Rheumatoid Arthritis: Gottenberg JE

Pham T, Fautrel B, Gottenberg JE, Goupille P, Hachulla E, Masson C, Morel J, Mouthon L, Saraux A, Schaeverbeke T, Wendling D, Mariette X, Sibilia, Anonymous00011. · No affiliation provided · Joint Bone Spine. · Pubmed #18708020 No free full text.

This publication has no abstract.

Sibilia J, Gottenberg JE, Mariette X. · Service de Rhumatologie, CHU Strasbourg, Centre National de Référence des Maladies Auto-immunes Systémiques Rares, Strasbourg, France. · Joint Bone Spine. · Pubmed #18571968 No free full text.

Abstract: Rituximab is a chimeric anti-CD20 monoclonal antibody targeting B cells, which play numerous pathogenic roles in rheumatoid arthritis (RA). This review summarises the results of three controlled studies using rituximab in RA and the data regarding tolerance and repeated treatment in 1053 patients included in the clinical studies. These studies demonstrated the efficacy of rituximab in patients with RA, including those who had been unresponsive or intolerant to one or more TNF inhibitor therapies. Rituximab was globally well-tolerated. The current informations on the efficacy and the tolerance of rituximab led us to propose recommendations for the screening of patients, the use of rituximab, and the follow-up of patients. A longer follow-up duration and data from off-trial patients, included in registries, are now required.

Gottenberg JE, Chiocchia G. · Département d'Immunologie, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France. · Biochimie. · Pubmed #17562353 No free full text.

Abstract: Dendritic cells (DCs) are central cells of the immune responses. They can be considered as the most influential antigen-presenting cells in the body because of their unique role in initiating immunity against most types of antigens. Recent studies have clearly established that the state of maturation of DC can be crucial for the ability of these antigen-presenting cells to inhibit or induce T-cell-mediated autoimmune diseases. Type I interferon has been shown to be produced at very high amounts by a specific type of DC (pDC). In recent years, the study of multiple autoimmune diseases has pointed to a central role for type I interferon (IFN-I) in disease pathogenesis, in particular through the IFN-molecular signature deciphered in some of these diseases. One hypothesis would be that IFN directly affects multiple actors of the immune reaction such as T cells and B cells and that it can induce the unabated activation of peripheral dendritic cells. On the other hand, type II IFN has been considered as pathogenic in multiple autoimmune diseases leading to the paradigm of TH-1 type autoimmune diseases. The discovery of the TH-17 type of cells and the protective role IFN-gamma can exert on particular phases of these diseases urge one to re-evaluate this assumption.

Salliot C, Mouthon L, Ardizzone M, Sibilia J, Guillevin L, Gottenberg JE, Mariette X. · Rheumatology Department, Paris-Sud 11 University, INSERM U802, France. · Rheumatology (Oxford). · Pubmed #16877466 links to  free full text

Abstract: OBJECTIVES: When Sjögren's syndrome (SS) is secondary to rheumatoid arthritis, the sicca syndrome is less serious and anti-SSA/SSB antibodies are found less frequently than in primary SS (pSS). When SS is associated with systemic lupus erythematosus, clinical and serological patterns are similar to those of pSS. We aimed to determine whether SS, accompanying systemic sclerosis (SSc), could be considered secondary to or associated with SSc and whether the coexistence of both modifies the severity and the outcome of each disease. Patients and METHODS: A retrospective multicentric study was conducted to compare (i) characteristics and complications of SS between 27 patients with SS and SSc (SS-SSc) and 202 patients with pSS, and (ii) the characteristics of SSc and complications between the SS-SSc group and 94 patients with SSc alone. RESULTS: SS features were similar in both SS-SSc and pSS patients, except for peripheral neuropathy and arthritis, which was more common in SS-SSc than in the pSS patients (P = 0.02 and 0.05, respectively). SSc appears to be less severe in patients with SS-SSc than SSc alone with a lower frequency of lung fibrosis (P = 0.05). Compared with patients with pSS or SSc alone, SS-SSc patients were more likely to have another autoimmune disorder and other autoantibodies (SS-SSc vs pSS, P = 0.02 and P = 0.03, respectively). CONCLUSION: SS seems to be associated with and not secondary to SSc. SS associated with SSc has the same features as pSS, but SSc seems to be less serious. Moreover, the association of SS and SSc is frequently accompanied by a spreading of autoimmunity.

Pham T, Claudepierre P, Constantin A, Fautrel B, Gossec L, Gottenberg JE, Goupille P, Hachulla E, Masson C, Morel J, Saraux A, Schaeverbeke T, Wendling D, Mariette X, Sibilia J. · Service de Rhumatologie, CHU Conception, Marseille, France. · Joint Bone Spine. · Pubmed #19560051 No free full text.

Abstract: OBJECTIVES: To elaborate a how-to-use abatacept material intended to help physicians in the management of patients with inflammatory diseases treated with this drug in routine practice. METHODS: 1) Selection of the relevant domains by a rheumatologists' panel; 2) Search for published evidence in each domain; 3) Elaboration of the clinical tool guide with a 3-level gradation of evidence (evidence-based medicine EBM, official recommendations and expert's opinion). The experts were 11 academic rheumatologists with a large experience in prescribing abatacept and in managing rheumatoid arthritis. They were all members of the CRI (Club Rhumatismes et Inflammation), a section of the French Rheumatology Society dedicated to the inflammatory rheumatic diseases. Each fact sheet was reviewed by two other experts; 4) Regular updating based on medical literature and postmarketing surveillance data. RESULTS: Four domains were considered relevant: abatacept contraindications, management of side effects or associated diseases appearing during abatacept treatment, management of "practical situations" such as surgery or pregnancy, physician and patient information. After the literature analysis and discussion during an experts' meeting, a consensus was reached on: a pre-treatment checklist aimed at searching abatacept contraindications; a what-to-do document when facing side effects or associated diseases (autoimmune pathology, bacterial or viral infections, cardiovascular diseases, intolerance to abatacept, solid or haematological malignancy) or "practical situations" (surgery, pregnancy, vaccination, travel, drug-drug interactions); an example of standard information letter to be addressed to the attending physician (rheumatologist and general practitioner); an example of standard information letter to be addressed to the patient. CONCLUSION: Based on both an EBM approach and an expert's opinion approach, this abatacept clinical tool guide should provide assistance to all physicians attending patients treated with abatacept. For a better implementation in clinical practice, this tool guide will be available online at www.cri-net.com and regularly updated.

Alsaleh G, Suffert G, Semaan N, Juncker T, Frenzel L, Gottenberg JE, Sibilia J, Pfeffer S, Wachsmann D. · Laboratoire Physiopathologie des Arthrites, EA3432, Université Louis Pasteur de Strasbourg, Unité de Formation et de Recherche Sciences Pharmaceutiques, Illkirch, France. · J Immunol. · Pubmed #19342689 No free full text.

Abstract: MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the "antiinflammatory" response of LPS-activated RA FLS. LPS challenge modulated the expression of 63 miRNAs as assessed by microarray analysis. Fifteen miRNAs were up-regulated, including miR-346, for which overexpression upon LPS treatment was validated by quantitative RT-PCR. We then transfected FLS with an antisense oligonucleotide targeting miR-346 and found that, in these conditions, IL-18 release could be measured upon LPS activation of FLS. Moreover, we also demonstrated that miR-346 indirectly regulated IL-18 release by indirectly inhibiting LPS-induced Bruton's tyrosine kinase expression in LPS-activated RA FLS. These findings suggest that miRNAs function as regulators that help to fine-tune the inflammatory response in RA.

Messer L, Alsaleh G, Freyssinet JM, Zobairi F, Leray I, Gottenberg JE, Sibilia J, Toti-Orfanoudakis F, Wachsmann D. · Laboratoire Physiopathologie des Arthrites, Université de Strasbourg, UFR Sciences Pharmaceutiques, Illkirch, France. · Arthritis Res Ther. · Pubmed #19291304 links to  free full text

Abstract: INTRODUCTION: In the present study, we investigated the ability of microparticles isolated from synovial fluids from patients with rheumatoid arthritis or osteoarthritis to induce the synthesis and release of key cytokines of B-lymphocyte modulation such as B cell-activating factor, thymic stroma lymphopoietin, and secretory leukocyte protease inhibitor by rheumatoid fibroblast-like synoviocytes. METHODS: Microparticles were analyzed in synovial fluids from patients with rheumatoid arthritis, osteoarthritis, microcristalline arthritis, and reactive arthritis. In addition, microparticle release after activation from various cell lines (CEM lymphocyte and THP-1 cells) was assessed. Microparticles were isolated by differential centrifugation, and quantitative determinations were carried out by prothrombinase assay after capture on immobilized annexin V. B cell-activating factor, thymic stroma lymphopoietin, and secretory leukocyte protease inhibitor release was evaluated by enzyme-linked immunosorbent assay. RESULTS: Microparticles isolated from synovial fluids obtained from rheumatoid arthritis and osteoarthritis patients or microparticles derived from activated THP-1 cells were able to induce B cell-activating factor, thymic stroma lymphopoietin, and secretory leukocyte protease inhibitor release by rheumatoid arthritis fibroblast-like synoviocytes. Conversely, CEM-lymphocytes-derived microparticles generated by treatment with a combination of PHA, PMA and Adt-D did not promote the release of B cell-activating factor but favored the secretion of thymic stroma lymphopoietin and secretory leukocyte protease inhibitor by rheumatoid arthritis fibrobast-like synoviocytes. However, microparticles isolated from actinomycin D-treated CEM lymphocytes were not able to induce B cell-activating factor, thymic stroma lymphopoietin, or secretory leukocyte protease inhibitor release, indicating that microparticles derived from apoptotic T cells do not function as effectors in B-cell activation. CONCLUSIONS: These results demonstrate that microparticles are signalling structures that may act as specific conveyors in the triggered induction and amplification of autoimmunity. This study also indicates that microparticles have differential effects in the crosstalk between B lymphocytes and target cells of autoimmunity regarding the parental cells from which they derive.

Candon S, Gottenberg JE, Bengoufa D, Chatenoud L, Mariette X. · INSERM U580, Hôpital Necker-Enfants Malades, Paris, France. · Ann Rheum Dis. · Pubmed #18713786 No free full text.

Abstract: OBJECTIVES: To assess the added value of using a radioligand assay (RLA) compared with ELISA to detect antibodies to SSA, SSB and RNP, and to analyse the correlation between autoantibody levels, B-cell biomarkers and disease activity. PATIENTS AND METHODS: Antibodies to SSA, SSB and RNP were assessed in 127 patients with primary Sjögren syndrome (pSS) using an RLA and ELISA. In parallel, measures of B-cell activation were determined including serum levels of B-cell-activating factor of the tumour necrosis factor family or BLyS (BAFF). RESULTS: RLA was more sensitive than ELISA for the detection of antibodies to SSB (54% of positive samples versus 37%, respectively) and antibodies to RNP (9% vs 3%). No difference was seen for the sensitivity of detection of antibodies to SSA. Anti-SSA and anti-SSB levels were correlated with both techniques. Mean levels of antibodies to SSA were significantly higher in patients presenting antibodies to both SSA and SSB than in those exhibiting antibodies to SSA only (RLA: mean (SEM) anti-SSA levels 2343 (158) cpm vs 1348 (286) cpm, respectively, p = 0.02; ELISA: 6.8 (0.8) vs 3.8 (0.4), respectively, p = 0.003). Levels of antibodies to SSA and SSB significantly correlated with those of circulating BAFF (r = 0.4, p = 0.004 and r = 0.6, p<0.001, respectively) and with B-cell biomarkers, including levels of gammaglobulins, beta(2) microglobulin and rheumatoid factor. CONCLUSION: RLA allowed a quantitative and more sensitive detection of antibodies to SSB and RNP in pSS. Quantitative assessment of autoantibodies might disclose a biomarker of disease activity and enable further insight into the pathogenesis of the spreading of the autoantibody response.

Sellam J, Miceli-Richard C, Gottenberg JE, Proust A, Ittah M, Lavie F, Loiseau P, Mariette X. · Rhumatologie, INSERM U802, Hôpital Bicêtre, Assistance Publique des Hôpitaux de Paris, Université Paris-Sud, Le Kremlin Bicêtre, France. · Rheumatology (Oxford). · Pubmed #18296721 No free full text.

Abstract: OBJECTIVES: Inhibitor of differentiation 3 (Id3)-deficient mice show sicca symptoms, lymphocyte infiltration of exocrine glands and positive anti-Ro/SSA and anti-La/SSB antibodies, all hallmarks of primary Sjögren's syndrome (pSS). The impairment of Id3 in T cells and, possibly, in salivary glandular epithelial cells (SGECs) seems to be involved. This animal model prompted us to investigate the role of Id3 in human pSS. METHODS: Quantitative Id3 expression in peripheral T cells, cultured SGECs and in total minor salivary glands was assessed by RT-PCR in pSS patients and controls. After Id3 sequencing, we investigated two single nucleotide polymorphisms (SNPs) (c.313G>A and g.-156A>G) in a case-control study of 212 Caucasian pSS patients and 168 controls. RESULTS: Quantitative Id3 expression was not decreased in pSS patients nor in SGECs, in T cells or in minor salivary glands. As well, patients and controls did not differ in allele and genotype frequencies of Id3 SNPs (P = 0.67 and P = 0.71 for the c.313G>A and the g.-156A>G, respectively). Neither SNP was associated with a pattern of autoantibody secretion. CONCLUSION: Although the Id3-deficient mouse model represents an attractive model for human pSS, Id3 expression is not impaired in SGECs, peripheral T cells and in labial salivary glands in pSS patients and Id3-relevant SNPs do not give evidence of genetic predisposition in Caucasian pSS patients.

Semaan N, Alsaleh G, Gottenberg JE, Wachsmann D, Sibilia J. · Laboratoire Physiopathologie des Arthrites, Université Louis Pasteur de Strasbourg, Unité de Formation et de Recherche Sciences Pharmaceutiques, Illkirch, France. · J Immunol. · Pubmed #18292575 links to  free full text

Abstract: MyD88 and focal adhesion kinase (FAK) are key adaptors involved in signaling downstream of TLR2, TLR4, and integrin alpha5beta1, linking pathogen-associated molecule detection to the initiation of proinflammatory response. The MyD88 and integrin pathways are interlinked, but the mechanism of this cross-talk is not yet understood. In this study we addressed the involvement of Etk, which belongs to the Tec family of tyrosine kinases, in the cross-talk between the integrin/FAK and the MyD88 pathways in fibroblast-like synoviocytes (FLS) and in IL-6 synthesis. Using small interfering RNA blockade, we report that Etk plays a major role in LPS- and protein I/II (a model activator of FAK)-dependent IL-6 release by activated FLS. Etk is associated with MyD88, FAK, and Mal as shown by coimmunoprecipitation. Interestingly, knockdown of Mal appreciably inhibited IL-6 synthesis in response to LPS and protein I/II. Our results also indicate that LPS and protein I/II induced phosphorylation of Etk and Mal in rheumatoid arthritis FLS via a FAK-dependent pathway. In conclusion, our data provide support that, in FLS, Etk and Mal are implicated in the cross-talk between FAK and MyD88 and that their being brought into play is clearly dependent on FAK.

Lavie F, Miceli-Richard C, Ittah M, Sellam J, Gottenberg JE, Mariette X. · Rheumatology Department, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Institut Pour Santé et Recherche Médicale (INSERM) U802, Université Paris-Sud 11, Le Kremlin Bicêtre, France. · Scand J Immunol. · Pubmed #18201372 No free full text.

Abstract: We investigated B-cell activating factor of the tumour necrosis factor family (BAFF) level in peripheral blood mononuclear cells (PBMCs), monocytes and T cells from patients with primary Sjögren's syndrome (pSS) and controls both ex vivo and in vitro after cytokine stimulation. PBMCs, monocytes and T cells were isolated from 15 patients with pSS and 17 controls. Cells were cultured alone or with interferon (IFN)alpha, IFNgamma and interleukin 10 (IL-10). T cells were stimulated with phytohaemagglutin and anti-CD3. BAFF protein was assessed by enzyme-linked immunosorbent assay. Ex vivo, no difference was observed in BAFF mRNA level in PBMCs and monocytes from patients and controls. Blood monocytes were the main cell type secreting BAFF both in patients and controls. In vitro, after IFNalpha stimulation, BAFF mRNA level was significantly higher in cells from patients than from controls (63.8 versus 20.7, P = 0.03). T cells from patients secreted a higher level of BAFF protein than those from healthy donor cells (17.4 versus 2.9 pg/ml, respectively, P = 0.04) but at a lower level than that from monocytes. Stimulation of T cells did not change BAFF secretion level. The induction of Th17 cells showed no increased BAFF expression. In conclusion, similar to epithelial cells, blood monocytes in patients with pSS show increased production of BAFF under IFNalpha, which confirms the involvement of IFNalpha in pSS. BAFF expression is also increased in blood T cells of such patients, independently of T-cell stimulation.

Terrier B, Lacroix C, Guillevin L, Hatron PY, Dhote R, Maillot F, Diot E, Sarrot-Reynauld F, Sordet C, Dubourg O, Meyer L, Mariette X, Gottenberg JE, Anonymous00097. · Assistance Publique Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France. · Arthritis Rheum. · Pubmed #18050172 links to  free full text

Abstract: OBJECTIVE: To evaluate the clinicobiologic presentation in patients with primary Sjögren's syndrome (SS)-related peripheral neuropathy, the histologic results of neuromuscular biopsy (NMB), and clinical outcome, and to identify prognostic factors. METHODS: We retrospectively studied clinical and biologic presentation of 40 patients with primary SS-related neuropathy who underwent NMB. Prognostic factors of clinical outcome were assessed by univariate and multivariate analysis. RESULTS: Patients with vasculitis (lymphocytic [n = 8] or necrotizing [n = 14]) had a higher prevalence of acute-onset neuropathy, multiple mononeuropathy, sensorimotor involvement, vascular purpura, general symptoms, increased C-reactive protein level, positivity for rheumatoid factor, hypocomplementemia, and monoclonal gammopathy compared with those without vasculitis (n = 18). Comparison between patients with necrotizing or lymphocytic vasculitis did not reveal significant differences in clinical or biologic presentation except for the presence of general symptoms and rheumatoid factor. Regarding clinical evolution, the results of NMB (P < 0.0001), in particular the presence of necrotizing vasculitis (P < 0.001), an acute neuropathy onset (P < 0.0001), general symptoms (P < 0.0001), multiple mononeuropathy (P = 0.0007), presence of sensorimotor involvement (P = 0.002), and increased C-reactive protein level (P = 0.008), were significantly associated with a better outcome in univariate analysis. In multivariate analysis, NMB resulting in the identification of patients with necrotizing vasculitis was the only variable that remained significantly associated with a better outcome (P = 0.01). CONCLUSION: NMB is necessary to identify patients with necrotizing vasculitis, who have a better response to immunosuppressive therapy. NMB might therefore have both a diagnostic and prognostic relevance in primary SS-related neuropathy.

Salliot C, Gottenberg JE, Bengoufa D, Desmoulins F, Miceli-Richard C, Mariette X. · Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Service de Rhumatologie, Université Paris-Sud 11, 78 rue de Général Leclerc, Le Kremlin-Bicêtre, France. · J Rheumatol. · Pubmed #17937465 No free full text.

Abstract: OBJECTIVE: To assess the prevalence and clinical and immunological significance of anticentromere antibodies (ACA) in patients with primary Sjögren's syndrome (pSS). METHODS: We retrospectively investigated the prevalence of ACA in patients with SS. We compared ACA-positive SS patients with ACA-negative pSS patients. RESULTS: The prevalence of ACA among patients with pSS was 4.7% (10/212). Among the patients with SS and an associated autoimmune disease, 10 patients had ACA and limited cutaneous sclerosis (SSc). Clinical and immunological patterns did not differ between the 10 pSS patients with ACA alone and the 10 SS patients with ACA and SSc, except for presence of limited cutaneous SSc (lcSSc). Moreover, all ACA-positive sera recognized centromere protein-B on ELISA, regardless of the presence of SSc. The entire SS-ACA group (n = 20) showed greater frequency of Raynaud's phenomenon, objective xerophthalmia, peripheral neuropathy, and additional autoimmune disorders, especially primary biliary cirrhosis, compared to pSS patients without ACA (p = 0.005, p = 0.04, p = 0.001, p = 0.05, p < 0.0001, respectively). SS patients with ACA less frequently showed anti-SSA or anti-SSB antibodies than those without ACA (p = 0.0002, p = 0.01, respectively) but greater prevalence of autoantibodies other than anti-SSA/SSB or ACA (p = 0.001). CONCLUSION: Clinical and immunological features of SS were largely similar among SS patients with ACA with and without SSc. However, the presence of ACA among patients with SS allows identification of a subset of patients with "SS overlap syndrome," who show a wide diversity of autoimmunity, encompassing but not limited to SSc.

Alsaleh G, Messer L, Semaan N, Boulanger N, Gottenberg JE, Sibilia J, Wachsmann D. · EA 3432, Université Louis Pasteur de Strasbourg, Illkirch, France. · Arthritis Rheum. · Pubmed #17907168 links to  free full text

Abstract: OBJECTIVE: It was recently demonstrated that synoviocytes (FLS) from rheumatoid arthritis (RA) patients express BAFF transcripts that are up-regulated by tumor necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma). Thus, BAFF increases in RA target cells might be related to activation of the receptors of innate immunity. The purpose of this study was to determine whether ligands of Toll-like receptor 2 (TLR-2), TLR-4, TLR-9, and alpha5beta1 integrin are able to induce BAFF synthesis by RA FLS. METHODS: Quantitative reverse transcription-polymerase chain reaction analyses and enzyme-linked immunosorbent assays were performed to evaluate BAFF messenger RNA induction and BAFF release from FLS after stimulation by ligands for TLR-2, TLR-4, TLR-9, alpha5beta1 integrin (bacterial lipopeptide [BLP] palmitoyl-3-cysteine-serine-lysine-4, lipopolysaccharide [LPS], CpG, and protein I/II, respectively), TNFalpha, and IFNgamma. RESULTS: In contrast to IFNgamma, neither TNFalpha, LPS, BLP, nor CpG induced the de novo synthesis and release of BAFF by FLS. Priming of cells with IFNgamma did not have a synergistic effect on BAFF synthesis by FLS stimulated with bacterial products known as pathogen-associated molecular patterns. Moreover, we found that IFNgamma-induced BAFF synthesis is inhibited by simultaneous stimulation with either TLR ligands or TNFalpha. We also showed that interplay between TLRs, TNF receptors, and IFNgamma signaling induces the expression of suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 and reduces IFNgamma-dependent STAT-1 phosphorylation, which might explain this inhibition. In contrast, we demonstrated that stimulation of alpha5beta1 integrin can induce BAFF synthesis and release per se and that stimulation of this pathway has no inhibitory effect on IFNgamma-induced BAFF synthesis. CONCLUSION: Our findings indicate that BAFF secretion by resident cells in target organs of autoimmunity is tightly regulated by innate immunity, with positive and negative controls, depending on the receptors and the pathways triggered.

Gottenberg JE, Loiseau P, Azarian M, Chen C, Cagnard N, Hachulla E, Puechal X, Sibilia J, Charron D, Mariette X, Miceli-Richard C. · Rhumatologie, Institut Pour la Santé et la Recherche Médicale U802, Université Paris-Sud 11, Hôpital Bicêtre, 78 rue du Général Leclerc, Assistance Publique-Hôpitaux de Paris, 94275 Le Kremlin Bicêtre, France. · Arthritis Res Ther. · Pubmed #17341301 links to  free full text

Abstract: CTLA-4 encodes cytotoxic T lymphocyte-associated antigen-4, a cell-surface molecule providing a negative signal for T-cell activation. CTLA-4 gene polymorphisms have been widely studied in connection with genetic susceptibility to various autoimmune diseases, but studies have led to contradictory results in different populations. This case-control study sought to investigate whether CTLA-4 CT60 and/or +49A/G polymorphisms were involved in the genetic predisposition to primary Sjögren syndrome (pSS). We analysed CTLA-4 CT60 and +49A/G polymorphisms in a first cohort of 142 patients with pSS (cohort 1) and 241 controls, all of Caucasian origin. A replication study was performed on a second cohort of 139 patients with pSS (cohort 2). In cohort 1, the CTLA-4 +49A/G*A allele was found on 73% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.036; odds ratio (OR) 1.41, 95% confidence interval (CI) 1.02 to 1.95). No difference in CTLA-4 CT60 allelic or genotypic distribution was observed between patients (n = 142) and controls (n = 241). In the replication cohort, the CTLA-4 +49A/G*A allele was found on 62% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.30; OR 0.85, 95% CI 0.63 to 1.16). Thus, the CTLA-4 +49A/G*A allele excess among patients from cohort 1 was counterbalanced by its under-representation in cohort 2. When the results from the patients in both cohorts were pooled (n = 281), there was no difference in CTLA-4 +49A/G allelic or genotypic distribution in comparison with controls. Our results demonstrate a lack of association between CTLA-4 CT60 or +49A/G polymorphisms and pSS. Premature conclusions might have been made if a replication study had not been performed. These results illustrate the importance of case-control studies performed on a large number of patients. In fact, sampling bias may account for some contradictory results previously reported for CTLA-4 association studies in autoimmune diseases.

Sellam J, Miceli-Richard C, Gottenberg JE, Ittah M, Lavie F, Lacabaratz C, Gestermann N, Proust A, Lambotte O, Mariette X. · Service de Rhumatologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #17185325 No free full text.

Abstract: OBJECTIVE: To analyse B cell activating factor (BAFF) receptor (BAFF-R) expression on peripheral lymphocytes from patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Peripheral blood mononuclear cells from 20 patients with pSS, 19 patients with SLE and 15 controls were examined by flow cytometry to investigate BAFF-R mean fluorescence intensity (MFI) on lymphocytes. BAFF-R mRNA level from isolated blood B cells of nine patients with pSS and eight controls was assessed by real-time quantitative reverse transcription-PCR. BAFF serum level was determined by ELISA. RESULTS: In all subjects, BAFF-R was expressed on all naïve CD27- and memory CD27+ B-cells and was present on <0.5% of T cells. The expression of BAFF-R on B cells was significantly decreased in patients with pSS as compared with controls (MFI = 7.8 vs 10.6, p = 0.001), and was intermediate in patients with SLE (MFI = 9.5). Serum BAFF level was inversely correlated with BAFF-R MFI (p = 0.007), but not because of competition between endogenous BAFF (at observed concentrations in patients) and the monoclonal antibody (11C1) detecting BAFF-R. BAFF-R mRNA levels did not differ between patients with pSS and controls (p = 0.48). BAFF-R MFI decreased after overnight culture with recombinant human BAFF (from 32.5 to 25.4, p = 0.03). Contrary to the serum BAFF level, BAFF-R expression was correlated with extraglandular involvement in pSS and SLE Disease Activity Index. CONCLUSIONS: BAFF-R expression is reduced on peripheral B cells of patients with pSS and SLE. This down-regulation occurs through a post-transcriptional mechanism and could be the consequence of chronic increase in BAFF. BAFF-R levels on B cells could be a novel activity biomarker in autoimmune diseases.

Lavie F, Miceli-Richard C, Ittah M, Sellam J, Gottenberg JE, Mariette X. · Rheumatology Department, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Institut Pour la Santé et la Recherche Médicale (INSERM) U802, Université Paris-Sud 11, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #17040963 No free full text.

Abstract: BACKGROUND: The cytokine B cell-activating factor of the TNF family (BAFF) is involved in the pathogenesis of autoimmune diseases. OBJECTIVE: To access changes in serum protein and mRNA levels of BAFF after rituximab treatment. METHODS: Serum and peripheral blood mononuclear cells (PBMCs) were isolated from five patients (two with lupus, two with Sjögren's syndrome, one with rheumatoid arthritis) before and 12 weeks (range 7-17) after a first course of rituximab infusion. Monocytes and B cells were selected from healthy controls and cocultured for 72 h. BAFF protein and mRNA levels were assessed by ELISA and real-time PCR, respectively. RESULTS: After rituximab treatment, median serum BAFF protein level and BAFF to actin mRNA ratio in PBMCs significantly increased. In monocytes cocultured with autologous B cells, BAFF protein level decreased, whereas the mRNA level was stable. In one closely monitored patient, the mRNA ratio of BAFF to actin in PBMCs increased later than the BAFF serum level. CONCLUSIONS: Two distinct mechanisms are probably involved in the increase in BAFF level after B cell depletion: (1) the decrease in its receptors leading to a release of BAFF; (2) a delayed regulation of BAFF mRNA transcription. This could favour the re-emergence of autoreactive B cells.

Seror R, Sordet C, Guillevin L, Hachulla E, Masson C, Ittah M, Candon S, Le Guern V, Aouba A, Sibilia J, Gottenberg JE, Mariette X. · Department of Rheumatology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université paris-Sud 11, INSERM U802, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #16950808 No free full text.

Abstract: OBJECTIVE: To investigate the safety and efficacy of rituximab (RTX) for systemic symptoms in patients with primary Sjögren's syndrome (pSS), and changes in B cell biomarkers. PATIENTS AND METHODS: The records of 16 patients with pSS according to the American European consensus group criteria were reviewed retrospectively. RESULTS: Patients, all women, had a median age of 58.5 (range 41-71) years and a disease duration of 9.5 (range 0-25) years. RTX was prescribed for lymphoma (n = 5), refractory pulmonary disease with polysynovitis (n = 2), severe polysynovitis (n = 2), mixed cryoglobulinaemia (n = 5), thrombocytopenia (n = 1) and mononeuritis multiplex (n = 1). The median follow-up duration was 14.5 (range 2-48) months. Three patients experienced adverse events, including one mild serum sickness-like reaction with the presence of human antichimeric antibodies. Efficacy of treatment was observed in 4 of 5 patients with lymphomas and in 9 of 11 patients with systemic involvement. Dryness was improved in only a minority of patients. Corticosteroid dose was reduced in 11 patients. RTX induced decreased rheumatoid factor, gamma-globulin and beta2-microglobulin levels, and the level of B cell activating factor of the tumour necrosis factor family (BAFF) increased concomitantly with B cell depletion. Five patients were re-treated, with good efficacy and tolerance, except for one with probable serum sickness-like reaction. CONCLUSION: This study shows good efficacy and fair tolerance of RTX for systemic features. In addition, RTX allows for a marked reduction in corticosteroid use. Except for BAFF, the level of which increases, serum B cell biomarker levels decrease after taking RTX. Controlled trials should be performed to confirm the efficacy of RTX in pSS.

Bettembourg-Brault I, Gossec L, Pham T, Gottenberg JE, Damiano J, Dougados M. · Rheumatology B Department, Cochin Hospital, AP-HP, Rene Descartes University, Paris, France. · Clin Exp Rheumatol. · Pubmed #16762152 No free full text.

Abstract: OBJECTIVE: To evaluate the treatment discontinuation rate of leflunomide in rheumatoid arthritis (RA) in comparison with the discontinuation of other disease modifying anti-rheumatic drugs (DMARDs), in daily practice, in a single center and during the same period of time. METHODS: Study design: 3-year, retrospective, monocenter. Patients: RA patients for whom leflunomide or another DMARD was initiated between 1998 and 2001 (several DMARDs could be initiated for a given patient during this period). Collected data: For each patient, demographic and disease data. For each treatment course, date of initiation, if relevant date of discontinuation and reason for discontinuation. Analysis: Percentage of patients discontinuing treatment over time (life table method; Kaplan-Meier), comparison between leflunomide and the "any other DMARD" or methotrexate groups using the Log-Rank test. RESULTS: During the study period, 515 DMARDs were initiated in 285 patients. Leflunomide was initiated in 161 patients who were older and had a longer disease duration than the other treated patients (59 +/- 13 years and 14 +/- 9 years versus 54 +/- 15 years and 11 +/- 10 years in the leflunomide group and other DMARDs group respectively). Discontinuation rate of leflunomide after 1 year was 56.7%, mainly because of adverse drug reactions (41.6%). The discontinuation rate whatever the reason and for toxicity was higher for leflunomide than for other DMARDs studied. However discontinuation for inefficacy was similar in both groups. CONCLUSION: This study conducted in conditions of daily practice when leflunomide was first available suggests a higher discontinuation rate of leflunomide because of adverse events when compared to other DMARDs.

Champey J, Corruble E, Gottenberg JE, Buhl C, Meyer T, Caudmont C, Bergé E, Pellet J, Hardy P, Mariette X. · Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-11, Le Kremlin Bicêtre, France. · Arthritis Rheum. · Pubmed #16739213 links to  free full text

Abstract: OBJECTIVE: To compare pain, fatigue, and sicca symptoms; quality of life; and psychological status between patients with primary Sjögren's syndrome (SS) and those with sicca symptoms but no autoimmune features (sicca asthenia polyalgia syndrome [SAPS]), and to determine whether a psychological pattern can be detected in patients with SAPS, which could suggest psychological distress as the cause. METHODS: This cross-sectional, prospective study included 111 patients with primary SS according to the American-European Consensus Group criteria and 65 SAPS patients with no focus on lip biopsy and no anti-SSA/SSB antibodies. Pain, fatigue, and sicca symptoms were assessed using visual analog scales; quality of life was assessed using the Short Form 36 (SF-36); and psychological distress by the Symptom Checklist-90-Revised (SCL-90-R) questionnaire. RESULTS: No difference was observed between primary SS and SAPS patients for pain, fatigue, sicca symptoms, quality of life, and psychological status. Fatigue and pain, but not dryness, were correlated with both quality of life and psychological distress in both groups. For primary SS patients, physical and mental composite scores on the SF-36 correlated well with global severity index (GSI) scores of the SCL-90-R (r = -0.29, P = 0.006 and r = -0.61, P < 0.0001, respectively). CONCLUSION: Patients with primary SS and SAPS do not differ in quality of life or psychological status. Although both diseases probably have a different origin, they may require the same psychological support or psychiatric care. The strong correlation between the composite physical and mental scores of the SF-36 and the GSI scores of the SCL-90-R in primary SS patients emphasizes the importance of the psychological dimension in results of the SF-36.

Gottenberg JE, Pallier C, Ittah M, Lavie F, Miceli-Richard C, Sellam J, Nordmann P, Cagnard N, Sibilia J, Mariette X. · Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France. · Arthritis Rheum. · Pubmed #16732567 links to  free full text

This publication has no abstract.

Gottenberg JE, Aucouturier F, Goetz J, Sordet C, Jahn I, Busson M, Cayuela JM, Sibilia J, Mariette X. · Rhumatologie, Université Paris-Sud 11, INSERM U802, Hôpital Bicêtre, Assistance Publique des Hôpitaux de Paris, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #16569685 No free full text.

Abstract: BACKGROUND: B cell activation may result in an increased secretion of immunoglobulin free light chains (FLCs) in autoimmune diseases. OBJECTIVE: To analyse serum FLC levels in patients with rheumatoid arthritis and in those with primary Sjögren's syndrome (pSS). PATIENTS AND METHODS: Blood samples were collected from 80 healthy blood donors, 50 patients with rheumatoid arthritis and 139 patients with pSS. Serum FLC level was measured using a new quantitative immunoassay. RESULTS: Mean (standard error (SE)) serum kappa and lambda FLC levels were significantly higher in patients with rheumatoid arthritis and in those with pSS than in controls (kappa : 18.9 (1.1) and 16.3 (1.4) v 10.5 (0.4) mg/l, p<0.001 and p = 0.001, respectively; lambda: 16.7 (1.2) and 19.3 (1.5) v 11.6 (0.6) mg/l, p<0.001 for both). 18 (36%) patients with rheumatoid arthritis and 31 (22.3%) patients with pSS had abnormal serum FLC levels (increased kappa or lambda levels and abnormal ratio of kappa:lambda). Serum kappa and lambda levels were correlated with other B cell activation markers in both diseases. FLC levels increased with disease activity, because, unlike total gammaglobulin and immunoglobulin G levels, they were significantly correlated with Disease Activity Score 28 in patients with rheumatoid arthritis (p = 0.004 for kappa, p = 0.05 for lambda) and with extraglandular involvement in pSS (p = 0.01 for kappa, p = 0.04 for lambda). CONCLUSION: FLC levels are increased and correlate with disease activity in patients with rheumatoid arthritis and in those with pSS, two diseases in which increased risk of lymphoma could result from persistent B cell activation and disease activity. Further studies are required to determine whether FLC assessment could represent a relevant biomarker for response to treatment (especially B cell depletion) and for the risk of lymphoma in autoimmune diseases.

Gottenberg JE, Sellam J, Ittah M, Lavie F, Proust A, Zouali H, Sordet C, Sibilia J, Kimberly RP, Mariette X, Miceli-Richard C. · Rhumatologie, INSERM E 109, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud 11, Le Kremlin Bicêtre, France. · Arthritis Res Ther. · Pubmed #16507129 links to  free full text

Abstract: Polyclonal B cell activation might be related to pathogenic over-expression of B-cell-activating factor (BAFF) in primary Sjögren's syndrome (pSS) and other autoimmune diseases. We therefore investigated whether BAFF over-expression in pSS could be a primary, genetically determined event that leads to the disease. The complete BAFF gene was sequenced in Caucasian pSS patients and control individuals. The only single nucleotide polymorphism frequently observed, namely -871 T/C in the promoter region, was then genotyped in 162 French patients with pSS and 90 French control individuals. No significant differences in allele (T allele frequency: 49.7% in patients with pSS versus 50% in controls; P = 0.94) and genotype frequencies of BAFF polymorphism were detected between pSS patients and control individuals. BAFF gene polymorphism was not associated with a specific pattern of antibody secretion either. T allele carriers had significantly increased BAFF protein serum levels (mean values of 8.6 and 5.7 ng/ml in patients with TT and TC genotypes, respectively, versus 3.3 ng/ml in patients with CC genotype; P = 0.01), although no correlation was observed between BAFF polymorphism and mRNA level. In conclusion, BAFF gene polymorphism is neither involved in genetic predisposition to pSS nor associated with a specific pattern of antibody production.

Gottenberg JE, Cagnard N, Lucchesi C, Letourneur F, Mistou S, Lazure T, Jacques S, Ba N, Ittah M, Lepajolec C, Labetoulle M, Ardizzone M, Sibilia J, Fournier C, Chiocchia G, Mariette X. · Institut Pour la Santé et de la Recherche Médicale E 802 and Service de Rhumatologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, 94275 Le Kremlin Bicêtre, France. · Proc Natl Acad Sci U S A. · Pubmed #16477017 links to  free full text

Abstract: Gene expression analysis of target organs might help provide new insights into the pathogenesis of autoimmune diseases. We used global gene expression profiling of minor salivary glands to identify patterns of gene expression in patients with primary Sjögren's syndrome (pSS), a common and prototypic systemic autoimmune disease. Gene expression analysis allowed for differentiating most patients with pSS from controls. The expression of 23 genes in the IFN pathways, including two Toll-like receptors (TLR8 and TLR9), was significantly different between patients and controls. Furthermore, the increased expression of IFN-inducible genes, BAFF and IFN-induced transmembrane protein 1, was also demonstrated in ocular epithelial cells by quantitative RT-PCR. In vitro activation showed that these genes were effectively modulated by IFNs in salivary gland epithelial cells, the target cells of autoimmunity in pSS. The activation of IFN pathways led us to investigate whether plasmacytoid dendritic cells were recruited in salivary glands. These IFN-producing cells were detected by immunohistochemistry in all patients with pSS, whereas none was observed in controls. In conclusion, our results support the pathogenic interaction between the innate and adaptive immune system in pSS. The persistence of the IFN signature might be related to a vicious circle, in which the environment interacts with genetic factors to drive the stimulation of salivary TLRs.

Ittah M, Gottenberg JE, Proust A, Hachulla E, Puechal X, Loiseau P, Mariette X, Miceli-Richard C. · Service de Rhumatologie, Institut Pour la Santé et la Recherche Médicale E 109, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France. · Genes Immun. · Pubmed #15933742 No free full text.

Abstract: One-third of first-degree relatives of patients with primary Sjögren's syndrome (pSS) suffer from other autoimmune diseases, including type I diabetes, systemic lupus erythematosus and autoimmune thyroiditis. Recently, 1858 C/T polymorphism of PTPN22 gene was reported to predispose to these autoimmune diseases. We decided to investigate whether PTPN22 gene polymorphism was also involved in the genetic predisposition to pSS in a case-control study, including 183 patients with pSS and 172 healthy controls. No significant differences in allele (T allele frequency: 7.7% in patients with pSS vs 7.8% in controls, P=0.9) and genotype frequencies of PTPN22 polymorphism were detected between patients with pSS and controls. PTPN 22 gene polymorphism was not associated with a specific pattern of autoantibody secretion either. Thus, 1858 C/T polymorphism of PTPN22 gene is not involved in genetic predisposition to pSS.