Rheumatoid Arthritis: Tron F

Vittecoq O, Goeb V, Le Loët X, Tron F. · No affiliation provided · Joint Bone Spine. · Pubmed #15996501 No free full text.

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Vittecoq O, Jouen-Beades F, Tron F, Le Loët X. · Inserm U-519, IFR 23, Rhumatology Department, Centre Hospitalier Universitaire de Rouen, Hĵpitaux de Rouen, France. · Joint Bone Spine. · Pubmed #11808982 No free full text.

Abstract: The vascular endothelium is a common target of inflammatory joint disease. Autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome can be responsible for a spectrum of vascular disorders that encompasses vasculitis, thrombosis and/or atheroma associated with the antiphospholipid syndrome, and vascular damage caused by cryoglobulin deposition. These mechanisms can coexist, particularly in lupus patients. Joint disease is sometimes the presenting manifestation in primary vasculitis. Autoantibodies are detectable in most patients with vascular involvement and inflammatory joint disease. They are not merely markers for vascular involvement: in vitro and in vivo data suggest that some autoantibodies may contribute to the genesis of endothelial lesions, together with other factors. For instance, evidence of pathogenic effects has been found for antineutrophil cytoplasmic antibody (ANCA), most notably with antimyeloperoxidase or antiproteinase-3 specificity, in small-vessel vasculitides (Wegener's granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis); for immune complexes, particularly those containing cryoglobulins, in vasculitides secondary to CTDs; and for circulating anticoagulant and anticardiolipin antibodies, above all anti-beta2-glycoprotein I, in antiphospholipid syndrome. Antibodies to annexin V, modified lipoproteins, and endothelial cells may be of interest; their clinical relevance is unclear, however, and no standardized assays are available, so thatthese antibodies are not looked for in everyday practice. When deciding which antibody tests should be performed in a given patient, the circumstances surrounding the onset of the vasculopathy should be borne in mind. In patients with previous CTD, the tests are selected based on the diagnosis. In contrast, in a patient with no previous diagnosis, a vasculopathy can be either primary or secondary to undiagnosed CTD or to antiphospholipid syndrome: consequently, a broader array of tests is needed in this situation.

Vittecoq O, Jouen-Beades F, Krzanowska K, Bichon-Tauvel I, Ménard JF, Daragon A, Tron F, Le Loët X. · Service de rhumatologie, CHU de Rouen, France. · Joint Bone Spine. · Pubmed #11324930 No free full text.

Abstract: OBJECTIVE: To determine whether measurements of different autoantibodies (Ab) and cytokines are useful to distinguish very early rheumatoid arthritis (RA) from other inflammatory rheumatisms. METHODS: From a population-based recruitment, 32 patients with very early polyarthritis (median duration: 4 months) were studied. Evaluations at entry (M0), and at 6 (M6) and 12 months (M12). Ab tested: rheumatoid factors (RF) by agglutination methods and ELISA, antiperinuclear factor (APF), antikeratin Ab (AKA), anti-Sa and antinuclear Ab. Cytokine production (TNFalpha, IL2, IFNgamma, IL1beta, IL10) in whole blood cell culture (WBCC) was determined at M0. At M12, patients were classified as having RA (N = 15) or other rheumatic diseases. RESULTS: At M0, AKA/APF and anti-Sa Ab frequencies were low, 13% and 7%, respectively. While most Ab detected at M0 persisted, others appeared during follow-up, particularly APF, which rose from 13 to 40% at M12. At M6, IgM-RF was detected in two RA patients exclusively by ELISA. AKA/APF were found to be highly specific markers for RA (100% specificity). At some time during follow-up, two RF-negative RA patients were AKA-positive. In two patients, AKA and APF were present at M0 before they satisfied ACR criteria. IL2 and IFNgamma production was significantly lower (P < 0.05) for RA patients. CONCLUSION: AKA/APF and anti-Sa Ab were detected in community cases of very early RA. AKA/APF and RF detected by ELISA might contribute to an earlier diagnosis of RA. Low production of IFNgamma and IL2 in WBCC constituted a distinct immunopathological feature in very early RA patients.

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.

Goëb V, Jouen F, Gilbert D, Le Loët X, Tron F, Vittecoq O. · Service de Rhumatologie, Institut de Recherche Biomédicale, CHU-Hôpitaux de Rouen, France. · Joint Bone Spine. · Pubmed #19524474 No free full text.

Abstract: The diagnosis of rheumatoid arthritis (RA) must be made early, because prompt initiation of treatments tailored to disease activity is crucial to improve structural and functional outcomes. Anti-citrullinated peptide antibodies (ACPAs) are well-established diagnostic markers for RA and should be included in the classification criteria. Here, we describe the main tests for detecting ACPAs and we underline the diagnostic and prognostic usefulness of ACPAs in patients with RA. The presence of ACPAs predicts poorer functional and structural outcomes, and ACPA titers respond to some of the medications used in RA. Therefore, ACPA titers should be determined at regular intervals throughout follow-up.

Goëb V, Thomas-L'Otellier M, Daveau R, Charlionet R, Fardellone P, Le Loët X, Tron F, Gilbert D, Vittecoq O. · Department of Rheumatology and Inserm Unit 905, IFRMP 23, Institute for Biomedical Research, University of Rouen, Rouen University Hospital, Rouen 76031 cedex, France. · Arthritis Res Ther. · Pubmed #19284558 links to  free full text

Abstract: INTRODUCTION: The aim of our study was to identify new early rheumatoid arthritis (RA) autoantibodies. METHODS: Sera obtained from 110 early untreated RA patients (<6 months) were analyzed by western blot using HL-60 cell extract, separated on one-dimensional and two-dimensional gel electrophoresis (1-DE, 2-DE). Sera from 50 healthy blood donors and 20 patients with non-RA rheumatisms were used as controls for 1-DE and 2-DE, respectively. The immunoreactive proteins were identified by MALDI-TOF mass spectrometric analysis and the presence of potential sites of citrullination in each of these proteins was evaluated. FT-ICR mass spectrometry was used to verify experimentally the effect of citrullination upon the mass profile observed by MALDI-TOF analysis. RESULTS: The 110 1-DE patterns allowed detection of 10 recurrent immunoreactive bands of 33, 39, 43, 46, 51, 54, 58, 62, 67 and 70 kDa, which were further characterized by 2-DE and proteomic analysis. Six proteins were already described RA antigens: heterogeneous nuclear ribonucleoprotein A2/B1, aldolase, alpha-enolase, calreticulin, 60 kDa heat shock protein (HSP60) and BiP. Phosphoglycerate kinase 1 (PGK1), stress-induced phosphoprotein 1 and the far upstream element-binding proteins (FUSE-BP) 1 and 2 were identified as new antigens. Post-translational protein modifications were analyzed and potentially deiminated peptides were found on aldolase, alpha-enolase, PGK1, calreticulin, HSP60 and the FUSE-BPs. We compared the reactivity of RA sera with citrullinated and noncitrullinated alpha-enolase and FUSE-BP linear peptides, and showed that antigenicity of the FUSE-BP peptide was highly dependent on citrullination. Interestingly, the anti-cyclic citrullinated peptide antibody (anti-CCP2) status in RA serum at inclusion was not correlated to the reactivity directed against FUSE-BP citrullinated peptide. CONCLUSIONS: Two categories of antigens, enzymes of the glycolytic family and molecular chaperones are also targeted by the early untreated RA autoantibody response. For some of them, and notably the FUSE-BPs, citrullination is involved in the immunological tolerance breakdown observed earlier in RA patients. Autoantibodies recognizing a citrullinated peptide from FUSE-BP may enhance the sensibility for RA of the currently available anti-CCP2 test.

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.

Goëb V, Dieudé P, Daveau R, Thomas-L'otellier M, Jouen F, Hau F, Boumier P, Tron F, Gilbert D, Fardellone P, Cornélis F, Le Loët X, Vittecoq O. · Department of Rheumatology, Rouen University Hospital & Inserm, Institute for Biomedical Research, University of Rouen, France. · Rheumatology (Oxford). · Pubmed #18535030 No free full text.

Abstract: OBJECTIVES: To evaluate the predictive value of TNFRII 196R, PTPN22 1858T and HLA-shared epitope (SE) alleles, RFs and anti-citrullinated protein antibodies (ACPAs) for RA diagnosis in a cohort of patients with very early arthritis. METHODS: We followed up 284 patients who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for <6 months. At 2 yrs, patients were classified as having RA or non-RA rheumatic diseases according to the ACR criteria. Patients were genotyped with respect to TNFRII 196M/R and PTPN22 1858C/T polymorphisms and HLA-SE. The presence of IgA, IgG and IgM RF isotypes and ACPA was sought in sera collected at disease onset. RESULTS: HLA-SE alleles alone, concomitant presence of TNFRII 196R and PTPN22 1858T alleles, IgA, IgG and IgM RF alone and ACPA were found to be significantly associated with RA diagnosis. Using logistic regression analysis, the concomitant presence of RF and ACPA at disease onset was the best association to predict RA diagnosis. In patients (n = 34) who did not fulfil the ACR criteria for RA at inclusion but who progressed to ACR positivity, the study of the genetic risk markers did not contribute to predict RA diagnosis at 2 yrs. CONCLUSIONS: PTPN22 1858T, TNFRII 196R and HLA-SE alleles do not improve the predictive value of RF and ACPA for RA diagnosis in our cohort, and do not contribute to an earlier diagnosis in undifferentiated patients initially negative for RF and ACPA.

Goëb V, Salle V, Duhaut P, Jouen F, Smail A, Ducroix JP, Tron F, Le Loët X, Vittecoq O. · Department of Rheumatology, Rouen University Hospital & Inserm U519 (IFRMP23), Institute for Biomedical Research, University of Rouen, Rouen, France. · Clin Exp Immunol. · Pubmed #17286756 links to  free full text

Abstract: The aim of our study was (i) to compare the clinical and biological characteristics of 148 (137 women, 11 men) primary Sjögren's syndrome (pSS) patients at diagnosis as a function of their sex and (ii) to assess the prognostic value of anti-calpastatin and anti-alpha-fodrin autoantibodies. In addition, the presence of anti-nuclear antibodies (ANA), anti-52- and 60-kDa Sjögren's syndrome A (SSA), anti-Sjögren's syndrome B (SSB), anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factors (RF) of IgA, IgG and IgM isotypes was sought in sera collected at pSS onset. Raynaud's syndrome, significantly more frequent in women, was the only systemic manifestation of pSS whose frequency differed significantly as a function of the patient's sex (P = 0.02). ANA (P = 0.001) and anti-60-kDa SSA autoantibodies (P = 0.03) were significantly more common in women, while men never synthesized detectable levels of anti-SSB, anti-calpastatin or IgG anti-alpha-fodrin autoantibodies. In addition, anti-CCP autoantibodies were found in low percentages of pSS patients (4% F/18% M). The absence of autoantibodies does not exclude the diagnosis of pSS in men that will be based mainly on the anatomopathological findings of a minor salivary gland biopsy. Positivity of anti-60-kDa SSA, anti-SSB, anti-calpastatin, IgA and IgG anti-alpha-fodrin antibodies is not associated with pSS clinical and biological severity.

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.

Goëb V, Dieudé P, Vittecoq O, Mejjad O, Ménard JF, Thomas M, Gilbert D, Boumier P, Pouplin S, Daragon A, Fardellone P, Tron F, Cornélis F, Le Loët X. · Rheumatology Department, University Hospital of Rouen, Rouen, France. · Arthritis Res Ther. · Pubmed #16207322 links to  free full text

Abstract: Tumour necrosis factor (TNF)-alpha plays a key role in the pathogenesis of rheumatoid arthritis (RA). It binds to two receptors, namely TNF receptor (TNFR)I and TNFRII. Several studies have suggested an association between TNFRII 196R/R genotype and RA. The objective of the present study was to evaluate the predictive value of the TNFRII 196R allele for RA diagnosis and prognosis in a cohort of patients with very early arthritis. We followed up a total of 278 patients recruited from the community, who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for less than 6 months, and who had not received disease-modifying antirheumatic drugs or steroid therapy. At 2 years, patients were classified according to the American College of Rheumatology criteria. All patients were genotyped with respect to TNFRII 196M/R polymorphism. Radiographs of hands and feet (read according to the modified Sharp method) and the Health Assessment Questionnaire were used to quantify structural and functional severity. The cohort of 278 patients was found to include 156 and 122 RA and non-RA patients, respectively. The TNFRII 196R allele was found to be associated with RA (P = 0.002). However, progression of radiographic severity and Health Assessment Questionnaire scores over 1 year did not differ between carriers of the 196R allele and noncarriers. Our findings suggest that the TNFRII 196R allele may be associated with RA diagnosis but that it does not predict early radiographic progression or functional severity in patients with very early, unclassified arthritis.

Salle V, Vittecoq O, Jouen-Beades F, Ménard JF, Ducroix JP, Godin M, Le Loët X, Tron F. · Inserm U519 and Institut Fédératif de Recherche Multidisciplinaire sur les Peptides (IFR 23), Faculté de Médecine et de Pharmacie, Rouen, France. · Lupus. · Pubmed #15540513 No free full text.

Abstract: The objective of this study was to determine in systemic lupus erythematosus (SLE) the prevalence and clinical significance of anticalpastatin antibodies (ACAST), an autoantibody population previously detected in sera from patients with various connective tissue diseases. Eighty-four patients with SLE (mean age: 30 years at diagnosis, females 77) that fulfilled ACR criteria were included in the study retrospectively. Several clinical and biological data were collected. ACAST were detected by a solid-phase enzyme linked immunosorbent assay (ELISA) using as antigen a synthetic peptide corresponding to the 27 C-terminal amino acids of calpastatin (CAST-C27). The prevalence of ACAST-C27 was 13% (11/84) in SLE patients. No correlation was found between the presence of ACAST-C27 and clinical manifestations such as thrombosis and vasculitis. Furthermore, no correlation was observed with the presence ofantiphospholipid antibodies (APL). However, we found a statistically significant association between the presence of ACAST-C27 and that of secondary Sjögren syndrome (P = 0.01). The conclusion is ACAST-C27 are not associated with thrombosis in SLE patients. The association observed between ACAST-C27 and secondary Sjögren syndrome suggests that ACAST-C27 might be useful in discriminating a clinical subgroup of SLE patients.

Jouen F, Vittecoq O, Leguillou F, Tabti-Titon I, Menard JF, Mejjad O, Pouplin S, Boumier P, Fardellone P, Gayet A, Gilbert D, Tron F, Le Loët X. · INSERM 519, Institut Fédératif de Recherche Multidisciplinaire sur les Peptides (IFR MP 23), Faculté de Médecine et de Pharmacie, Rouen, France. · Clin Exp Immunol. · Pubmed #15320914 links to  free full text

Abstract: The objective of this study was to determine the diagnostic and prognostic values of antiglucose-6-phosphate isomerase (GPI) antibodies in patients with very early arthritis. Anti-GPI antibodies were measured by ELISA using purified GPI from rabbit muscle in: (i) 383 sera from healthy blood donors (n = 120), well-established rheumatoid arthritis (RA) (n = 99) and non-RA differentiated arthritis (NRADA) (n = 164) patients; (ii) 195 sera obtained from community-recruited patients with very early inflammatory arthritis (VErA cohort) that were studied for 1 year and classified as having RA (n = 116), NRADA (n = 41), and undifferentiated arthritis (UA) (n = 38) after the follow-up period. The criterion for severity was the progression of radiographic damage. Prevalence of anti-GPI antibodies was significantly higher in well-established RA patients (45.4%) compared to healthy subjects (2.5%). Anti-GPI antibodies were also present in sera from NRADA: systemic lupus erythematosus 53%, polymyositis 45.4%, adult-onset Still's disease 44%, systemic sclerosis 42.8%, spondylarthropathies 25% and primary Sjögren's syndrome 5.8%. No significant association was found between the presence of anti-GPI antibodies and the 3 diagnostic groups from the VErA cohort. No correlation was observed between anti-GPI and autoantibodies usually associated with RA. Anti-GPI antibodies were not predictive of radiological progression in patients with very early arthritis. Thus, anti-GPI antibodies are not useful for discriminating RA from non-RA rheumatic diseases and do not constitute a predictive factor of structural damage.

Vittecoq O, Incaurgarat B, Jouen-Beades F, Legoedec J, Letourneur O, Rolland D, Gervasi G, Ménard JF, Gayet A, Fardellone P, Daragon A, Jolivet M, le Loët X, Tron F. · INSERM unité 519 and Institut Fédératif de Recherche Multidisciplinaire sur les Peptides (IFR 23), Faculté Mixte de Médecine et de Pharmacie, Department of Rheumatology, Centre Hospitalier Universitaire de Rouen, France. · Clin Exp Immunol. · Pubmed #14678280 links to  free full text

Abstract: The objective of the study was to determine the diagnostic value for rheumatoid arthritis (RA) of anti-filaggrin autoantibodies (autoAb) recognizing citrullinated recombinant rat filaggrin (ACRF) in community cases of very early arthritis. To evaluate the diagnostic value of ACRF, were studied sera from patients with different classified rheumatic diseases and healthy subjects (group 1, n= 422) and 314 community cases of very early arthritis (group 2) that were classified as RA (n = 176), non-RA (n = 63) and undifferentiated (n = 75) arthritides after 1 years of follow-up. ACRF were measured using a new ELISA, with results expressed as the difference between the OD value obtained on citrullinated minus that on noncitrullinated rat filaggrin (differential ACRF; dACRF). For both groups, rheumatoid factors (RF), anti-keratin autoAb (AKA) and anti-perinuclear factor (APF) were tested; for group 2, anti-CCP autoAb were also tested. Different reactivity patterns against citrullinated and noncitrullinated filaggrin were observed. Almost all sera reacting with citrullinated but not noncitrullinated filaggrin were from RA patients. Among RA and non-RA sera that recognized both forms of filaggrin, a positive result was obtained only with RA sera. For groups 1 and 2, dACRF sensitivity was 58.4% and 30.7%, and specificity for RA was 99.5% and 98.4%, respectively. In group 2, dACRF specificity for RA was better than that of RF (92.1%), APF (95.2%), AKA (96.8%) and anti-CCP (95.2%). dACRF positive predictive value was high (98.2) and close to that given by the concomitant positivity of RF and anti-CCP autoAb. Despite a high positive correlation between AKA, APF, anti-CCP and dACRF test results, they were complementary since some sera were positive for only one test. Thus, in a community setting, anti-citrullinated rat filaggrin reactivity detected by a new ELISA, whose originality is based on the difference between serum's reactivities on the citrullinated and native forms of filaggrin, had a higher diagnostic value for RA than other autoAb.

Vittecoq O, Pouplin S, Krzanowska K, Jouen-Beades F, Menard JF, Gayet A, Daragon A, Tron F, Le Loet X. · Inserm Unité 519 and Institut Fédératif de Recherche Multidisciplinaire sur les Peptides (IFRMP 23), Faculté de Médecine et de Pharmacie, Rouen, France. · Rheumatology (Oxford). · Pubmed #12730503 links to  free full text

Abstract: OBJECTIVE: To evaluate the predictive value of clinical, biological and radiological parameters for the prognosis of rheumatoid arthritis (RA) in a community-recruited cohort. METHODS: Ninety-one patients (mean age 49 yr, female/male ratio 2.9) with RA of limited duration (median 2 yr), 80% recruited from the community, were prospectively enrolled in 1996 (T1) and followed until 1999 (T2). Data collected at T1 were demographic characteristics, Ritchie articular index (RAI), extra-articular manifestations, Health Assessment Questionnaire (HAQ) score, C-reactive protein (CRP) and autoantibodies (autoAbs) [rheumatoid factors (RF), detected by latex fixation test and ELISA (IgM, IgA and IgG isotypes), anti-filaggrin, detected by immunofluorescence (anti-keratin antibodies, AKA; anti-perinuclear factor antibodies, APF) and ELISA (anti-citrullinated rat filaggrin antibodies, ACRFA), anti-Sa, anti-calpastatin recognizing the 27 C-terminal fragment (ACAST-C27) and domain I (ACAST-DI), anti-cardiolipin (ACL), antineutrophil cytoplasmic antibodies (ANCA), anti-annexin V (aANX V) and anti-Ro]. Hands were radiographed at T1 and T2, and read using the Sharp method as modified by van der Heijde. The main assessment criterion was progression of radiologically detected damage between T1 and T2. RESULTS: At T1, RA activity was mild (RAI 11/78; mean CRP 14 mg/ml), with minor functional disability (HAQ 0.8/3) and mild X-ray destruction (mean total Sharp score 9.2/280). At T1, 96% of the patients were on treatment (prednisone 72%, DMARDs 95%). The latex test detected autoAb in 46% of patients, RF-IgM was detected in 51%, RF-IgA in 36%, RF-IgG in 32%, AKA in 33%, APF in 45%, ACRFA in 45%, ACAST-C27 in 14%, ACAST-DI in 5%, anti-Sa in 22%, ACL in 3%, ANCA in 28%, aANX V in 9% and anti-Ro in 2%. At T2, the mean total Sharp score was 22.9. According to univariate analysis, T1 parameters associated with the independent variable were RAI, HAQ, CRP, latex test positivity and T1 Sharp scores. Multivariate analysis retained only latex test positivity and, to a lesser degree, joint-space narrowing score as independent predictors of radiological progression. CONCLUSION: RF is the main factor that can predict radiological progression in community cases of RA of limited duration.

Saulot V, Vittecoq O, Salle V, Drouot L, Legoedec J, Le Loët X, Godin M, Ducroix JP, Ménard JF, Tron F, Gilbert D. · INSERM Unité 519, IFRMP-23, Faculté Mixte de Médecine et Pharmacie, 22, bd Gambetta, 76183, Rouen Cedex, France. · J Autoimmun. · Pubmed #12367559 No free full text.

Abstract: To identify new autoantibody populations in patients with rheumatic diseases, a cDNA expression library was immunoscreened with a rheumatoid arthritis (RA) patient's serum which contains autoantibodies binding to uncharacterized polypeptides by Western-blotting. One clone encoding the amino-terminal region (Nt) [domain L and half of domain I] of human calpastatin was selected. Different fragments of the selected cDNA were prepared and the corresponding recombinant polypeptides were produced by in vitro translation and analysed by Western blotting. Most RA sera bound to recombinant amino-terminal region and domain I but not to domain L. This prompted us to use a recombinant polypeptide corresponding to the domain I of calpastatin as the antigen in a solid-phase ELISA to test sera from patients with various systemic rheumatic diseases and healthy controls.Anti-calpastatin domain I antibodies (ACAST-DI Ab), were detected by ELISA in RA, systemic lupus erythematosus (SLE), Sjögren's syndrome and control sera at respective frequencies of 10, 9, 0 and 1%. These Ab did not have prognostic value in early RA; high levels were significantly associated with vasculitis in SLE.Antibodies reacting with the calpastatin amino-terminal region are produced during systemic rheumatic diseases and are predominantly directed against domain I. High levels of these Ab may constitute a marker of vasculitis in SLE.

Saulot V, Vittecoq O, Charlionet R, Fardellone P, Lange C, Marvin L, Machour N, Le Loët X, Gilbert D, Tron F. · Institut National de la Santé et de la Recherche Médicale, Rouen, France. · Arthritis Rheum. · Pubmed #12115223 links to  free full text

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

Vittecoq O, Salle V, Jouen-Beades F, Krzanowska K, Ménard JF, Gayet A, Fardellone P, Tauveron P, Le Loët X, Tron F. · Unité INSERM 519 et Institut Fédératif de Recherche Multidisciplinaire sur les Peptides (IFRMP 23), Faculté de Médecine et de Pharmacie, Rouen, France. · Rheumatology (Oxford). · Pubmed #11600742 links to  free full text

Abstract: BACKGROUND: Calpastatin is the natural inhibitor of calpains, a protease that is overexpressed in rheumatoid synovial tissue and plays a key role in cartilage destruction. Autoantibodies to calpastatin (ACAST) were recently detected in rheumatoid arthritis (RA). Our aim was to determine their prevalence and their clinical significance. METHODS: ACAST were detected in a solid-phase enzyme-linked immunosorbent assay (ELISA) using a synthetic peptide corresponding to the 27 C-terminal amino acids of calpastatin (CAST-C27) as the antigen. All sera reacting with this peptide also bound to purified erythrocyte calpastatin in an ELISA and/or an immunoblot assay. The frequencies and clinical significance of ACAST-C27 were assessed in sera from a well-documented population of 102 community-recruited patients (76 females; mean age 50 yr) with RA that had been evolving for <5 yr (median 2 yr) (group 1), 109 healthy blood donors, 289 patients with non-RA rheumatic disease and 88 community cases of very early (median 4 months) arthritis, i.e. 58 RA and 30 non-RA patients (group 2). RESULTS: The sensitivity of ACAST-C27 for RA was 19.5% (20/102) in group 1 and 10.3% (6/58) in group 2. These antibodies were also found in patients with anti-double-stranded DNA-positive systemic lupus erythematosus (SLE) (15.5%) and patients with anti-Ro-positive Sjögren's syndrome (18.5%). However, they were not detected in cases of rheumatism resembling early RA, i.e. peripheral spondylarthropathies. ACAST-C27 were not detected in the 30 non-RA patients of group 2. They were predominantly of immunoglobulin isotype G3 and exclusively expressed lambda chains. Among ACAST-C27-positive sera, eight out of 20 (group 1) and four out of six (group 2) were negative for rheumatoid factor and anti-keratin antibodies/antiperinuclear factor. No relationship was found between ACAST-C27 and clinical, biological or radiological findings. CONCLUSION: ACAST-C27 are detected only in a restricted set of connective tissue diseases and therefore appear to be specific for RA when antibodies that are usually associated with SLE or primary Sjögren's syndrome are negative. Because of their presence in community cases of very early RA, particularly in some seronegative forms, ACAST-C27 may be useful in discriminating recent-onset RA from the more common non-RA rheumatic diseases, such as spondylarthropathies.

Daragon A, Krzanowska K, Vittecoq O, Ménard JF, Hau I, Jouen-Beades F, Lesage C, Bertho JM, Tron F, Le Loët X. · Rheumatology department, INSERM U-519 and IFR 23, Centre Hospitalier Universitaire de Rouen, France. · Joint Bone Spine. · Pubmed #11235778 No free full text.

Abstract: OBJECTIVE: Bone demineralization observed in early rheumatoid arthritis is not easily measured. To measure bone loss and to discriminate between rheumatoid arthritis and other rheumatic diseases, we used two methods: dual-energy X-ray absorptiometry and ultrasonography. METHODS: From a population-based recruitment, 32 patients with early peripheral polyarthritis (median disease duration: 4 months) were studied. Clinical, laboratory, functional, hand-bone assessments were made at the entry an at months 6 and 12. Bone X-ray densitometry measurements were made on 16 areas of the hand. Speed of sound was measured across the proximal phalanges of the four fingers. X-rays of both hands were scored according to the modified Sharp's score. At 12 months, patients were classified as rheumatoid arthritis (N = 15; 9 F) or as other rheumatic diseases. RESULTS: We found: 1) significantly decreased bone mineral density (BMD) of the whole hand, in the rheumatoid arthritis group versus the other rheumatic diseases group, at 6 and 12 months (P < 0.05); 2) no significant decrease of bone mineral density (BMD) in other areas in the rheumatoid arthritis group; 3) no significant change of ultrasounds in either group; and 4) no significant correlation between the decrease of BMD in the rheumatoid arthritis group and clinical, biological or radiologic parameters, except for IFNgamma, whose production in whole blood cell culture was lower at entry in the rheumatoid arthritis group. CONCLUSION: DEXA bone assessment in rheumatoid arthritis was able t detect bone loss in the whole hand at 6 months.

Vittecoq O, Jouen-Beades F, Krzanowska K, Bichon-Tauvel I, Menard JF, Daragon A, Gilbert D, Tron F, Le Loët X. · Service de Rhumatologie, INSERM U 519 et Institut Fédératif de Recherche Multidisciplinaire sur les Peptides, Centre Hospitalier Universitaire de Rouen, France. · Rheumatology (Oxford). · Pubmed #10852977 links to  free full text

Abstract: OBJECTIVES: To evaluate the frequencies of antineutrophil cytoplasmic (ANCA), anticardiolipin (aCLA) and anti-beta(2)-glycoprotein 1 antibodies (abeta(2)-GP1A) in rheumatoid arthritis (RA) of limited duration in patients recruited primarily from private practitioners (80%), and to attempt to correlate the presence of these antibodies with certain clinical and/or biological criteria. Patients and methods. Patients (n = 102) with RA evolving for <5 yr (mean 2.2 yr) were recruited. A home evaluation collected clinical data [Ritchie articular index, Health Assessment Questionnaire (HAQ) index, extra-articular manifestations] and blood for biological analyses [C-reactive protein (CRP), rheumatoid factor, ANCA, aCLA, abeta(2)-GP1A]. ANCA were detected by indirect immunofluorescence on neutrophils and their specificity was determined by enzyme-linked immunosorbent assay (ELISA) and confirmed by immunoblotting; aCLA and abeta(2)-GP1A were detected by ELISA. RESULTS: Patients had mild RA (Ritchie = 11/78 +/- 9.6; HAQ = 0.79/3 +/- 0.7), probably due to the recruitment procedure. ANCA, aCLA and abeta(2)-GP1A frequencies were 18.5, 7 and 0%, respectively. Titres of ANCA and aCLA were low. A perinuclear ANCA staining pattern was exclusively observed and lactoferrin was shown to be the major antigen recognized. No relationship was found between ANCA and aCLA and/or rheumatoid factor, or any clinical manifestations. ANCA were more common in RA of longer duration (cut-off: 4 yr; P = 0.05) and aCLA were correlated with the CRP level (P = 0.05). CONCLUSIONS: In RA of recent onset, ANCA and aCLA were detected at low titres and frequencies, and were not associated with any clinical manifestations. A longitudinal study is needed to determine whether their early appearance is predictive of subsequent disease severity.