Rheumatoid Arthritis: Devauchelle V

Youinou P, Daridon C, Saraux A, Devauchelle V, Pers JO. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #17181915 No free full text.

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Pers JO, Le Pottier L, Devauchelle V, Saraux A, Youinou P. · Laboratoire d'immunologie, centre hospitalier universitaire de Brest, B.P. 824, 29609 Brest, France. · Rev Med Interne. · Pubmed #18403061 No free full text.

Abstract: INTRODUCTION: Sjögren's syndrome (SS) is an autoimmune epithelitis hallmarked by a disruption of epithelial cells, the subsequent lymphocytic infiltration of lachrymal and salivary glands (SGs), and their ensuing dryness. One may posit that SS is triggered by viruses, and/or modulated by sex steroid hormones, and there is indeed a consensus that its aetiology is multifactorial, with genetic factors interacting with environmental agents. CURRENT KNOWLEDGE AND KEY POINTS: T-cells have long occupied central stage of the debate on the type of lymphocytes involved in the pathogenesis of SS. The relevance of B cells has, however, been emphasized over the past five years and new insights into their functions revealed. Furthermore, increased levels of the B-cell activating factor (BAFF) may be responsible for quantitative and qualitative anomalies of B-cells found in SS such as emergence of self reactive B-cells. This review reports compelling evidence that B-cells are involved in the pathophysiology of SS. PROSPECTS: Since SS may thus be conceived as a model for B-cell-induced autoimmunity, it is no surprise that B-cell ablative-treatment has proven to be relatively effective in SS.

Youinou P, Devauchelle V, Hutin P, Le Berre R, Saraux A, Pers JO. · Department of Immunopathology, Brest University Medical School, Brest, France. · Clin Rev Allergy Immunol. · Pubmed #17992590 No free full text.

Abstract: Although the relative contributions of T cells and B cells in Sjögren's syndrome (SS) are far from being settled, recent studies have suggested a crucial role for B cells in its pathophysiology. Early investigations have focused on the ability of B cells to produce autoantibodies, and new studies have enlarged the range of their functions. For example, beyond the paradigm that T lymphocytes maintain strict control over B cells, the latter cells are now acknowledged to solicit their own help from the former cells and release a flurry of cytokines. Further, some of these B cells act as antigen-presenting cells. Increased levels of the B cell activating factor (BAFF) found in SS may be responsible for high numbers of circulating Bm2/Bm2' cells and associated functional abnormalities of B cells, such as a BAFF-induced increased expression of CD19, which decreases the required strength generated by antigen binding for transmitting its signal. This review reports compelling evidence that B cells are involved in the pathophysiology of SS. As this brings novel prospects for the treatment of the disease, it is no surprise that B cell ablative treatment has proven to be relatively efficacious in SS.

Daridon C, Guerrier T, Devauchelle V, Saraux A, Pers JO, Youinou P. · Laboratory of Immunology, Brest University Medical School Hospital, Brest, France. · Autoimmun Rev. · Pubmed #17643928 No free full text.

Abstract: Analysis of salivary glands of patients with primary Sjögren's syndrome has yielded conflicting results with respect to T helper (Th)1/Th2 polarization. This balance might parallel the progress of the local lesions. B-cells are now taking center stage in this disease. They can also be primed to differentiate into two cytokine-production pathways, dubbed B effector (Be) 1 and Be2 cells. This is discussed in the light of our recent finding that Be1 accompany Th1, while Be2 accompany in the tissue lesions.

Bosello S, Pers JO, Rochas C, Devauchelle V, De Santis M, Daridon C, Saraux A, Ferraccioli GF, Youinou P. · Laboratory of Immunology, Medical School, Brest, France. · Int J Immunopathol Pharmacol. · Pubmed #17346422 No free full text.

Abstract: Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.

Devauchelle V, Chiocchia G. · Unité Inserm 567, institut Cochin, pavillon Hardy-A, 1 étage, 27 rue du Faubourg-Saint-Jacques, 75674 Paris, France. · Rev Med Interne. · Pubmed #15471599 No free full text.

Abstract: PURPOSE: DNA chip is a recently developed technique allowing analysis of thousands of genes at the same time in multiple biological samples. In few years it has become an obligatory step in massive gene expression study. The enormous quantity of results generated and the new way of thinking allowed make this kind of study a true revolution. KEY MESSAGE AND RECENT FACTS: The enormous discovery potential permitted by the accomplishment of multiple genomes sequencing and the advent of technologies allowing massive gene expression analyses have totally modified the diseases approach. Considering the obtainment of a real full picture of the transcriptional activity in an organ, tissue or cell is now legitimate. DNA microarray is obviously not the only technique allowing such type of analysis but it is without contest the technology which is the most popular and the one which has been recently the subject of the most important developments. It is certainly the technology which brought the main advances in tumour classification and discovery of new biomarkers. The first results based on this technology in inflammatory diseases have recently been reported. PERSPECTIVE AND PROJECTS: The optimal use of DNA microarrays will necessitate a powerful statistical analysis and an high quality biological experimentation. Strict standard and quality criteria are developing. Obviously, the DNA chips have a role to play in multifactorial inflammatory diseases mainly through their potential to bring new answers to diagnostic and pathophysiological problems. One potential development of the technique in such diseases will be the definition of disease specific gene profiles and the generation of chips allowing the detection of few targeted genes with all the known mutations of these genes. The correlation of global or targeted gene expression with clinical and pathological data will allow a new step forward in the understanding and taking care of inflammatory diseases.

Durand V, Lamour A, Devauchelle V, Youinou P, Jamin C. · Laboratory of Immunology, Institut de Synergie des Sciences et de la Santé, Brest, France. · Clin Rev Allergy Immunol. · Pubmed #10907104 No free full text.

This publication has no abstract.

Rochas C, Hillion S, Saraux A, Mageed RA, Youinou P, Jamin C, Devauchelle V. · Université Européenne de Bretagne, Université de Brest, IFR 148 ScInBioS, and Laboratory of Immunology, Centre Hospitalier Universitaire, Brest Hôpital Morvan and Cavale Blanche, Brest, France. · Arthritis Rheum. · Pubmed #19404965 No free full text.

Abstract: OBJECTIVE: B cells that accumulate in the synovial tissue of rheumatoid arthritis (RA) patients revise their receptors due to coordinate expression of recombination-activating gene 1 (RAG-1) and RAG-2 genes. The aim of this study was to determine the mechanisms that control this re-expression. METHODS: B cells from healthy control subjects were cocultured with fibroblast-like synoviocytes (FLS) from patients with RA and osteoarthritis (OA). Re-expression of RAG messenger RNA (mRNA) and proteins was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and indirect immunofluorescence. Activity of RAG enzymes was evaluated by flow cytometry to measure variations in immunoglobulin kappa and lambda light chain expression and by ligation-mediated-PCR to assess specific DNA breaks. Blocking antibodies, short hairpin RNA, and recombinant cytokine were used to identify the molecules involved in RAG re-expression. RESULTS: RA FLS, but not OA FLS, induced B cells to re-express RAG mRNA and proteins. Enzymes were functional, since the kappa-to-lambda ratios decreased and specific DNA breaks were detectable after coculture with RA FLS. Transmembrane BAFF provided the first signal of RAG re-expression, since its down-regulation in RA FLS prevented RAG gene transcription in B cells. The failure of transmembrane BAFF from OA FLS to induce RAG suggests that a second signal was provided by RA FLS. Interleukin-6 (IL-6) is a candidate, since blockade of its receptors precluded transcription of RAG genes by RA FLS. Unless supplemented with IL-6, OA FLS were unable to induce RAG gene expression in normal B cells. CONCLUSION: Two independent signals are required for the induction of RAG gene expression in B cells that infiltrate the synovium of patients with RA.

Le Pottier L, Devauchelle V, Fautrel A, Daridon C, Saraux A, Youinou P, Pers JO. · Equipe d'Accueil 2216 and Institut Fédératif de Recherche 418, Science et Ingénierie en Biologie-Santé, Université de Brest, Brest, and Université Européenne de Bretagne, Brest, France. · J Immunol. · Pubmed #19265132 No free full text.

Abstract: This study reports on the characterization of B cells of germinal center (GC)-like structures infiltrating the salivary glands (SGs) of patients with Sjögren's syndrome. Eight two-color combinations were devised to characterize the phenotype of these B cells in 11 SG specimens selected from biopsies obtained from 40 Sjögren's syndrome patients and three normal tonsils. The 9G4 mAb, which recognizes V4.34-encoded autoAbs, enabled us to identify autoreactive B cells. Quantitative RT-PCR was used to determine the level of mRNAs for activation-induced cytidine deaminase (AICDA), repressors and transcription factors. CD20(+)IgD(-)CD38(+)CD21(+)CD24(-) B cells, similar to those identified in tonsil GCs, were seen in the SGs of four patients and, and since they expressed AICDA, they were termed "real GCs". CD20(+)IgD(+)CD38(-)CD21(+)CD24(+) B cells, seen in aggregates from the remaining seven samples, were characteristically type 2 transitional B cells and marginal zone-type B cells. They lacked AICDA mRNAs and were termed "aggregates". Real GCs from SGs contained mRNAs for Pax-5 and Bcl-6, like tonsil GC cells, whereas aggregates contained mRNAs for Notch-2, Blimp-1, IRF-4, and BR3, similar to marginal zone B cells. Further experimental data in support of this dichotomy included the restriction of CXCR5 expression to real GC cells, while sphingosine 1-phosphate receptor 1 was expressed only in aggregates. In contrast, both types of B cell clusters expressed the idiotype recognized by the 9G4 mAb. Our data indicate that, in SGs, a minority of B cell clusters represent genuine GC cells, while the majority manifest features of being type 2 transitional B cells and marginal zone cells. Interestingly, both types of B cell aggregates include autoreactive B cells.

Pers JO, Daridon C, Bendaoud B, Devauchelle V, Berthou C, Saraux A, Youinou P. · Department of Immunopathology, Brest University Medical School, Brest, France. · Clin Rev Allergy Immunol. · Pubmed #18270858 No free full text.

Abstract: Although T-lymphocytes have long been regarded as the prime effector of autoimmune diseases, numerous studies have since highlighted a key role for B-lymphocytes. For example, disturbances in the distribution of circulating B-cell subsets were reported in primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Consequently, this was the rationale to treat such patients for B-cell depletion with anti-CD20 monoclonal antibody (rituximab). The aim of this review is to describe and analyze the B-cell subset distribution at baseline and after rituximab therapy in patients with SLE, rheumatoid arthritis, and pSS. Finally, we will compare factors that may interfere with anti-CD20-mediated B-cell depletion in these autoimmune diseases.

Guennoc X, Samjee I, Jousse-Joulin S, Devauchelle V, Roudaut A, Saraux A. · Rheumatology Department, Brest Teaching Hospital, CHU de Brest, 29609 Brest, France. · Joint Bone Spine. · Pubmed #17574895 No free full text.

Abstract: OBJECTIVE: To evaluate the quality of patient information about fluoroscopy-guided rheumatologic procedures, and to look for an impact on the patient's experience of the procedure. METHODS: One hundred and nineteen patients completed questionnaires before and after undergoing fluoroscopy-guided interventions. We looked for associations between the information supplied by the rheumatologist who recommended the procedure and pain, anxiety, awareness of potential complications, and the match between patient expectations and actual experience. RESULTS: 62.8% of patients reported receiving information about the procedure. Only 20.5% reported receiving specific information about potential adverse events, although 80.9% felt this information would have been useful. Most patients (74.8%) would have liked to receive additional information. Only 10.1% patients were given written information. Mean (+/-SD) anticipated pain severity as assessed in the waiting room before the procedure on a 0-10 scale was 4.5+/-2.4 in women and 4.2+/-2.3) in men. Actual pain severity during the procedure as assessed on the same scale was 2.7+/-2.6 in women and 2.2+/-1.6 in men. The level of information about the procedure did not influence anticipated or actual pain severity. Anxiety was reported by 59.8% patients and was more common in women (P<0.001), in patients given written information (P=0.05), and in patients undergoing their first intervention (P=0.05). Information was perceived as alleviating anxiety by 69.9% patients, and 77.3% of patients felt they would experience less anxiety if they had the procedure a second time. Only 21.2% patients were able to name a potential adverse event, and this proportion was not influenced by receiving written information. A mismatch between expectations about the procedure or its duration and actual experience was reported by 17 (17/69, 24.6%) and 34 (34/98, 34.7%) patients, respectively, with no significant differences across study subgroups. CONCLUSION: Information about interventional rheumatology procedures is required for ethical principles and legislation. Patients increasingly expect detailed information, which may increase the likelihood that the procedure unfolds smoothly. Our results indicate a need for optimizing patient information. Standardized written material deserves to be evaluated as a means of better meeting the informational needs of patients.

Pers JO, Devauchelle V, Daridon C, Bendaoud B, Le Berre R, Bordron A, Hutin P, Renaudineau Y, Dueymes M, Loisel S, Berthou C, Saraux A, Youinou P. · Brest University Medical School, Brest, France. · Arthritis Rheum. · Pubmed #17469105 links to  free full text

Abstract: OBJECTIVE: Treatment with rituximab depletes B cells from the peripheral blood (PB) and salivary glands (SGs) of patients with primary Sjögren's syndrome (SS). The purpose of this study was to track the repopulation of B cell subsets in PB as well as their subsequent homing into SGs in patients with primary SS treated with rituximab. METHODS: A series of 4-color flow cytometry experiments delineated B cell subsets in 15 patients with primary SS. All were tested on days 8 and 15 of treatment. Nine of the patients were followed up monthly for 10 months, and the remaining 6 patients were followed up monthly for 24 months. Enzyme-linked immunosorbent assays were developed to measure serum levels of BAFF and rituximab. SGs were biopsied at the start of the study and 4 months after treatment in 15 patients, 12 months after treatment in 3 patients, and 24 months after treatment in 2 patients. RESULTS: Baseline serum levels of BAFF correlated inversely (r = -0.92, P < 5 x 10(-4)) with the duration of B cell depletion: the higher the BAFF levels, the shorter the duration of B cell depletion. Four B cell subsets repopulated the PB: plasmablasts (CD19+, CD5-,IgD-,CD38++), transitional type 1 (T1) B cells (CD19+,CD5+,IgD+,CD38++), mature Bm2 cells (CD19+,CD5+/-,IgD+,CD38+/-), and memory B cells (CD19+,CD5-,IgD-,CD38-). Increased numbers of Bm2 cells and decreased memory B cells reappeared with time. Sequential SG biopsies revealed that B cells were absent in these glands for 12 months: they were detected 24 months after rituximab treatment. Memory and T1 B cells were the first B cells identified locally. CONCLUSION: The timing of B cell repopulation is modulated by BAFF and is followed by reconstitution of the preexisting abnormalities.

Daridon C, Devauchelle V, Hutin P, Le Berre R, Martins-Carvalho C, Bendaoud B, Dueymes M, Saraux A, Youinou P, Pers JO. · Laboratory of Immunology, Brest University Medical School Hospital, Brest, France. · Arthritis Rheum. · Pubmed #17393395 links to  free full text

Abstract: OBJECTIVE: To identify the cells that produce BAFF in the salivary glands of patients with primary Sjögren's syndrome (SS), and to analyze BAFF receptor expression by local T and B lymphocytes. METHODS: We used 3 methods to identify the source of BAFF: in situ hybridization of the transcripts for BAFF combined with staining of membrane markers, regular and real-time reverse transcription-polymerase chain reaction (RT-PCR) of cultured epithelial cells, and RT-PCR of sorted single-cell T and B lymphocytes eluted from salivary glands. Cells expressing TACI, BCMA, and B lymphocyte stimulator receptor 3 (BR-3) were disclosed by combining each specific staining of the receptors with each specific staining of the cells. The function of BAFF generated by epithelial cells on B lymphocytes was determined in short-term cocultures. RESULTS: Transcripts for BAFF were seen in epithelial cells and infiltrating T lymphocytes and, for the first time, were detected in local B cells. It is interesting that BR-3 was present on these B cells but not on T cells. In contrast, TACI and, to a lesser degree, BCMA were observed on transitional B lymphocytes, whereas T lymphocytes were devoid of receptors for BAFF. Furthermore, this cytokine was shown to be functional, in that epithelial cell-bound BAFF extended the survival of normal B cells, but cell-free BAFF released in the supernatants did not. CONCLUSION: These experiments establish that in primary SS, BAFF is produced not only by epithelial cells and T cells but also by B cells. The expression of receptors for BAFF would thus allow these receptors to participate in an autocrine pattern of self-stimulation.

Le Pottier L, Devauchelle V, Pers JO, Jamin C, Youinou P. · Brest University Medical School, Brest, France. · Autoimmun Rev. · Pubmed #17289550 No free full text.

Abstract: Major breakthroughs have occurred with classification of B-cells into populations and subpopulations. With respect to their expression of CD5, they comprise the B1 and B2 populations, with the former further divided into B1a and B1b subpopulations. The oncologic process starts from transitional type 1 (T1) and T2 immature B-cells, through marginal zone or germinal center B-cells, ending up with memory B-cells and plasma cells (PCs). They may also be categorized based on their functional commitment with polarized B effector (Be)1 and Be2, with B-activating factor of the tumor-necrosis factor-producing B-cells, and with short-lived and long-lived PCs. Such a seemingly homogeneous family of cells has thus turned out to be a genuine mosaic of B-lymphocyte subsets.

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

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

Daridon C, Pers JO, Devauchelle V, Martins-Carvalho C, Hutin P, Pennec YL, Saraux A, Youinou P. · Laboratory of Immunology, Brest University Medical School Hospital, BP824, F-29609 Brest, France. · Arthritis Rheum. · Pubmed #16802367 links to  free full text

Abstract: OBJECTIVE: To identify B cell subpopulations participating in the lymphocyte infiltrate of salivary glands from patients with primary Sjögren's syndrome. A special emphasis was placed on those B lymphocytes included in the ectopic germinal centers (GCs). METHODS: The presence of B cells in salivary glands and their polyclonality were ascertained by phenotyping and reverse transcription-polymerase chain reaction in salivary gland samples from 18 patients. Their phenotype was thoroughly analyzed using a number of double-staining combinations. The results obtained in tissue sections were confirmed by fluorescence-activated cell sorting analysis of B cells eluted from salivary glands, and these findings were compared with those in tonsils. RESULTS: Memory-type B cells were defined as CD20+, CD27+ and were seen in all specimens, whereas GCs were found in only 7 specimens. Furthermore, B cells found in these GCs lacked certain characteristics of centroblasts and centrocytes. Instead, they fulfilled the criteria for transitional type II (TII) B cells and resembled marginal-zone B cells. BAFF (the assistance of which is required for proper transformation of transitional TI B cells into transitional TII B cells) accumulated adjacent to transitional and marginal-zone-like B lymphocytes. Further evidence for the involvement of BAFF came from the expression of its receptors on infiltrating B cells. CONCLUSION: These transitional TII and marginal-zone-like B cells are probably instrumental in the local production of autoantibodies and possibly influential in the ensuing destruction of epithelial cells.

Cagnard N, Letourneur F, Essabbani A, Devauchelle V, Mistou S, Rapinat A, Decraene C, Fournier C, Chiocchia G. · Institut Cochin, Département d'Immunologie, Hôpital Cochin, Pavillon Hardy A, 27 rue du Faubourg Saint-Jacques, 75674 Paris Cedex 14, France. · Eur Cytokine Netw. · Pubmed #16464743 No free full text.

Abstract: Since cytokines and chemokines are important actors in rheumatoid arthritis (RA), the aim of this study was to compare the gene expression profiles in cultured fibroblast-like synoviocytes (FLS) obtained from patients with either RA, or osteoarthritis (OA), focusing our analysis on genes for cytokines and chemokines, and their respective receptors. Gene expression in cultured FLS (third passage) from eight patients with RA (RA-FLS) were compared with gene expression in cultured FLS from nine patients with OA (OA-FLS) using Affymetrix Human Genome U133 Plus 2.0 Array microarray, allowing analysis of over 54,000 transcripts. Among the 171 genes studied (241 probes), limiting the selection of differentially expressed genes to a significant value (p < 0.05), and a differential ratio of expression > 1.6, only four genes, namely IL-32, CCL2, PF4F1 and GDF10 were found to be differentially expressed. Out of these four genes, only higher expression of CCL2 has been reported previously in RA. The newly described cytokine IL-32 was the most prominently differentially expressed gene in the present study, with higher expression in RA-FLS than in OA-FLS (p < 0.0073). IL-32 might have a previously unidentified pivotal role in RA.

d'Arbonneau F, Pers JO, Devauchelle V, Pennec Y, Saraux A, Youinou P. · Immunology Laboratory, Brest University Medical School, F-29609 Brest, France. · Arthritis Rheum. · Pubmed #16385503 links to  free full text

Abstract: OBJECTIVE: To determine the effect of excessive production of BAFF on the distribution and function of B cell subsets in patients with primary Sjögren's syndrome (SS). METHODS: The phenotype of B lymphocytes was analyzed by flow cytometry. Differences in the expression level of membrane IgD and CD38 were used to identify B lymphocyte subsets evolving from naive Bm1 through memory Bm5 cells. Based on our finding of a low expression of CD45RA, we sorted Bm2/Bm2' cells to determine the time course of translocation of the CD19 molecule and the B cell receptor into lipid rafts, by confocal microscopy. Serum levels of BAFF were measured by an enzyme-linked immunosorbent assay developed in-house. RESULTS: "Circulating" Bm2/Bm2' cells were expanded in patients with primary SS compared with rheumatic disease controls and with normal controls. In addition, these B cell subsets were functionally abnormal. Prolonged residency of the B cell receptor in lipid rafts in these cells was associated with elevated CD19 expression in B cells, most notably, Bm2 and Bm2' cells, obtained from the patients with primary SS. BAFF levels were higher in the patients than in the normal controls and correlated with the percentage of Bm2/Bm2' cells and their expression of CD19 in primary SS patients. These correlations were confirmed by placing sorted Bm1 or Bm2 cells from normal controls in culture in the presence or absence of BAFF. CONCLUSION: Bm2/Bm2' cells express more CD19 molecules in primary SS patients than in normal controls. BAFF might participate in this elevated expression of CD19. These patients might be suitable candidates for treatment with BAFF antagonists.

Pers JO, Daridon C, Devauchelle V, Jousse S, Saraux A, Jamin C, Youinou P. · Department of Immunology, Brest University Medical School Hospital, BP824, F29609, Brest, France. · Ann N Y Acad Sci. · Pubmed #16014518 No free full text.

Abstract: The B-cell activity factor (BAFF) acts as a positive regulator of B-cell function. To gain further insight into the understanding of B-cell hyperactivity in autoimmune diseases, the serum level of BAFF was determined in 43 systemic lupus erythematosus (SLE) patients, 58 primary Sjögren's syndrome (pSS) patients, 28 rheumatoid arthritis (RA) patients, and 68 normal control subjects using an in-house sandwich ELISA. A commercial kit was used to detect soluble CD23 (sCD23) reflecting B-cell activation. In-house assays for the detection of autoantibodies also were used. We found an increased level of BAFF in SLE, pSS, and RA sera compared with normal subjects (respectively, 10.6 +/- 8.5, 15.8 +/- 12.9, 9.7 +/- 1.5 ng/mL vs. 4.6 +/- 2.9 ng/mL, P < .001). sCD23 released on B-cell activation also was found to be elevated in SLE, pSS, and RA compared with normal sera. However, no correlation was found between the circulating BAFF and the level of sCD23. By contrast, we observed that high levels of BAFF were associated with the presence of autoantibodies (anti-double-stranded DNA antibodies in SLE, anti-SSA antibodies in pSS, and rheumatoid factors in RA). Our data suggest that BAFF is influential in driving antibody production rather than activation of the B lymphocytes in autoimmune diseases.

Devauchelle V, Marion S, Cagnard N, Mistou S, Falgarone G, Breban M, Letourneur F, Pitaval A, Alibert O, Lucchesi C, Anract P, Hamadouche M, Ayral X, Dougados M, Gidrol X, Fournier C, Chiocchia G. · Institut Cochin, Paris, France. · Genes Immun. · Pubmed #15496955 No free full text.

Abstract: This study was undertaken to evaluate the possibility to obtain a molecular signature of rheumatoid arthritis (RA) comparatively osteoarthritis (OA), and to lay the bases to develop new diagnostic tools and identify new targets. Microarray technology was used for such an analysis. The gene expression profiles of synovial tissues from patients with confirmed RA, and patients with OA were established and compared. A set of 63 genes was selected, based, more specifically, on their overexpression or underexpression in RA samples compared to OA. Results for six of these genes have been verified by quantitative PCR using both samples identical to those used in the microarray experiments and entirely separate samples. Expression profile of the 48 known genes allowed the correct classification of additional RA and OA patients. Furthermore, the distinct expression of three of the selected genes was also studied by quantitative RT-PCR in cultured synovial cells. Detailed analysis of the expression profile of the selected genes provided evidence for dysregulated biological pathways, pointed out to chromosomal location and revealed novel genes potentially involved in RA. It is proposed that such an approach allows valuable diagnosis/prognostics tools in RA to be established and potential targets for combating the disease to be identified.

Saraux A, Berthelot JM, Devauchelle V, Bendaoud B, Chalès G, Le Henaff C, Thorel JB, Hoang S, Jousse S, Baron D, Le Goff P, Youinou P. · Unit of Rheumatology and the Laboratory of Immunology, Hôpital de la Cavale Blanche, CHU Brest, BP 824, F-29609 Brest-Cedex, France. · J Rheumatol. · Pubmed #14719190 No free full text.

Abstract: OBJECTIVE: To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and anti-cyclic citrullinated peptides (anti-CCP) to discriminate between patients with and without rheumatoid arthritis (RA) and to determine the diagnostic value of anti-CCP used alone or with other tests. METHODS: Two hundred and seventy patients with early arthritis underwent standardized investigations in 1995-1997. The clinical utility of APF, AKA, and anti-CCP in first-visit sera was evaluated using receiver-operating characteristic curves. Combinations of anti-CCP with other laboratory tests were assessed by multiple logistic regression. RESULTS: Anti-CCP, APF, and AKA were not perfectly correlated with one another. Anti-CCP with 53 UI as the cutoff was 47% sensitive and 93% specific, versus 52% and 79%, and 47% and 94%, for APF and AKA, respectively. Multiple logistic regression selected anti-CCP, AKA, IgM-rheumatoid factor (RF) ELISA, and the latex test. CONCLUSION: Rheumatologists can routinely use 2 or 3 tests for diagnosing RA (latex and/or IgM RF ELISA, and either AKA or anti-CCP ELISA) and can add a third or fourth test when the diagnosis remains in doubt.

Saraux A, Berthelot JM, Chalès G, Le Henaff C, Mary JY, Thorel JB, Hoang S, Dueymes M, Allain J, Devauchelle V, Baron D, Le Goff P, Youinou P. · Rheumatology Unit, Hôpital de la Cavale Blanche, Brest, France. · Arthritis Rheum. · Pubmed #11954009 No free full text.

Abstract: OBJECTIVE: To determine which laboratory test or tests at presentation best predicted a diagnosis of rheumatoid arthritis (RA) 2 years later. METHODS: Two hundred seventy patients with early arthritis seen in 7 hospitals underwent comprehensive evaluations at 6-month intervals for 2 years, when the diagnosis of RA was assessed by 5 rheumatologists. The sensitivity and specificity of each test at the first visit for discriminating between RA (38%, n = 98) and non-RA patients were determined. Optimal cutoffs for continuous tests were derived from receiver operating characteristic curves. Sensitivity and specificity of test combinations selected by multiple logistic regression were determined. RESULTS: IgM rheumatoid factor (RF) by enzyme-linked immunosorbent assay, IgG-antikeratin antibody (AKA), and latex test had the strongest associations with RA. These 3 tests formed the most powerful combination for distinguishing RA from non-RA. CONCLUSION: IgM-RF, IgG-AKA, and the latex test are the best laboratory tests for discriminating between patients with and without RA. Combining these tests slightly improves diagnostic value.

Saraux A, Berthelot JM, Chalès G, Le HC, Thorel J, Hoang S, Martin A, Allain J, Nouy-Trolle I, Devauchelle V, Youinou P, Le GP. · Rheumatology department of Brest, hĵpital de la Cavale-Blanche, France. · Joint Bone Spine. · Pubmed #11858354 No free full text.

Abstract: OBJECTIVE: The management of recent-onset rheumatoid arthritis (RA) is not well standardized. We conducted a survey of drugs prescribed to RA patients in Brittany at presentation and during the first 1 to 3 years of follow-up. METHODS: A cohort of 270 patients with recent-onset inflammatory joint disease was recruited between 1995 and 1997. The evaluation at presentation included a medical history, a thorough physical examination, and a standard battery of investigations. Follow-up at 6-month intervals was offered. At the last visit, between June and December 1999, a panel of five rheumatologists established that 98 patients had RA. RESULTS: At presentation, hydroxychloroquine and injectable gold were the most widely used second-line drugs, and only two patients were offered a combination of second-line drugs. At the last visit, the most commonly used drugs were methotrexate, injectable gold, and hydroxychloroquine (23, 23, and 21 patients, respectively); only three patients were on more than one second-line drug and 38 (38/98, 39%) patients were on glucocorticoid therapy. CONCLUSION: Rheumatologists in Brittany prefer monotherapy with hydroxychloroquine or injectable gold as the initial treatment. Later, they rely mainly on methotrexate, injectable gold, and hydroxychloroquine, often in combination with glucocorticoid therapy.

Saraux A, Bourdon V, Devauchelle V, Le Goff P. · Rheumatology department, CHU de Brest, France. · Joint Bone Spine. · Pubmed #11808985 No free full text.

Abstract: OBJECTIVE: Serum CH50 and C4 levels are usually normal or elevated in rheumatoid arthritis (RA) but are classically decreased in patients with serious extra-articular manifestations (SEAMs) of the disease. The objective of this study was to evaluate whether complement assays are useful in diagnosing or predicting SEAMs of RA. METHODS: First, a cross-sectional study of 405 patients admitted for RA compared patients with and without hypocomplementemia. Then, a retrospective longitudinal design was used to investigate within-patient complement level variations overtime. RESULTS: In the univariate analysis, patients with low CH50 and C4 levels were more likely to have vasculitis and/or cryoglobulinemia than those with normal CH50 and C4 levels, and nodules were more common in the patients with low than with normal C4 levels. In a multivariate model based on symptoms, low C4 was associated with vasculitis and pleurisy and low CH50 with vasculitis. However, these associations were too weak to make CH50 and C4 determination useful for detecting SEAMs, and the within-subject variations in patients with SEAMs limited the predictive value of these assays. CONCLUSION: Hypocomplementemia is of limited usefulness for detecting or predicting SEAMs.

Saraux A, Berthelot JM, Chalès G, Le Henaff C, Thorel JB, Hoang S, Valls I, Devauchelle V, Martin A, Baron D, Pennec Y, Botton E, Mary JY, Le Goff P, Youinou P. · Rheumatology Unit, la Cavale Blanche Hospital, Brest Teaching Hospital, France. · Arthritis Rheum. · Pubmed #11710704 No free full text.

Abstract: OBJECTIVE: To determine how well the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 classification criteria for rheumatoid arthritis (RA), when used at study inclusion in a cohort of 270 patients with early (<1 year) arthritis, predicted a diagnosis of RA 2 years later and how well they classified these patients at the end of the 2 years. METHODS: Patients were evaluated during 1995-1997 at 7 hospitals in the Brittany region of France. Patients were evaluated at 6-month intervals until November 1999. The diagnosis made by a panel of 5 rheumatologists (P5R) after the last visit was used as the "gold standard." The ACR 1987 criteria for RA were applied prospectively, without taking into account the initial diagnosis. RESULTS: At the last visit (mean +/- SD followup 29.1 +/- 11.8 months; median 30 months), the P5R diagnosed RA in 98 patients. At the last visit, classification by the ACR criteria was satisfactory, and the combination of an office-based rheumatologist's (OBR's) diagnosis of RA and fulfillment of the ACR criteria was sensitive (87%; 85 of 98 RA patients had both) and highly specific (99%; 170 of 172 non-RA patients did not have both). Application of the criteria at the first visit was of limited value for predicting a diagnosis of RA 2 years later. CONCLUSION: After a 2-year followup, the ACR 1987 classification criteria used in combination with an OBR's diagnosis were effective in distinguishing patients with and without RA. The criteria were not useful for predicting RA in patients with arthritis onset within the previous year. Some patients who met the criteria at baseline and after 2 years did not have RA, suggesting that incorporating exclusion criteria may improve the performance of the ACR criteria when used without taking into account the diagnosis by a rheumatologist, particularly in early arthritis.