Infliximab in the treatment of rheumatoid arthritis

Infliximab was the first monoclonal antibody to human necrosis factor alpha (TNFα) developed for treating rheumatoid arthritis (RA). This chimeric antibody binds with high affinity to both soluble and trans-membrane TNF and is able to reduce synovial inflammation, bone resorption and cartilage degradation. The efficacy of infliximab has been observed in active RA despite treatment with multiple disease modifying anti-rheumatic drugs (DMARDs), and in early disease with no prior treatment by methotrexate (MTX). Infliximab has been shown to reduce joint inflammation and to slow radiographic progression, in both clinical and non-clinical responders. Recent data suggest that using infliximab early in RA treatment increases the percentage of clinical remission and allows infliximab discontinuation. The recommended dosage of 3 mg/kg could be increased up to 10 mg/kg with partial efficacy of the dose escalation. Antibodies to infliximab have been observed in 7% to 61% of patients and are associated with a low trough level of infliximab and secondary response failure. Their occurrence could be prevented by co-medication with MTX. The combination of DMARDs other than MTX with infliximab was found to be safe and efficacious. Infections, principally tuberculosis, are increased in treated patients, and the risk is greater at higher dose. Even if the treatment is generally safe and well tolerated, patients treated with infliximab should be closely monitored

Identification of distinct subgroups of Sj\uf6gren\u27s disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts

\ua9 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: Sj\uf6gren\u27s disease is a heterogenous autoimmune disease with a wide range of symptoms—including dryness, fatigue, and pain—in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. Methods: This study included patients with Sj\uf6gren\u27s disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sj\uf6gren\u27s Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sj\uf6gren\u27s Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sj\uf6gren\u27s Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. Findings: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43–64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43–63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0\ub70001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42–104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13–83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. Interpretation: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sj\uf6gren\u27s disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. Funding: Fondation pour la Recherche M\ue9dicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. / Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. / Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. / Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. / Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Definition of B cell helper T cells in rheumatoid arthritis and their behavior during treatment

International audienceBackground: Immunopathogenesis of rheumatoid arthritis (RA) is not yet clearly defined. Besides known B-cell involvement, RA development and evolution involves CD4+ T helper cell homeostasis dysregulation. Imbalance between Th17 cells and regulatory T cells have been reported and may contribute to sustained inflammation. Since the last decade, increasing reports focused on a newly described CD4+ T helper cell subset, called T follicular helper (Tfh) cells, functionally distinct from other subsets due to their own property to provide help to B cells by enhancing their survival and differentiation into long-lasting antibody secreting cells. More recently, another B cell helper subset, named T peripheral helper (Tph) cells, has been specifically described in synovial tissues and blood of RA patients. Methods: We conducted an exhaustive and careful literature search focusing our interest on T cells specialized on B cell help, Tfh cells and Tph cells, in RA pathogenesis and focused on their modulation during treatments. Results: Tfh cells and in higher proportions Tph cells were described in synovial tissue and liquid of RA patients. In blood of RA patients, despite the use of diverse Tfh cell definitions, a vast majority of reports revealed an increase of circulating Tph and Tfh cell frequency, compared to healthy controls. However, discordant correlations between disease activity score and either effector or activated circulating Tfh cell subsets were highlighted, probably due to heterogeneity of cohort design in term of definition of disease activity, cohort size and use of different treatments. Indeed, frequencies of circulating Tfh and Tph cells are modulated depending on the nature and duration of RA treatment. Interestingly, it has been demonstrated that the proportion of ICOS-expressing blood Tfh cells before abatacept initiation was an independent and significant predictor of DAS28-ESR improvement at week 24. This report may encourage to conduct further investigations based on T-cell subsets as predictive biomarkers of response to biotherapies. Conclusion: Mounting evidences hypothesize that circulating Tfh and Tph cells may be involved in RA pathogenesis and response to treatment

Risk factors of mortality during the first year after low energy osteoporosis fracture: A retrospective case-control study

International audienceIntroduction. Osteoporotic fractures are a major public health problem because of the morbidity and mortality of fracture complications. The objective of this study was to examine predictive factors of mortality during the first year after an osteoporotic fracture. Methods. It is a retrospective case-control study using data of a group of 1081 patients aged over 50 years with severe osteoporotic fractures by the Rennes university hospital emergency department from August 2007 to September 2008. Patients (cases) who died during the year following the fracture were compared with others who had survived (controls) one year after the fracture, matched on age, sex and type of fracture. Pre-fracture comorbidities and complications after the fractures were studied. Results. Forty-two cases and 126 controls were analyzed without significant differences in age, sex or type of fracture. On univariate analysis, previous neoplasia, neurodegenerative disease, walking aids, thromboembolic complication, post fracture infection, post fracture heart failure, post fracture acute respiratory failure were associated with more mortality after osteoporotic fracture. After multivariate analysis, only previous neoplasia (OR = 4.63 [1.79 - 11.95]; p = 0.02) and acute respiratory failure after fracture (OR = 28.15 [5.75 - 137.9]; p<0.001) were retained as predictive factors during the year following the fracture. Conclusion. Patients died more often from their co-morbidities than direct complications of their fractures. Osteoporotic fracture seems to be a marker of poor health status and a factor which may hasten the death. © Copyright 2016 CIC Edizioni Internazionali Unauthorized reproduction of this article is prohibited

La combinaison des données cytologiques et de la recherche des microcristaux dans le liquide synovial non purulent améliore les performances diagnostiques d'arthrite septique [Combining cytology and microcrystal detection in nonpurulent joint fluid benefits the diagnosis of septic arthritis]

National audienceObjectifÉvaluer les performances diagnostiques de la combinaison des données cytologiques et de la recherche des microcristaux dans le liquide synovial pour le diagnostic d’arthrite septique.MéthodesÉtude rétrospective monocentrique à partir de liquides synoviaux de patients présentant un tableau d’arthrites aiguës ou chroniques. Étaient analysés sur les liquides synoviaux : numération leucocytaire (/mm3), formule leucocytaire avec taux de polynucléaires neutrophiles (PNN) (%), la recherche de microcristaux et les cultures bactériologiques. Le diagnostic d’arthrite septique était retenu lorsque les cultures étaient positives sur le liquide synovial ou dans les hémocultures. Pour évaluer la performance diagnostique, ont été calculés, sensibilité, spécificité, courbe ROC avec l’aire sous la courbe et le rapport de vraisemblance positif (LR+) ou négatif (LR−).RésultatsDeux cent huit liquides synoviaux ont été analysés : 28 arthrites septiques, 41 chondrocalcinoses, 28 gouttes, 33 polyarthrites rhumatoïdes, 31 spondyloarthrites, 18 arthroses, 29 arthrites indifférenciées. Les données cytologiques avec les meilleures performances diagnostiques étaient la numération en PNN (seuil > 50 000/mm3), la numération en leucocyte (seuil > 50 000/mm3) et le pourcentage de PNN (seuil > 95 %), avec des LR+ correspondant de 8,93, 5,76 et 4,55. Pour un seuil de PNN 95 %, PNN > 50 000/mm3 et leucocytes > 50 000/mm3.ConclusionLa combinaison des données cytologiques des liquides synoviaux avec l’absence de microcristaux permet d’améliorer les performances diagnostiques dans le diagnostic d’arthrite septique