Rheumatology
Recent Submissions
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Using autoantibodies to diagnose systemic autoimmune diseases triggered by immune checkpoint inhibitors: a clinical perspective.Immunotherapies, such as immune checkpoint inhibitors (ICIs), have significantly advanced the treatment of cancer and other conditions. However, these therapies can also cause immune-related adverse events (irAEs), which are unintended side effects due to their effects on the immune system of the treated patient. These effects can be classified as organ-specific or systemic, with the latter being of particular interest due to their potential overlap with systemic autoimmune diseases (SADs). Autoantibodies, which are proteins produced by the immune system that react with self components, are often used to diagnose and classify SAD. However, the diagnostic value of autoantibodies in the context of systemic irAEs (sirAEs) triggered by ICIs is not well understood. This review aims to evaluate the diagnostic value of conventional autoantibodies in the identification and classification of sirAEs. A comprehensive search of the literature was conducted using the PubMed database, with a focus on articles published in the past 10 years. The results of the review suggest that, although autoantibodies can be useful in the diagnosis and classification of some SAD triggered by ICIs, there is a clear predominance of seronegative irAEs. The lack of traditional autoantibodies may suggest a unique mechanism for sirAEs and increases the already complex diagnostic approach of these manifestations, requiring evaluation by multidisciplinary teams with extensive experience in immunomediated diseases. Further research is needed to fully understand the diagnostic value of autoantibodies in this context and to determine the optimal approach for their detection and interpretation.
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Very low prevalence of ultrasound-detected tenosynovial abnormalities in healthy subjects throughout the age range: OMERACT ultrasound minimal disease study.Objectives: This study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range. Methods: Adult HS (age 18-80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1-5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort. Results: 939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups. Conclusions: Ultrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.
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Digital health and self-management in idiopathic inflammatory myopathies: a missed opportunity?Purpose of review: This paper explored the potential of digital health in idiopathic inflammatory myopathies (IIMs), with a focus on self-management. Digital self-management technology includes tailored treatment plans, symptom tracking, educational resources, enhanced communication, and support for long-term planning. Recent findings: After arguing the importance of digital health in IIMs management, from diagnosis until treatment, our literature review revealed a notable gap in research focusing on the efficacy of digital self-management interventions for individuals with IIMs, with no randomised controlled trials or observational studies addressing this topic. Our review further highlighted the significant unmet need for research in self-management interventions for individuals with IIMs. The absence of studies underscores the necessity for collaborative efforts to address this gap and develop personalised, effective strategies for managing IIMs using digital technology. Individuals with IIMs deserve tailored self-management approaches akin to those available for other rheumatic and musculoskeletal diseases.
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Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial.Background: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. Methods: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. Findings: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). Interpretation: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. Funding: Novartis.
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NKp30 receptor upregulation in salivary glands of sjögren's syndrome characterizes ectopic lymphoid structures and is restricted by rituximab treatment.Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. NCR3/NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the NCR3/NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 (NCR3) and its ligand B7/H6 (NCR3LG1) in pSS salivary gland tissues. Levels of NCR3/NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between NCR3/NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, NCR3/NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory foci, while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of NCR3/NKp30 within the glands.
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Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial.Background: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. Methods: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. Findings: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. Interpretation: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation-as measured by CRP concentration-in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. Funding: Medical Research Council.
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Perspectives of at-risk individuals on preventive intervention for rheumatoid arthritis: a mini review.There has been intense research focus on the biological mechanisms underlying the transition from health to disease for rheumatoid arthritis (RA) over recent years, and it is now well established that a state of autoimmunity precedes the development of symptoms for a large proportion of patients. This has led to an increased interest in the identification of at-risk groups and the potential for preventive intervention. The ability of several immunomodulatory agents to delay or prevent RA is under investigation and novel cellular therapies are in development. Preventive approaches are also being assessed in other chronic autoimmune diseases. For example, an anti-CD3 antibody has recently been shown to delay progression to type 1 diabetes in non-diabetic relatives of patients identified as being at high risk. The identification and treatment of individuals as being at risk of a disease where there is a degree of uncertainty around the potential for benefit is socially and ethically challenging. Recently reported difficulties in recruitment to RA prevention trials have underlined the importance of understanding the perspectives of at-risk individuals to identify barriers and facilitators that need to be addressed in order for preventive strategies to be acceptable. Understanding of their preferences for benefits and risks of preventive interventions can inform efficient intervention prioritization, prevention trial design and the development of informational resources for those at risk. In this review we summarize current knowledge of preferences for RA prevention and make recommendations for further research needed to ensure efficient development of preventive therapies and clinical implementation.
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Tailoring the treatment of inflammatory rheumatic diseases by a better stratification and characterization of the clinical patient heterogeneity. Findings from a systematic literature review and experts' consensus.Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients. Keywords: Adult-onset Still's disease; Precision medicine; Randomized controlled trials; Rheumatoid arthritis; Sjogren's disease; Spondylarthritis; systemic lupus erythematosus; systemic sclerosis.
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Systematic review of imaging tests to predict the development of rheumatoid arthritis in people with unclassified arthritis.Objective: To estimate and compare the diagnostic accuracy of magnetic resonance imaging (MRI) and ultrasound, for the prediction of rheumatoid arthritis (RA) in unclassified arthritis (UA). Methods: MEDLINE, Embase and BIOSIS were searched from 1987 to May 2019. Studies evaluating any imaging test in participants with UA were eligible. Reference standards were RA classification criteria or methotrexate initiation. Two authors independently extracted data and assessed validity using QUADAS-2. Sensitivities and specificities were calculated for each imaging characteristic and joint area. Summary estimates with 95% confidence intervals (CI) were estimated where possible. Results: Nineteen studies were included; 13 evaluated MRI (n=1,143; 454 with RA) and 6 evaluated ultrasound (n=531; 205 with RA). Studies were limited by unclear recruitment procedures, inclusion of patients with RA at baseline, differential verification, lack of blinding and consensus grading. Study heterogeneity largely precluded meta-analysis, however summary sensitivity and specificity for MRI synovitis in at least one joint were 93% (95% CI 88%, 96%) and 25% (95% CI 13%, 41%) (3 studies). Specificities may be higher for other MRI characteristics but data are limited. Ultrasound results were difficult to synthesise due to different diagnostic thresholds and reference standards. Conclusion: The evidence for MRI or ultrasound as single tests for predicting RA in people with UA is heterogeneous and of variable methodological quality. Larger studies using consensus grading and consistently defined RA diagnosis are needed to identify whether combinations of imaging characteristics, either alone or in combination with other clinical findings, can better predict RA in this population.
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Management of fatigue with physical activity and behavioural change support in vasculitis: a feasibility study.Objective: Patients with ANCA-associated vasculitis (AAV) experience high levels of fatigue, despite disease remission. This study assessed the feasibility and acceptability of a definitive randomized controlled trial of a behavioural-based physical activity intervention to support fatigue self-management in AAV patients. Methods: AAV patients in disease remission with fatigue (Multidimensional Fatigue Inventory-20 general fatigue domain ≥14) were randomly allocated to intervention or standard care in this single-centre open-label randomized controlled feasibility study. The intervention lasted 12 weeks and comprised eight face-to-face physical activity sessions with a facilitator and 12 weekly telephone calls. Participants were encouraged to monitor their physical activity using a tracker device (Fitbit). Standard care involved sign-posting to fatigue websites. The primary outcome was feasibility of a phase III trial assessed against three stop/go traffic light criteria, (recruitment, intervention adherence and study withdrawal). A qualitative study assessed participant views about the intervention. Results: A total of 248 patients were screened and 134 were eligible to participate (54%). Stop/go criteria were amber for recruitment; 43/134 (32%, 95% CI: 24, 40) eligible participants randomized, amber for adherence; 73% of participants attended all eight physical activity sessions, but only 11/22 (50%, 95% CI: 29, 71%) completed the intervention as per the intended schedule, and green for study withdrawal; 2/43 participants withdrew before 24 weeks (5%, 95% CI: 0, 11). Qualitative results suggested the intervention was acceptable. Conclusion: This study suggests a behavioural-based physical activity intervention targeting fatigue self-management was acceptable to patients with AAV, although recruitment and protocol adherence will need modification prior to a definitive trial. Clinical trial registration number: ISRCTN11929227.
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Navigating the path of progress: The OMERACT 2023 emerging leaders programObjectives: The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Emerging Leaders Program (ELP) aims to cultivate a cohort of skilled leaders within the OMERACT community empowering them with expertise and knowledge to help shape and steer the organization into the future. This publication highlights the significance of the ELP in driving leadership excellence, its impact on OMERACT's evolution, and the outcomes and learnings from the OMERACT 2023 ELP. Methods: Insights from the 2018 ELP report informed 2023 program improvements. Engagement was measured by attendance and WhatsApp interactions. Positive program aspects, areas for improvement and ideas for enhancing future ELPs were captured via anonymous survey and participant focus groups. Results: Engagement with the ELP was high with 9 participants, 96 % attendance at all workshops, 154 WhatsApp interactions. All program components were highly rated, with the highest being the 'Psychological Safety' and 'Methodology/Process/Politics' workshops. Future enhancements included creating further networking, connection and support activities, practical leadership and methodological skill development opportunities, and a new stream focussing on organisational advancement. Conclusions: The 2023 OMERACT ELP was well received and successfully addressed areas previously identified as requiring improvement. New educational enhancements were valued, and the importance of fostering psychological safety at all levels was highlighted. The ELP fortifies OMERACT by nurturing a diverse array of skilled leaders who embody OMERACTs core values. Continuing to refine and evolve the ELP over time will help OMERACT sustain its global influence in patient-centered outcome research.
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Granulocyte-macrophage colony-stimulating factor neutralisation in patients with axial spondyloarthritis in the UK (NAMASTE): a randomised, double-blind, placebo-controlled, phase 2 trial.Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial spondyloarthritis. Namilumab is a human IgG1 monoclonal anti-GM-CSF antibody that potently neutralises human GM-CSF. We aimed to assess the efficacy of namilumab in participants with moderate-to-severe active axial spondyloarthritis. Methods: This proof-of-concept, randomised, double-blind, placebo-controlled, phase 2, Bayesian (NAMASTE) trial was done at nine hospitals in the UK. Participants aged 18-75 years with axial spondyloarthritis, meeting the Assessment in SpondyloArthritis international Society (ASAS) criteria and the ASAS-defined MRI criteria, with active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), were eligible. Those who had inadequately responded or had intolerance to previous treatment with an anti-TNF agent were included. Participants were randomly assigned (6:1) to receive subcutaneous namilumab 150 mg or placebo at weeks 0, 2, 6, and 10. Participants, site staff (except pharmacy staff), and central study staff were masked to treatment assignment. The primary endpoint was the proportion of participants who had an ASAS ≥20% improvement (ASAS20) clinical response at week 12 in the full analysis set (all randomly assigned participants). This trial is registered with ClinicalTrials.gov (NCT03622658). Findings: From Sept 6, 2018, to July 25, 2019, 60 patients with moderate-to-severe active axial spondyloarthritis were assessed for eligibility and 42 were randomly assigned to receive namilumab (n=36) or placebo (n=six). The mean age of participants was 39·5 years (SD 13·3), 17 were women, 25 were men, 39 were White, and seven had previously received anti-TNF therapy. The primary endpoint was not met. At week 12, the proportion of patients who had an ASAS20 clinical response was lower in the namilumab group (14 of 36) than in the placebo group (three of six; estimated between-group difference 6·8%). The Bayesian posterior probability η was 0·72 (>0·927 suggests high clinical significance). The rates of any treatment-emergent adverse events in the namilumab group were similar to those in the placebo group (31 vs five). Interpretation: Namilumab did not show efficacy compared with placebo in patients with active axial spondyloarthritis, but the treatment was generally well tolerated. Funding: Izana Bioscience, NIHR Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC, and Clinical Research Facility.
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Cranial involvement in giant cell arteritis.Since its first clinical description in 1890, extensive research has advanced our understanding of giant cell arteritis, leading to improvements in both diagnosis and management for affected patients. Imaging studies have shown that the disease frequently extends beyond the typical cranial arteries, also affecting large vessels such as the aorta and its proximal branches. Meanwhile, advances in comprehending the underlying pathophysiology of giant cell arteritis have given rise to numerous potential therapeutic agents, which aim to minimise the need for glucocorticoid treatment and prevent flares. Classification criteria for giant cell arteritis, as well as recommendations for management, imaging, and treat-to-target have been developed or updated in the last 5 years, and current research encompasses a broad spectrum covering basic, translational, and clinical research. In this Series paper, we aim to discuss the current understanding of giant cell arteritis with cranial manifestations, describe the clinical approach to this condition, and explore future directions in research and patient care.
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Cenerimod, a selective S1P receptor modulator, improves organ-specific disease outcomes in animal models of Sjögren's syndrome.Background: Sjögren's syndrome is a systemic autoimmune disease characterized by immune cells predominantly infiltrating the exocrine glands and frequently forming ectopic lymphoid structures. These structures drive a local functional immune response culminating in autoantibody production and tissue damage, associated with severe dryness of mucosal surfaces and salivary gland hypofunction. Cenerimod, a potent, selective and orally active sphingosine-1-phosphate receptor 1 modulator, inhibits the egress of lymphocytes into the circulation. Based on the mechanism of action of cenerimod, its efficacy was evaluated in two mouse models of Sjögren's syndrome. Methods: Cenerimod was administered in two established models of Sjögren's syndrome; firstly, in an inducible acute viral sialadenitis model in C57BL/6 mice, and, secondly, in the spontaneous chronic sialadenitis MRL/lpr mouse model. The effects of cenerimod treatment were then evaluated by flow cytometry, immunohistochemistry, histopathology and immunoassays. Comparisons between groups were made using a Mann-Whitney test. Results: In the viral sialadenitis model, cenerimod treatment reduced salivary gland immune infiltrates, leading to the disaggregation of ectopic lymphoid structures, reduced salivary gland inflammation and preserved organ function. In the MRL/lpr mouse model, cenerimod treatment decreased salivary gland inflammation and reduced T cells and proliferating plasma cells within salivary gland ectopic lymphoid structures, resulting in diminished disease-relevant autoantibodies within the salivary glands. Conclusions: Taken together, these results suggest that cenerimod can reduce the overall autoimmune response and improve clinical parameters in the salivary glands in models of Sjögren's syndrome and consequently may reduce histological and clinical parameters associated with the disease in patients.
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Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction.mmunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.
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Evaluation of the mechanisms of sarcopenia in chronic inflammatory disease: protocol for a prospective cohort study.Background: Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use. Methods: This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis. Discussion: This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups. Ethics and dissemination: The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server. Trial registration: ClinicalTrials.gov Identifier: NCT04734496.
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Flares in patients with systemic lupus erythematosus.Objective: SLE is characterized by relapses and remissions. We aimed to describe the frequency, type and time to flare in a cohort of SLE patients. Methods: SLE patients with one or more 'A' or 'B' BILAG-2004 systems meeting flare criteria ('new' or 'worse' items) and requiring an increase in immunosuppression were recruited from nine UK centres and assessed at baseline and monthly for 9 months. Subsequent flares were defined as: severe (any 'A' irrespective of number of 'B' flares), moderate (two or more 'B' without any 'A' flares) and mild (one 'B'). Results: Of the 100 patients, 94% were female, 61% White Caucasians, mean age (s.d.) was 40.7 years (12.7) and mean disease duration (s.d.) was 9.3 years (8.1). A total of 195 flares re-occurred in 76 patients over 781 monthly assessments (flare rate of 0.25/patient-month). There were 37 severe flares, 32 moderate flares and 126 mild flares. By 1 month, 22% had a mild/moderate/severe flare and 22% had a severe flare by 7 months. The median time to any 'A' or 'B' flare was 4 months. Severe/moderate flares tended to be in the system(s) affected at baseline, whereas mild flares could affect any system. Conclusion: . In a population with active SLE we observed an ongoing rate of flares from early in the follow-up period with moderate-severe flares being due to an inability to fully control the disease. This real-world population study demonstrates the limitations of current treatments and provides a useful reference population from which to inform future clinical trial design.
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The Sjögren's Working Group: The 2023 OMERACT meeting and provisional domain generationSjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.