diagnostic pitfalls and ensuring prompt and exact diagnosis, which is essential for optimal patient outcomes.
6. Stool N, Johnson EW Jr. Gout masquerading as abscess of the thenar space. Postgrad Med. 1959;25(4):424-6.
7. Flevas DA et al. Infections of the hand: an overview. EFORT Open Rev. 2019;4(5):183-93.
8. Neogi T et al. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 2015;67(10):2557-68. Erratum in: Arthritis Rheumatol. 2016;68(2):515.
9. Lee JH et al. Elderly patients exhibit stronger inflammatory responses during gout attacks. J Korean Med Sci. 2017;32(12):1967-73.
10. FitzGerald JD et al. 2020 American
College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72(6):74460. Erratum in: Arthritis Care Res (Hoboken). 2021;73(3):458.
11. National Institute for Health and Care Excellence. Gout: diagnosis and management. 2022. Available at: https:// www.nice.org.uk/guidance/ng219. Last accessed: 16 December 2023.
12. Abrahamsson SO. Gouty tenosynovitis simulating an infection. A case report. Acta Orthop Scand. 1987;58(3):282-3.
