Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the 'JAK-pot' study).

BACKGROUND: In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept. OBJECTIVE: Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population. METHODS: Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the 'JAK-pot' collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi. RESULTS: Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97). CONCLUSION: While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design.

Susceptibility to COVID-19 and Immunologic Response to Vaccination in Patients With Immune-Mediated Inflammatory Diseases.

Immune-mediated inflammatory diseases (IMIDs) are a highly heterogeneous group of diseases that share a common etiology of immune dysregulation, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, among others. It is estimated that the prevalence of IMIDs ranges between 5% and 7% in developed countries. As current management of IMIDs includes the use of immunomodulatory medications, the resulting weakened immune response can increase the risk of infection, including with SARS-CoV-2 (the causative agent of COVID-19) and reduce response to vaccination, placing these individuals at continued risk of severe outcomes from COVID-19. In this article, we summarize the current literature related to COVID-19 outcomes and the immunogenicity and reactogenicity of COVID-19 mRNA vaccination among patients with rheumatologically dominated IMIDs, as well as the effect of immunomodulatory therapies on these outcomes. We conclude by providing current COVID-19 vaccination recommendations for individuals with IMID.

[Rheumatology: what's new in 2023]. / Rhumatologie: ce qui a changé en 2023.

In rheumatology, this year has been characterized by a broader knowledge of the pathogenesis of rheumatoid arthritis and mechanisms involved in the onset and persistence of low back pain. Studies relevant to the management of of gout, axial spondyloarthritis, autoinflammatory diseases and systemic vasculitides were published. New data on the safety of JAK inhibitors have been published. The ASAS-EULAR recommendations for the treatment of axial spondyloarthritis were updated, and the 2023 EULAR/PReS guidelines for the diagnosis and treatment of systemic juvenile idiopathic arthritis and adult-onset Still's disease are now available. New molecules and different glucocorticoid sparing strategies were introduced for giant cell arteritis.

En 2023, en rhumatologie, une avancée des connaissances sur la pathogenèse de la polyarthrite rhumatoïde et des mécanismes impliqués dans l'apparition et la persistance des lombalgies a été notée. Des études relevantes pour le traitement de la goutte, de la spondylarthrite axiale, des maladies auto-inflammatoires et des vascularites systémiques ont été publiées. De nouvelles données concernant la sécurité des inhibiteurs de Janus kinase sont disponibles. Les directives ASAS-EULAR pour le traitement de la spondylarthrite axiale ont été actualisées et les recommandations EULAR/PReS 2023 pour le diagnostic et le traitement de l'arthrite juvénile idiopathique systémique et de la maladie de Still de l'adulte sont désormais disponibles. De nouvelles molécules et différentes stratégies d'épargne des glucocorticoïdes ont été proposées pour l'artérite à cellules géantes.

After JAK inhibitor failure: to cycle or to switch, that is the question - data from the JAK-pot collaboration of registries.

OBJECTIVES: The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi. METHODS: This is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders. RESULTS: 365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies. CONCLUSIONS: After failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi.

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

OBJECTIVES: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. METHODS: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. RESULTS: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. CONCLUSIONS: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.

A potential role for chlamydial infection in rheumatoid arthritis development.

OBJECTIVES: To assess the relationship between self-reported and serologic evidence of prior chlamydial infection, rheumatoid arthritis (RA)-related autoantibodies and risk of RA-development. METHODS: This is a nested study within a prospective Swiss-based cohort including all first-degree relatives of RA patients (RA-FDR) who answered a question on past chlamydial infections. Primary outcome was systemic autoimmunity associated with RA (RA-autoimmunity) defined as positivity for anti-citrullinated peptide antibodies (ACPA) and/or rheumatoid factor (RF). Secondary outcomes were high levels of RA-autoimmunity, RA-associated symptoms and RA-autoimmunity, and subsequent seropositive RA diagnosis. We conducted a nested case-control analysis by measuring the serological status against Chlamydia trachomatis' major outer membrane protein. We replicated our analysis in an independent United States-based RA-FDR cohort. RESULTS: Among 1231 RA-FDRs, 168 (13.6%) developed RA-autoimmunity. Prevalence of self-reported chlamydial infection was significantly higher in individuals with RA-autoimmunity compared with controls (17.9% vs 9.8%, OR = 2.00, 95%CI: 1.27-3.09, p < 0.01). This association remained significant after adjustments (OR = 1.91, 95%CI: 1.20-2.95). Stronger effect sizes were observed in later stages of RA development. There was a similar trend between a positive C. trachomatis serology and high levels of RA-autoimmunity (OR = 3.05, 95% CI: 1.10-8.46, p= 0.032). In the replication cohort, there were significant associations between chlamydial infection and RF positivity and incident RA, but not anti-CCP positivity. CONCLUSIONS: Self-reported chlamydial infections are associated with elevated RA-autoimmunity in at risk individuals. The differing association of chlamydial infections and ACPA/RF between cohorts will need to be explored in future studies but is consistent with a role of mucosal origin of RA-related autoimmunity.

[Can we prevent the occurrence of Rheumatoid Arthritis in 2023?] / Peut-on prévenir la survenue de la polyarthrite rhumatoïde en 2023 ?

The improvement of our knowledge about the pathogenic mechanisms, the identification of the risks factors and the development of new antirheumatic drugs have enabled significant progress in the management of patients suffering of Rheumatoid Arthritis (RA). We know now that the disease develops long before the first clinical signs appear (immunological onset of the disease or asymptomatic period). One of the current lines of research is the prevention of the disease using early interventions during the asymptomatic stage. In this article, we will summarize the current knowledge concerning the risk factors, the identification of asymptomatic patients at high risk developing rheumatoid arthritis, as well as potential interventions that would allow prevention of the disease.

L'amélioration de nos connaissances sur les mécanismes pathogéniques, l'identification des facteurs de risque, ainsi que le développement de nouveaux traitements antirhumatismaux, ont permis un progrès significatif dans la prise en charge des patients souffrant d'une polyarthrite rhumatoïde (PR). On sait maintenant que la maladie se développe bien avant l'apparition des premiers signes de la maladie (début immunologique de la maladie ou période asymptomatique). Un des axes de recherche actuel est de prévenir la maladie par une intervention précoce, au stade asymptomatique. Dans cet article, nous allons résumer les connaissances actuelles sur les facteurs de risque, l'identification des patients asymptomatiques à haut risque de développer une PR, ainsi que sur les mesures étudiées qui permettraient la prévention de cette maladie.

Robust T-Cell Responses in Anti-CD20-Treated Patients Following COVID-19 Vaccination: A Prospective Cohort Study.

BACKGROUND: Patients treated with anti-CD20 therapy are particularly at risk of developing severe coronavirus disease 2019 (COVID-19); however, little is known regarding COVID-19 vaccine effectiveness in this population. METHODS: This prospective observational cohort study assesses humoral and T-cell responses after vaccination with 2 doses of mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (n = 37), compared to immunocompetent individuals (n = 22). RESULTS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4 T cells were equally detected in immunocompetent and anti-CD20 treated patients (85-90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8 T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). S-specific CD4 and CD8 T cells were polyfunctional but expressed more effector molecules in patients than in controls. During follow-up, 3 MS patients without SARS-CoV-2-specific antibody response had a mild breakthrough infection. One of them had no detectable S-specific T cells after vaccination. CONCLUSIONS: Our study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the reduction of complications of severe COVID-19.

Accounting for missing data caused by drug cessation in observational comparative effectiveness research: a simulation study.

OBJECTIVES: To assess the performance of statistical methods used to compare the effectiveness between drugs in an observational setting in the presence of attrition. METHODS: In this simulation study, we compared the estimations of low disease activity (LDA) at 1 year produced by complete case analysis (CC), last observation carried forward (LOCF), LUNDEX, non-responder imputation (NRI), inverse probability weighting (IPW) and multiple imputations of the outcome. All methods were adjusted for confounders. The reasons to stop the treatments were included in the multiple imputation method (confounder-adjusted response rate with attrition correction, CARRAC) and were either included (IPW2) or not (IPW1) in the IPW method. A realistic simulation data set was generated from a real-world data collection. The amount of missing data caused by attrition and its dependence on the 'true' value of the data missing were varied to assess the robustness of each method to these changes. RESULTS: LUNDEX and NRI strongly underestimated the absolute LDA difference between two treatments, and their estimates were highly sensitive to the amount of attrition. IPW1 and CC overestimated the absolute LDA difference between the two treatments and the overestimation increased with increasing attrition or when missingness depended on disease activity at 1 year. IPW2 and CARRAC produced unbiased estimations, but IPW2 had a greater sensitivity to the missing pattern of data and the amount of attrition than CARRAC. CONCLUSIONS: Only multiple imputation and IPW2, which considered both confounding and treatment cessation reasons, produced accurate comparative effectiveness estimates.

EULAR points to consider when analysing and reporting comparative effectiveness research using observational data in rheumatology.

BACKGROUND: Comparing treatment effectiveness over time in observational settings is hampered by several major threats, among them confounding and attrition bias. OBJECTIVES: To develop European Alliance of Associations for Rheumatology (EULAR) points to consider (PtC) when analysing and reporting comparative effectiveness research using observational data in rheumatology. METHODS: The PtC were developed using a three-step process according to the EULAR Standard Operating Procedures. Based on a systematic review of methods currently used in comparative effectiveness studies, the PtC were formulated through two in-person meetings of a multidisciplinary task force and a two-round online Delphi, using expert opinion and a simulation study. Finally, feedback from a larger audience was used to refine the PtC. Mean levels of agreement among the task force were calculated. RESULTS: Three overarching principles and 10 PtC were formulated, addressing, in particular, potential biases relating to attrition or confounding by indication. Building on Strengthening the Reporting of Observational Studies in Epidemiology guidelines, these PtC insist on the definition of the baseline for analysis and treatment effectiveness. They also focus on the reasons for stopping treatment as an important consideration when assessing effectiveness. Finally, the PtC recommend providing key information on missingness patterns. CONCLUSION: To improve the reliability of an increasing number of real-world comparative effectiveness studies in rheumatology, special attention is required to reduce potential biases. Adherence to clear recommendations for the analysis and reporting of observational comparative effectiveness studies will improve the trustworthiness of their results.

Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the 'JAK-pot' collaboration.

BACKGROUND: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. METHODS: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. RESULTS: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA. CONCLUSION: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

Comparison of drug retention of TNF inhibitors, other biologics and JAK inhibitors in RA patients who discontinued JAK inhibitor therapy.

OBJECTIVES: JAK Inhibitors (JAKi) are recommended DMARDs for patients with moderate-to-severe RA who failed first-line therapy with methotrexate. There is a lack of data allowing an evidence-based choice of subsequent DMARD therapy for patients who had discontinued JAKi treatment. We aimed to compare the effectiveness of TNF inhibitor (TNFi) therapy vs JAKi vs other mode of action (OMA) biologic DMARD (bDMARD) in RA patients who were previously treated with a JAKi. METHODS: RA patients who discontinued JAKi treatment within the Swiss RA registry SCQM were included for this observational prospective cohort study. The primary outcome was drug retention for either TNFi, OMA bDMARD or JAKi. The hazard ratio for treatment discontinuation was calculated adjusting for potential confounders. A descriptive analysis of the reasons for discontinuation was performed. RESULTS: Four hundred treatment courses of JAKi were included, with a subsequent switch to either JAKi, TNFi or OMA bDMARD. The crude overall drug retention was higher in patients switching to another JAKi as compared with TNFi and comparable to OMA. A significant difference of JAKi vs TNFi persisted after adjusting for potential confounders. CONCLUSION: In a real-world population of RA patients who discontinued treatment with a JAKi, switching to another JAKi resulted in a higher drug retention than switching to a TNFi. A switch to a second JAKi seems an effective therapeutic option.

[Vaccine prevention in patients with rheumatic diseases]. / Prévention vaccinale chez les patients avec des maladies rhumatismales.

Patients with inflammatory rheumatologic diseases are at increased risk for infectious complications, including SARS-CoV-2, which represent one of the leading causes of death in this population. This risk is due to both the numerous comorbidities of this patient's group and the immunosuppressive therapies they receive. Vaccination reduces the incidence, complications, and mortality from infections. For patients receiving immunosuppressors, exacerbation of underlying diseases is rarely observed after immunization and only live-attenuated vaccines are contraindicated. A vaccination history and updated vaccination plan should be part of the clinical follow-up of patients with inflammatory rheumatism.

Les patients souffrant de maladies rhumatologiques inflammatoires sont plus à risque de complications infectieuses, y compris avec le SARS-CoV-2, qui représentent l'une des premières causes de mortalité dans cette population. Ce risque est attribuable à la fois aux nombreuses comorbidités de ces patients et aux thérapies immunosuppressives qu'ils reçoivent. La vaccination diminue l'incidence, les complications et la mortalité dues aux infections. Pour les patients recevant des immunosuppresseurs, une exacerbation significative des maladies sous-jacentes n'est qu'exception nellement observée après vaccination et seuls les vaccins vivants atténués sont en principe contre-indiqués. Une anamnèse vaccinale et une mise à jour du plan vaccinal doivent faire partie du suivi clinique de patients souffrant d'un rhumatisme inflammatoire.

[Rheumatology: 2021 update]. / Rhumatologie.

In rheumatology, this year has seen an expansion of knowledge about the effects of COVID and the vaccine response in patients with autoimmune diseases, but also a re-examination of the usual doses of glucocorticoids in vasculitides and new treatments strategies for diseases such as systemic lupus erythematosus, spondylarthritis and rheumatoid arthritis. New criteria for imaging assessment in spondylarthritis and new management guidelines for patients with low back pain have also been proposed.

En rhumatologie, dans les nouveautés que nous avons choisi de mettre en avant, cette année a vu l'élargissement des connaissances sur le Covid et la réponse vaccinale chez les patients avec maladies autoimmunes, la remise en question des doses habituelles des corticostéroïdes dans les vascularites et la possibilité de nouveaux traitements ou stratégies de prise en charge, dans le lupus érythémateux systémique, les spondylarthrites et la polyarthrite rhumatoïde. De nouveaux critères pour l'évaluation de l'imagerie des spondylarthrites ont aussi été proposés et des précisions quant au type de prise en charge nécessaire pour les patients lombalgiques ont également été apportées.

Impact of the COVID-19 pandemic on the disease course of patients with inflammatory rheumatic diseases: results from the Swiss Clinical Quality Management cohort.

OBJECTIVES: To investigate whether the transient reduction in rheumatology services imposed by virus containment measures during the COVID-19 pandemic was associated with disease worsening in axial spondyloarthritis (axSpA), rheumatoid arthritis (RA) or psoriatic arthritis (PsA). METHODS: Patient-reported disease activity assessed during face-to-face visits and/or via a smartphone application were compared between three periods of each 2 months duration (before, during and after the COVID-19-wave) from January to June 2020 in 666 patients with axSpA, RA and PsA in the Swiss Clinical Quality Management cohort. RESULTS: The number of consultations dropped by 52%, whereas the number of remote assessments increased by 129%. The proportion of patients with drug non-compliance slightly increased during the pandemic, the difference reaching statistical significance in axSpA (19.9% vs 13.2% before the pandemic, p=0.003). The proportion of patients with disease flares remained stable (<15%). There was no increase in mean values of the Bath Ankylosing Disease Activity Index, the Rheumatoid Arthritis Disease Activity Index-5 and the Patient Global Assessment in patients with axSpA, RA and PsA, respectively. CONCLUSION: A short interruption of in-person patient-rheumatologist interactions had no major detrimental impact on the disease course of axSpA, RA and PsA as assessed by patient-reported outcomes.

Influence of COVID-19 pandemic on decisions for the management of people with inflammatory rheumatic and musculoskeletal diseases: a survey among EULAR countries.

OBJECTIVES: To investigate how the first wave of COVID-19 pandemic influenced decisions of rheumatologists and health professionals in rheumatology regarding the management of patients with inflammatory rheumatic and musculoskeletal diseases (RMDs). METHODS: An English-language questionnaire was developed by a EULAR working group and distributed via national rheumatology societies of EULAR countries, EMEUNET and individual working group members. Responses were collected using an online survey tool. Descriptive statistics were calculated. RESULTS: We analysed 1286 responses from 35/45 EULAR countries. Due to containment measures, 82% of respondents indicated cancellation/postponement of face-to-face visits of new patients (84% of them offering remote consultation) and 91% of follow-up visits (96% with remote consultation). The majority of respondents (58%) perceived that the interval between symptom onset and first rheumatological consultations was longer during containment restrictions than before. Treatment decisions were frequently postponed (34%), and the majority (74%) of respondents stated that it was less likely to start a biological disease modifying anti-rheumatic drug (DMARD)/targeted synthetic DMARD during the pandemic, mainly because of patients' fear, limited availability of screening procedures and decreased availability of rheumatological services. Use of (hydroxy)chloroquine (HCQ) and tocilizumab (TCZ) for the COVID-19 indication was reported by 47% and 42% of respondents, respectively, leading to a shortage of these drugs for RMDs indications according to 49% and 14% of respondents, respectively. CONCLUSION: Measures related to containment of COVID-19 pandemic led to a perceived delay between symptom onset and a first rheumatological visit, postponement of treatment decisions, and shortage of HCQ and TCZ, thereby negatively impacting early treatment and treat-to-target strategies.

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis.

BACKGROUND: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA). METHODS: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC. RESULTS: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach. CONCLUSION: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Associations between serum antibodies to periodontal pathogens and preclinical phases of rheumatoid arthritis.

OBJECTIVES: To examine whether serum antibodies against selected periodontal pathogens are associated with early symptoms of RA development in healthy individuals at risk of developing the disease. METHODS: Within an ongoing study cohort of first-degree relatives of patients with RA (RA-FDRs), we selected four groups corresponding to specific preclinical phases of RA development (n = 201). (i) RA-FDR controls without signs and symptoms of arthritis nor RA-related autoimmunity (n = 51); (ii) RA-FDRs with RA-related autoimmunity (n = 51); (iii) RA-FDRs with inflammatory arthralgias without clinical arthritis (n = 51); and (iv) RA-FDRs who have presented at least one swollen joint ('unclassified arthritis') (n = 48). Groups were matched for smoking, age, sex and shared epitope status. The primary outcome was IgG serum levels against five selected periodontal pathogens and one commensal oral species assessed using validated-in-house ELISA assays. Associations between IgG measurements and preclinical phases of RA development were examined using Kruskal-Wallis or Mann-Whitney tests (α = 0.05). RESULTS: None of the IgGs directed against individual periodontal pathogens significantly differed between the four groups of RA-FDRs. Further analyses of cumulated IgG levels into bacterial clusters representative of periodontal infections revealed significantly higher IgG titres against periodontopathogens in anti-citrullinated protein antibodies (ACPA)-positive RA-FDRs (P = 0.015). Current smoking displayed a marked trend towards reduced IgG titres against periodontopathogens. CONCLUSION: Our results do not suggest an association between serum IgG titres against individual periodontal pathogens and specific preclinical phases of RA development. However, associations between cumulative IgG titres against periodontopathogens and the presence of ACPAs suggest a synergistic contribution of periodontopathogens to ACPA development.

Detection of circulating highly expanded T-cell clones in at-risk individuals for rheumatoid arthritis before the clinical onset of the disease.

OBJECTIVES: To quantitatively profile the T-cell repertoire in the peripheral blood of individuals genetically at risk for RA, namely first-degree relatives of RA patients (RA-FDR) at different phases of disease development. METHODS: Next-generation sequencing of the TCR CDR3ß repertoire was performed on genomic DNA isolated from whole blood samples of RA-FDR selected at three different pre-clinical stages and of matched RA patients (n = 20/group). T-cell clones were identified by their unique sequence and their degree of expansion (frequency) within each sample was characterized. Clones with a frequency over 0.5% were considered highly expanded clones (HEC). RESULTS: The absolute number of HEC was significantly higher in established RA patients (mean 4.65) and tended to be higher in symptomatic RA-FDR (mean 3.4) compared with asymptomatic RA-FDR (mean 1.55, P =0.003 and P =0.07, respectively). Asymptomatic individuals with high levels of ACPA did not differ from asymptomatic RA-FDR in terms of absolute number and frequency of clones. The number of HEC tended to be slightly higher at the time of RA onset (P =0.055). Neither clones shared by several patients, nor clones previously associated with RA, were preferentially present within or between the different groups. Finally, a longitudinal analysis did not allow to uncover a kinetic expansion of RA-specific clones closely correlated with disease development. CONCLUSIONS: HEC were detected in the peripheral blood before the clinical onset of RA, in particular in the later pre-clinical phase of RA development, and their presence increased over time.