Rheumatoid Arthritis: Falgarone G

Boissier MC, Assier E, Falgarone G, Bessis N. · No affiliation provided · Joint Bone Spine. · Pubmed #18571969 No free full text.

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Falgarone G, Duclos M, Boissier MC. · No affiliation provided · Joint Bone Spine. · Pubmed #18092377 No free full text.

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Boissier MC, Bessis N, Falgarone G. · No affiliation provided · Joint Bone Spine. · Pubmed #12184428 No free full text.

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Boissier MC, Assier E, Biton J, Denys A, Falgarone G, Bessis N. · Inserm ERI18, Bobigny, France. · Joint Bone Spine. · Pubmed #19028128 No free full text.

Abstract: Modulation of the T-cell response depends chiefly on regulatory T cells (Treg), which express CD4 and CD25. Some Treg cells are present naturally, whereas others are induced in response to antigens. The immunomodulating effects of Treg cells are mediated by membrane molecules (e.g., CTLA4, GITR, and OX40) and cytokines. IL-35 seems to be a crucial mediator, although IL-10 and TGFbeta are also important. The role for Treg cells in rheumatoid arthritis (RA) has been established in both patients and animal models. Treg function is deficient in RA, whereas Treg counts vary. Treg counts increase in patients who are responding to TNFalpha antagonist therapy. Among current hypotheses, Treg expansion or transfer may hold promise for the treatment of RA.

Lormeau C, Falgarone G, Roulot D, Boissier MC. · Rheumatology Department and INSERM ERI-18, Avicenne Teaching Hospital (AH-HP) and Paris 13 University, 125, rue de Stalingrad, 93009 Bobigny, France. · Joint Bone Spine. · Pubmed #17056293 No free full text.

Abstract: The many rheumatologic manifestations associated with chronic hepatitis C virus (HCV) infection include arthralgia, myalgia, arthritis, vasculitis, and sicca syndrome. Arthralgia is the most common extrahepatic manifestation and may indicate mixed cryoglobulinemia or an adverse reaction to interferon therapy. HCV arthritis unrelated to cryoglobulinemia is far less common but constitutes an independent entity. The picture may mimic rheumatoid arthritis (RA), particularly as rheumatoid factor is present in 50-80% of cases. Tests are usually negative for antibodies to cyclic citrullinated peptides (anti-CCP), which may help to differentiate the two conditions. The management of HCV arthritis is empirical and poorly standardized. Although low-dose glucocorticoid therapy, hydroxychloroquine, and methotrexate have been used successfully in several patients, little is known about their hepatic safety profile. Arthritis associated with cryoglobulinemia usually responds to antiviral treatment. Sicca syndrome is common in patients with chronic HCV infection and shares similarities with primary Sjögren syndrome, suggesting that HCV infection may deserve to be included among the causes of secondary Sjögren syndrome. HCV-associated vasculitis is usually related to cryoglobulinemia, although a few cases of polyarteritis nodosa-like disease affecting the medium-sized vessels have been reported. Other conditions reported in patients with chronic HCV infection include fibromyalgia, systemic lupus erythematosus (SLE), antiphospholipid syndrome, and osteosclerosis.

Falgarone G, Jaen O, Boissier MC. · Rheumatology Department, UPRES EA-3408, Hôpital Avicenne (AP-HP), Paris 13 University, Bobigny, France. · Joint Bone Spine. · Pubmed #15681243 No free full text.

Abstract: Innate immunity is the first line of defense against pathogenic microorganisms (bacteria, viruses, fungi, and parasites). After a long period of neglect, innate immunity is again recognized as a key mechanism not only in preventing invasion of the body by microorganisms, but also in contributing to the pathogenesis of autoimmune and inflammatory diseases by deviating the immune response or promoting the emergence of a regulatory response. The many factors involved in innate immunity often act in parallel or in alternation to generate adaptive immune responses. Innate immune responses are specific for groups of molecules or macromolecules found in components of microorganisms, usually the cell wall. The cellular and protein effectors of innate immunity are found in the rheumatoid synovium, and an increasing body of evidence indicates that they are directly involved in joint inflammation and in destruction of the joint cartilage and bone. In addition, they may have regulatory effects on inflammation and immunity. Whether innate immune mechanisms are causes or consequences of inflammation, and whether they regulate or amplify adaptive immune responses, they constitute a target of choice for new antiinflammatory and immunoregulating treatment strategies.

Falgarone G, Semerano L, Rullé S, Boissier MC. · University of Paris 13, Li2P, EA4222, Bobigny, France. · Joint Bone Spine. · Pubmed #19535279 No free full text.

Abstract: The introduction of targeted treatments has radically changed the management of patients with rheumatoid arthritis (RA). Abatacept is among these new treatments emerging from recent insights into joint immunopathology. Abatacept blocks the interaction between antigen-presenting cells and T-cells, thereby diminishing T-cell activation and possibly improving overall cell regulation. In RA patients, abatacept is effective in decreasing the arthritis, pain, disability, fatigue, and radiological joint damage. Abatacept provides lasting remissions or low levels of disease activity and therefore constitutes a valuable addition to the current therapeutic armamentarium for RA, which is hoped to make a full remission an attainable goal in the overall population of RA patients.

Jaen O, Petit-Teixeira E, Kirsten H, Ahnert P, Semerano L, Pierlot C, Cornelis F, Boissier MC, Falgarone G, Anonymous00012. · EA-4222, University of Paris 13, Bobigny Cedex, Paris, France. · Arthritis Res Ther. · Pubmed #19134200 links to  free full text

Abstract: INTRODUCTION: The objective was to study the potential genetic contribution of Toll-like receptor (TLR) genes in rheumatoid arthritis (RA). TLRs bind to pathogen-associated molecular patterns, and TLR genes influence both proinflammatory cytokine production and autoimmune responses. Host-pathogen interactions are involved in RA physiopathology. METHODS: We tested SNPs of five TLR genes (TLR9, TLR2, TLR6, TLR1, and TLR4) in a cohort of 100 French families with RA. Genotypes were analyzed using the transmission disequilibrium test. As TLR2, TLR6, and TLR1 are located on chromosome 4, we determined the haplotype relative risk. Analyses were performed in subgroups defined by status for rheumatoid factor, anti-cyclic citrullinated peptide autoantibodies, and erosions. RESULTS: We found no disequilibrium in allele transmission for any of the SNPs of the five TLR genes. In subgroup analyses, no associations were detected linking TLR9, TLR2, or TLR9/TLR2 to rheumatoid factor, anti-cyclic citrullinated peptide autoantibodies, or erosions. Haplotype analysis of the polymorphisms showed no haplotype associations in any of the subgroups. CONCLUSIONS: We found no evidence of major effects of TLR gene polymorphisms in RA, although we tested different TLR phenotypes. Moreover, no associations were noted with autoantibody production or erosions.

Jaen O, Rullé S, Bessis N, Zago A, Boissier MC, Falgarone G. · INSERM ERI18, Paris 13 University, AP-HP Rheumatology Department, Avicenne Hospital, Bobigny, France. · Immunology. · Pubmed #18754812 No free full text.

Abstract: Dendritic cells (DCs) mediate interactions between innate and specific immunity and may induce regulatory mechanisms. We investigated the effects of modulated DCs in mice with collagen-induced arthritis (CIA) and tested the responses of cells to induced naturally occurring regulatory T cells. DCs were stimulated or not with DNA or lipopolysaccharide (LPS) for 24 hr. DC maturation was assayed, and then modulated DCs were intraperitoneally injected on day 14 into DBA/1 mice to treat CIA. In addition to arthritis scores and type 2 collagen (CII) response, the induction of CD4(+) CD25(+) T cells was analysed by flow cytometry in peripheral blood and the expression of Foxp3, transforming growth factor (TGF)-beta, interleukin (IL)-10 and cytotoxic T-lymphocyte antigen (CTLA)-4 was quantified. Finally, the expression of indoleamine-2,3-dioxygenase (IDO) was assayed in DCs. In comparison with LPS-stimulated DCs, plasmid-stimulated DCs expressed lower levels of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86 molecules and secreted less IL-12p70, interferon (IFN)-gamma, IL-10 and TNF-alpha, displaying a semi-mature phenotype. Compared with non-stimulated DCs, stimulated DCs improved arthritis scores when injected after immunization, without modifying the T helper type 1 (Th1)/Th2 balance of the immune response against collagen. Stimulated DCs induced markers for regulatory T cells (Foxp3, TGF-beta1 and CTLA-4) in vivo. Only LPS-stimulated DCs expressed IDO, which may explain their better therapeutic efficacy. Regulatory mechanisms were induced using DCs modulated by innate immunity stimulators. Innate immunity mechanisms do not require the presence of the disease-causing antigen, even in T- and B-cell specific diseases. Our results have implications for the treatment of rheumatoid arthritis, an autoimmune disease whose triggering antigen has not been identified, and substantially clarify the role of regulatory T cells in CIA.

Falgarone G, Zerkak D, Bauer C, Messow M, Dougados M. · Paris Nord University, Avicenne Hospital AP-HP, Rheumatology Department UPRES EA-3408, Bobigny, France. · Clin Exp Rheumatol. · Pubmed #15895896 No free full text.

Abstract: OBJECTIVES: Pain is frequently the primary variable in symptomatic clinical trials for the evaluation of rheumatological disorders. The protocol of such trials mention a minimum level of pain as an entry criterion [e.g. a level above the Patient Acceptable Symptoms State (PASS)] and the changes in pain as the primary variable. Usually, the results are expressed at a group level as the mean changes in pain. However, the presentation at an individual level and, in particular, the percentage of patients with a Low Disease Activity State at the end of the study seems more clinically relevant. Pain is usually evaluated using a continuous variable such as a 0-100 visual analogue scale. The cut-offs permitting one to define both the entry criterion and the LDAS are not well established. The objective of this study was to evaluate such cut-offs using a patient-derived perspective. METHODS: Study design: cross-sectional study. Patients: consecutive out patients suffering from chronic rheumatic diseases familiar with the use of a VAS to evaluate their level of pain. Data collected: two questions were asked the patients at the end of the visit: "Based on the experience you have because of your chronic rheumatic disorder, could you please specify the level of pain below which you consider your disease as inactive ? Moreover, could you please also specify the level of pain above which you consider taking a pain killer?" Before answering the second question, it was explained to the patient that their answer to the second question could be similar to their response to the first one. For the two questions, the cumulative percentage of patients (disease inactive and pain killer intake) were calculated for each level of pain. RESULTS: The underlying disease of the 137 evaluated patients (mean age: 57+/-16 and female sex: 76%) was rheumatoid arthritis (n = 59), ankylosing spondylitis (n = 19), SLE (n = 2), back pain (n = 20), or peripheral osteoarthritis (n = 37). The mean disease duration was 12+/-10 years. At the time of the study, the current level of pain evaluated on a 0-100 VAS was 33+/-22. The LDAS was 49, 36 and 25 for our patient population at the 25th, 50th and 75th percentiles, respectively. The pain killer intake level was 32, 48, 64 at the 25th, 50th, 75th percentile respectively. CONCLUSION: This study suggests that LDAS and PASS may be distinct concepts. The methodological approach adopted here could be of interest for specifying the minimum level of symptoms at entry in a symptomatic trial (PASS) and also to present results in terms of the percentage of patients in good condition (LDAS) at the end of a trial.

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.

Maillefert JF, Muller G, Falgarone G, Bour JB, Ratovohery D, Dougados M, Tavernier C, Breban M. · Department of Rheumatology, René Descartes University, AP-HP, Cochin Hospital, Paris, France. · Ann Rheum Dis. · Pubmed #12079907 links to  free full text

Abstract: BACKGROUND: Various viruses have been implicated in the cause and pathogenesis of rheumatoid arthritis (RA). Hepatitis C virus (HCV) infection, which has been recognised as a cause of some autoimmune diseases, and which has been described as sometimes presenting with rheumatic manifestations indistinguishable from RA, might be a candidate. OBJECTIVE: To evaluate the prevalence of HCV infection in patients with RA. METHODS: Consecutive patients with RA admitted to hospital in two departments of rheumatology were prospectively studied. Patients' serum samples were screened for the presence of anti-HCV antibodies. Patients with positive serology were further evaluated for the presence of HCV ribonucleic acid by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: 309 patients (232 women, 77 men, mean age (SD) 54.1 (14.8) years) were studied. Their mean (SD) disease duration was 74.1 (91) months. Tests for rheumatoid factors and antinuclear antibodies were positive in 213 (69%) and 114 (37%) of the patients respectively. Systemic vasculitis was found in 12 (4%) of the patients. Mean erythrocyte sedimentation rate was 36.4 (SD 30.5) mm at the first hour (normal <10 mm) and C reactive protein was 36.8 (SD 45.8) mg/l (normal range <5 mg/l), respectively, with 181(58.6%) of patients considered as having active disease. Aspartate transaminases were increased in 14 (4%) patients, and alkaline phosphatase in 14 (4%). A positive anti-HCV serology was found in two (0.65%) patients, including one with a previously diagnosed HCV infection. HCV RNA was positive by RT-PCR in one of those two patients. CONCLUSION: A 0.65% prevalence of past or active HCV infection was found in patients with RA, which did not differ from the prevalence of HCV in the general French population. This result does not support the participation of HCV infection in the pathogenesis of RA.