To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis.
Population based ...prospective study.
53 university and 54 non-university clinical centres in France.
3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months.
Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis.
The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LED
), which measures the difference between average duration of survival without failure.
Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LED
4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (-0.7, -1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events.
Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.
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.
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.
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.
These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.
To evaluate efficacy and safety of abatacept in adults with active primary Sjögren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.
Eligible patients ...(moderate-to-severe pSS 2016 ACR/European League Against Rheumatism (EULAR) criteria, EULAR Sjögren's Syndrome Disease Activity Index ESSDAI ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored.
Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI -3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified.
Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.
To characterise safety of the Janus kinase-1 preferential inhibitor filgotinib in patients with moderately to severely active rheumatoid arthritis.
Data were integrated from seven trials ...(NCT01668641, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700, NCT03025308). Results are from placebo (PBO)-controlled (through week (W)12) and long-term, as-treated (all available data for patients receiving ≥1 dose filgotinib 200 (FIL200) or 100 mg (FIL100) daily) datasets. We calculated exposure-adjusted incidence rates (EAIRs)/100 patient-years filgotinib exposure (100PYE) for treatment-emergent adverse events (TEAEs).
3691 patients received filgotinib for 6080.7 PYE (median 1.6, maximum 5.6 years). During the PBO-controlled period, TEAEs, including those of grade ≥3, occurred at comparable rates with filgotinib or PBO; long-term EAIRs of TEAEs grade ≥3 were 6.4 and 7.6/100PYE for FIL200 and FIL100. EAIRs for deaths were 0.6/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.5 and 0.3/100PYE for FIL200 and FIL100. EAIRs for serious infection were 3.9, 3.3 and 2.4/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.6 and 3.1/100PYE for FIL200 and FIL100. EAIRs for herpes zoster were 0.6, 1.1, and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.8 and 1.1/100PYE for FIL200 and FIL100. EAIRs for major adverse cardiovascular events were 0, 1.7 and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.4 and 0.6/100PYE for FIL200 and FIL100. No venous thromboembolism occurred during the PBO-controlled period; long-term EAIRs were 0.2 and 0/100PYE for FIL200 and FIL100.
Over a median of 1.6 and maximum of 5.6 years of exposure, safety/tolerability of FIL200 and FIL100 were similar, with a lower incidence of infections with FIL200 among the long-term, as-treated dataset.
To develop a disease activity index for patients with primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI).
Thirty-nine ...SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific 'domains' contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0-10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain.
All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.001). Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true.
The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.
Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per ...year (95% confidence interval 7.38-8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple-source capture-recapture method during a 6-year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers.
Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture-recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease.
Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log-linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76-9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded.
The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population-based cohort, the systemic nature of IM.
To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögren's syndrome (SS) disease activity indexes: ...European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI).
For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI.
Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%.
This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.
Despite major recent advances in the therapeutic management of Giant cell arteritis (GCA), the diagnosis accuracy of temporal artery ultrasound remains controversial in this disease. We performed a ...systematic review to determine the sensitivity, specificity, and summary positive (LR+) and negative (LR-) likelihood ratios of temporal artery ultrasound for the diagnosis of GCA. For this, we searched EMBASE, MEDLINE and the Cochrane Database of Systematic Reviews without language restriction. Original articles reporting on diagnostic accuracy of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA, were selected. Sensitivity and specificity from each study were used to fit a bivariate diagnosis accuracy model. Of 1280 articles identified, 48 underwent full-text review, and 25 were included. Based on a total of 20 studies, the sensitivity and specificity of hypoechoic halo compared to positive temporal artery biopsy were respectively of 68% (95% CI: 57–78) and 81% (95%CI: 75–86). The summary mean positive and negative likelihood ratios were respectively of 3.64 (95%CI: 2.76–4.73) and 0.40 (0.28–0.52). Taking into account 11 studies reporting on the presence of any abnormal sign on temporal artery ultrasound yielded similar results with largely overlapping 95% confidence interval regions. This study provides the summary estimates of the diagnostic properties of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA. Those parameters allow the calculation of the post-test probability of GCA in a given patient, based on the results of temporal artery ultrasound and will help improving the diagnosis strategy for this common disease.
•Color duplex sonography (CDS) of superficial temporal artery and large vessels is an emerging diagnostic tool for giant cell arteritis (GCA).•This meta-analysis provides summary sensitivity, specificity, positive and negative likelihood ratios of temporal artery ultrasound compared to TAB for the diagnosis of GCA.•These summary parameters prove very useful to assess the risk of GCA routinely at the bed-side.
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