Etudes d'association entre des polymorphismes de gènes candidats et la sévérité structurale ou la réponse au traitement dans la polyarthrite rhumatoïde

La polyarthrite rhumatoïde (PR) est une maladie multifactorielle complexe résultant de l'interaction entre des facteurs génétiques et environnementaux. Elle est notamment caractérisée par la présence d'auto-anticorps anti-peptides citrullinés (ACPA) et par l'apparition d'érosions. Parmi les facteurs génétiques associés à la susceptibilité de la maladie, certains allèles du gène HLA-DRB1, encodant la chaîne bêta des molécules HLA de classe 2, ainsi que certains polymorphismes mononucléotidiques (SNPs) situés dans de nombreux gènes intervenant dans la physiopathologie de la maladie ont été identifiés comme associés à la susceptibilité de la maladie ou la présence d'ACPA. L'objectif de cette thèse est de rechercher une association entre des SNPs de gènes candidats et la sévérité structurale ou la réponse au traitement dans la PR. Ce travail s'est décomposé en 3 grandes parties:1) L'identification de SNPs associés à la sévérité structurale à partir de 2 cohortes de PR récentes (cohortes ESPOIR et RMP). 2) Le développement d'une nouvelle classification des allèles de HLA-DRB1 en fonction de leur propriétés acido-basiques des acides aminés situés en position 70 et 71 à partir d'une cohorte de PR récentes (cohorte ESPOIR). 3) L'identification de SNPs associés à la réponse au traitement dans chez des patients issus d'un essai randomisé (SMART) évaluant l'efficacité du rituximab dans la PR. Deux SNPs situés sur le gène IL2RB ont été identifiés comme associés à la présence d'érosions dans la cohorte ESPOIR et après méta analyse sur les cohortes ESPOIR et RMP. Une nouvelle classification des allèles de HLA-DRB1 en fonction des propriétés acido-basiques des acides aminés présents aux positions 70 et 71 a été développée et démontre un intérêt en termes d'association avec la production d'ACPA et la progression structurale. Deux SNPs situés sur le gène FCGR3A ou sur le promoteur de BAFF ont identifiés comme associés à la réponse EULAR chez les patients recevant un premier cycle de rituximab dans l'essai randomisé SMART.Rheumatoid arthritis (RA) is a multifactorial complex disease resulting from the interactions between genes and environment and immunity. RA is characterized by the presence of anti-citrullinated peptide antibodies and leads to bone erosions. In 1987, an association between some alleles of the HLA-DRB1 gene, encoding the beta chain of MHC class II molecules, and RA susceptibility was reported. With the development of molecular biology, several associations between several single nucleotide polymorphisms (SNPs) located in different genes implicated in RA physiopathology and RA susceptibility or ACPA presence were identified. Other studies found significant associations between some SNPs located in genes implicated in drug metabolism or in drug target expression and the response to treatment. The objective of the thesis was to study the association between several SNPs of candidate genes and the structural severity or the response to treatment in RA. The work is composed of 3 parts: 1) The identification of SNPs associated with the severity or structural progression based on 2 cohorts of early RA (ESPOIR and RMP). The severity was defined according to the presence of erosions and the structural progression according to the Total Sharp Score progression within one year. 2) The elaboration of an alternative classification of HLA-DRB1 alleles, based on acid-base properties of amino acids, and the assessment of the association between allele groups and ACPA presence or structural progression in a cohorts of early RA (ESPOIR). 3) The identification of SNPs associated with the response to treatment in patients included in a randomized controlled trial assessing the clinical response to rituximab in RA (SMART). The response to treatment was defined according to the EULAR response criteria. Two SNPs located in IL2RB gene were associated with the presence of erosion in ESPOIR cohort and after meta-analysis of ESPOIR and RMP cohorts. An alternative classification of HLA-DRB1 alleles according to the acid-base properties of the amino acid at positions 70 and 71 was developed and was relevant in terms of prediction of ACPA presence and structural progression. Two SNPs located on FCGR3A gene or in the promoter of BAFF gene were associated with EULAR response after a first course of rituximab in RA in SMART trial. We identified several associations between SNPs located on candidate genes and the severity or the response to treatment in RA. These findings contribute to the knowledge about RA physiopathology and could participate to the development of a personalized medicine

Polarization of Rheumatoid Macrophages by TNF Targeting Through an IL-10/STAT3 Mechanism

Macrophages contribute to the pathogenesis of rheumatoid arthritis (RA). They can display different states of activation or “polarization,” notably the so-called inflammatory “M1” and the various alternative “M2” polarizations, characterized by distinct functions. Data regarding the effects of RA anti-cytokine biological disease-modifying anti-rheumatic drugs (bDMARDs) on macrophage polarization are scarce. We aimed to assess in vitro modulation of macrophage polarization by bDMARDs targeting pro-inflammatory cytokines in RA. We generated monocyte derived macrophages using blood samples from 20 RA patients with active RA and 30 healthy controls. We evaluated in vitro the impact on M1 inflammatory macrophages of: etanercept (ETA), adalimumab (ADA), certolizumab (CZP), tocilizumab (TCZ), and rituximab (RTX). We assessed the impact on macrophage polarization using flow cytometry and RTqPCR to study the expression of surface markers and perform functional studies of cytokine production, phagocytosis, and negative feedback control of inflammation. Among evaluated bDMARDs, anti-TNF agents modulated the polarization of inflammatory macrophages by decreasing inflammatory surface markers (CD40, CD80) and favoring alternative markers (CD16, CD163, MerTK). Anti-TNF agents also induced alternative functions in macrophages activated in inflammatory condition with (i) the inhibition of inflammatory cytokines (TNF, IL-6, IL-12), (ii) an increase in phagocytosis. These findings were mechanistically related to an increase in early IL-10 production, responsible for higher negative feedback control of inflammation involving SOCS3 and Gas6. This IL-10 effect was STAT3-dependent. Anti-TNF agents not only inhibit in vitro inflammatory functions of macrophages, but also favor resolution of inflammation through polarization toward alternative features specifically involving the IL-10/STAT3 axis

Determining factors related to impaired spinal and hip mobility in patients with axial spondyloarthritis : longitudinal results from the DESIR cohort

Copyright information: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objective: To investigate the determinants of impaired spinal and hip mobility in patients with early axial spondyloarthritis (axSpA). Methods: Five-year longitudinal data from the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort were analysed. Associations were investigated using generalised estimating equations, using Bath Ankylosing Spondylitis Metrology Index (BASMI) linear or each of the five components of BASMI as dependent variables, and clinical and demographic variables as independent variables in univariable models. Multivariable analyses were performed, adjusting for potential confounders. Results: Data from 644 patients and 5152 visits were analysed. Higher BASMI values were independently and positively associated with Ankylosing Spondylitis Disease Activity Score C reactive protein (ASDAS-CRP) (adjusted B (adjB)=0.21; 95% CI=0.15 to 0.28), MRI spinal inflammation score (adjB=0.11; 95% CI=0.04 to 0.19), enthesitis score (adjB=0.02; 95% CI=0.01 to 0.04) and age (adjB=0.02; 95% CI=0.01 to 0.03). All BASMI components were independently associated with ASDAS-CRP and MRI spinal inflammation, except for maximal intermalleolar distance (reflecting hip mobility), which was not associated with MRI spinal inflammation. Conclusion: In early axSpA, spinal mobility impairment is independently determined by clinical disease activity, MRI spinal inflammation, enthesitis and age. The influence of spinal inflammation prevails in early axSpA, as opposed to spinal structural damage, which may become more relevant in later disease stages.info:eu-repo/semantics/publishedVersio

Do Smoking and Socioeconomic Factors Influence Imaging Outcomes in Axial Spondyloarthritis? Five-Year Data From the DESIR Cohort

Objective: To investigate the relationship between smoking and imaging outcomes over 5 years in axial spondyloarthritis (SpA) and to assess whether socioeconomic factors influence these relationships. Methods: Axial SpA patients from the Devenir des Spondylarthropathies Indifferérenciées Récentes cohort were included. The following 4 imaging outcomes were assessed by 3 central readers at baseline, 2 years, and 5 years: spine radiographs (using the modified Stoke Ankylosing Spondylitis Spine Score [mSASSS]), sacroiliac (SI) joint radiographs (using the modified New York criteria), magnetic resonance imaging (MRI) of the spine (using the Spondyloarthritis Research Consortium of Canada [SPARCC] score), and MRI of the SI joint (using the SPARCC score). The explanatory variable of interest was smoking status at baseline. Interactions between smoking and socioeconomic factors (i.e., job type [blue-collar or manual work versus white-collar or nonmanual work] and education [low versus high]) were first tested, and if significant, analyses were run using separate strata. Generalized estimating equations models were used, with adjustments for confounders. Results: In total, 406 axial SpA patients were included (52% male, 40% smokers, and 18% blue collar). Smoking was independently associated with more MRI-detected SI joint inflammation at each visit over the 5 years, an effect that was seen only in patients with blue-collar professions (β = 5.41 [95% confidence interval (95% CI) 1.35, 9.48]) and in patients with low education levels (β = 2.65 [95% CI 0.42,4.88]), using separate models. Smoking was also significantly associated with spinal inflammation (β = 1.69 [95% CI 0.45, 2.93]) and SI joint damage (β = 0.57 [95% CI 0.18, 0.96]) across all patients, irrespective of socioeconomic factors and other potential confounders. Conclusion: Strong associations were found between smoking at baseline and MRI-detected SI joint inflammation at each visit over a time period of 5 years in axial SpA patients with a blue-collar job or low education level. These findings suggest a possible role for mechanical stress amplifying the effect of smoking on axial inflammation in axial SpA.publishersversionpublishe

Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis

Objectives: To identify groups of people with rheumatoid arthritis (RA) with different disability trajectories over ten years, despite comparable levels of inflammation.Methods: Data for this analysis came from three European prospective cohort studies of people with RA (Norfolk Arthritis Register [NOAR], Early Rheumatoid Arthritis Network [ERAN], Étude et Suivi des Polyarthrites Indifférenciées Récentes [ESPOIR]). Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1/1/2000, <24 months baseline symptom duration, and disability (Health Assessment Questionnaire [HAQ]) and inflammation (two-component disease activity score [DAS28-2C]) recorded at baseline and one other follow-up. People in each cohort also completed patient reported outcome measures at each assessment (pain, fatigue, depression). Group-based trajectory models (GBTM) were used to identify distinct groups of people with similar HAQ and DAS28-2C trajectories over follow-up.Results: This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). People in ESPOIR were younger and included more women (mean [standard deviation] age: NOAR: 57.1 [14.6], ESPOIR: 47.6 [12.5], ERAN: 56.8 [13.8]; women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories that followed the hypothesised pattern (comparable DAS28-2C but different HAQ) were identified. Higher pain, fatigue and depression were associated with increased odds of being in the high HAQ trajectories. Conclusion: Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function

Evaluation globale standardisée systématique des rhumatismes inflammatoires chroniques: intérêts et limites

Introduction: National and international recommendations call for an annual standardized systematic holistic review in the management of chronic inflammatory rheumatism (CIR). This includes an assessment of disease activity and severity, as well as patient education on the disease, knowledge of pharmacological and non-pharmacological treatments, adherence to treatment and screening for comorbidities. Our study aims to recall the definition of a holistic review (HR), to present the evidence of their effectiveness and to give an overview of HR practices in France. Methods: A literature review was conducted in the Pubmed database to identify randomized controlled trials (RCTs) or meta-analyses reporting the efficacy of a multidisciplinary intervention in ICR or other chronic diseases. Two online surveys were sent to all rheumatology departments in France and to a sample of independent rheumatologists, with 34 and 19 questions respectively. These questionnaires were used to determine the profile of the responding center/rheumatologist, the existence of an HR and the obstacles or facilitators to its implementation. Results: Literature search yielded 872 articles, 24 of which were finally included: 16 RCTs and 8 meta-analyses. Only 3 articles concerned ICRs, including one meta-analysis of 10 RCTs in rheumatoid arthritis (RA). Of these 3 studies, 2 RCTs in systemic lupus and systemic sclerosis showed a favorable impact of a multidisciplinary approach on SLEDAI and grip strength and mouth opening respectively, while the meta-analysis in RA showed no benefit on disability or disease activity.The questionnaire was answered by 72 centers and 186 rheumatologists. A third of the centers had already implemented a HR during an day hospitalization. 70 % of centers estimated that they managed more than 10 patients per month, devoting an average of 35 minutes of rheumatologist time and 90 minutes of cumulative time for all other healthcare professionals (HCPs) involved in the program. Most of the HCPs involved were nurses (92 %), dieticians (56 %) and physiotherapists (56 %). The main obstacles to setting up a HR were the lack of paramedical resources, lack of economic value and lack of support from treating rheumatologists, while patient motivation was seen as a facilitating factor. Conclusion: Although HR is recommended, there is little evidence of its effectiveness in ICR. Only 36 % of responding centers have implemented such a program. This survey helps to identify the obstacles and facilitators, and to find solutions for extending this practice

An international multicentre analysis of current prescribing practices and shared decision-making in psoriatic arthritis

Objectives Shared decision-making (SDM) is advocated to improve patient outcomes in PsA. We analysed current prescribing practices and the extent of SDM in PsA across Europe. Methods The ASSIST study was a cross-sectional observational study of PsA patients ≥18 years of age attending face-to-face appointments between July 2021 and March 2022. Patient demographics, current treatment and treatment decisions were recorded. SDM was measured by the clinician’s effort to collaborate (CollaboRATE questionnaire) and patient communication confidence (PEPPI-5 tool). Results A total of 503 patients were included from 24 centres across the UK, France, Germany, Italy and Spain. Physician- and patient-reported measures of disease activity were highest in the UK. Conventional synthetic DMARDs constituted a higher percentage of current PsA treatment in the UK than continental Europe (66.4% vs 44.9%), which differed from biologic DMARDs (36.4% vs 64.4%). Implementing treatment escalation was most common in the UK. CollaboRATE and PEPPI-5 scores were high across centres. Of 31 patients with low CollaboRATE scores (<4.5), no patients with low PsAID-12 scores (<5) had treatment escalation. However, of 465 patients with CollaboRATE scores ≥4.5, 59 patients with low PsAID-12 scores received treatment escalation. Conclusions Higher rates of treatment escalation seen in the UK may be explained by higher disease activity and a younger cohort. High levels of collaboration in face-to-face PsA consultations suggests effective implementation of the SDM approach. Our data indicate that in patients with mild disease activity, only those with higher perceived collaboration underwent treatment escalation. Prospective studies should examine the impact of SDM on PsA patient outcomes

How do patient-reported outcome measures affect treatment intensification and patient satisfaction in the management of psoriatic arthritis? A cross sectional study of 503 patients

Objectives The AsseSSing Impact in pSoriatic Treatment (ASSIST) study investigated prescribing in routine PsA care and whether the patient-reported outcome—PsA Impact of Disease questionnaire (PsAID-12)—impacted treatment. This study also assessed a range of patient and clinician factors and their relationship to PsAID-12 scoring and treatment modification. Methods Patients with PsA were selected across the UK and Europe between July 2021 and March 2022. Patients completed the PsAID questionnaire and the results were shared with their physician. Patient characteristics, disease activity, current treatment methods, treatment strategies, medication changes and patient satisfaction scores were recorded. Results A total of 503 patients were recruited. Some 36.2% had changes made to treatment, and 88.8% of these had treatment escalation. Overall, the mean PsAID-12 score was higher for patients with treatment escalation; increase in PSAID-12 score is associated with increased odds of treatment escalation (odds ratio 1.58; P < 0.0001). However, most clinicians reported that PsAID-12 did not impact their decision to escalate treatment, instead supporting treatment reduction decisions. Physician’s assessment of disease activity had the most statistically significant effect on likelihood of treatment escalation (odds ratio 2.68, per 1-point score increase). Escalation was more likely in patients not treated with biologic therapies. Additional factors associated with treatment escalation included: patient characteristics, physician characteristics, disease activity and disease impact. Conclusion This study highlights multiple factors impacting treatment decision-making for individuals with PsA. PsAID-12 scoring correlates with multiple measures of disease severity and odds of treatment escalation. However, most clinicians reported that the PsAID-12 did not influence treatment escalation decisions. Psoriatic Arthritis Impact of Disease (PsAID) scoring could be used to increase confidence in treatment de-escalation

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update

Objectives: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. Methods: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. Results: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. Conclusions: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325