Rheumatoid Arthritis: Flipo RM

Boutry N, Morel M, Flipo RM, Demondion X, Cotten A. · Department of Musculoskeletal Radiology, Centre Hospitalier Universitaire de Lille and Hôpital Roger Salengro, CHRU de Lille, Blvd. du Pr. J Leclercq, 59037 Lille, France. · AJR Am J Roentgenol. · Pubmed #18029892 links to  free full text

Abstract: OBJECTIVE: The introduction of anti-tumor necrosis factor alpha agents has opened new prospects in therapeutic management of patients with early rheumatoid arthritis, thereby creating new demands on radiologists to identify patients with aggressive disease at an early stage. As a result, imaging techniques such as MRI and sonography have developed during the past few years. CONCLUSION: This article illustrates the imaging findings that may be encountered with these techniques in patients with early rheumatoid arthritis.

Fautrel B, Pham T, Gossec L, Combe B, Flipo RM, Goupille P, Le Loët X, Mariette X, Puéchal X, Wendling D, Schaeverbeke T, Sibilia J, Sany J, Dougados M. · Service de rhumatologie, groupe hospitalier Pitié-Salpêtrière, Paris, France. · Joint Bone Spine. · Pubmed #15797498 No free full text.

Abstract: OBJECTIVES: To develop recommendations for the information and education of patients with rheumatoid arthritis (RA) seen in everyday practice, using evidence from the literature, supplemented with expert opinion when needed. METHODS: A scientific committee developed eight questions using the Delphi consensus procedure. A task force reviewed the literature for answers to these questions, using the PubMed Medline database (1980-2004) and the 2002-2004 databases of the annual meetings held by the French Society for Rheumatology (SFR), the European League Against Rheumatism (EULAR), and the American College of Rheumatology (ACR); the indexing terms for the search were rheumatoid, arthritis, patient, education, information, knowledge, general practitioner, family doctor, and continuing medical education. Only articles in French or English were included. A panel of rheumatologists used the evidence thus compiled to develop recommendations for each question; gaps in evidence were filled by calling on the panelists' expert opinion. For each recommendation, the level of evidence and extent of agreement among panelists were specified. RESULTS: There were four general questions about the objectives, supports, and mode of delivery (group or one-on-one) of patient information and education, as well as on evaluating knowledge, and four specific questions on program content. The search identified 1235 articles; 144 were selected on the title and 118 of those on the abstract. Three abstracts presented at meetings were also kept. The evidence from the literature was presented to the panelists during interactive workshops. The panelists then developed eight recommendations, all of which were grade D because no published studies specifically addressed everyday clinical practice. Agreement among panelists ranged across recommendations from 85.7% to 100%. CONCLUSION: Recommendations about educating and informing patients with RA in everyday practice were developed. They should increase practice uniformity and ultimately optimize the management of patients with RA.

Boutry N, Lardé A, Demondion X, Flipo RM, van Holsbeeck M, Cotten A. · Département de Radiologie Ostéo-Articulaire, Hôpital Roger Salengro, CHRU de Lille, Boulevard du Pr. J Leclercq, 59037 Lille Cedex. · J Radiol. · Pubmed #12910171 links to  free full text

Abstract: Technological advances in the field of ultrasound imaging may have, especially in metacarpophalangeal joints, an impact on decision making in patients with early rheumatoid arthritis. First, the normal anatomy of the metacarpophalangeal joints is briefly reviewed. Then, the authors describe the main ultrasound imaging findings of early RA. The role of ultrasound imaging in the assessment of therapeutic response as well as the benefit of microbubble ultrasound contrast agents are considered.

Ducoulombier V, Solau E, Coquerelle P, Houvenagel E, Siame JL, Desprez X, Fauquert P, Guyot MH, Delcambre B, Flipo RM. · Rheumatology Department, Roger Salengro Teaching Hospital, Lille University Hospitals, 59037 Lille Cedex, France. · Joint Bone Spine. · Pubmed #17182267 No free full text.

Abstract: OBJECTIVE: Infliximab is effective in patients with rheumatoid arthritis (RA). Add-on infliximab therapy in patients on methotrexate results in a rapid gain in effectiveness, which lasts at least 1 year. The objective of this study was to evaluate the effectiveness and continuation rate of infliximab in patients with RA after the first year of treatment. METHODS: The first 50 patients with RA who were given infliximab in the North-Pas-de-Calais region of France were included in a multicenter open-label study. The patients had severe RA or failed to respond to conventional medications. Infliximab was given in a dosage of 3 mg/kg every 8 weeks in combination with methotrexate. Effectiveness was evaluated using the DAS28-3 score and EULAR response criteria. The dates and reasons of infliximab discontinuations were recorded. RESULTS: The 2-year infliximab continuation rate was 70%. Serious adverse events requiring infliximab discontinuation occurred in 7 patients. Mean DAS28-3 scores in the 35 patients who took infliximab for at least 2 years were 6.42 at baseline, 4.33 after 30 weeks, 4.31 after 54 weeks, and 3.86 after 102 weeks. According to EULAR criteria after 102 weeks, there were 12 good responders, 18 moderate responders, and 5 nonresponders. CONCLUSION: Experience acquired in the North-Pas-de-Calais district of France suggests that infliximab is continued for more than 2 years in more than two-thirds of patients and remains effective over this period.

Solau-Gervais E, Legrand JL, Cortet B, Duquesnoy B, Flipo RM. · Department of Rheumatology, Lille University Hospital, Lille, France. · J Rheumatol. · Pubmed #16832852 No free full text.

Abstract: OBJECTIVE: To assess the practical usefulness of magnetic resonance imaging (MRI) in establishing a positive diagnosis of rheumatoid arthritis (RA) in a cohort of patients with early inflammatory polyarthralgia, in the absence of anti-cyclic citrullinated peptide (anti-CCP) antibodies. METHODS: We prospectively followed 30 outpatients with inflammatory polyarthralgia and/or synovitis of at least one joint. Patients were disease modifying antirheumatic drug-naive and received no corticosteroids. At the initial visit a clinical examination, radiographs of hands, wrists and feet, and MRI of hands were performed. Rheumatoid factor and anti-CCP antibodies were assessed. The MRI procedure was T1 fat saturation with gadolinium injection [scores were established on the basis of the axial view of the carpal and metacarpal joints, using the RA MRI scoring system (RAMRIS) defined in the OMERACT study]. In all patients, radiographs at baseline were normal and anti-CCP antibodies were negative. RESULTS: At one-year followup, the final diagnosis was: 16 RA; the non-RA group was composed of 4 cases of spondyloarthropathy, 2 cases of fibromyalgia, 4 cases of undifferentiated arthritis (3 of which were self-limiting), 1 sicca syndrome, 1 hemochromatosis, 1 polymyositis, and 1 paraneoplastic syndrome. No statistical difference was found between patients with and without RA for carpal erosion, synovitis, and tenosynovitis. However, a statistical difference was observed between the RA and non-RA group where metacarpophalangeal (MCP) erosion scores were concerned (p = 0.024). This difference persisted when we compared erosions of the second and third MCP in the 2 groups (p = 0.044). ROC curve analysis revealed a positive MCP score at 15, with a specificity of 70% and a sensitivity of 64%. CONCLUSION: In our population of 30 anti-CPP negative patients with normal radiographs, MRI of hands, showing MCP erosions, can be helpful for the diagnosis of RA.

Boutry N, Lardé A, Lapègue F, Solau-Gervais E, Flipo RM, Cotten A. · Department of Musculoskeletal Radiology, Hopital Roger Salengro, Lille, France. · J Rheumatol. · Pubmed #12672183 No free full text.

Abstract: OBJECTIVE: To describe the magnetic resonance (MRI) imaging findings of the feet in patients with early rheumatoid arthritis (RA), and to compare MRI appearance of the feet with that of the hands. METHODS: Thirty consecutive patients (18 women, 12 men; age range 19-64 yrs) with early RA underwent MRI of hands and feet. Axial fat suppressed gadolinium enhanced T1 weighted spin-echo and gadolinium enhanced 3-dimensional gradient-echo (FLASH) images were obtained. RESULTS: In the hands, MRI findings suggested active synovitis of the wrist and metacarpophalangeal (MCP) joints in 28 (93%) and 27 (90%) patients, respectively. In the feet, active synovitis was observed in 29 (97%) patients. Bone erosions were seen in the wrist joints in 24 (80%) patients. Observers found as many bony changes in the MCP as in the metatarsophalangeal joints [23 (77%) patients]. MRI detected tenosynovitis in 16 (53%) patients in the hands, and in 18 (60%) patients in the feet. Bursitis located between or beneath the metatarsal heads was a common MRI finding [19 (63%) patients]. CONCLUSION: Additional MRI of the feet may be useful when evaluation of the hands does not help identify early RA.

Yocum DE, Allard S, Cohen SB, Emery P, Flipo RM, Goobar J, Jayawardena S, Job-Deslandre C, Jubb RW, Krüger K, Lopes Vaz A, Manger B, Mur E, Nygaard H, Weiner SM, Rainer F, Sack MR, Schiff MH, Schnitzer TJ, Trigg LB, Whatmough I, Schmidt AG. · Arizona Arthritis Center, University of Arizona, Tucson, Arizona, USA. · Rheumatology (Oxford). · Pubmed #10725065 links to  free full text

Abstract: OBJECTIVE: To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral) and the original CyA formulation (Sandimmun), in patients with severe active rheumatoid arthritis (RA), over a 12-month period. METHODS: In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients' assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals. RESULTS: Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients' assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups. CONCLUSION: These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.

Tebib J, Mariette X, Bourgeois P, Flipo RM, Gaudin P, Le Loët X, Gineste P, Guy L, Mansfield CD, Moussy A, Dubreuil P, Hermine O, Sibilia J. · Service de Rhumatologie, Centre Hospitalier Lyon-Sud, 765 chemin du Grand-Revoyet, 69495 Pierre-Bénite, France. · Arthritis Res Ther. · Pubmed #19549290 links to  free full text

Abstract: INTRODUCTION: Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA. METHODS: This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12. RESULTS: Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends. CONCLUSIONS : Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00831922.

Fautrel B, Guillemin F, Meyer O, de Bandt M, Berthelot JM, Flipo RM, Lioté F, Maillefert JF, Wendling D, Saraux A, Combe B, Le Loët X, Anonymous00044, Anonymous00045, Anonymous00046. · Department of Rheumatology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Arthritis Rheum. · Pubmed #19333993 No free full text.

Abstract: OBJECTIVE: To survey rheumatologists' preferences for the choice of a second-line disease-modifying antirheumatic drug (DMARD) after inadequate response with methotrexate (MTX) therapy in rheumatoid arthritis (RA). METHODS: Thirty-six rheumatologists stated their preferences for RA treatment after inadequate response with MTX therapy (optimal dose at least 6 months). From the initial scenario, we derived 54 vignettes varying by rheumatoid factor or anti-cyclic citrullinated peptide antibody presence, swollen joint count, Disease Activity Score in 28 joints, and structural damage. Respondents stated their preference among 5 therapeutic options: MTX continuation, switch to another conventional DMARD, addition of another conventional DMARD, addition of anakinra, or addition of a tumor necrosis factor (TNF) blocker. Presentation by pairs yielded 10 combinations of strategies for each variant, totaling 540 vignettes; participants evaluated a random sample of 180 vignettes. Determinants of each top-ranked option were analyzed by logistic regression. The compilation of these data served to define a therapeutic algorithm. RESULTS: The responses of 33 rheumatologists were analyzable. Therapeutic preferences corresponded to the top-ranked options. For patients with mild or moderately active RA, either a switch or step-up strategy to another conventional DMARD was top ranked. TNF blockers were preferred for RA patients with high disease activity or progressive structural damage. On the basis of these preferences, we developed a simple decision tree for use in daily clinical practice. CONCLUSION: Our simple, easy-to-use decision tree developed from rheumatologists' preferences for therapy after failure of MTX therapy in RA treatment may guide rheumatologists in daily practice to choose a second-line DMARD.

Gandjbakhch F, Fajardy I, Ferré B, Dubucquoi S, Flipo RM, Roger N, Solau-Gervais E. · Department of Rheumatology, Lille University Hospital, Lille, France. · J Rheumatol. · Pubmed #19332633 No free full text.

Abstract: OBJECTIVE: A functional haplotype of peptidyl arginine deiminase 4 (PADI4) was associated with susceptibility to rheumatoid arthritis (RA) in Asian populations, but the results are contradictory in Europeans. We investigated (1) the association of 2 single-nucleotide polymorphisms (SNP) located in exon 2 of PADI4 with RA in another Caucasian population; and (2) the association between PADI4 and anti-citrullinated protein (anti-CCP) antibodies. METHODS: DNA samples were obtained from 405 French RA patients and 275 controls. All RA patients met the revised criteria of the American College of Rheumatology. PADI4_89 163(G-->A) and PADI4_90 245(T-->C) SNP were genotyped using a PCR-RFLP method confirmed by direct sequencing. All patients and controls were genotyped for HLA-DRB1. The presence of anti-CCP antibodies was tested in 243 RA patients using an ELISA technique. RESULTS: We focused on PADI4_89 163(G-->A) and PADI4_90 245(T-->C) SNP that distinguished 2 main haplotypes: AC haplotype (PADI4_89*A PADI4_90*C) and GT haplotype (PADI4_89*G PADI4_90*T), described, respectively, as "nonsusceptible" and "susceptible." A positive association between RA and presence of the GT haplotype was found in the heterozygous state (p = 0.002) and the homozygous state (RA patients 22%, controls 13%; p = 0.005). A correlation was observed between the presence but not the level of anti-CCP antibodies and the GT heterozygous (p = 0.03) and homozygous (p = 0.05) haplotypes. No correlation was found between the HLA-DRB1 shared epitope and any of the PADI4 haplotypes. CONCLUSION: Our findings confirm those of Japanese, Korean, and Canadian studies and suggest that PADI4 may be a new susceptibility gene independent of HLA-DRB1 for RA in Caucasian populations.

Fautrel B, Flipo RM, Saraux A. · Service de Rhumatologie, Groupe Hospitalier Pitié-Salpêtrière, 83, boulevard de l'Hôpital, 75651 Paris Cedex 13, France. · Rheumatology (Oxford). · Pubmed #18794185 No free full text.

Abstract: OBJECTIVES: Several anti-TNF-alpha prescription guidelines in RA have been published, among which those issued by the British (BSR) and French (SFR) Societies for Rheumatology in 2005 are the most comprehensive. Objectives of the PRISME II survey were to assess and compare eligibility for anti-TNF-alpha therapy of RA patients consulting their usual rheumatologist according to (i) the SFR and BSR guidelines and (ii) the rheumatologist's opinion. METHODS: PRISME II was a postal, cross-sectional, observational survey proposed to all office-based rheumatologists practising in France in 2005. Rheumatologists were to include three consecutive consulting anti-TNF-alpha-naïve RA patients. Disease activity was assessed using the disease activity score 28 (DAS28). Structural damage progression was estimated based on the reading by the usual rheumatologist. The factors determining eligibility in the rheumatologists' opinion were identified by a logistic regression analysis. RESULTS: Four hundred and thirty-four rheumatologists included 1132 patients. Ongoing RA structural progression was reported for 41% of the patients. According to the SFR and BSR criteria, 64 patients (7.0%) and 10 patients (0.9%), respectively, were eligible for anti-TNF-alpha therapy, while 10% were deemed eligible according to the rheumatologists' opinion. Determinants of eligibility according to the rheumatologists were: high disease activity (DAS28 >5.1), ongoing structural progression and elevated daily corticosteroid intake. These three determinants feature in the SFR guideline. CONCLUSIONS: The proportion of RA patients eligible for anti-TNF-alpha therapy varies greatly according to the BSR or SFR guidelines. In France, there is a remarkable convergence between rheumatologists' opinion and SFR guideline regarding the main factors to consider for initiation of an anti-TNF-alpha therapy.

Burmester GR, Ferraccioli G, Flipo RM, Monteagudo-Sáez I, Unnebrink K, Kary S, Kupper H. · Charité University Medicine Berlin, Berlin, Germany. · Arthritis Rheum. · Pubmed #18163417 links to  free full text

Abstract: OBJECTIVE: To evaluate the effect of adalimumab treatment on clinical remission and/or minimal disease activity (MDA) in 6,610 patients with active rheumatoid arthritis (RA) who were enrolled in the Research in Active RA trial, a multinational, open-label, 12-week study with an optional extension period. METHODS: Clinical remission was defined as a Disease Activity Score in 28 joints (DAS28)<2.6, Simplified Disease Activity Index (SDAI) score<or=3.3, or Clinical Disease Activity Index (CDAI) score<or=2.8. MDA required absence of tender and swollen joints plus erythrocyte sedimentation rate (ESR)<or=10 mm/hour; DAS28 score<or=2.85; or achievement of 5 of 7 core criteria for pain, swollen/tender joints, physical function, physician/patient global assessment, and ESR. Time to and time in remission/MDA and response predictors were analyzed using Kaplan-Meier estimates and Cox proportional hazards regression analysis, respectively. RESULTS: A total of 38%, 24%, and 27% of patients achieved remission defined as DAS28<2.6, SDAI<or=3.3, and CDAI<or=2.8, respectively. MDA was observed in 45% of patients by DAS28<or=2.85, in 43% by the core set of criteria, and in 13% by absence of tender/swollen joints plus ESR<or=10 mm/hour. Median times in continuous remission and MDA were 3.4 and 4.4 months, respectively. Predictors for remission (DAS28<2.6) and MDA (DAS28<or=2.85) were male sex; younger age; concomitant disease-modifying antirheumatic drug use; lower baseline DAS28, CRP concentration, and Health Assessment Questionnaire disease index score; <or=1 comorbidity; and tumor necrosis factor antagonist naivety. CONCLUSION: During adalimumab treatment, 25% of patients experienced clinical remission and nearly half achieved MDA. To our knowledge, this analysis represents the largest prospective clinical trial data set to be assessed using Outcome Measures in Rheumatology Clinical Trials MDA criteria.

Denis B, Lefort A, Flipo RM, Tubach F, Lemann M, Ravaud P, Salmon D, Mariette X, Lortholary O, Anonymous00380. · Université Paris V, Hôpital Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Paris, France. · Clin Microbiol Infect. · Pubmed #18076664 No free full text.

Abstract: This study investigated the long-term outcome of patients with tuberculosis (TB) as a complication of tumour necrosis factor (TNF)-alpha blocker therapy. All TB cases (n = 21) complicating TNF-alpha blocker therapy from French university hospitals were collated between January 2000 and September 2002. Outcome was assessed via a postal questionnaire during September 2005. The mortality rate after 4 years was 4.8%, and one patient had relapsed and six (29%) patients had recommenced TNF-alpha antagonist treatment, after appropriate anti-TB therapy, without reactivation. These data support the concept that TNF-alpha antagonists can be restarted in TB patients provided that adequate anti-TB treatment has been completed.

Solau-Gervais E, Zerimech F, Lemaire R, Fontaine C, Huet G, Flipo RM. · Department of Rheumatology, Roger Salengro Hospital, Lille, France. · Scand J Rheumatol. · Pubmed #17963167 No free full text.

Abstract: OBJECTIVE: To compare the activities of cathepsin B (EC 3.4.22.1) and L (EC 3.4.22.15), calpain (EC 3.4.22.17), and dipeptidyl peptidase (EC 3.4.14.5 or DPP IV or CD26) in synovial membrane from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and post-traumatic joint injury (PT). METHODS: Forty RA patients were divided into two groups on the basis of surgical procedure: the RAs group comprised 18 patients requiring surgical synovectomy; the RAr group comprised 22 patients requiring a total joint replacement or arthrodesis. A third group (the OA group) comprised 19 OA patients while six patients with post-traumatic joint injury were included in the fourth group (the PT group). Cathepsin and calpain activity was assessed using a Cobas Fara II centrifugal analyser. DPP IV activity was determined kinetically using a fluorogenic substrate. RESULTS: RAs patients were significantly younger than RAr patients, and the mean duration of RA was shorter in the RAs group than in the RAr group. Cathepsin and calpain activity in synovial membrane was higher in RA and OA patients than in the control group, but no statistical difference was observed between RA and OA. However, cathepsin, calpain, and DPP IV synovial activity was significantly higher in the RAs group than in either the OA or the PT group. CONCLUSION: Our results show that proteinase activity tends to be higher in joints with early synovitis in RA, and suggest that these enzymes are not all involved at the same stage of the disease.

Combe B, Benessiano J, Berenbaum F, Cantagrel A, Daurès JP, Dougados M, Fardellone P, Fautrel B, Flipo RM, Goupille P, Guillemin F, Le Loet X, Logeart I, Mariette X, Meyer O, Ravaud P, Rincheval N, Saraux A, Schaeverbeke T, Sibilia J. · University Hospital, Montpellier, France. · Joint Bone Spine. · Pubmed #17905631 No free full text.

Abstract: OBJECTIVES: The French Society of Rheumatology initiated a large national multicenter, longitudinal and prospective cohort, the so-called "ESPOIR cohort study" in order to set up databases to allow various investigations on diagnosis, prognostic markers, epidemiology, pathogenesis and medico-economic factors in the field of early arthritis and rheumatoid arthritis. METHODS: Patients were recruited if they had undifferentiated arthritis or rheumatoid arthritis, of less than 6 months disease duration and if they were DMARD and steroids naïve. Patients have then to be followed every 6 months during the first 2 years then every year during at least 10 years. Clinical, biological, radiographic and medico-economic databases have been constituted to fit in the different objectives of the project and more than 20 scientific studies have already been accepted by the scientific committee. RESULTS: 813 patients were included (76.75% were female). The mean age was 48.07+/-12.55 years. The mean delay from the onset of symptoms to referral to the rheumatologist was 74.8+/-76.6 days. Baseline swollen and tender joint counts were 7.19+/-5.37 and 8.43+/-7.01; DAS28 score was 5.11+/-1.31. CRP was abnormal in 38.9% of the patients; 44.2%, 45.8% and 38.8% had respectively IgM rheumatoid factor (RF), IgA RF and anti-CCP antibodies. HLA DRB1*01 or 04 genes were found in 56.7% of them. Finally, 22% of these patients had erosions on hand or feet at baseline.

Meyer O, de Bandt M, Berthelot JM, Cantagrel A, Combe B, Fautrel B, Flipo RM, Lioté F, Maillefert JF, Saraux A, Wendling D, Guillemin F, Le Loët X, Anonymous00174. · Department of Rheumatology, AP-HP, Bichat Paris 7 University Hospital, CHU Bichat, 46 rue Henri Huchard, 75018 Paris, France. · Joint Bone Spine. · Pubmed #17194614 No free full text.

Abstract: BACKGROUND: The objective was to develop a clinical practice format for choosing a second-line disease-modifying anti-rheumatic drug (DMARD) after a 6-month course of a first-line DMARD in patients with early RA. METHODS: A panel of 34 experts selected treatment option from various scenarios using the Thurstone pairwise method. The experts had to choose between two proposed DMARDs without proposing other options. The scenarios were obtained using the three items: DAS28, rheumatoid factor status and radiographic structural damage. A sample of 240 among 480 scenarios for each expert was taken at random. Responses given by at least 20% of the experts were considered pertinent. RESULTS: Recommendations for choosing a second DMARD for early RA after failure of a 6-month course of a first-line DMARD were established according to 4 parameters: type of first-line DMARD, activity, RF status and radiographic joint damage. The results of this study suggest that in patients with early RA who fail a 6-month course of first-line DMARD therapy, the best options may be addition of corticosteroid when disease activity is moderate to high and switching to a biologic agent when further radiographic joint damage occurs, particularly in patients with positive tests for RF. CONCLUSION: Although our scenarios did not include step-up (add instead of substitute) strategies, except for corticosteroids, we feel that the format presented here can optimise the management of patients with early RA seen in clinical practice.

Roux CH, Saraux A, Le Bihan E, Fardellone P, Guggenbuhl P, Fautrel B, Masson C, Chary-Valckenaere I, Cantagrel A, Juvin R, Flipo RM, Euller-Ziegler L, Coste J, Guillemin F. · Department of Rheumatology, University Hospital, Nice, France. · J Rheumatol. · Pubmed #17117490 No free full text.

Abstract: OBJECTIVE: To determine geographical variation in the prevalence of rheumatoid arthritis (RA) and spondyloarthropathies (SpA) in France. METHODS: The survey sample was drawn from 7 areas of France. Households were randomly selected using the national telephone directory, and an individual within each household was randomly chosen by the next-birthday method. All cases of suspected RA and SpA were confirmed by the patient's rheumatologist or by clinical examination. Standardized estimates of prevalence were compared between regions and groups of regions. RESULTS: In total 15,219 anonymous telephone numbers were selected. An average response rate of 64% led to a total of 9395 respondents included in the study. The highest regional rates of RA were observed in the south (range 0.59-0.66%), and the lowest in the north (range 0.14-0.24%), with a national rate of 0.31% (95% CI 0.18-0.48%). Regional heterogeneity was observed for SpA, with the highest rates in Bretagne (0.47%) and the Sud-Est (0.53%) and a national rate of 0.30% (95% CI 0.17-0.46%). CONCLUSION: This study is the largest of its kind conducted in France. It shows inter-regional variations, mainly in RA, with a higher prevalence in the south of the country. The many potential reasons for the heterogeneity observed, including genetic and environmental factors, warrant further research.

Hamdi H, Mariette X, Godot V, Weldingh K, Hamid AM, Prejean MV, Baron G, Lemann M, Puechal X, Breban M, Berenbaum F, Delchier JC, Flipo RM, Dautzenberg B, Salmon D, Humbert M, Emilie D, Anonymous00131. · INSERM UMR-S764, Service d'Hépato-Gastro-Entérologie, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Institut Paris-Sud sur les Cytokines, Université Paris-Sud, INSERM U764, 32 rue des Carnets, 92140, Clamart, France. · Arthritis Res Ther. · Pubmed #16859506 links to  free full text

Abstract: Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-alpha treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-gamma. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-alpha treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-gamma-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-gamma release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-gamma upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.

Saraux A, Devauchelle-Pensec V, Engerran L, Flipo RM. · Department of Rheumatology, La Cavale Blanche Teaching Hospital, Brest, France. · J Rheumatol. · Pubmed #16783865 No free full text.

Abstract: OBJECTIVE: To evaluate the proportion of patients with rheumatoid arthritis (RA) visiting office-based rheumatologists for persistently active RA despite past or current methotrexate (MTX) treatment, and to describe the management of these patients in France in 2003. METHODS: All French rheumatologists were invited to participate in a cross-sectional postal survey. During a predetermined week, they were to include the first 2 patients seen for RA with a history of past or current MTX treatment. Adequacy of current treatment was assessed based on the 28-joint Disease Activity Score 28 (DAS28) and on current MTX and corticosteroid regimens. RESULTS: Of the 1800 French rheumatologists, 492 returned 838 assessable patient questionnaires. Mean patient age was 58 years and mean time since RA diagnosis was 10 years; 77% of patients were currently taking MTX, and 51% a corticosteroid. High dosages were noted for MTX (> 15 mg/week) in 20% of patients and for corticosteroid therapy (> 10 mg/day) in 5%. Nevertheless, 41% of patients had active RA (DAS28 score 3.2 to 5.1) and 7% had very active RA (DAS28 score > 5.1). The treatment was left unchanged in 78% of patients, and biological therapy was contemplated in only 16% of patients. CONCLUSION: Although half of MTX-treated patients with RA visiting office-based rheumatologists had active or very active disease, a change in treatment was rarely considered.

Pham T, Gossec L, Constantin A, Pavy S, Bruckert E, Cantagrel A, Combe B, Flipo RM, Goupille P, Le Loët X, Mariette X, Puéchal X, Schaeverbeke T, Sibilia J, Tebib J, Wendling D, Dougados M. · Service de rhumatologie, CHU de la Conception, Marseille, France. · Joint Bone Spine. · Pubmed #16690341 No free full text.

Abstract: OBJECTIVE: To develop clinical practice guidelines for the evaluation and management of cardiovascular risk in patients with rheumatoid arthritis (RA), using the evidence-based approach and expert opinion. METHODS: Recommendations were developed using the evidence-based approach and expert opinion: A scientific committee used a Delphi procedure to select five questions, which formed the basis for developing the recommendations; Evidence providing answers to the five questions was sought in the literature; Based on this evidence, recommendations were developed by a panel of experts. RESULTS: The recommendations were as follows: 1) In patients with RA, attention should be given to the risk of cardiovascular disease, which is responsible for an excess burden of morbidity and mortality; 2) It must be recognized that RA may be an independent cardiovascular risk factor. Persistent inflammation is an additional risk factor; 3) The cardiovascular risk should be evaluated, and modifiable risk factors should be corrected; 4) In patients with RA requiring glucocorticoid therapy, the need for cardiovascular risk minimization is among the reasons that mandate the use of the minimal effective dose; 5) It should be recognized that methotrexate may protect against cardiovascular mortality in patients with RA; 6) It should be recognized that TNFalpha antagonists remain contraindicated in patients with RA and severe heart failure. TNFalpha antagonists do not seem to worsen moderate heart failure and may protect against cardiovascular mortality; 7) AFSSAPS recommendations about LDL-cholesterol objectives should be followed, with active RA being counted as a cardiovascular risk factor; 8) In patients with RA, statin therapy should be considered only when cholesterol levels are elevated despite appropriate dietary treatment; 9) RA per se does not indicate aspirin for primary prevention. When aspirin is used for secondary prevention, it should be recognized that concomitant treatment with nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the antiplatelet effects and increase the gastrointestinal side effects of aspirin therapy.

Gossec L, Pavy S, Pham T, Constantin A, Poiraudeau S, Combe B, Flipo RM, Goupille P, Le Loët X, Mariette X, Puéchal X, Wendling D, Schaeverbeke T, Sibilia J, Tebib J, Cantagrel A, Dougados M. · Service de rhumatologie B, CHU de Cochin, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France. · Joint Bone Spine. · Pubmed #16626995 No free full text.

Abstract: OBJECTIVE: To develop clinical practice guidelines for the use of nonpharmacological treatments in patients with early rheumatoid arthritis (RA), using the evidence-based approach and expert opinion. METHODS: A scientific committee used a Delphi prioritization procedure to select five questions. Evidence providing answers to the five questions was sought in the literature and presented to a panel of rheumatologists. The panel developed five detailed recommendations, filling gaps in evidence with their expert opinion. The strength of each recommendation was determined. RESULTS: Of the 565 publications retrieved by the literature review, 198 were included in the analysis. The five recommendations on nonpharmacological treatments for early RA were validated by a final vote among all participants. The recommendations are as follows: (1) physicians may decide to provide joint protection education to patients with potentially severe early RA, with the knowledge that structured joint protection programs have not been found effective; (2) physical exercise and sports can be recommended to patients with early RA; muscle strength exercises are advisable; (3) in patients with early RA, metatarsal pain and/or foot alignment abnormalities should be looked for regularly, and appropriate insoles should be prescribed if needed; (4) dietary measures and nutritional supplements are not indicated as part of the treatment of early RA; (5) elimination diets, particularly those with low intakes of dairy products, should be discouraged in patients with early RA. CONCLUSION: These recommendations should help to improve practice uniformity and, ultimately, to improve the management of RA.

Pavy S, Constantin A, Pham T, Gossec L, Maillefert JF, Cantagrel A, Combe B, Flipo RM, Goupille P, Le Loët X, Mariette X, Puéchal X, Schaeverbeke T, Sibilia J, Tebib J, Wendling D, Dougados M. · Service de rhumatologie A, CHU Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France. · Joint Bone Spine. · Pubmed #16626993 No free full text.

Abstract: OBJECTIVES: To develop clinical practice guidelines for the use of methotrexate in rheumatoid arthritis (RA), using the evidence-based approach and expert opinion. METHODS: A scientific committee used a Delphi procedure to select five questions, which formed the basis for developing recommendations. Evidence providing answers to the five questions was sought in the Cochrane databases, PubMed, and proceedings of meetings of the French Society for Rheumatology, European League Against Rheumatism, and American College of Rheumatology. Using this evidence, a group of rheumatologists developed and validated the recommendations. For each recommendation, the level of evidence and the extent of agreement among experts were specified. RESULTS: The recommendations were as follows: 1: The starting dosage for methotrexate in patients with RA should not be less than 10 mg/week and should be determined based on disease severity and patient-related factors; 2: When a patient with RA shows an inadequate response to methotrexate, the dosage should be increased at intervals of 6 weeks, up to 20 mg/week, according to tolerance and patient-related factors; 3: When starting methotrexate treatment in a patient with RA, preference should be given to the oral route. A switch to the intramuscular or subcutaneous route should be considered in patients with poor compliance, inadequate effectiveness, or gastrointestinal side effects; 4: At present, there is no evidence indicating that a change in methotrexate dosage is in order when a TNF antagonist is given concomitantly; 5: The investigations that are mandatory before starting methotrexate therapy in a patient with RA consist of a full blood cell count, serum transaminase levels, serum creatinine with computation of creatinine clearance, and a chest radiograph. In addition, serological tests for the hepatitis viruses B and C and a serum albumin assay are recommended. In patients with a history of respiratory disease or current respiratory symptoms, lung function tests with determination of the diffusing capacity for carbon monoxide are recommended; 6: Investigations that are mandatory for monitoring methotrexate therapy in patients with RA consist of full blood cell counts and serum transaminase and creatinine assays. These tests should be obtained at least once a month for the first 3 months then every 4-12 weeks; 7: Folate supplementation can be given routinely to patients treated with methotrexate for RA. In practice, a minimal dosage of 5 mg of folic acid once a week, at a distance from the methotrexate dose, is appropriate; 8: In the event of respiratory symptoms possibly related to methotrexate toxicity, the drug must be stopped and symptom severity evaluated. Should evidence of serious disease be found, the patient should be admitted immediately or advice from a pulmonologist should be obtained immediately. CONCLUSION: Recommendations about methotrexate therapy for RA were developed. These recommendations should help to improve practice uniformity and, ultimately, to improve the management of RA.

Saraux A, Fautrel B, Maillefert JF, Flipo RM, Kaye O, Lafforgue P, Gourves K, Guillemin F, Anonymous00195. · Rheumatology Units of the Brest, Dijon, Paris La Pitiè, Lille, and Marseille La Timone Teaching Hospitals, France. · J Rheumatol. · Pubmed #16583465 No free full text.

Abstract: OBJECTIVE: To conduct a practice survey of laboratory and imaging studies used by French rheumatologists to identify the cause of recent-onset arthritis. METHODS: We selected a random sample of 210 rheumatologists, who were asked to recruit all patients with recent-onset arthritis (at least one joint involved, for less than one year) during a 2 week period, and to record laboratory and imaging studies performed. Results were analyzed in the overall group, in diagnostic subgroups, and in clinical presentation subgroups. RESULTS: The 119 rheumatologists who participated recruited 104 patients. Investigations done in 50% to 75% of patients were blood cell counts; erythrocyte sedimentation rate; serum assays of C-reactive protein, rheumatoid factors, antinuclear antibodies; and hand radiographs. Investigations in 50% to 74% of patients were serum ASAT/ALAT, creatinine, and uric acid; and foot radiographs. Finally, 25% to 49% of patients were tested for proteinuria; antikeratin antibodies; hepatitis B, hepatitis C, and Lyme serologies; creatine phosphokinase; blood iron; HLA-B27; and radiographs of chest and pelvis. No differences were found between investigations in patients with suspected rheumatoid arthritis and/or undifferentiated arthritis and those in other patients. In contrast, suspected diagnoses and presence of extraarticular manifestations classically associated with specific diseases modified the selection of investigations. CONCLUSION: Although considerable variability occurred, our study suggests that a limited panel of laboratory and imaging studies is performed in at least 25% of patients with recent-onset arthritis, regardless of clues suggesting a specific diagnosis.

Solau-Gervais E, Laxenaire N, Cortet B, Dubucquoi S, Duquesnoy B, Flipo RM. · Service de Rhumatologie, Centre Hospitalier Régional et Universitaire de Lille, 59037 Lille cedex, France. · Rheumatology (Oxford). · Pubmed #16510526 links to  free full text

Abstract: OBJECTIVE: Some studies have highlighted the potential benefits of switching from infliximab to etanercept, or after failure of one or the other treatment. To our knowledge, no study has assessed the potential benefits of using the three anti-TNF-alpha agents that are currently available. The objective of this retrospective study was to assess the response to treatment in RA patients who had received the three anti-TNF-alpha agents, namely infliximab, etanercept and adalimumab. METHODS: Among a cohort of 364 patients undergoing biological treatments since the year 2000, 284 had been treated with only one anti-TNF-alpha agent. Our assessment focused on the records of 70 patients who had received at least two anti-TNF-alpha agents. Twenty of the 70 patients had received all three anti-TNF-alpha agents (infliximab, etanercept and adalimumab). Effectiveness was assessed using the 28-joint Disease Activity Score (DAS28), and adverse events were reported for each anti-TNF-alpha treatment. RESULTS: Of the 70 patients who had received two anti-TNF-alpha agents, 32 had switched from an antibody to a soluble receptor; 45% of them had a good clinical response to the soluble receptor. Thirty patients had switched from a soluble receptor to an antibody; 45% of them had a good clinical response to the antibody. Only eight patients had switched from an antibody to another antibody with an efficiency score of 33%. Of the 20 patients who had received three anti-TNF-alpha agents, seven had stopped receiving the third anti-TNF-alpha agent due to lack of effectiveness. In this group of non-responders to the third anti-TNF-alpha treatment, all patients except one had stopped receiving the two previous anti-TNF-alpha agents, without adverse events, for lack of effectiveness. These patients were deemed resistant to anti-TNF-alpha therapy. CONCLUSIONS: Resistance to anti-TNF-alpha agents is rare. The lack of effectiveness of a soluble receptor and of one of the anti-TNF-alpha antibodies predicts the lack of effectiveness of the third anti-TNF-alpha treatment.

Doyen V, Fournier C, Bautin N, Cortet B, Flipo RM, Wallaert B. · Centre de Ressources et Compétences pour la Mucoviscidose, Clinique des maladies respiratoires, Hôpital Calmette, CHRU, Lille, France. · Rev Mal Respir. · Pubmed #16294184 No free full text.

Abstract: INTRODUCTION: Inflammatory arthropathies are rare complications of cystic fibrosis (CF). We describe three cases of rheumatoid arthritis (RA) occurring in patients with this disease.OBSERVATIONS: Among the 100 patients under the care of the adult CF centre in Lille 3 presented with RA. This developed at the ages of 17, 44 and 19 years with a FEV1 of 53%, 42% and 94% respectively. They were 2 women and 1 man, with CFTR gene mutation delta F508 (1 homozygote and 2 heterozygotes) and positive sweat tests. They were colonised with Staphylococcus aureus, and rheumatoid factor and/or anti CCP antibodies were positive. The appearance and progression of RA were associated with exacerbations of bronchial infection and deterioration of respiratory function. In 2 patients the RA was continuously progressive despite intensive treatment involving high dose cortico-steroids, methotrexate (ineffective) followed by leflunomide (complicated by intractable respiratory infection).CONCLUSION: There is an increased incidence of RA in our patient population with CF. The new serum markers of RA including anti CCP are of diagnostic interest. The evolution of the two diseases is related and seems to be dependent on the level of infection leading to therapeutic problems.