Background: Rhupus syndrome is better characterized, but uncertainties remain, and therapeutic management must be defined. The objective was to analyze therapeutic procedures with a focus on biologic disease-modifying antirheumatic drugs (bDMARDs). Methods: This 10-year medical records review was based on diagnosis codes (rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]) and biological data (anti-CCP testing, anti-dsDNA, and anti-RNP antibodies). Patients fulfilling 2010 ACR/EULAR and 2012 SLICC and/or 2019 ACR/EULAR classification criteria for RA and SLE, respectively, were included. Results: Sixteen patients were identified. Rheumatoid arthritis most often preceded rhupus, with predominant articular pattern; 11 of them had erosive arthropathy. Skin involvement was the most frequent associated manifestation (n = 12). Serious events were reported, including active glomerulonephritis (n = 3), ischemic stroke (n = 1), and myocardial infarction (n = 1). Immunological profiles showed positivity for antinuclear (n = 16), anti-dsDNA (n = 9), and anti-CCP (n = 9). Ten patients required bDMARDs. All types of RA-approved bDMARDs were used. Abatacept was considered effective in 3 of the 4 patients, with 1 primary failure, 1 secondary escape, and 2 therapeutic maintenances, whereas primary or secondary failure was observed under tocilizimub and TNF-blocking agents. Rituximab was the most prescribed (n = 9) and the most effective with a sustained response in 6 patients. Conclusions: In rhupus refractory to conventional treatment, T or B lymphocytes targeted therapies, and particularly rituximab, seem to be a relevant therapeutic option unlike anticytokine biologics.

A 54-year-old woman presented to the rheumatology department with bilateral gonalgia, exacerbated by movement, which had progressively worsened during the last 6 months, without relief, in mornings. She had systemic lupus that was diagnosed in 1988 on neuropsychiatric, articular, and cutaneous symptoms. Her lupus was well controlled using both corticosteroids and hydroxychloroquine. Of Congolese descent, she had not returned to the Democratic Republic of Congo (DRC) since 1984; however, she regularly consumed food brought from the DRC by her family when they visited France. She reported having eaten snake meat 1 or 2 years ago. She worked as a hotel employee, had a long history of light cigarette smoking, had recurrent cough with expectorations, and had a body mass index of 30.1. On arrival at the rheumatology department, she did not have fever. Physical examination showed swollen knees with local skin redness. X-ray imaging revealed bilateral femoral-tibial osteoarthritis and subcutaneous calcifications on the right knee. Calcifications were palpable on clinical examination without the patient feeling any pain. Right knee aspiration revealed joint effusion, and the articular fluid exhibited cytopathological features of lymphocytic arthritis and the presence of foreign bodies (Fig. 1).

To identify the targets recognized by anti-carbamylated protein antibodies (anti-CarP) in patients with early Rheumatoid Arthritis (RA), to study the cross-reactivity between anti-CarP and anti-citrullinated protein antibodies (ACPA) and to evaluate their prognostic value. 331 patients (184 RA and 147 other rheumatisms) from the Very Early Arthritis (VErA) French cohort were analyzed. We performed mass spectrometry analysis of RA sera displaying anti-CarP activity and epitope mapping of the carbamylated fibrinogen γ chain to identify immunodominant peptides. The specificity of these targets was studied using competition assays with the major antigens recognized by ACPA. The prognostic value of anti-carbamylated fibrinogen IgG antibodies (ACa-Fib IgG) was compared to that of anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-CarP using an in-house ELISA. Besides the α chain, the γ chain of fibrinogen, particularly one immunodominant epitope that has a specific reactivity, was identified as a circulating carbamylated target in sera. The prevalence of ACa-Fib was 37% at baseline and 10.9% for anti-CCP-negative RA. In anti-CCP-negative patients, ACa-Fib positivity was associated with a more inflammatory and erosive disease at baseline but not with rapid radiological progression, which remains strongly related to anti-CCP antibodies. Fibrinogen seems to be one of the antigens recognized in vivo by the anti-CarP response, particularly 2 epitopes of the γ chain, one of which is not cross reactive with ACPA. This specificity might be associated with a distinct clinical phenotype since ACa-Fib IgG were shown to be linked to systemic inflammation in very early RA but not to rapid radiological progression.

•A Whipple's disease can mimic Still's disease.•A Whipple's disease can be unmasked by an anti-IL-1RA.•Whipple's disease can lead to pulmonary hypertension and severe heart failure.•High blood pressure and right heart failure are totally regressive under well-managed antibiotic treatment.•PCR Whipple on urine is not sensitive and should not be used (negative PCR while the patient had a disseminated disease).

et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

•La maladie de Whipple peut mimer la maladie de Still de l’adulte.•La maladie de Whipple peut être révélée par la prise d’un anti-IL-1RA.•La maladie de Whipple peut conduire à une hypertension pulmonaire et une insuffisance cardiaque sévère.•La pression artérielle élevée et l’insuffisance ventriculaire droite sont complètement résolutives sous une antibiothérapie adaptée.•La PCR T. Whipplei sur les urines n’est pas fiable et ne devrait pas être utilisée (PCR négative chez un patient qui présentait une maladie à caractère disséminé).

Objective To determine predictive/predictable factors of relapse in rheumatoid arthritis (RA) patients undergoing biologic Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) dose reduction/discontinuation. Patients and methods RA patients receiving the same bDMARD for more than 1 year, in Simplified Disease Activity Index (SDAI) remission, were selected in an observational monocentric real-life study. The 18-month follow-up included spacing (6 months) and withdrawal (12 months) periods of bDMARD. Clinical, biological and ultrasonographic (US) parameters were collected regularly. Relapse was defined by SDAI>11. Results Fifty-three RA patients (mean age: 58 years; 72% women; median duration: 11 years) were enrolled. Forty-two received anti-cytokinic bDMARD targeting tumour necrosis factor (n=39) or interleukin-6R (n=3) and 11 were treated by abatacept. The number of relapses during the spacing and discontinuation periods were 19 and 20, respectively. After 18 months of follow-up, among the 53 patients, 12 maintained bDMARD-free remission, 39 had relapsed and 2 were lost of follow-up. Median time to relapse was 11.8 months. In multivariate analysis, baseline factors predictive of relapse were corticosteroid intake, female gender, longer disease duration and no methotrexate intake with bDMARD. Concerning the survival analysis, also taking into account the factors of predictability, the main risk factor of relapse after discontinuation was an increase of SDAI>0 during the spacing period (p=0.03). US findings were not contributive. Conclusion In the context of RA in remission under bDMARDs, variation of SDAI during the dose-reduction phase is more relevant than baseline parameters to predict success of drug withdrawal.

L’accroissement du nombre de molécules disponibles pour le traitement de la polyarthrite rhumatoïde incite les rhumatologues à identifier et valider des biomarqueurs de réponse ou biomarqueurs théranostiques, capables de prédire la réponse aux traitements, préalablement à toute exposition. Cette démarche s’inscrit dans le contexte de médecine personnalisée afin de traiter efficacement un patient donné et à un instant donné. Les anticorps anti-peptides citrullinés, les facteurs rhumatoïdes et la signature interféron sont les biomarqueurs les plus robustes et validés parmi tous ceux identifiés. Les matrices utilisant des paramètres cliniques ou biologiques, diagnostiques ou pronostiques, semblent pertinentes pour définir un traitement à l’échelon individuel. Par ailleurs, le développement des approches à grande échelle sans a priori, comme la génomique fonctionnelle ou la métabolomique, représentent une voie de recherche tout à fait prometteuse, bien que la réplication des résultats reste difficile. La complexité de la réponse thérapeutique chez un même patient et la variabilité interindividuelle incitent à identifier des combinaisons de biomarqueurs plutôt qu’un seul biomarqueur. L’objectif de cette revue est de faire le point sur les différentes approches utilisées pour identifier des biomarqueurs théranostiques et de recenser l’ensemble des biomarqueurs disponibles en discutant de leur performance en pratique clinique. Cependant, le nombre de biomarqueurs actuellement utilisables en pratique quotidienne reste très limité.

Background Despite a wide range of biological treatments (bDMARDs) in the management of rheumatoid arthritis (RA), some patients fail in different lines of treatment. Currently, there is no consensual definition of multiresistance to bDMARDs in RA. Objectives The aim of our study was to describe the characteristics of « multiresistant » patients and to establish associated factors with multiresistance to bDMARDs in RA. Methods In this observational and retrospective study were identified patients with RA admitted for administration of a bDMARD at Rouen University Hospital (France) between January 2007 and July 2017 (sources : diagnostic coding using International Classification of Diseases 10th revision and traceability of intra-hospital pharmacy). In the absence of a consensual definition, multiresistance to bDMARD was defined in this study by failure, primary and/or secondary, to at least 2 bDMARDs. The clinical and paraclinical characteristics of these patients at the initiation of the first bDMARD were collected using data from their standardized monitoring, then compared to those of patients who received a single bDMARD effective for 10 years or more, constituting the “responder” group. Results We identified 794 patients: 385 constituted our active RA file under bDMARD, 192 patients excluded for different reasons (6 patients not fulfilling the ACR/EULAR 2010 criteria, 18 followed in another department, 45 for missing data at bDMARD’s initiation, 50 not found in computerized file, 73 for whom the expected bDMARD was never started) and 217 lost to follow-up. Among our active RA file under bDMARD (385 patients), 53 were « multiresistant » (at least 2 bDMARDs failed), and 50 patients received a single and effective bDMARD for 10 years or more, after excluding some patients for missing data (Figure 1). The mean age of « multiresistant » patients at initiation of bDMARD was 50.3 years (±13.2 years), and the sex ratio was 2.8 women/1 man. They presented erosive RA (77.4%), rheumatoid factor and anti-citrullinated peptide antibodies positive (73.6%), highly active (median number of tender and swollen joints 8/28, median visual analog scale disease activity 70/100, median C-reactive protein (CRP) 21 mg/L, mean Disease Activity Score 28 CRP mean 5.36±1.28), and with high functional impact (Health Questionnaire Median Assessment: 1,500/3). The age of disease onset was significantly later in « multiresistant » patients than in « responder » patients (43±14.2 years versus 37.9±10.7 years, p = 0.042). No demographic, anamnestic, clinical and paraclinical characteristics differed significantly between « multiresistant » and « responder » patients. Conclusion It is an original work, counting in the literature as a single similar study [1], with nevertheless significant methodological differences. There is no consensual definition of multiresistance to bDMARD in RA, and its mechanisms remain misunderstood. Identifying predictive factors would make it possible to early identified patients with a refractory profile, in order to adapt the therapeutic strategy. Multidrug resistance in RA remains one of the challenges in the management of this pathology. Reference [1] Kearsley-Fleet L, Davies R, De Cock D, Watson KD, Lunt M, Buch MH, et al. Biologic refractory disease in rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum DisEpub ahead of print : 8 July 2018 Disclosure of Interests None declared

The expanding array of drugs available for treating rheumatoid arthritis is creating challenges in drug selection for the individual patient. The identification of biomarkers that predict the treatment response prior to drug exposure is therefore a current priority. This new approach, known as theranostics, is a component of personalized medicine, which involves selecting the management strategies that are most effective for a given patient at a given point in time. Antibodies to citrullinated peptides, rheumatoid factor, and the interferon signature are the most robust and best validated biomarkers identified to date. Matrices containing clinical or laboratory parameters of diagnostic or prognostic relevance may help to select the best treatment for the individual patient. Furthermore, the development of large-scale approaches requiring no a priori knowledge, such as functional genomics and metabolomics, hold considerable promise, despite persistent difficulties in replicating findings. The complexity of the treatment response in a given patient and substantial variability across patients suggest that biomarkers may be more helpful in combination than singly. The objectives of this review article are to discuss the approaches used to identify theranostic biomarkers and to present an overview of currently available biomarkers and of their performance in everyday clinical practice. However, the range of biomarkers suitable for use in daily practice remains extremely narrow.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 31 juillet 2018

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 31 juillet 2018

Background Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatism. RA is multifactorial involving genetic, environmental, endocrine, psychological and immunological factors. In 2002, our research team has discovered alpha-enolase (ENO1) as an autoantigen in RA and has recently demonstrated its effect on monocytes, inducing inflammation mediated through CD14-dependent TLR4 signalling pathway. Monocytes can differentiate into dendritic cells, osteoclasts or macrophages. Macrophages are involved in RA pathophysiology and can be polarised in different phenotypic profiles, pro-inflammatory (M1 macrophages) or immuno-regulatory (M2 macrophages). The main objective of this study was to determine the effect of ENO1 on monocytes differentiation into macrophages and on their polarisation. Materials and methods Monocytes of healthy donors were cultured with M-CSF (Macrophage-Colony Stimulating) or GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor) for 5 days for their differentiation into macrophages and for 3 supplemental days with IFN-γ and/or LPS or IL-4 and/or IL-10 for M1 or M2 polarisation respectively. Monocytes and monocytes-derived macrophages were also cultured with recombinant ENO1 (produced in E. coli), or control BSA, to investigate its effect on monocytes differentiation and macrophages polarisation. Microscopy, flow cytometry and ELISA were performed to determine the macrophages polarisation profile (M1 or M2) induced by ENO1. Results Firstly, we showed that ENO1 did not induce monocytes differentiation into macrophages in contrast to M-CSF and GM-CSF. However, in macrophages differentiated with M-CSF or GM-CSF, ENO1 induces M1 polarisation in terms of morphology, surface markers and cytokines production. ENO1 can also initiate repolarization in M1 of macrophages previously polarised in M2. Finally, we showed that ENO1 induced a cytokine inflammatory response higher in macrophages differentiated with GM-CSF compared to M-CSF. Conclusions These results showed for the first time the potential role of native ENO1 in the inflammatory process of RA through its interaction with macrophages, promoting their polarisation into pro-inflammatory M1 profile. Our project, aimed to understand the role ENO1 in RA pathophysiology, opens interesting research perspectives on cell types derived from monocytes.