Rheumatoid Arthritis: Guis S

Poullin P, Announ N, Mugnier B, Guis S, Roudier J, Lefèvre P. · No affiliation provided · Joint Bone Spine. · Pubmed #15797486 No free full text.

This publication has no abstract.

Rak JM, Maestroni L, Balandraud N, Guis S, Boudinet H, Guzian MC, Yan Z, Azzouz D, Auger I, Roudier C, Martin M, Didelot R, Roudier J, Lambert NC. · INSERM U639, Marseille, France. · Arthritis Rheum. · Pubmed #19117368 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease that affects mostly women and is associated with HLA-DRB1 genes having in common a shared epitope sequence. In parallel, cells and/or DNA originating from pregnancy (microchimerism) persist for decades and could contribute to autoimmunity. The aim of this study was to examine whether microchimerism may be a source of the shared epitope among women with RA. METHODS: Women with RA and healthy women who lacked RA-associated genes such as HLA-DRB1*01 (n=33 and n=46, respectively) and/or HLA-DRB1*04 (n=48 and n=64, respectively), were tested for DRB1*01 or DRB1*04 microchimerism by HLA-specific quantitative polymerase chain reaction assays. As controls, alleles not associated with RA (DQB1*02 and DRB1*15/16) were also analyzed. RESULTS: Compared with healthy women, women (42% with RA had a higher frequency and higher levels of DRB1*04 microchimerism versus 8%; P=0.00002) as well as DRB1*01 microchimerism (30% versus 4%; P=0.0015). Moreover, no difference in microchimerism was observed for alleles not associated with RA. CONCLUSION: Women with RA had microchimerism with RA-associated HLA alleles, but not with non-RA-associated HLA alleles, more often and at higher levels compared with healthy women. These observations are the first to indicate that microchimerism can contribute to the risk of an autoimmune disease by providing HLA susceptibility alleles.

Charpin C, Balandraud N, Guis S, Roudier C, Toussirot E, Rak J, Lambert N, Martin M, Reviron D, Roudier J, Auger I. · INSERM UMR 639, Université de la Méditerranée and Rheumatology, APHM, Marseille, France. · Clin Exp Rheumatol. · Pubmed #18799094 No free full text.

Abstract: OBJECTIVE: To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS: The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined. RESULTS: RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025). CONCLUSIONS: The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.

Guis S, Balandraud N, Bouvenot J, Auger I, Toussirot E, Wendling D, Mattei JP, Nogueira L, Mugnier B, Legeron P, Landt O, Serre G, Roudier J, Roudier C. · INSERM UMR 639 and Assistance Publique Hôpitaux de Paris, Hôpital de la Conception, Marseille, France. · Arthritis Rheum. · Pubmed #18050183 links to  free full text

Abstract: OBJECTIVE: To determine whether the -308 A/G tumor necrosis factor alpha (TNFalpha) gene polymorphism can predict the outcome of etanercept therapy in 86 patients with rheumatoid arthritis (RA), as already observed in patients treated with infliximab. METHODS: Eighty-six RA patients treated with etanercept were genotyped for -308 A/G TNFalpha gene polymorphism by polymerase chain reaction and melting curve analysis, using specific gene primers and probes. Patients were subdivided into group A (G/A genotype) and group G (G/G genotype). We compared clinical responses to etanercept between groups A and G after 6 months, using the Disease Activity Score in 28 joints (DAS28). After 12-month treatment, 48 of 86 patients were evaluated again. RESULTS: Of 86 patients, 18 (21%) belonged in group A and 68 (79%) belonged in group G. After 6-month treatment, 55.6% of patients in group A and 82.4% of patients in group G had DAS28 improvement >1.2 (P = 0.027 by chi-square). The mean +/- SD DAS28 improvement was 1.69 +/- 1.31 in group A and 2.23 +/- 1.19 in group G (P = 0.098 by t-test). After 1-year treatment 48 patients were tested again: 10 (21%) belonged in group A and 38 (79%) belonged in group G. Forty percent of patients in group A and 87% in group G had DAS28 improvement >1.2 (P = 0.005 by chi-square). The mean +/- SD DAS28 improvement was 1.334 +/- 1.37 in group A and 2.29 +/- 1.47 in group G (Mann-Whitney U test = 115, P = 0.0057). CONCLUSION: RA patients with a -308 G/G TNFalpha genotype respond to etanercept better than patients with a -308 A/G genotype.

Balandraud N, Guis S, Meynard JB, Auger I, Roudier J, Roudier C. · INSERM Unité 639, Marseille, France. · Arthritis Rheum. · Pubmed #17530675 links to  free full text

Abstract: OBJECTIVE: We previously demonstrated that patients with rheumatoid arthritis (RA) have a 10-fold systemic Epstein-Barr virus (EBV) overload, very similar to that observed in healthy organ transplant recipients. Our objective was to monitor EBV load over time in patients with RA receiving methotrexate, infliximab, or etanercept to detect possible immunosuppression-associated EBV dysregulation, as described in posttransplant lymphoproliferative disease. METHODS: The EBV load in the peripheral blood mononuclear cells (PBMCs) from 19 patients receiving methotrexate, 68 patients receiving infliximab, and 48 patients receiving etanercept was monitored for durations ranging from 6 months to 5 years using a real-time polymerase chain reaction assay previously developed for that purpose. The effect of treatment duration on EBV load and the link between the Disease Activity Score in 28 joints and EBV load were analyzed by generalized estimating equations. RESULTS: Methotrexate tended to decrease EBV load over time, but this did not reach significance. Tumor necrosis factor alpha (TNFalpha) inhibitors did not significantly modify EBV load over time. Finally, high disease activity was significantly associated with high EBV load. CONCLUSION: Long-term usage of methotrexate or TNFalpha inhibitors in patients with RA does not significantly influence EBV load in PBMCs.

Auger I, Roudier C, Guis S, Balandraud N, Roudier J. · INSERM UMR 639, Faculté de Médecine, 27 BD Jean Moulin, 13005 Marseille, France. · Ann Rheum Dis. · Pubmed #17324966 No free full text.

Abstract: OBJECTIVE: To test whether HLA-DR alleles influence the production of particular autoantibodies in rheumatoid arthritis (RA) patients, we screened synovial proteins with sera of RA patients homozygous for different HLA-DR alleles by using 2D blots. We found that sera of RA patients homozygous for HLA-DRB1*0404 recognised a 100-kDa synovial protein identified as calpastatin. We studied B and T cell epitopes on calpastatin and their association with HLA-DRB1*0404. METHODS: The frequency of positive sera in patients expressing different RA-associated HLA-DR allele combinations was calculated by inhouse ELISA using purified synovial calpastatin or calpastatin peptides encompassing the entire calpastatin protein as immunosorbent. Interaction between calpastatin peptides and HLA-DR alleles was tested by a direct binding assay. T cell responses to calpastatin were measured in RA patients and controls. RESULTS: We found that RA-associated HLA-DR alleles are associated with presence of autoantibodies to synovial calpastatin in RA patients' sera. HLA-DRB1*0404 is strongly associated with antisynovial calpastatin in RA sera. One linear B cell epitope is preferentially associated with HLA-DRB1*0404. Multiple peptides from calpastatin bind every tested HLA-DR allele associated or not with RA. Peptides from domain 1 and 4 of calpastatin are the best HLA-DR allele binders. The T cell response to calpastatin is frequent in RA patients and independent of the HLA-DR background. CONCLUSIONS: HLA-DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis.

Auger I, Sebbag M, Vincent C, Balandraud N, Guis S, Nogueira L, Svensson B, Cantagrel A, Serre G, Roudier J. · INSERM UMR 639, La Conception Hospital, Faculté de Médecine, 27 Boulevard Jean Moulin, 13005 Marseille, France. · Arthritis Rheum. · Pubmed #16255019 links to  free full text

Abstract: OBJECTIVE: Antibodies directed against citrullinated fibrinogen are highly specific for rheumatoid arthritis (RA). This study was undertaken to test whether RA-associated HLA-DR alleles are associated with anti-citrullinated fibrinogen in RA patient sera and whether replacement of arginyl by citrullyl residues on fibrinogen peptides modifies their binding to HLA-DR molecules and their recognition by T cells. METHODS: Antikeratin, antifilaggrin, and anti-citrullinated fibrinogen antibodies were assayed in RA patients who had undergone HLA-DR typing. Direct assays were performed to investigate binding of citrullinated or native fibrinogen peptides (encompassing the entire alpha- and beta-chains of fibrinogen) to purified HLA-DR molecules. T cell proliferative responses to citrullinated or native fibrinogen peptides were measured in RA patients and controls. RESULTS: HLA-DRB1*0404 was associated with anti-citrullinated fibrinogen in RA sera (P = 0.002). For the RA-associated alleles HLA-DRB1*0401 and HLA-DR1, there was a nonsignificant trend toward association (P = 0.07). Multiple peptides from the alpha- and beta-chains of fibrinogen bound many HLA-DR alleles; DRB1*0404 was the best fibrinogen peptide binder. Citrullination did not influence fibrinogen peptide binding to HLA-DR or fibrinogen peptide recognition by T cells. Peripheral blood T cells that recognized native or citrullinated fibrinogen peptides were common in RA patients but not in healthy controls. CONCLUSION: The RA-associated HLA-DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen. DRB1*0401 and DRB1*01 tend to be associated with anti-citrullinated fibrinogen, but this is not statistically significant. Citrullination of fibrinogen peptide does not influence peptide-DR-T cell interaction. Finally, T cell proliferation in response to citrullinated or uncitrullinated fibrinogen peptides is frequent in RA patients and very infrequent in controls.

Alcaraz P, Aubran C, Jaoua S, Roudier C, Mattei JP, Announ N, Chagnaud C, Roudier J, Guis S. · Rheumatology Department, Pr Roudier, Conception Hospital, Marseille, France. · Joint Bone Spine. · Pubmed #16226476 No free full text.

Abstract: Calcaneal osteomyelitis is uncommon and difficult to treat. Cases due to fistulization of an infected rheumatoid nodule are exceedingly rare. PATIENT: A 65-year-old patient with nodular rheumatoid arthritis (RA) experienced osteomyelitis of the left calcaneus due to inoculation from a fistula draining an ulcerated rheumatoid nodule. Pseudomonas aeruginosa and Enterobacter cloacae were recovered. The conventional treatment of calcaneal osteomyelitis relies on antibiotics and calcanectomy or foot amputation. We used two appropriate antibiotics and monthly intravenous injections of 90 mg of pamidronate. RESULT: One year into treatment, the patient was free of pain and the skin wound was fully healed. On a follow-up computed tomography (CT) scan, the fistulous tract was seen to be closed and the large calcaneal defect almost completely filled with new bone. CONCLUSION: Combining two antibiotics and pamidronate may be a viable alternative to excision surgery or amputation in some patients with bone infection carrying a risk of fracture.

Reviron D, Perdriger A, Toussirot E, Wendling D, Balandraud N, Guis S, Semana G, Tiberghien P, Mercier P, Roudier J. · EFS Alpes Méditerranée, Marseilles, France. · Arthritis Rheum. · Pubmed #11263767 links to  free full text

Abstract: OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS: HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS: Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.

Reviron D, Foutrier C, Guis S, Mercier P, Roudier J. · Department of Immunogenetics, EFS Alpes-Méditerranée, Marseille, France. · Eur J Immunogenet. · Pubmed #11251689 No free full text.

Abstract: To investigate the association of HLA-DRB1 alleles with polymyalgia rheumatica (PMR) and rheumatoid arthritis (RA), 55 patients with PMR without giant cell arteritis, 203 patients with RA and 230 controls, all from the European population of Marseille, were HLA-DRB1 genotyped by PCR-SSO. HLA-DRB1*01 was significantly increased in both the PMR and RA groups compared to controls (35% versus 17%, P(c) < 0.05, and 41% versus 17%, P(c) < 0.001, respectively). HLA-DRB1*04 was significantly increased in the RA group compared to controls (48% versus 23%, P(c) < 0.001) but not in the PMR group. HLA-DRB1*04 subtype frequencies were significantly different between PMR patients and RA patients. Shared epitope-positive HLA-DRB1*04 alleles (DRB1*0401, 0404, 0405, 0408) were significantly overrepresented in RA patients compared to PMR patients and shared epitope-negative HLA-DRB1*04 alleles were overrepresented in PMR patients compared to RA patients. In conclusion, in the Mediterranean population studied, HLA-DRB1*01 is associated with RA and PMR whereas HLA-DRB1*04 is associated with RA only.

Reviron D, Tezenas du Montcel S, Foutrier C, Guis S, Benazet JF, Auquier P, Busson M, Roux H, Mercier P, Roudier J. · Department of Immunogenetics, Etablissement de Transfusion Sanguine Alpes-Provence, Marseille, France. · Hum Immunol. · Pubmed #10321961 No free full text.

Abstract: OBJECTIVE: To study the influence of DMA and DMB genes on susceptibility to Rheumatoid Arthritis (RA). METHODS: HLA-DRB1, DMA and DMB polymorphisms were defined by PCR SSOP in 203 European Mediterranean RA patients and 181 unrelated healthy controls. RESULTS: No significant difference in the phenotype frequencies of DMA and DMB alleles was observed between patients and controls. We found decreased frequencies of DMA*0102 and DMB*0104 in patients but this did not reach significance. These decreased frequencies could be due to a positive linkage disequilibrium with DRB1*0701, an allele which is underrepresented in RA patients. In stratified analysis with RA susceptibility Epitope positive (SE) DRB1 alleles, there was no significant difference in DMA and DMB phenotype frequencies between SE/SE, SE/X, and X/X patients versus controls. Among SE/X subjects, no significant difference in DM distribution frequencies was observed in DRB1*0101/X, 0102/X, 0401/X, 0404/X and 0405/X groups. CONCLUSION: DMA and DMB polymorphism does not seem to influence susceptibility to develop RA. Differences in DMA phenotype frequencies between patients and controls are secondary to linkage disequilibrium with DRB1 alleles.

Guis S, Schiano de Colella JM, Bonnet N, Andrac-Meyer L, Balandraud N, Mattei JP, Franck B, Roudier C, Roudier J, Berbis P. · No affiliation provided · Eur J Dermatol. · Pubmed #18573737 No free full text.

This publication has no abstract.