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Background: To compare the 10-year structural and functional prognosis between patients in sustained remission versus patients in sustained low disease activity (LDA) in early rheumatoid arthritis (RA). Methods: We included 256 patients from the ESPOIR cohort who fulfilled the 2010 ACR/EULAR criteria for RA and who were in sustained remission using the Simple Disease Activity Index (SDAI) score (n= 48), in sustained LDA (n= 139) or in sustained moderate to high disease activity (MDA or HDA, n= 69) over 10 years. The mTSSs progression over 10 years and the 10-year HAQ-DI scores were compared between the 3 groups. A longitudinal latent process mixed model was used to assess the independent effect of SDAI status over time on 10-year mTSS progression and HAQ-DI at 10 years. Results: Patients in sustained remission group were younger, had lower baseline HAQ-DI and mTSS scores and were less exposed to glucocorticoids, methotrexate or biologic disease-modifying anti-rheumatic drugs over 10 years. Patients in sustained remission had lower 10-year structural progression (variation of mTSS in the remission group: 4.06 (± 4.75) versus 14.59 (± 19.76) in the LDA group and 21.04 (± 24.08), p< 0.001 in the MDA or HDA groups) and lower 10-year HAQ-DI scores (10-year HAQ-DI in the remission group: 0.14 (± 0.33) versus 0.53 (± 0.49) in the LDA group and 1.20 (± 0.62) in the MDA or HDA groups, p< 0.001). The incidence of serious adverse events over 10 years was low, about 3.34/100 patient years, without any difference between the three groups. Conclusion: RA patients in sustained SDAI remission have better long-term structural and functional outcomes in comparison to patients in sustained LDA.

Evaluating lymphocytic infiltration of minor salivary gland biopsy in primary Sjögren’s syndrome is challenging. We developed and evaluated a digital method for quantifying B and T lymphocytes in whole minor salivary gland biopsy slides. Minor salivary gland biopsies were immunostained with anti-CD20/anti-CD3 antibodies using red/brown chromogens. Slides were digitised and spliced into mosaics of smaller JPEG format images in which red and brown pixels were counted. ImageJ Cell counter was used for validation. Agreement between the digital and manual methods was evaluated using Bland-Altman plots and the interclass correlation coefficient. External validation relied on the Chisholm-Mason, Tarpley, and focus-score methods. Of 62 minor salivary gland biopsy slides, 61.3 % had a Chisholm-Mason grade ≥ III or a focus score ≥1. The number of pixels correlated well with manual cell counts (r = 0.95 for red pixels vs. B cell count and r = 0.91 for brown pixels vs. T cell count). Interclass correlation coefficients between digital and manual counts were excellent (0.92 for B/T cells). B-cell proportion showed a significant positive correlation with the focus score (Spearman’s coefficient 0.463, p< 0.0001). Median B-cell proportion was lower in minor salivary gland biopsies with Chisholm grades I–II (2.5 % (0.2–13.9)) than III–IV (30.0 % (15.5–45.2)) and increased with Tarpley’s class (1, 2.2 % (0.2–6.6); 2, 27.2 % (13.0–38.9); and 3–4, 48.5 % (29.4–56.4); p< 0.001 for all comparisons). Minor salivary gland biopsy B-cell proportion was also significantly correlated with several markers of clinical and biological activity of the disease, especially with markers of systemic B-cell hyperactivation. The digital procedure proved accurate compared to the reference standard, producing reliable results for whole tissue sections. ClinicalTrials.gov [NCT00740948]. Registered 22 August 2008.

Background: To validate the ability of PROS (vitamin K-dependent protein S) and CO7 (complement component C7) to predict response to the methotrexate (MTX)/etanercept (ETA) combination in rheumatoid arthritis (RA) patients who received this therapeutic combination in a well-documented cohort. Method: From the ESPOIR cohort, RA patients having received the MTX/ETA or MTX/adalimumab (ADA) combination as a first-line biologic treatment were included. Serum concentrations of PROS and CO7 were measured by ELISA prior to the initiation of ETA or ADA, at a time where the disease was active (DAS28 ESR > 3.2). The clinical efficacy (response/non-response) of both combinations has been evaluated after at least 6 months of treatment, according to the EULAR response criteria with some modifications. Results: Thirty-two were treated by MTX/ETA; the numbers of responders and non-responders were 24 and 8, respectively. Thirty-three patients received the MTX/ADA combination; 27 and 5 patients were respectively responders and non-responders. While there were no differences for demographic, clinical, biological, and X-rays data, as well as for CO7, serum levels of PROS tended to be significantly higher in responders to the MTX/ETA combination (p= 0.08) while no difference was observed in the group receiving MTX/ADA. For PROS, the best concentration threshold to differentiate both groups was calculated at 40 μg/ml using ROC curve. The theranostic performances of PROS appeared better for the ETA/MTX combination. When considering the response to this combination, analysis of pooled data from ESPOIR and SATRAPE (initially used to validate PROS and CO7 as potential theranostic biomarkers) cohorts led to a higher theranostic value of PROS that became significant (p= 0.009). Conclusion: PROS might be one candidate of a combination of biomarkers capable of predicting the response to MTX/ETA combination in RA patients refractory to MTX. Trial registration: ClinicalTrials.gov identifiers: NCT03666091and NCT00234234.

B and T cells play a key role in rheumatoid arthritis (RA) pathophysiology. RasGRP1 and RasGRP3 are involved in T and B cell receptors signaling, and belong to gene combination able to predict infliximab responsiveness, leading to the question of RasGRP1 and RasGRP3 involvement in RA. RasGRP1 and RasGRP3 expression levels were measured by qRT-PCR and/or western-blot in peripheral blood mononuclear cells (PBMCs), in T and B cells from untreated RA patients and in RA patients treated by TNFa inhibitors. T and B cells from healthy controls (HC) were cultured with TNFa, and TNFa receptors neutralizing antibodies to highlight the TNFa effects on RasGRP1 and RasGRP3 pathways. MAPK pathways and apoptosis were respectively analyzed using the Proteome Profiler arrays and flow cytometry. In PBMCs from RA patients, gene expression levels of RasGRP1were invariant while RasGRP3was downregulated under TNFa inhibitors and upregulated under TNFa. In T cells from RA patients, RasGRP1 was decreased and its gene expression level was correlated with disease activity. In T cells from HC, TNFa stimulation increased RasGRP1gene expression level while it reduced RasGRP1 protein expression level. Bryostatin-1 experiments have confirmed that the TNFa effect observed on T cells proliferation was due to the decrease of RasGRP1 expression. Besides, RasGRP3expression level increased in PBMCs from RA patients under TNFa and in B cells from HC leading us to conclude that RasGRP3 in B cells was modulated by TNFa. This study demonstrates RasGRP1 dysregulation in RA patients while RasGRP3 is characterized as a biomarker linked to TNFa inhibitors. After binding to TNFR1, TNFa reduced RasGRP1 protein expression resulting in inhibition of T cell activation. Clinicaltrials.gov NCT00234234, registered 04 November 2008; NCT00767325, registered 05 October 2005.

We previously reported that low ratio of osteoprotegerin (OPG) to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was associated with Disease Activity Score in 28 joints (DAS28) remission at 6 months in patients with early rheumatoid arthritis (RA). Here, we aimed to evaluate the value of baseline OPG/TRAIL ratio in predicting clinical and radiological outcomes in patients with early RA in the ESPOIR cohort. OPG and TRAIL serum concentrations were assessed in the ESPOIR cohort patients. Patients with definite RA were included in this study. Patients were excluded if they had high erosion score at baseline (>90thpercentile) or received biological therapy during the first 2 years of follow-up. Data were analyzed by univariate analysis and multivariate logistic regression to predict 1-year DAS28 remission and 2-year radiographic disease progression. On univariate analysis of 399 patients, OPG/TRAIL ratio at baseline was significantly lower in patients with than without remission at 1 year (p= 0.015). On multivariate logistic regression including age, gender, body mass index and DAS28, low OPG/TRAIL ratio was independently associated with remission at 1 year (odds ratio 1.68 [95 % confidence interval 1.01–2.79]). On univariate analysis, high OPG/TRAIL ratio at baseline was associated with rapid progression of erosion at 2 years (p= 0.041), and on multivariate logistic regression including age, anti-citrullinated protein antibody positivity and C-reactive protein level, OPG/TRAIL ratio independently predicted rapid progression of erosion at 2 years. OPG/TRAIL ratio at baseline was an independent predictor of 1-year remission and 2-year rapid progression of erosion for patients with early rheumatoid arthritis. Thus, OPG/TRAIL ratio could be included in matrix prediction scores to predict rapid radiographic progression. Further confirmation in an independent cohort is warranted.

OBJECTIVE: To suggest recommendations for management of acute infusion reactions induced by infliximab in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). METHODS: In total, 203 patients were treated with infliximab (120 ml/h). Prevalence of acute infusion reaction was evaluated. To manage these conditions, recommendations were devised according to the type and the severity of clinical manifestations, which were classified beforehand in 2 groups: A (hypertension, pruritus, sudden flush, vomiting, tachycardia or bradycardia, shivers, fever) and B (urticaria, tickling throat, Quincke's edema, dyspnea, and hypotension). Recommendations were based mainly on adjustment of the infusion rate. RESULTS: It was observed that 23/203 patients (11.3%) had acute infusion reactions. Among them and prior to our recommendations, infliximab was completely discontinued in 8/23 patients. After our recommendations were implemented, 15/23 patients presented an acute infusion reaction: 8 and 7 patients with symptoms of Group A and B, respectively. In Group A (8 patients), reducing the infusion rate to 60-80 ml/h led to disappearance of symptoms; the modified treatment was then maintained. In Group B (7 patients), the infusion was immediately stopped and appropriate drugs were administered. Once clinical manifestations were alleviated, the infusion was resumed (60 ml/h). Prior to subsequent infusions (60 ml/h), a premedication was administered. CONCLUSION: Based on these recommendations, infliximab could be maintained with great efficacy on disease activity in every patient with an acute infusion reaction. Our recommendations permit sustained administration of infliximab and allow every patient to benefit from this therapy.

Au cours d’une même maladie auto-immune, la réponse B auto-immunitaire est diverse. Cette diversité n’est probablement pas présente à l’origine du processus auto-immun, mais semble plutôt survenir durant l’évolution de la maladie. Elle est une conséquence d’un processus d’extension épitopique au cours duquel l’immunité se développe séquentiellement d’un determinant antigénique B à un autre. En outre, les anticorps spécifiques d’un antigène donné peuvent réagir avec des structures moléculaires apparemment dissemblables, portant (réactivité croisée) ou ne portant pas (polyspécificité) un motif antigénique commun. Ces phénomènes participent à la constitution du répertoire des auto-anticorps au cours des maladies auto-immunes. Ils jouent un rôle important dans l’initiation et le maintien des réponses auto-immunes, ainsi que dans la pathogénie des maladies. Ils contribuent aussi à établir un profil de réponse auto-anticorps caractéristique d’une même maladie auto-immune ou d’un sous-groupe de maladie. Différentes strategies méthodologiques ont été récemment mises en oeuvre pour explorer le répertoire des auto-anticorps et proposer des approches diagnostiques fondées sur l’analyse non plus d’un seul couple auto-antigène/auto-anticorps, mais sur des profiles de modification du repertoire.

To identify a new autoantigen/autoantibody population in rheumatoid arthritis (RA) sera. Following a population-based recruitment effort, 255 patients with very early arthritis (median disease duration 4 months) were studied using different clinical, biologic, and radiologic assessments. After a followup period of 1 year, patients were classified as having RA (n = 145), non-RA rheumatic diseases (n = 70), and undifferentiated arthritis (n = 40). Patients' sera were analyzed by one-dimensional (1D) and 2D Western blotting. The recognized 50-kd protein was analyzed by matrix-assisted laser desorption ionization–time-of-flight (MALDI-TOF) mass spectrometry (MS). RA serum reactivities were evaluated against the recombinant protein synthesized by an in vitro coupled transcription–translation system. On 1D Western blots, 36 of the 145 RA sera bound to a 50-kd polypeptide. On 2D Western blots, anti–50-kd+ RA sera recognized a triplet of isoelectric point 6.5–7.0 and a molecular mass of 50 kd. The 3 spots of the triplet were analyzed by MALDI-TOF MS and were shown to correspond to human α-enolase. A goat anti-enolase antiserum, which recognized a band comigrating with the 50-kd antigen on 1D Western blots, gave a labeling pattern on 2D Western blots similar to that observed with anti–50-kd+ RA sera. Among the 36 RA sera that identified α-enolase in protein maps, only 8 recognized the recombinant (unmodified) α-enolase. The specificity of anti–α -enolase antibodies for RA was 97.1%. Half of the anti–α -enolase–positive RA patients were negative for both rheumatoid factor and antifilaggrin antibodies. The presence of anti–α-enolase antibodies was the greatest predictive factor of radiologic progression in the first 66 RA patients included. Autoantibodies to α-enolase, an enzyme of the glycolytic pathway, are present in the sera of patients with very early RA and have potential diagnostic and prognostic value for RA.

Propionibacterium acnes is an anaerobic bacillus implicated in certain chronic arthritides. This report describes an HLA–B27+ 17-year-old woman with acne vulgaris who presented with rapidly destructive arthritis in the left shoulder as well as an evolving left subclavicular adenopathy. One year later, arthritis was detected in the left knee; the inflammatory synovial fluid was sterile. Growth of P acnes was observed in cultures of the shoulder synovium and lymph nodes, but polymerase chain reaction was negative for Borrelia, Chlamydia, and Ureaplasma DNA. Three months of treatment with amoxicillin and rifampicin led to clinical disappearance of the oligoarthritis, but arthritis recurred in the left knee after discontinuation of therapy. On biopsy, bacteria were undetectable in the knee synovium, but chronic arthritis was evident histologically. Antibiotics were reintroduced for 12 months and were again effective against the clinical symptoms. Although the asymmetry, histologic features, arthritis–acne association, and genetic predisposition of this chronic destructive oligoarthritis would seem to indicate a reactive arthropathy, the isolation of P acnes from 2 distinct specimens prompted us to propose calling this a case of septic-reactive arthritis, which is further supported by the absence of progression after antibiotic therapy and the persistence of the rheumatism. To our knowledge, this is the first demonstration of the efficacy of prolonged antibiotic therapy on the joint manifestations of chronic rheumatism associated with acne.

Propionibacterium acnesis an anaerobic bacillus implicated in certain chronic arthritides. This report describes an HLA–B27+ 17‐year‐old woman with acne vulgaris who presented with rapidly destructive arthritis in the left shoulder as well as an evolving left subclavicular adenopathy. One year later, arthritis was detected in the left knee; the inflammatory synovial fluid was sterile. Growth of P acneswas observed in cultures of the shoulder synovium and lymph nodes, but polymerase chain reaction was negative for Borrelia, Chlamydia,and UreaplasmaDNA. Three months of treatment with amoxicillin and rifampicin led to clinical disappearance of the oligoarthritis, but arthritis recurred in the left knee after discontinuation of therapy. On biopsy, bacteria were undetectable in the knee synovium, but chronic arthritis was evident histologically. Antibiotics were reintroduced for 12 months and were again effective against the clinical symptoms. Although the asymmetry, histologic features, arthritis–acne association, and genetic predisposition of this chronic destructive oligoarthritis would seem to indicate a reactive arthropathy, the isolation of P acnesfrom 2 distinct specimens prompted us to propose calling this a case of septic‐reactive arthritis, which is further supported by the absence of progression after antibiotic therapy and the persistence of the rheumatism. To our knowledge, this is the first demonstration of the efficacy of prolonged antibiotic therapy on the joint manifestations of chronic rheumatism associated with acne.

To retrospectively assess, with a sufficiently long followup (mean 11.6 years; median 9 years), the long-term outcome of chronic recurrent multifocal osteitis (CRMO), a multifocal, inflammatory bone disease. Patients included were 8 children/adolescents and 7 adults with no family history of rheumatic disease who had been diagnosed as having CRMO between 1979 and 1995. Ten patients had undergone at least 1 bone biopsy of the lesions, with histologic examination and multiple cultures. In 1996, in addition to an in-depth interview, 12 patients underwent an extensive physical examination, laboratory evaluation, HLA–A, B, C, and DR typing, bone radiography and scintigraphy, and computed tomography scan of the sternoclavicular and sacroiliac joints. Remission was observed in 3 patients. The other 12 patients developed various associations of vertebral (n = 10), sacroiliac (n = 6), anterior thoracic (n = 7), peripheral articular (n = 2), enthesopathic (n = 4), or dermatologic (palmoplantar pustulosis in 3 cases and psoriasis in 2) involvements. Spine involvement was the most common and occurred the earliest (median time to appearance after the onset of osteitis 5.63 years). Clinical sacroiliitis was always unilateral. No patients carried the HLA–B27 haplotype. CRMO responded well to nonsteroidal antiinflammatory drugs. Twelve patients met the European Spondylarthropathy Study Group criteria for spondylarthopathy. After 10 years, CRMO had usually evolved to spondylarthropathy, but with certain features not usually seen in the latter: predominantly, unilateral sacroiliitis, no familial form, and no link with HLA–B27.

Report of a rare case of spinal actinomycosis in a young immunocompetent woman.

Toxoplasmosis is a parasitic infection that may affect several viscera. The locomotor system is rarely involved, and no case has been published of a septic arthritis in which Toxoplasma gondiiwas identified in the cultures of the joint fluid and of the synovial specimen.

ObjectiveTo compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis.DesignPopulation based prospective study.Setting53 university and 54 non-university clinical centres in France.Participants3162 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.InterventionInitiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis.Main outcome measureThe 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 (LEDwf), which measures the difference between average duration of survival without failure.ResultsAverage 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 (LEDwf4.1, 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.ConclusionAmong 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.

The aims of this present study were firstly to assess the outcome, including functional course, in anti-Jo1 positive patients with antisynthetase syndrome (ASS), and secondly to determine predictive parameters of poor outcome in these patients.

Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia.

The aim of our study was to identify new early rheumatoid arthritis (RA) autoantibodies.