Alain Cantagrel

Targeting monocytes/macrophages in the treatment of rheumatoid arthritis

Biotherapies have revolutionized the treatment of RA. However, much work is needed to understand all the mechanisms of these biotherapies, and alternatives are needed to circumvent adverse effects and the high cost of these long-lasting treatments. In this article we outline some of the approaches we have used to target monocytes/macrophages as major components of inflammation and bone homeostasis. We also discuss how anti-TNF-α antibodies target monocytes/macrophages in the complex mechanisms contributing to inhibition of inflammation.

Pneumomediastinum in interstitial lung disease associated with dermatomyositis and polymyositis

OBJECTIVEnSpontaneous pneumomediastinum is a rare complication of dermatomyositis (DM) and polymyositis (PM). The aim of this study was to characterize this complication and determine its prognostic factors.nnnMETHODSnWe retrospectively collected a multicenter series of PM/DM cases complicated by pneumomediastinum. We analyzed all published cases and combined those that were exploitable with ours for an investigation of the factors associated with poor survival.nnnRESULTSnWe collected 11 PM/DM cases complicated by interstitial lung disease and pneumomediastinum. Five of the 9 DM patients had clinically amyopathic DM without muscle weakness and high serum creatine kinase levels. The outcome was favorable in 7 of these patients and 6 had no sequelae. In total, approximately 25% of our patients of the 21 analyzable cases studied died within 1 month. With a median followup of 240 days, the cumulative estimated Kaplan-Meier survival rate was 64% at 1 year and 55% at 2 years. Poor survival was associated with absence of muscle weakness (P = 0.02), initial low vital capacity (P = 0.006), and initial low carbon monoxide diffusion capacity (P = 0.04).nnnCONCLUSIONnIn this first large series of patients with connective tissue disease complicated by pneumomediastinum to be reported, most patients had DM and half amyopathic DM, as in previous reports. Pneumomediastinum may occur before DM diagnosis and may thus reveal DM with minimal or no muscle involvement. Death was associated with an absence of muscle weakness and severe pulmonary involvement before the onset of pneumomediastinum. Corticosteroids and immunosuppressive therapy can result in complete recovery, as in half our cases.

Association of Anti–Porphyromonas gingivalis Antibody Titers With Nonsmoking Status in Early Rheumatoid Arthritis: Results From the Prospective French Cohort of Patients With Early Rheumatoid Arthritis

To investigate the possible link between Porphyromonas gingivalis infection and rheumatoid arthritis (RA), according to antibody profile, genetic and environmental factors, and RA severity.

Anti‐Porphyromonas gingivalis antibodies titres are associated with non‐smoking status in early rheumatoid arthritis: Results from the ESPOIR cohort

To investigate the possible link between Porphyromonas gingivalis infection and rheumatoid arthritis (RA), according to antibody profile, genetic and environmental factors, and RA severity.

Effect of periodontal treatment on the clinical parameters of patients with rheumatoid arthritis: study protocol of the randomized, controlled ESPERA trial

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disorder that leads to joint damage, deformity, and pain. It affects approximately 1% of adults in developed countries. Periodontitis is a chronic oral infection, caused by inflammatory reactions to gram-negative anaerobic bacteria, and affecting about 35 to 50% of adults. If left untreated, periodontitis can lead to tooth loss. A significant association has been shown to exist between periodontitis and RA in observational studies. Some intervention studies have suggested that periodontal treatment can reduce serum inflammatory biomarkers such as C-reactive protein, or erythrocyte sedimentation rate. We hypothesize that periodontitis could be an aggravating factor in patients with RA, and that its treatment would improve RA outcomes. The aim of this clinical trial is to assess the effect of periodontal treatment on the biological and clinical parameters of patients with RA.Methods/designThe ESPERA (Experimental Study of Periodontitis and Rheumatoid Arthritis) study is an open-label, randomized, controlled trial. Subjects with both RA and periodontitis will be recruited at two university hospitals in southwestern France. In total, 40 subjects will be randomized into two arms (intervention and control groups), and will be followed up for 3 months. Intervention will consist of full-mouth supra-gingival and sub-gingival non-surgical scaling and root planing, followed by systemic antibiotic therapy, local antiseptics, and oral hygiene instructions. After the 3-month follow-up period, the same intervention will be applied to the subjects randomized to the control group.The primary outcome will be change of in Disease Activity Score in 28 Joints (DAS28) at the end of the follow-up period. Secondary outcomes will be the percentages of subjects with 20%, 50%, and 70% improvement in disease according to the American College of Rheumatology criteria. Health-related quality of life assessments (the Health Assessment Questionnaire and the Geriatric Oral Health Assessment Index) will also be compared between the two groups.DiscussionEvidence-based management of potential aggravating factors in subjects with active RA could be of clinical importance, yet there are few randomized controlled trials on the effect of periodontal treatment on the clinical parameters of RA. The ESPERA trial is designed to determine if non-surgical periodontal treatment could improve clinical outcomes in patients with active RA, and the quality of life of these patients.Trial registrationThe ESPERA Trial was registered in Current Controlled Trials [ISRCTN79186420] on 2012/03/20. The trial started recruiting on 2012/03/06.

The fibrin-derived citrullinated peptide β60–74Cit60,72,74 bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies

Objectives To evaluate the proportions of rheumatoid arthritis (RA) sera containing anticitrullinated proteins autoantibodies (ACPA) reactive to α36–50Cit38,42 and/or β60–74Cit60,72,74, two peptides identified as bearing the immunodominant epitopes of their major target, citrullinated fibrin. To analyse the relationships of anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 autoantibodies with autoantibodies reactive to the complete citrullinated human fibrinogen molecule (AhFibA) and with anti-CCP2 antibodies. Methods 617 sera from 181 patients with established RA and 436 with non-RA rheumatic diseases were tested by ELISA for AhFibA, anti-CCP2, anti-α36–50Cit38,42, anti-β60–74Cit60,72,74 autoantibodies, and by nephelometry for rheumatoid factor (RF). Diagnostic indexes, correlations and concordances between tests were analysed. Crossreactivity of anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 autoantibodies was assessed in competition experiments. Results At a diagnostic specificity of 95%, the diagnostic sensitivity of AhFibA (83%) was significantly higher than that of all other tests. The diagnostic sensitivity of anti-β60–74Cit60,72,74 (71%) was significantly higher than that of anti-α36–50Cit38,42 autoantibodies (51%) but similar to that of anti-CCP2 (74%). Titres of RF, anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 autoantibodies were weakly correlated with each other, whereas titres of anti-β60–74Cit60,72,74 were strongly correlated with those of AhFibA (r=0.633) and anti-CCP2 (r=0.634). Anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 mainly corresponded to two non-crossreactive subfamilies of ACPA. More than 90% of AhFibA-positive or anti-CCP2-positive sera recognised the α36–50Cit38,42 and/or the β60–74Cit60,72,74 peptide. Conclusions Autoantibodies reactive to α36–50Cit38,42 and β60–74Cit60,72,74 form two distinct, non-overlapping subfamilies of ACPA that, together, cover practically all the ACPA reactivity to citrullinated fibrinogen and to CCP2 antigens. In established RA, anti-β60–74Cit60,72,74 autoantibodies show diagnostic indexes similar to those of anti-CCP2.

Oral health-related quality of life among outpatients with rheumatoid arthritis

OBJECTIVESnThe aims of the Oral Status And Rheumatoid Arthritis (OSARA) cross-sectional study were to study the oral health-related quality of life and to assess the associated factors in a population of outpatients with rheumatoid arthritis in France.nnnMETHODSnThe data were collected by five trained and standardised dentists who asked each subject the questions of a socio-demographic, behavioural and medical questionnaire, which was completed with the medical records, and performed the dental examination. Each subject filled out two self-assessment questionnaires: the Health Assessment Questionnaire and the General Oral Health Assessment Index.nnnRESULTSnSeventy-three subjects were included. The mean age of the participants was 60.2 ± 11.9 years and 75.3% were women. For 58.3% of the subjects, their self-perceived oral health-related quality of life was described as poor. The logistic regression analysis found that a small number of teeth and marked difficulties in dressing and grooming were associated with bad oral health-related quality of life [ORa = 10.5 (1.96-56.19) and ORa = 4.3 (1.15-15.77), respectively].nnnCONCLUSIONSnMore care should be given to the prevention of dental diseases in order to improve the oral health-related quality of life of patients with rheumatoid arthritis and their self-esteem, which will already be heavily affected.

Association of IL-2RA and IL-2RB genes with erosive status in early rheumatoid arthritis patients (ESPOIR and RMP cohorts).

OBJECTIVESnTo assess the impact of single nucleotide polymorphisms (SNPs) in IL-2RA (rs2104286) and IL-2RB (rs743777 and rs3218253) genes on the risk of erosions in rheumatoid arthritis (RA) patients.nnnMETHODSnThis work is derived from 2 prospective cohorts of early RA: ESPOIR (n = 439) and RMP (n = 180). The proportions of patients with erosions at baseline and 1 year according to the genotypes of IL2RA (rs2104286) or the haplotypes constructed with the 2 SNPs of IL2RB were compared in the whole population and in ACPA positive patients. A meta-analysis assessing the risk of erosion depending on the haplotypes of the 2 SNPs of IL-2RB was performed using the Mantel-Haenszel method. A multivariate model was used to assess the independent effect of the haplotypes of IL-2RB on the risk of erosions.nnnRESULTSnThe AC haplotype of IL-2RB carriage was significantly associated with the rate of erosions in ACPA positive patients in ESPOIR cohort (rate of erosions: AC/AC: 78% versus GC or GT/GC or GT: 44%, p = 0.001). A meta-analysis of ESPOIR and RMP cohorts confirmed that the carriage of AC haplotype was significantly associated with the rate of erosions at 1 year in the whole sample (OR[95%CI] = 1.92[1.14-3.22], p = 0.01) and in ACPA positive patients (OR[95%CI] = 3.34[1.68-6.67], p = 0.0006). A multivariate model in ESPOIR cohort demonstrated the independent effect of the carriage of the AC haplotype (6.03[1.94-18.69], p = 0.002) on the risk of erosions in ACPA+ patients.nnnCONCLUSIONnA haplotype constructed with 2 SNPs located on IL-2RB gene was associated with erosive status in early RA.

Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort.

OBJECTIVESnTo investigate whether age at disease onset determines clinical, radiographic or functional outcomes in a cohort of early RA.nnnMETHODSnThe ESPOIR cohort is a multicenter cohort of patients with early arthritis. We selected patients fulfilling the 2010 ACR/EULAR criteria for RA during the first 3years of follow-up. Patients were pooled into 3xa0groups by age at RA onset: <45years (young-onset RA [YORA]), 45 to 60years (intermediate-onset RA [IORA]) and>60years (late-onset RA [LORA]). The following outcomes were compared at baseline and during the first 3years of follow-up: Simple Disease Activity Index (SDAI) remission rate, one additional erosion, Health Assessment Questionnaire Disability Index (HAQ-DI)<0.5 and first disease-modifying anti-rheumatic drug (DMARD) continuation rate.nnnRESULTSnWe included 698xa0patients (median [interquartile range] age 50.3 [39.8-57.2]years), 266 YORA, 314 IORA, and 118 LORA. At 1year, SDAI remission was greater for YORA than IORA and LORA (P<0.0001). Having at least one additional erosion was greater for LORA and IORA than YORA after 1year (P=0.009) and 3years (P=0.017). The proportion of patients with HAQ score<0.5 was greater for YORA than IORA and LORA at 1 (P=0.007), 2 and 3years. First DMARD continuation rate was lower for YORA than other groups during the 3years (P=0.005).nnnCONCLUSIONSnIn a cohort of early RA, young age at disease onset is associated with high rate of remission at 1year, no radiographic progression at 3years and low functional score during 3-year follow-up.

IL2RA is associated with persistence of rheumatoid arthritis

IntroductionAlthough rheumatoid arthritis (RA) is generally a chronic disease, a proportion of RA-patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission, reflecting loss of disease-persistence. To explore mechanisms underlying RA-persistence, we performed a candidate gene study. We hypothesized that variants associating with lack of radiographic progression also associate with DMARD-free sustained remission.Methods645 Dutch RA-patients were studied on DMARD-free sustained remission during a maximal follow-up duration of 10-years. Variants associated with radiographic progression under an additive model in the total RA-population (Human Leukocyte Antigens (HLA)-DRB1-shared epitope (SE), Dickkopf-1 (DKK1)-rs1896368, DKK1-rs1896367, DKK1-rs1528873, C5Orf30-rs26232, Interleukin-2 receptor-α (IL2RA)-rs2104286, Matrix metalloproteinase-9 (MMP-9)-rs11908352, rs451066 and Osteoprotegerin (OPG)-rs1485305) were studied. Cox-regression analyses were performed and Bonferroni correction applied. Soluble IL2Rα (sIL2Rα)-levels were studied. For replication, 622 RA-patients included in the French Evaluation et Suivi de POlyarthrites Indifférenciées Récentes cohort (ESPOIR)-cohort were investigated. Results were combined in inverse-variance weighted meta-analysis.ResultsSimilar as previously reported, the SE-alleles associated with less remission (hazard ratio (HR)u2009=u20090.57, 95xa0% confidence interval (95 % CI)u2009=u20090.42-0.77, pu2009=u20092.72×10−4). Variants in DKK-1, C5orf30, MMP-9 and OPG were not associated with remission. The IL2RA-rs2104286 minor allele associated with a higher chance on remission (HRu2009=u20091.52, 95 % CIu2009=u20091.16-1.99, pu2009=u20092.44×10−3). The rs2104286 minor allele associated with lower sIL2Rα-levels (pu2009=u20091.44×10−3); lower sIL2Rα-levels associated with a higher chance on remission (HR per 100xa0pg/Lu2009=u20090.81, 95 % CIu2009=u20090.68-0.95, pu2009=u20090.012). When including rs2104286 and sIL2Rα-levels in one analysis, the HR for rs2104286 was 2.27 (95 % CIu2009=u20091.06-4.84, pu2009=u20090.034) and for sIL2Rα 0.83 (95 % CIu2009=u20090.70-0.98, pu2009=u20090.026). Within ESPOIR, the HR of rs2104286 was 1.31 (95 % CIu2009=u20090.90-1.90). The meta-analysis revealed a p-value of 1.01×10−3.ConclusionIL2RA-rs2104286 and sIL2Rα-level associated with RA-persistence. IL2RA variants are known to protect against multiple sclerosis, diabetes mellitus and RA. Besides HLA-SE, IL2RA-rs2104286 is thus far the only known genetic variant associated with both joint destruction and RA-persistence. This underlines the relevance of IL2RA for RA.