Rheumatoid Arthritis: Lequerré T

Le Loët X, Lequerré T, Vittecoq O. · No affiliation provided · Joint Bone Spine. · Pubmed #16256398 No free full text.

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Vittecoq O, Lequerré T, Goëb V, Le Loët X, Abdesselam TA, Klemmer N. · Department of Rheumatology, Rouen University Hospital & Inserm U905, Rouen, France. · Best Pract Res Clin Rheumatol. · Pubmed #19028372 No free full text.

Abstract: Smoking has an impact on the development and outcome of rheumatoid arthritis (RA) and lupus. In RA, smoking is associated with the development of the anti-cyclic citrullinated peptide (CCP2)-positive subset. This risk is increased in heavy smokers carrying at least one copy of the HLA DRB1 shared epitope (SE) alleles. Whereas this interaction between smoking and SE relevant in northern Europe, discrepant results have been observed in other geographic locations, suggesting the involvement of other environmental stimuli and/or gene polymorphisms. There is no interaction between tobacco exposure and PTPN22 1858T for the development of anti-CCP-positive or anti-CCP-negative RA. A strong association exists between smoking and the occurrence of extra-articular manifestations (subcutaneous nodules and cardiovascular events), but smoking has no influence on radiographic outcome. In lupus, tobacco exposure has an impact on the production of anti-double-stranded Desoxyribonuclic (dsDNA) and possibly on the development of the disease, as well as on disease activity/severity. In both diseases, smoking might interfere with drug efficacy.

Lequerré T, Coulouarn C, Derambure C, Lefebvre G, Vittecoq O, Daveau M, Salier JP, Le Loët X. · Rheumatology department, Hôpital de Boisguillaume, CHU de Rouen - Hôpitaux de Rouen, 76031 Rouen cedex, France. · Joint Bone Spine. · Pubmed #12951306 No free full text.

Abstract: Large-scale analysis of gene expression with cDNA arrays is spreading over many biological fields, including rheumatology. In this report, we wish to explain the principle and main advantages of this tool in the context of our discipline. Until 1995, analysis of gene expression was conducted for a few genes at a time but DNA chips now allow one to monitor the expression of thousands of genes in a single experiment and analyze the transcriptome, i.e. the whole of the transcripts in a given cell or tissue. Whatever the platform used (macro- or microarrays, oligo-chips), this technology rests upon the hybridization of i) a set of cDNA clones tethered to a solid support (nylon or glass) as probes, and ii) labelled cDNAs that are reverse-transcribed from bulk mRNAs extracted from a cell or tissue sample as a target. The end result is information on the relative abundance of every mRNA between two or more samples. The transcriptome analysis has two main objectives in rheumatology: i) identifying a gene expression profile that is a hallmark of a pathology and using it for a diagnostic or prognostic purpose, and ii) gathering genes with similar changes of expression, which allows one to specify the identity of novel proteins involved in a well-known intracellular cascade of regulation or even to identify new cascades.

Lequerré T, Quartier P, Rosellini D, Alaoui F, De Bandt M, Mejjad O, Kone-Paut I, Michel M, Dernis E, Khellaf M, Limal N, Job-Deslandre C, Fautrel B, Le Loët X, Sibilia J, Anonymous00361, Anonymous00362. · Rheumatology Department, Rouen University Hospital & Inserm 905, 76031 Rouen, France. · Ann Rheum Dis. · Pubmed #17947302 No free full text.

Abstract: BACKGROUND: Anakinra treatment has been reported to be effective in some patients with systemic-onset juvenile idiopathic arthritis (SoJIA) or adult-onset Still disease (AoSD). OBJECTIVES: To assess the efficacy and the safety of anakinra treatment in SoJIA and AoSD. METHODS: SoJIA and AoSD patients were treated with anakinra (1-2 mg/kg/day in children, 100 mg/day in adults); we analysed its effect on fever, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, numbers of swollen and tender joints, the assessment of disease activity (by physician and parent/patient) and pain (by parent/patient), and American College of Rheumatology (ACR) pediatric core set criteria for JIA activity. RESULTS: A total of 35 patients were included, 20 with SoJIA and 15 with AoSD. Their mean age (range) at the onset of treatment was 12.4 (3-23) and 38.1 (22-62) years, respectively; disease duration was 7.0 (1-16) and 7.8 (2-27) years, respectively. Active arthritis was present in all cases but one. Of the 20 SoJIA patients, 5 achieved ACR 50% improvement in symptoms (ACR50) response criteria at 6 months. Steroid dose had been decreased by 15% to 78% in 10 cases. A total of 11 of the 15 AoSD patients achieved at least a 50% improvement for all disease markers (mean follow-up: 17.5 (11-27) months). Steroids had been stopped in two cases and the dose was decreased by 45% to 95% in 12 patients. Two patients stopped anakinra due to severe skin reaction, and two patients due to infection: one visceral leishmaniasis and one varicella. CONCLUSION: Anakinra was effective in most AoSD patients, but less than half SoJIA patients achieved a marked and sustained improvement.

Lequerré T, Bansard C, Vittecoq O, Derambure C, Hiron M, Daveau M, Tron F, Ayral X, Biga N, Auquit-Auckbur I, Chiocchia G, Le Loët X, Salier JP. · Department of Rheumatology, Rouen University Hospital and Inserm 905 & Institut Fédératif de Recherche Multidisciplinaire sur les Peptides 23, Institute for Biomedical Research, University of Rouen, 76031 Rouen Cedex, France. · Arthritis Res Ther. · Pubmed #19563633 links to  free full text

Abstract: INTRODUCTION: Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. METHODS: Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation. RESULTS: Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. CONCLUSIONS: Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment.

Lanfant-Weybel K, Lequerré T, Vittecoq O. · Service de rhumatologie, CHU de Rouen-Hôpitaux de Rouen, Inserm 905, F-76031 Rouen Cedex, France. · Presse Med. · Pubmed #19327945 No free full text.

Abstract: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are, with psoriatic arthritis, the most frequent rheumatic diseases. A better understanding of pathophysiology of these diseases had led to the development of new treatments refered as to biologic agents and, among them, TNF blocking agents have a major role. The knowledge of these drugs in terms of mechanisms of action, indications and potentials side effects has to be known to improve the efficacy/tolerance balance. Although these 3 anti-TNFalpha agents are currently used, new TNF blocking agents are under evaluation and should increase the number of drugs available within the next months.

Bacquet-Deschryver H, Jouen F, Quillard M, Ménard JF, Goëb V, Lequerré T, Mejjad O, Daragon A, Tron F, Le Loët X, Vittecoq O. · Department of Rheumatology, Rouen University Hospital & Inserm U905 (IFRMP 23), Institute for Biomedical Research, University of Rouen, 76031 Rouen Cedex, France. · J Clin Immunol. · Pubmed #18587633 No free full text.

Abstract: OBJECTIVE: The objective of this study was to analyze the effects of 3 anti-TNFalpha agents on markers of autoimmunity in rheumatoid arthritis (RA) and spondylarthropathy (SPA) patients. METHODS: First-time anti-TNFalpha biologics (infliximab, etanercept, or adalimumab) were prescribed to 156 RA and 95 SPA (58 ankylosing spondylarthritides, 37 psoriatic arthritides). During 1-2 years of follow-up, clinical, biological [antinuclear (ANA) and anti-double-stranded (dsDNA) antibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP) for RA], and therapeutic data were collected biannually. RESULTS: ANA appeared or ANA and anti-dsDNA titers increased significantly (P < 0.001) more under infliximab than etanercept in both rheumatisms and than adalimumab in RA patients. During the 2-year follow-up, ANA appeared more in RA patients taking adalimumab than etanercept (P = 0.003), but independently of the anti-TNFalpha used; anti-dsDNA titers rarely became positive. Under etanercept or infliximab, ANA and anti-dsDNA were not influenced by the underlying pathology nor were they affected by infliximab intensification over 18 months. Only one case of cutaneous lupus was observed in a patient having IgG anti-dsDNA. The therapeutic responses were independent of ANA and anti-dsDNA titers for all rheumatisms and biologics. In RA patients, RF titers, but not anti-CCP levels, declined with the therapeutic response for all biologics. CONCLUSION: This is the first study that has evaluated the impact of three TNFalpha blockers on ANA and anti-dsDNA antibodies in RA and SPA patients. Autoimmunity was more induced with infliximab than etanercept and to a lesser degree to adalimumab but, more importantly, this emergent autoimmunity was exceptionally associated to clinical manifestations of lupus.

Devauchelle V, Essabbani A, De Pinieux G, Germain S, Tourneur L, Mistou S, Margottin-Goguet F, Anract P, Migaud H, Le Nen D, Lequerré T, Saraux A, Dougados M, Breban M, Fournier C, Chiocchia G. · Institut Cochin, Département d'Immunologie, 27 rue du Faubourg Saint-Jacques, 75674 Paris Cedex 14, France. · J Immunol. · Pubmed #17056579 links to  free full text

Abstract: We previously compared by microarray analysis gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) tissues. Among the set of genes identified as a molecular signature of RA, clusterin (clu) was one of the most differentially expressed. In the present study we sought to assess the expression and the role of CLU (mRNA and protein) in the affected joints and in cultured fibroblast-like synoviocytes (FLS) and to determine its functional role. Quantitative RT-PCR, Northern blot, in situ hybridization, immunohistochemistry, and Western blot were used to specify and quantify the expression of CLU in ex vivo synovial tissue. In synovial tissue, the protein was predominantly expressed by synoviocytes and it was detected in synovial fluids. Both full-length and spliced isoform CLU mRNA levels of expression were lower in RA tissues compared with OA and healthy synovium. In synovium and in cultured FLS, the overexpression of CLU concerned all protein isoforms in OA whereas in RA, the intracellular forms of the protein were barely detectable. Transgenic overexpression of CLU in RA FLS promoted apoptosis within 24 h. We observed that CLU knockdown with small interfering RNA promoted IL-6 and IL-8 production. CLU interacted with phosphorylated IkappaBalpha. Differential expression of CLU by OA and RA FLS appeared to be an intrinsic property of the cells. Expression of intracellular isoforms of CLU is differentially regulated between OA and RA. We propose that in RA joints, high levels of extracellular CLU and low expression of intracellular CLU may enhance NF-kappaB activation and survival of the synoviocytes.

Lequerré T, Jouen F, Brazier M, Clayssens S, Klemmer N, Ménard JF, Mejjad O, Daragon A, Tron F, Le Loët X, Vittecoq O. · Department of Rheumatology, Rouen University Hospital, Rouen Cedex, France. · Rheumatology (Oxford). · Pubmed #16899502 links to  free full text

Abstract: OBJECTIVES: To identify biochemical, immunological and bone markers as predictors of rheumatoid arthritis (RA) patients' responses to infliximab. METHODS: A total of 76 patients with active RA (American College of Rheumatology criteria), refractory to disease-modifying anti-rheumatic drugs, including methotrexate, received infliximab (3 mg/kg) infusions at weeks 0, 2, 6, and then every 8 weeks in combination with methotrexate or leflunomide. At week 14, infliximab efficacy was evaluated using disease activity score (DAS)28. A serum sample, collected just before starting infliximab, was tested by ELISA (unless stated otherwise) for the following immunological markers: rheumatoid factor by agglutination and ELISA (IgA, IgG and IgM isotypes); anti-cyclic citrullinated protein; autoantibodies recognizing calpastatin domain I and its 27 C-terminal fragment, glucose-6-phosphate isomerase, alpha-enolase; anti-keratin and anti-perinuclear factor antibodies (immunofluorescence); biochemical markers: C-reactive protein (nephelometry), metalloproteinase-1 and -3, tissue inhibitors of metalloproteinases-1 and -2, antioxidants (vitamins A and E; selenium); bone resorption markers: pyridinoline, deoxypyridinoline, osteoprotegerin, soluble receptor activator of nuclear factor-kappaB ligand, cartilage oligomeric matrix protein. Each parameter's predictive value of the response to infliximab was analysed using Fisher's exact, Mann-Whitney and chi-square tests. Hierarchical clustering was performed with The Institute for Genomic Research (TIGR) multiple experiment viewer software. RESULTS: Good, moderate and non-responder rates were 6.5, 61.8 and 31.5%, respectively. No significant difference was observed between responders and non-responders, regardless of the serum parameters considered. Analysis of dichotomous or continuous variables failed to identify markers predictive of a good or poor response to infliximab. CONCLUSION: The search for soluble markers in RA patients' sera likely to predict response to infliximab because of their involvement in RA pathogenesis seems disappointing. However, because of the limited power to detect smaller differences in biomarkers, the present study is a preliminary exploratory analysis.

Lequerré T, Gauthier-Jauneau AC, Bansard C, Derambure C, Hiron M, Vittecoq O, Daveau M, Mejjad O, Daragon A, Tron F, Le Loët X, Salier JP. · CHU de Rouen, Hôpitaux de Rouen, Service de Rhumatologie, Rouen, F-76000, France. · Arthritis Res Ther. · Pubmed #16817978 links to  free full text

Abstract: As indicators of responsiveness to a tumour necrosis factor (TNF)alpha blocking agent (infliximab) are lacking in rheumatoid arthritis, we have used gene profiling in peripheral blood mononuclear cells to predict a good versus poor response to infliximab. Thirty three patients with very active disease (Disease Activity Score 28 >5.1) that resisted weekly methotrexate therapy were given infliximab at baseline, weeks 2 and 6, and every 8th week thereafter. The patients were categorized as responders if a change of Disease Activity Score 28 = 1.2 was obtained at 3 months. Mononuclear cell RNAs were collected at baseline and at three months from responders and non-responders. The baseline RNAs were hybridised to a microarray of 10,000 non-redundant human cDNAs. In 6 responders and 7 non-responders, 41 mRNAs identified by microarray analysis were expressed as a function of the response to treatment and an unsupervised hierarchical clustering perfectly separated these responders from non-responders. The informativeness of 20 of these 41 transcripts, as measured by qRT-PCR, was re-assessed in 20 other patients. The combined levels of these 20 transcripts properly classified 16 out of 20 patients in a leave-one-out procedure, with a sensitivity of 90% and a specificity of 70%, whereas a set of only 8 transcripts properly classified 18/20 patients. Trends for changes in various transcript levels at three months tightly correlated with treatment responsiveness and a down-regulation of specific transcript levels was observed in non-responders only. Our gene profiling obtained by a non-invasive procedure should now be used to predict the likely responders to an infliximab/methotrexate combination.

Lequerré T, Vittecoq O, Klemmer N, Goëb V, Pouplin S, Menard JF, Daragon A, Mejjad O, Le Loët X. · Department of Rheumatology, Rouen University Hospital, Rouen, France. · J Rheumatol. · Pubmed #16758513 No free full text.

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

Lequerré T, Vittecoq O, Le Loët X. · No affiliation provided · Joint Bone Spine. · Pubmed #16038851 No free full text.

This publication has no abstract.