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Background:Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis (RA) patients with suboptimal response or intolerance to conventional synthetic DMARDs (CsDMARDs). Currently, 9 biologic agents are approved in the RA treatment: and among them, three anti TNF agents are also approved in monotherapy (adalimumab, certolizumab and etanercept), but also abatacept, anakinra and tocilizumab. Registries of routine clinical practice treatment indicate that approximately one third of RA patients are being treated with a bDMARD in monotherapy and analyses from health care claims suggest that when methotrexate (MTX) is prescribed in combination with a bDMARD, more than half of the patients do not collect the MTX prescription and overall patients seem to taper MTX intake over time. So it is important to evaluate the benefit and harm associated with use of biological agents as monotherapy, and not only the traditional combination therapy strategies.Objectives:To compare the efficacy and safety of the individual biological agents used in monotherapy in patients with RA than the combination therapy strategy with CsDMARD + bDMARD.Methods:We used The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and MEDLINE in order to carry out our research, for published reports from inception of each database through December 2019. Search results were limited to randomised controlled trials (RCTs), with our two arms: biological agent in monotherapy and combination strategie (with any CsDMARDs). Major outcome was the ACR 20 reponse criteria at 24 week. The secondary outcomes were: the ACR 20 at 52 week, ACR 50, 70, 90 reponse criteria, the DAS 28 remission (with CRP and/or ESR), the score sharps modified non progressor, the proportion of patients who withdrawals the study due to adverse events, the proportion of patients who withdrawals the study due to lack of efficacy, the HAQ improvement > 0,22, CDAI and SDAI remission at week 24 and 52 if the data were available. The study of tolerance was also made. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in R (version 3.6.1) using fixed and random-effects.Results:The systematic review identified 2566 citations. The analysis comprises 22 trials (6358 patients), including six biological agents approved for RA (abatacept, adalimumab, etanercept, golimumab, rituximab and tocilizumab) as well as two other molecules: Clazakizumab, a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine and Anbainuo, recombinant human TNFRII:Fc fusion protein. No study satisfyies our search criteria for anakinra, certolizumab and infliximab. Compared to combination therapy with CsDMARD+bDMARD, bDMARD monotherapy has less probability to give a ACR20 response at 24 weeks (RR: 0,92 [0,89 – 0,96]) in fixed or random effect model and this result is similar at 52 weeks (RR: 0,94 [0,89 – 0,99]). For all other outcome mesures, we can see an increased of ACR50–70 and 90 responses, an improve of the DAS 28 remission score, an increase of the proportion of sharp’s score non progressors (Conclusion:Evidence from this meta-analysis suggests that combinaison strategy with bDMARD+CsDMARD remains the most efficacious option, being more effective than the use of biologics in monotherapy. The interest from this point of view is to sensitize prescribers to the use of other CsDMARDs when there is a contraindication or intolerance to MTX, but also to make patients aware of the superiority of the association of biological agents with CsDMARDs.figureDisclosure of Interests:Célia DELPECH: None declared, François-Xavier LABORNE: None declared, Pascal Hilliquin Consultant of: BMS, MSD, Novartis, Roche-Shugai.

La artritis reumatoide (AR) es la mas frecuente de las enfermedades reumaticas inflamatorias cronicas. La instauracion de un tratamiento de fondo o de accion lenta resulta esencial en el marco terapeutico de la AR. Los tratamientos de fondo actuan de forma diferida sobre los sintomas de la AR y se deben instaurar lo antes posible para evitar la progresion de la enfermedad. Los tratamientos de fondo convencionales han demostrado su eficacia en lo que respecta a los parametros clinicos y biologicos de actividad de la AR, pero su eficacia sobre la progresion de las lesiones articulares se revela inconstante. Entre ellos, el metotrexato (MTX) es el tratamiento de referencia, el que presenta la mejor relacion entre beneficios y riesgos y la mejor tasa de mantenimiento terapeutico. Los demas tratamientos de fondo mas utilizados son la salazopirina, la hidroxicloroquina y la leflunomida. La aparicion de los inhibidores del TNF α, que se han desarrollado en funcion de los conocimientos fisiopatologicos adquiridos en la AR, ha constituido un progreso terapeutico real. En la actualidad se pueden emplear tres farmacos: dos anticuerpos monoclonales (infliximab, adalimumab) y un receptor soluble del TNF (etanercept). Los inhibidores del TNF estan indicados despues del fracaso de los tratamientos de fondo convencionales, como el metotrexato. Aparte de su efecto sintomatico, pueden frenar, e incluso detener, la progresion de las lesiones osteoarticulares. Los antiinflamatorios no esteroideos constituyen el tratamiento de referencia de las enfermedades del grupo de las espondiloartropatias. Entre los tratamientos de fondo convencionales, solo la salazopirina tiene una eficacia probada en dicho grupo de trastornos. Tambien se ha propuesto el uso del infliximab y el etanercept tras el fracaso de los tratamientos de fondo convencionales en las formas refractarias de la espondilitis anquilosante.

Introduction Un rhumatisme psoriasique (PsA) peut s’associer a 30 % des cas de psoriasis (Pso) et doit etre depiste precocement pour reduire les destructions articulaires associees. Or, 15 % des patients avec un Pso auraient un PsA non diagnostique par les dermatologues. Les questionnaires de depistage du PsA deja valides (ToPAS, PEST, PASE, EARP) sont limites par leur relative complexite et longueur, une faible reproductibilite. L’objectif de cette etude etait de developper et realiser la validation interne d’un nouvel outil de depistage rapide du PsA destine aux dermatologues afin d’orienter vers le rhumatologue les patients pris en charge pour Pso : le questionnaire Psoriatic arthritis Uncluttered screening Evaluation (PURE). Materiel et methodes Un groupe d’experts dermatologues et rhumatologues a identifie par une revue de la litterature 23 items candidats pour la creation de ce questionnaire, soit : caracteristiques du Pso, symptomes douloureux (arthralgies peripheriques, axiales, fesses, paroi thoracique, doigts, orteils), signes inflammatoires evocateurs du PsA (raideurs matinales, gonflements et inflammation articulaires). Une etude de validation a ete realisee aupres de tous les patients vus consecutivement par un dermatologue pour un Pso entre 9/12 et 6/2014 a l’hopital St-Joseph, Paris. Les patients devaient completer le questionnaire avec l’aide du dermatologue avant d’etre adresses systematiquement a un rhumatologue qui etablissait ou non le diagnostic de PsA (criteres CASPAR). La sensibilite (Se), specificite (Sp), valeurs predictives neg et pos et l’aire sous la courbe ROC (AUC) etaient calculees pour chaque item et pour le score synthetique obtenu par regression logistique multivariee, avec validation interne par methodes de bootstrap. Resultats Au total, 137 patients inclus (âge median 43 ans, 59,6 % d’hommes, duree mediane du Pso de 12 ans), dont 21 cas (15,3 %) avec un diagnostic de PsA retenu par le rhumatologue. Sur les 23 variables candidates, 15 significativement associees au PsA en analyse univariee. En analyse multivariee, 4 items independants etaient retenus, incluant signes de dactylite, talagies, fessalgies bilaterales et douleurs articulaires peripheriques avec gonflement chez les moins de 50 ans, la dactylite etant l’item le plus specifique (VPP = Sp = 100 %). Les proprietes du score total sur 4 points (1 point/item positif) etaient excellentes (Se 85,7 % ; Sp 83,6 % ; AUC (valeur corrigee par validation interne) : 87,5 %). Discussion Malgre le faible effectif et en attente de validation externe, les performances diagnostiques du PURE-4 sont prometteuses, avec 4 items faciles a questionner pour un dermatologue, ne necessitant aucune formation specifique, et administrable dans la salle d’attente. Conclusion Le questionnaire PURE 4 pourrait etre utile en pratique dermatologique courante pour identifier les patients avec un Pso necessitant une consultation par un rhumatologue pour depister de facon optimale un PsA.

Objective. To investigate nitric oxide (NO) production and inducible NO synthase expression by cultured peripheral blood mononuclear cells (PBMC) in patients with systemic sclerosis (SSc). Methods. Eighteen patients with SSc were compared with two control groups: 16 patients with rheumatoid arthritis (RA) and 23 patients with mechanical sciatica. Nitrate was determined by fluorimetry in plasma and by spectrophotometry in supernatants. Inducible NO synthase (iNOS) was detected in cultured PBMC by immunofluorescence, immunoblotting and flow cytometry with or without treatment of the cells with interleukin (IL) 1b+ tumour necrosis factor a (TNF-a), IL-4 or interferon c (IFN-c) from day 1 to day 5. Results. NO metabolite concentrations were lower in SSc patients (mean " S.E.M. 34.3 " 2.63 mmolul) than in RA (48.3 " 2.82 mmolul; P< 0.02) and sciatica (43.3 " 5.24 mmolul; P< 0.03) patients. iNOS was detected in cultured monocytes in all three groups but induction occurred on day 1 in RA, day 2 in sciatica and only on day 3 in SSc, whatever the stimulus. Conclusions. The concentrations of NO metabolites are decreased in SSc patients and the metabolism of these compounds in PBMC is altered. Low levels of NO, a vasodilator, may be involved in vasospasm, which is critical in SSc. This may have therapeutic implications.

PAF-acether (PAF) is a pro-inflammatory phospholipid molecule potentially involved in the pathogenesis of arthritis. PAF and related metabolites have been isolated in the synovial fluid from patients with arthritis. The aim of this study was to determine fluid and blood in patients with rheumatoid arthritis. Blood neutrophils from normal donors were also studied for their capacity to form PAF. Neutrophils were stimulated with the calcium ionophore A23187 (2 microM) for 1 to 60 min. PAF released in the medium and PAF associated to cells were measured. In synovial fluid neutrophils. PAF production began as soon as 1 min of stimulation (16.1 +/- 6.3 pmol per 1 x 10(6) cells) and reached a maximum at 20 min: 29.2 +/- 2.8 pmol per 1 x 10(6) cells (mean +/- SEM, n = 5). The amount of PAF released in the supernatant increased with the length of stimulation, similar amounts of PAF were produced by blood neutrophils isolated from the joint had a lower capacity to produce PAF than blood neutrophils from the same patients. The present results demonstrate the synthesis and release of PAF by synovial fluid neutrophils. They suggest that neutrophils may be source of PAF locally present in the joint. Newly synthesized PAF could participate in the amplification of the local inflammatory reaction.

Background Adherence to treatment is the observance, by patients, of their doctors9 recommendations concerning their therapeutic management. There is no gold standard for the measurement of adherence to treatment, but validated self-administered questionnaires can be used to measure adherence indirectly. Few studies have evaluated the prevalence of adherence to all treatment (corticosteroid treatment, DMARDs and biological treatments) in patients with chronic inflammatory rheumatism. Objectives The aims of our study were to evaluate the prevalence of non-adherence to treatments in patients followed for rheumatoid arthritis (RA), spondylitis (SA) and psoriatic rheumatism (PsA), to identify the socioprofessional and demographic factors associated with non-adherence and to evaluate possible correlations between non-compliance and negative views concerning drugs doctors or medicine, or negative perceptions of the disease and of health in general. Methods We carried out a prospective study, between January and June 2014, of all patients followed at the hospital for chronic inflammatory rheumatism and treated with corticosteroids, DMARs and/or biotherapy. The patients completed a validated French-language questionnaire concerning their adherence to treatment and including the Morisky-Green adhesion scale (MMAS-4), with its visual analog scale (VAS), opinions about drugs (18-item BMQ), both specifically and in general, for each immunosuppressant used, together with questionnaires concerning the patients9 perception of their disease (BIPQ) and of their health in general (PHQ-2). Global non-adherence to treatment was defined as a negative response to one of the four questions of the MMAS-4 and/or a score on the Morisky VAS below 80%. Patients with a Morismy VAS score of 100% were also analyzed in uni- and multivariate analyses. Socioprofessional and demographic data were collected. Results In total, 109 complete questionnaires were obtained. The mean age of the respondents was 54 years; 58 patients were treated for RA, 41 for SA and eight for PsA; Overall, 39% of the patients were treated by monotherapy, 42% by bitherapy and 19% by tritherapy; 40% received corticosteroids, and 51% had at least one DMARD, 89% of these patients being treated with methotrexate. Biotherapies were prescribed for 89% of the patients, by subcutaneous injection in 25%, and by intravenous injection in 75%. The mean duration of treatment was 10 years. We found that 27 patients (24.7%) were globally non-adherent to corticosteroid, DMARD and biotherapy treatments.17 patients with RA and nine with SA. In univariate and multivariate analyses of patients with a VAS score of at least 80, no factors significantly associated with a lack of adherence were identified. By contrast, considering only patients with VAS scores of 100%, in univariate analysis, the duration of treatment (OR=0.95 [0.91-1], p=0.04), and treatment with DMARDs were found to be associated with poor adherence (OR=0.38 [0.15-0.9], p=0.03). In multivariate analysis, only DMARD treatment was associated with poor adherence (OR=0.25 [0.07-0.74], p=0.017). No significant differences were observed for adherence with biotherapy alone or for global adherence to treatment. Conclusions In this study, less than one third of the patients followed in a hospital environment were non-adherent, and poor adherence seemed to be linked to the duration of treatment and the use of DMARDs. Disclosure of Interest None declared

Objective. To determine the cumulative incidence and the point prevalence of atopy in patients with rheumatoid arthritis (RA). Patients and methods. A standardized questionnaire was sent to 300 RA patients. Questions concerned previous or present characteristics of atopy (hay fever, asthma and constitutive eczema) and RA. RA patients were matched with genetically unrelated controls (sister- or brother-in-law, neighbour or friend ). The same questionnaire (except for questions about RA) was sent to the control subjects. In cases of atopy, patients, controls and the treating physicians were contacted by a physician to check the validity of the responses. Results. Paired responses were obtained in 173 cases. Information about atopy was obtained for 69 other RA patients. The characteristics of RA were similar for patients who responded and those who did not respond. The frequency of atopy was significantly lower in RA patients than in controls, both for cumulative incidence (RA 7.5%, controls 18.8%; P < 0.01) and point prevalence (RA 3.5%, controls 16.2%; P < 0.0001). The clinical manifestations of atopy stopped before the onset of RA in eight of the 17 RA patients with an allergic condition, and there was no subsequent relapse. No effect of RA treatment could account for the remission of atopy. Conclusion. These data support the concept that atopy protects against the future development of RA and that the two diseases could counterbalance one another. K : Atopy, Hay fever, Asthma, Rheumatoid arthritis.

To investigate the expression of inducible nitric oxide synthase (iNOS) in subpopulations of peripheral blood and synovial fluid (SF) leukocytes in patients with rheumatoid arthritis (RA).iNOS was detected in peripheral blood and SF samples after cell permeabilization, by 2 color immunofluorescence flow cytometry. Samples from 14 patients with RA and 8 with osteoarthritis (OA) were studied. Nitrite concentration was determined by Griess reaction, interleukin 1beta and tumor necrosis factor alpha by an immunoenzymatic assay, and C-reactive protein (CRP) by an immunonephelometric method.In SF, iNOS was detected in 11 of 14 patients with RA and 2 of 8 with OA. In blood cells, iNOS was detected in 8 of 14 patients with RA and none of the OA group. iNOS was consistently detected in monocytes and was not detected in granular cells. In RA, there was no correlation between the number of iNOS positive mononuclear cells and cytokine concentrations. CRP concentration was correlated with the number of iNOS positive mononuclear cells in RA SF samples.SF mononuclear cells from patients with RA express iNOS and are involved in NO production in the joint. The number of positive cells is correlated with CRP concentration, suggesting the implication of NO production in the inflammatory process.

Meningeal metastatic disease usually occurs as a complication of a brain tumor and is exceptionally isolated in patients with solid tumors. We report the case of a 74-year-old woman admitted for mechanical S1 sciatica refractory to drug therapy. She had been treated for breast cancer three years earlier. Physical findings were pain upon hyperextension of the lumbar spine and absence of the ankle jerks. Analysis of cerebrospinal fluid sampled during an intrathecal glucocorticoid injection showed 1 g/L of protein and 11 normal cells per mm3. Grade 3 L5-S1 spondylolisthesis was seen on plain radiographs, computed tomography scans, and magnetic resonance imaging scans. At that point, the patient developed sphincter dysfunction and motor loss in the left lower limb in the distribution of several nerve roots. Findings were normal from a myelogram and a magnetic resonance imaging study of the brain. A repeat cerebrospinal fluid analysis showed 1.1 g/L of protein and 5 cells/mm3. Because of the discrepancy between the clinical and imaging study findings, the patient was transferred to a neurology department. A third cerebrospinal fluid study showed numerous adenocarcinoma cells, and a repeat magnetic resonance imaging demonstrated a mass in the dural sac opposite L2. A program of monthly intrathecal methotrexate injections was started. A fatal meningeal relapse occurred eight months later.This case shows that a leptomeningeal metastasis can cause isolated nerve root pain, and demonstrates the diagnostic value of magnetic resonance imaging and cerebrospinal fluid cytology in patients with atypical symptoms, particularly when there is a history of malignant disease.

To evaluate the efficacy and tolerance of a platelet activating factor-acether (PAF) antagonist, BN 50730, in patients with rheumatoid arthritis (RA).A total of 56 patients with active RA were enrolled in a multicenter, double blind, placebo controlled study of BN 50730. Patients received either BN 50730 (40 mg orally bid) or placebo for 84 days.Treatment with BN 50730 resulted in no improvement and was no more effective than placebo in improving clinical and biological indices of RA activity. Adverse events were observed in the 2 treatment groups, and BN 50730 was generally well tolerated.PAF antagonist BN 50730 at a daily dose of 80 mg was ineffective in the treatment of RA.

We report three cases of epidural lipomatosis including one in a patient with primary Cushing's disease. Our literature review found 16 additional cases of symptomatic epidural lipomatosis in patients who were not receiving corticosteroids. The presenting symptoms were nonspecific. The main clinical symptoms were nerve root pain, weakness of the lower limbs upon exertion, paraparesis or isolated back pain. Degenerative lesions were common and were sometimes the cause of the symptoms. Cases were evenly distributed between the thoracic and lumbar spine. Of the 18 patients, 14 were men and eight were older than 54 years. Three-fourths of patients were obese. Spinal cord or nerve root compression occurred in some instances. Modern imaging techniques (computed tomography and magnetic resonance imaging) can establish the diagnosis rapidly. In patients without neurologic compromise, surgery should be considered only if symptoms fail to respond to weight reduction. The rate of occurrence of epidural lipomatosis in patients with Cushing's disease is probably underestimated. Routine investigation by magnetic resonance imaging of Cushing's disease patients who have manifestations known to occur in epidural lipomatosis would allow to evaluate the role of increased production of endogenous corticosteroids in the occurrence of epidural lipomatosis.

Radioactive or chemical synovectomy (synoviorthesis) is widely used as local therapy for inflammatory joint disease in France. The objective of this retrospective study was to compare the efficacy of osmic acid or radiation synovectomy with that of joint lavage for the treatment of knee osteoarthritis with effusions.All study patients met American College of Rheumatology criteria for knee osteoarthritis, which was symptomatic despite conservative therapy including local corticosteroid injections. Fifty-four patients were treated by synoviorthesis (osmic acid, n = 16; yttrium 90, n = 76) and 45 by joint lavage (total 67 lavages).Thirty two per cent of the patients in the synoviorthesis group had a good or excellent outcome after six months. Results were better with yttrium 90 than with osmic acid. Improvements were most marked in patients with chondrocalcinosis. Efficacy was negatively correlated with the femorotibial lesions but not with the patellofemoral lesions. Patients with knee alignment disorders had poorer outcomes. In the joint lavage group, 30% of the knees showed improvements after three months and results were significantly better after three and six months when the lavage was followed by an injection of triamcinolone hexacetonide. No side effects were recorded.Our data suggest that chemical or radiation synovectomy or joint lavage followed by injection of a delayed-action steroid may be useful for the treatment of knee osteoarthritis with chronic or recurrent effusions.

Biological markers of inflammation are useful for the diagnosis and the monitoring of inflammatory rheumatisms and connective tissue diseases. These markers are not specific, and often poorly correlate with the long term evolution of the disease. C-reactive protein (CRP) is a sensitive marker, and is used to monitor inflammatory and infectious diseases. In rheumatoid arthritis (RA), CRP correlates with disease activity and response to therapy, and CRP levels are influenced by disease-modifying drugs and corticosteroids. Serum amyloid A (SAA) is another acute phase protein (APP) which appears in RA as a more sensitive marker than CRP. Several antinuclear antibodies serve as markers of systemic disorders; they are not implicated in the disease by themselves, but their production could be related to the genetic background underlying the pathogenesis of the disease. In systemic lupus erythematosus (SLE), the titer of anti-ds DNA antibodies often correlates with disease activity. DNA is poorly immunogenic and the production of anti-ds DNA antibodies could be linked to the association of DNA with more immunogenic protein antigens. Cellular DNA is associated with proteins in nucleosomes and it now appears more appropriate to consider the anti-DNA antibody production as a response to a DNA-protein complex. Antibodies can be directed to histones and DNA-protein complexes such as transcription or replication complexes. Antibodies to ribonuclear proteins are associated with different disease subsets and help to define the prognosis in SLE and connective tissue diseases. The identification of antibodies directed against proteins and RNA components is still a field of research.

To examine the clinicopathologic features of the noncompressive neuropathies in rheumatoid arthritis (RA).We studied 32 patients with RA and peripheral neuropathy whose nerve and/or muscle biopsy specimens exhibited necrotizing vasculitis. Morphologic analysis of nerve specimens included light and electron microscopy studies and teased fiber preparation. Survival was evaluated, and the prognostic values of clinical, biologic, and pathologic features were assessed by Cox proportional hazards model. A prognostic assessment based on the significant variables was devised to estimate the probability of survival of any individual patient.Epi- and/or perineurial vasculitis was observed with the same frequency in the 17 patients with sensory and motor deficit and the 15 patients with sensory neuropathies and was associated with axonal degeneration of an average of 77.7% of the nerve fibers. The mean followup was 7.2 years, and the overall survival rate at 5 years was 57%. A full prolonged remission of the vasculitis was observed in 53% of the patients; relapse occurred in 25%. The factors correlated with mortality, in decreasing order of significance, were clinical cutaneous vasculitis (P = 0.0003), neuropathy affecting 3 or 4 limbs (P = 0.03), and depressed level of C4 (P0.05). The prognostic assessment indicated a wide range of 5-year probabilities of survival, from1% to 93%.Necrotizing vasculitis is responsible for the different patterns of noncompressive neuropathies in RA, including mononeuritis multiplex and distal symmetric sensory or sensorimotor neuropathy. Cutaneous vasculitis, multifocal neuropathy, and depressed C4 level were the 3 independent variables which best predicted mortality. We propose a prognostic assessment according to these variables, to stratify patients to receive more aggressive or less aggressive therapy.

In order to address the issue of the role of mast cells (MC) and nitric oxide (NO) in rheumatic synovial-fluid diseases, synovial fluid (SF) collected from the knee of patients with osteoarthritis (OA), articular chondrocalcinosis (ACC) or rheumatoid arthritis (RA) was examined for the levels of mast cells (MC), histamine, tryptase, phospholipase A2 and nitrite. MC counts were found to be elevated in the SF of OA patients as compared with RA patients. Histamine content in SF parallelled the number of MC. Tryptase levels were elevated in OA in comparison to RA and ACC, but the difference was not statistically significant. Identical PLA2 levels were recorded among the 3 groups. Nitrite concentrations were also higher in SF from OA patients as compared to RA patients. These results suggest that mast cells (MC), in association with various inflammatory cells, may contribute to inflammation and cartilage breakdown in osteoarthritis (OA).