Rheumatoid Arthritis: Gottenberg JE

Gottenberg JE, Lavie F, Abbed K, Gasnault J, Le Nevot E, Delfraissy JF, Taoufik Y, Mariette X. · Department of Rheumatology, Assistance Publique-Hôpitaux de Paris, University Paris-Sud, Le Kremlin-Bicêtre, France. · J Autoimmun. · Pubmed #15848046 No free full text.

Abstract: In animal models of autoimmunity, CD4 CD25high T cells play a key role in the control of the autoimmune process. Few studies have investigated the role of these cells in human autoimmune diseases. We aimed to investigate CD4 CD25high T cells in the peripheral blood of patients with primary Sjogren's syndrome (pSS). The proportion of blood CD4 CD25high T cells was determined by flow cytometry in 21 patients with pSS as determined by the American-European consensus group criteria and two groups of controls (18 patients with lumbar back pain of mechanical origin and 15 healthy blood donors). The suppressive function of CD4 CD25 cells was assessed using co-culture assays. The Vbeta repertoire of CD4 CD25 T cells was examined by flow cytometry. The proportion of CD4 CD25 T cells depended on age in patients and controls. In an age-matched comparison, no significant difference was observed in the proportion of total CD4 CD25low T cells between patients with pSS and controls (P=0.36). In contrast, the pool of CD4 CD25high was significantly increased in patients with pSS (8.5% vs 4.1% in controls, P=0.04). There was a slight but not significant higher proportion of CD4 CD25high cells in patients with a more active disease. CD4 CD25 T cells in patients with pSS effectively suppressed the proliferation of CD4 CD25- autologous responder T cells. The Vbeta repertoire of regulatory T cells from patients with pSS was polyclonal and was not significantly restricted as compared with that in controls. Functional CD4 CD25high regulatory cells are increased in patients with established pSS, through a reactive feedback, despite ongoing autoimmunity. These results suggest that pSS does not occur as a result of reduced level of CD4 CD25high regulatory T cells, nor as a defect of inhibition of proliferation of responder cells.

Gottenberg JE, Busson M, Cohen-Solal J, Lavie F, Abbed K, Kimberly RP, Sibilia J, Mariette X. · Service de Rhumatologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #15640273 links to  free full text

Abstract: BACKGROUND: In primary Sjögren's syndrome (pSS), extraglandular involvement might result from more intense stimulation of autoreactive B cells. Thus markers of B cell activation could be useful in the clinical assessment of this disease. OBJECTIVE: To investigate the association of serum B lymphocyte stimulator (BLyS) and beta2 microglobulin with autoantibody production and extraglandular involvement in pSS. METHODS: Serum concentrations of BLyS and beta2 microglobulin were analysed in 177 patients with pSS according to the American-European consensus group criteria. Serum beta2 microglobulin was determined serially in 25 patients. RESULTS: Autoantibody secretion (presence of anti-SSA antibody alone or of both anti-SSA and anti-SSB) was associated with increased serum BLyS and beta2 microglobulin. No correlation was found between BLyS and beta2 microglobulin levels (p = 0.36). Serum concentrations of beta2 microglobulin and C reactive protein and positive anti-SSB antibody results were associated with extraglandular involvement on univariate analysis (p<10(-4), p = 0.003, and p = 0.004, respectively). Serum beta2 microglobulin was also significantly increased in patients with extraglandular involvement without autoantibodies (mean (SD): 1.75 (0.7) v 1.39 (0.5) mg/l, p = 0.039). Multivariate analysis showed that extraglandular involvement was associated only with increased serum beta2 microglobulin (p = 0.035, odds ratio = 2.78 (95% confidence interval, 1.07 to 7.22)). Among the 25 patients who had serial determinations of serum beta2 microglobulin, the concentrations were increased in all those with disease flare and decreased in three following treatment. Serum BLyS, gamma globulin, IgG, and rheumatoid factor levels were not associated with features of systemic involvement. CONCLUSIONS: Serum beta2 microglobulin and BLyS reflect B cell activation in different ways in pSS. Serum beta2 microglobulin assessment could be helpful as an activity marker in pSS.

Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, Larroche C, Soubrier M, Bouillet L, Dougados M, Fain O, Farge D, Kyndt X, Lortholary O, Masson C, Moura B, Remy P, Thomas T, Wendling D, Anaya JM, Sibilia J, Mariette X, Anonymous00301. · Service de Rhumatologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #15550531 links to  free full text

Abstract: OBJECTIVE: To assess the tolerance and efficacy of rituximab in patients with various autoimmune diseases seen in daily rheumatological practice. METHODS: 866 rheumatology and internal medicine practitioners were contacted by e-mail to obtain the files of patients treated with rituximab for systemic autoimmune diseases. Patients with lymphoma were analysed if the evolution of the autoimmune disease could be evaluated. RESULTS: In all, 43 of 49 cases could be analysed, including 14 with rheumatoid arthritis (RA), 13 with systemic lupus erythematosus (SLE), six with primary Sjogren's syndrome (pSS), five with systemic vasculitis, and five with other autoimmune diseases. Rituximab was prescribed for lymphoma in two patients with RA and two with pSS. In the 39 other cases, rituximab was given because of the refractory character of the autoimmune disease. The mean follow up period was 8.3 months (range 2 to 26). There were 11 adverse events in 10 patients and treatment had to be discontinued in six. Efficacy was observed in 30 patients (70%): RA 11, SLE 9, pSS 5, vasculitis 2, antisynthetase syndromes 2, sarcoidosis 1. The mean decrease in corticosteroid intake was 9.5 mg/d (range 0 to 50) in responders. Seven patients experienced relapse after mean 8.1 months (5 to 15). Three patients died because of refractory autoimmune disease. CONCLUSIONS: Despite absence of marketing authorisation, rituximab is used to treat various refractory autoimmune diseases in daily rheumatological practice. This study showed good tolerance and short term clinical efficacy, with marked corticosteroid reduction in patients with SLE, pSS, vasculitis, and polymyositis.

Gottenberg JE, Mignot S, Nicaise-Rolland P, Cohen-Solal J, Aucouturier F, Goetz J, Labarre C, Meyer O, Sibilia J, Mariette X. · Department of Rheumatology, Bicêtre Hospital, INSERM EMI 109, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #15231509 links to  free full text

Abstract: OBJECTIVE: To investigate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) and anti-keratin antibodies (AKA) in patients with primary Sjögren's syndrome. METHODS: 149 patients with a diagnosis of primary Sjögren's syndrome according to the European/American consensus criteria were recruited from three French medical centres. The presence of anti-CCP was determined by enzyme linked immunosorbent assay and of AKA antibodies by indirect immunofluorescence. Radiographs of hands and feet were evaluated at the time of anti-CCP analysis. RESULTS: Six patients with radiological erosions and nine patients with non-erosive arthritis fulfilling ACR criteria for rheumatoid arthritis were thought to have rheumatoid arthritis and secondary Sjögren's syndrome, while 134 were considered to have primary Sjögren's syndrome (mean (SD) disease duration, 11.1 (6.6) years). Of these, 80 tested positive for IgM rheumatoid factor (RF) (59%), 10 (7.5%) for anti-CCP, 7 (5.2%) for AKA, and 5 (3.7%) for both anti-CCP and AKA. There was no difference in clinical and biological features, including prevalence of RF, between anti-CCP positive and negative patients. The nine Sjögren patients with non-erosive arthritis, fulfilling ACR criteria for rheumatoid arthritis, were all CCP positive. Their response to disease modifying antirheumatic drugs could be different from classical rheumatoid patients. CONCLUSIONS: Most patients with primary Sjögren's syndrome are negative for AKA and anti-CCP, but positive test results should not rule out this diagnosis. Anti-CCP positive patients, who may be prone to developing rheumatoid arthritis, require cautious clinical and radiographic follow up.

Gottenberg JE, Busson M, Loiseau P, Dourche M, Cohen-Solal J, Lepage V, Charron D, Miceli C, Sibilia J, Mariette X. · Hôpital de Bicêtre, Assistance Publique Hôpitaux de Paris, INSERM EMI 109, Le Kremlin Bicêtre, France. · Arthritis Rheum. · Pubmed #14872501 links to  free full text

Abstract: OBJECTIVE: To determine whether cytokine gene polymorphisms of interferon-gamma (IFNgamma), interleukin-6 (IL-6), IL-10, tumor necrosis factor alpha (TNFalpha), and transforming growth factor beta1 (TGFbeta1) predispose subjects to the development of primary Sjögren's syndrome (SS). METHODS: Single-base-exchange cytokine gene polymorphisms were analyzed in 129 French patients with primary SS who fulfilled the American-European Consensus Group criteria, as well as in 96 unrelated healthy subjects. RESULTS: The frequency of the TNF-308A (TNF2) allele was significantly higher in the SS patients (26% versus 11%). This TNF2 association was restricted to patients with anti-SSB (37% versus 11% in controls). Stratification did not reveal an independent effect of TNF2 and HLA-DRB1*03 on disease or on anti-SSB antibody secretion. The frequency of allele C at codon 10 of TGFbeta1 was strongly increased in the subgroup of patients with anti-SSB; this allele acted synergistically with DRB1*03 to predispose patients to the secretion of anti-SSB. The IL-10 GCC haplotype carrier rate was significantly higher in SS patients than in controls (67% versus 48%), but the IL-10 allele and genotype frequencies were not significantly different. No association was found between IL-6 or IFNgamma polymorphisms and primary SS. CONCLUSION: TNF2 was associated with anti-SSB antibody secretion, although this association was not independent of the association with DRB1*03. Allele C at codon 10 of TGFbeta1 was found to act synergistically with DRB1*03 in predisposing patients to the secretion of anti-SSB. These results therefore suggest that most of the known genetic predisposition to primary SS might concern the pattern of autoantibody diversification.

Gottenberg JE, Busson M, Loiseau P, Cohen-Solal J, Lepage V, Charron D, Sibilia J, Mariette X. · Service de Rhumatologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM EMI 0109, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France. · Arthritis Rheum. · Pubmed #12905478 links to  free full text

Abstract: OBJECTIVE: To reevaluate, in a large series of patients with Sjögren's syndrome (SS) recruited from 2 French centers, the question of whether HLA is associated with SS itself or with a pattern of secretion of autoantibodies. METHODS: One hundred forty-nine white patients fulfilling the American-European Consensus Group criteria for SS were divided into 3 subgroups, according to their anti-Ro/SSA and anti-La/SSB status, as follows: group 1 (n = 53), no antibody; group 2 (n = 46), anti-SSA only; group 3 (n = 50), both anti-SSA and anti-SSB. Patients were compared with 222 unrelated healthy subjects representative of the white population in France. RESULTS: Comparisons between the 149 SS patients and 222 controls confirmed the association of SS with DRB1*03 (the frequency was 25% in patients versus 10% in controls) and DQB1*02 (32% versus 22%). The association between HLA and SS was restricted to patients with anti-SSA and/or anti-SSB; no association with HLA was observed in patients in group 1 (no antibody). The frequency of HLA-DRB1*15 was highest in group 2 (24%), compared with 11% in group 1 and 11% in controls, whereas the frequency of HLA-DRB1*03 was highest in group 3 (44%), compared with 12% in group 1, 19% in group 2, and 10% in controls. Group 2 and group 3 had more clinical and biologic markers of activity than did group 1 but were not clinically different. HLA alleles were not associated with clinical features of the disease, and were associated with only some biologic features: rheumatoid factor positivity, increased serum IgG, and thrombocytopenia were associated with HLA-DRB1*03, and neutropenia was associated with DQB1*01. CONCLUSION: HLA class II markers confer genetic susceptibility to Sjögren's syndrome. The association between HLA and SS is restricted to patients with anti-SSA and/or anti-SSB antibodies; HLA is not associated with SS in patients without these autoantibodies. The absence of a difference in disease severity between groups 2 and 3, as well as the restricted association of HLA-DRB1*03 in group 3, strongly suggest that HLA alleles predispose to autoantibody secretion, without being associated with clinical outcome. HLA class II phenotype might support epitope spreading: HLA-DR15 favors anti-SSA synthesis, whereas HLA-DR3 is associated with both anti-SSA and anti-SSB production.

Sordet C, Gottenberg JE, Goetz J, Bengoufa D, Humbel RL, Mariette X, Sibilia J. · No affiliation provided · Ann Rheum Dis. · Pubmed #16014693 links to  free full text

This publication has no abstract.

Sordet C, Gottenberg JE, Hellmich B, Kieffer P, Mariette X, Sibilia J. · No affiliation provided · Ann Rheum Dis. · Pubmed #15647445 links to  free full text

This publication has no abstract.

Gottenberg JE, Venancie PY, Mariette X. · No affiliation provided · J Rheumatol. · Pubmed #12180755 links to  free full text

This publication has no abstract.