Rheumatoid Arthritis: Cambon-Thomsen A

Barnetche T, Constantin A, Cantagrel A, Cambon-Thomsen A, Gourraud PA. · Department of Epidemiology and Public Health, UMR Inserm U 558, University Paul Sabatier Toulouse III, Faculty of Medicine Purpan, 37 Allées Jules Guesde, Toulouse cedex 7, 31073, France. · Arthritis Res Ther. · Pubmed #18307784 links to  free full text

Abstract: INTRODUCTION: Rheumatoid arthritis (RA) is a complex polygenic disease of unknown etiology. HLA-DRB1 alleles encoding the shared epitope (SE) (RAA amino acid pattern in positions 72 to 74 of the third hypervariable region of the DRbeta1 chain) are associated with RA susceptibility. A new classification of HLA-DRB1 SE alleles has been developed by Tezenas du Montcel and colleagues to refine the association between HLA-DRB1 and RA. In the present study, we used RA samples collected worldwide to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility across various Caucasoid and non-Caucasoid patients. METHODS: Eighteen subsamples were defined from a total number of 759 cases and 789 controls and grouped in 10 samples on the basis of their ethnic origin. HLA-DRB1 alleles were divided into five groups (S1, S2, S3D, S3P, and X) according to the new HLA-DRB1 allele classification. The whole analysis was performed by comparing carrier frequencies for the five HLA-DRB1 allele groups between RA patients and controls across the 10 Caucasoid and non-Caucasoid samples. The Mantel-Haenszel method of meta-analysis provided a global odds ratio (OR) estimate with 95% confidence interval (CI). RESULTS: A positive association with RA susceptibility was found for S2 allele carriers (OR 2.15, 95% CI 1.54 to 3.00; p < 10(-5)) and S3P allele carriers (OR 2.74, 95% CI 2.01 to 3.74; p < 10(-5)). A negative association was found for S1 alleles (OR 0.60, 95% CI 0.48 to 0.76; p < 10(-4)) and X alleles (OR 0.58, 95% CI 0.39 to 0.84; p = 4 x 10(-3)). No significant association was highlighted for the S3D group of alleles (OR 0.89, 95% CI 0.69 to 1.14; p = 0.89). The complementary genotype analysis fit with the genotype risk hierarchy previously reported in Caucasoid RA patients. CONCLUSION: So far, the present study is the first attempt to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility on both Caucasoid and non-Caucasoid samples. Our results support the hypothesis of a differential role played by different HLA-DRB1 allele groups in RA susceptibility across different ethnic backgrounds and confirm the interest of such an HLA-DRB1 classification in differentiating predisposing and protective alleles.

Juillard-Condat B, Constantin A, Cambon-Thomsen A, Bourrel R, Taboulet F. · INSERM U558, 37 allée Jules Guesde, 31073 Toulouse Cedex, France. · Joint Bone Spine. · Pubmed #17913554 No free full text.

Abstract: INTRODUCTION: Economical impact of rheumatoid arthritis (RA) has been widely modified thanks to TNF inhibitors. Our study aims to estimate the impact etanercept prescription, in term of health resources consumption, within a regional cohort of French RA patients. METHODS: The study included 148 RA patients, with a mean follow-up duration of 343 days before and after etanercept initiation. Data were anonymously collected from ERASME database of French Health Insurance in Midi-Pyrénées region. A patient-by-patient microcosting approach was performed. RESULTS: The average annual cost per patient, attributable to RA, was 2.8 times higher after treatment by etanercept than before (15,148.57euro versus 5248.95euro). We observed a rise in pharmaceutical costs, from 11.7% of direct medical costs before to 69.7% after etanercept initiation (120.12euro versus 9995.23euro). We observed a small decrease particularly for NSAIDs (142.14euro versus 102.21euro) and physiotherapy (286.40euro versus 138.77euro). Attributable act costs and indirect costs did not differ before and after etanercept initiation. DISCUSSION: In this short-term study, initiation of etanercept in RA patients did not come along with a decrease of consumption of health resources. Long-term studies are needed to reveal a potential economical advantage as a consequence of the clinical, structural and functional efficacy of anti-TNF.

Juillard-Condat B, Constantin A, Cambon-Thomsen A, Bourrel R, Taboulet F. · INSERM U558, Droit de la Pharmacie et Economie de la Santé, and Service Pharmacie, Hôtel Dieu, 2 rue Viguerie, 31059 Toulouse Cedex 9, France. · Therapie. · Pubmed #17582315 No free full text.

Abstract: Treatment of rheumatoid arthritis was deeply modified with the availability since 1999 of anti-TNFalpha. The clinical superiority of these drugs compared to traditional treatments is proven, but can one make the assumption that the cost of these innovative treatments is partially compensated by a reduction of consumption of other health resources? A retrospective observational study was carried out in the Midi-Pyrenees area, from the point of view of health insurance, to compare the consumed health resources between two cohorts of patients, one treated by etanercept (Enbrel) and the other by leflunomide (Arava). Two hundred and fifty three patients were included in the etanercept cohort and 539 in the leflunomide cohort. The average annual PR cost for a patient treated with etanercept is 13 936 euro and 5 764 euro for a patient treated with leflunomide. The health costs avoided by recourse to etanercept do not compensate the high cost of this drug.

Gourraud PA, Dieudé P, Boyer JF, Nogueira L, Cambon-Thomsen A, Mazières B, Cornélis F, Serre G, Cantagrel A, Constantin A. · Service d'Epidémiologie CHU Toulouse, INSERM, U558, Université Paul Sabatier Toulouse III, Faculté de Médecine, 37 allées Jules Guesde, Toulouse Cedex 7, 31073, France. · Arthritis Res Ther. · Pubmed #17328818 links to  free full text

Abstract: The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity. We investigated the relevance of this new classification of HLA-DRB1 SE+ alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients. We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification. The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity. The new classification of HLA-DRB1 SE+ alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production.

Barnetche T, Constantin A, Gourraud PA, Abbal M, Garnier JG, Cantagrel A, Cambon-Thomsen A. · Institut National de la Santé et de la Recherché Médicale, Unit 558, Department of Public Health and Epidemiology, Faculty of Medicine Purpan, University Paul Sabatier Toulouse III, F-31073 Toulouse, France. · Tissue Antigens. · Pubmed #17092252 No free full text.

Abstract: Within the major histocompatibility complex (MHC), the human leucocyte antigen (HLA)-DRB1 locus is clearly associated with rheumatoid arthritis (RA). Using a microsatellite (MSat) typing approach, we aimed to identify other loci associated with RA susceptibility and/or severity within the MHC. A panel of nine MSat HLA loci [D6S291, D6S2876 (G51152), D6S1666 (DQCAR II), D6S273, D6S2789 (TNFd), D6S2810 (MIB), D6S265, D6S2222, D6S2239], and HLA-A, -B and -DRB1 genes were typed in 170 RA cases and 282 controls. For susceptibility analysis, MSat and HLA allele distribution were compared between cases and controls, before and after stratification on HLA-DRB1*04. Haplotype frequencies were estimated using an expectation-maximization algorithm in a permutation test procedure. For severity analysis, we compared the distribution of structural damage score at onset and after 4 years of follow-up in RA cases carrying susceptibility alleles. Two MSat polymorphisms were positively associated with RA susceptibility: allele*136 of D6S265 [odds ratio, OR (confidence interval, CI) = 1.55 (1.11-2.17), P= 0.007], allele*116 of D6S2239 [OR = 1.34 (1-1.79), P= 0.03] and HLA-A2 [OR = 1.46 (1.08-1.98), P= 0.01]. Two MSat polymorphisms were negatively associated with RA susceptibility: allele*133 of D6S273 [OR = 0.3 (0.1-0.75), P= 0.005] and allele*177 of D6S291 [OR = 0.72 (0.53-0.96), P= 0.02]. The association between allele*136 of D6S265 and RA susceptibility remained unchanged after stratification on HLA-DRB1*04. The haplotypic analysis showed an overrepresentation of D6S265*136/HLA-A*02 haplotype, which suggests an effect independent of HLA-DRB1 locus in RA susceptibility. While HLA-A2 and HLA-DR4 were associated with RA severity, no MSat polymorphism was associated with structural damage score.

Gourraud PA, Boyer JF, Barnetche T, Abbal M, Cambon-Thomsen A, Cantagrel A, Constantin A. · INSERM U558, Toulouse, France. · Arthritis Rheum. · Pubmed #16447236 links to  free full text

Abstract: OBJECTIVE: A new classification of HLA-DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA. METHODS: The study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA-DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence-specific oligonucleotide probes. HLA-DRB1 alleles were classified according to the above-mentioned new system. The association between the HLA-DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests. RESULTS: The presence of S2 alleles (HLA-DRB1*0401 and HLA-DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA-DRB1*11001, HLA-DRB1*1104, HLA-DRB1*12, and HLA-DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01). CONCLUSION: The studied classification of HLA-DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70-74 of the third hypervariable region of the HLA-DRbeta chain.

Constantin A, Dieudé P, Lauwers-Cancès V, Jamard B, Mazières B, Cambon-Thomsen A, Cornélis F, Cantagrel A. · Centre Hospitalier Universitaire Rangueil, INSERM U558, and INSERM U563, Toulouse, France. · Arthritis Rheum. · Pubmed #15022314 links to  free full text

Abstract: OBJECTIVE: The gene encoding tumor necrosis factor receptor type II (TNFRII) is a strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association between a single-nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene and familial RA was recently reported. The present study was undertaken to test the hypothesis that there is an association between this polymorphism and the severity of RA. METHODS: One hundred two white patients with early RA were included in this prospective study. The French version of the Health Assessment Questionnaire (F-HAQ) and a radiographic damage score (modified Sharp/van der Heijde method) were used to quantify the functional and structural severity of RA at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Among the 102 patients with RA, 63 (61.8%) were homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and 196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median radiographic and F-HAQ scores did not differ between RA patients who carried the 196R allele and those who did not. After 4 years of followup, the F-HAQ score was higher in RA patients carrying the 196R allele (median 1 [interquartile range (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the median radiographic score did not differ between RA patients who carried the 196R allele and those who did not. CONCLUSION: The results of the present study support the hypothesis that there is an association between the TNFRII 196 M/R gene polymorphism and the functional severity of early RA.

Constantin A, Lauwers-Cancès V, Navaux F, Abbal M, van Meerwijk J, Mazières B, Cambon-Thomsen A, Cantagrel A. · Centre Hospitalier Universitaire Rangueil, INSERM U558, and INSERM U395, Toulouse, France. · Arthritis Rheum. · Pubmed #12124858 links to  free full text

Abstract: OBJECTIVE: To test the hypothesis of an association between a polymorphism in the matrix metalloproteinase 3 (MMP-3) gene promoter and the susceptibility, severity, and progression of rheumatoid arthritis (RA), and to further document the association between HLA-DRB1 alleles encoding the shared epitope (SE) and the severity and progression of RA. METHODS: Patients with early RA (n = 103) were included in this prospective study. A total radiographic damage score (TDS; by the Sharp/van der Heijde method) was used to quantify RA severity at baseline and after 4 years of followup. The 5A/6A biallelic polymorphism in the MMP-3 gene promoter was analyzed using fluorescence-based polymerase chain reaction (PCR). HLA-DRB1 genotyping was performed using PCR methods. Control subjects (n = 127) were unrelated healthy individuals. RESULTS: MMP-3 allele carriage rates and allele and genotype frequencies did not differ between patients and controls. The MMP-3 6A/6A genotype was associated with the highest TDS both at baseline and after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. The DRB1 SE+/+ genotype was associated with the highest TDS after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. Patients homozygous for MMP-3 6A and DRB1 SE had the highest progression of the TDS. CONCLUSION: This study provides the first evidence of an association between a polymorphism in the MMP-3 gene promoter and the severity and progression of RA, but not RA susceptibility. Investigation of this polymorphism could be combined with that of DRB1 gene polymorphism to improve the predictive accuracy and management strategy in early RA.

Constantin A, Lauwers-Cancès V, Navaux F, Abbal M, van Meerwijk J, Mazières B, Cambon-Thomsen A, Cantagrel A. · Department of Rheumatology and Immunology, CHU Rangueil, France. · J Rheumatol. · Pubmed #11824952 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is characterized by chronic synovitis leading to permanent damage of the joints. Collagenase-1 (MMP-1) is a matrix metalloproteinase involved in articular cartilage degradation. We investigated the association between a biallelic polymorphism in the MMP-1 gene promoter and the susceptibility to, and severity of, RA. We also investigated the association between HLA-DRB1 gene polymorphism and severity of RA. METHODS: One hundred and three patients with early RA were included in this prospective longitudinal study. A radiographic damage score was used to quantify disease severity at baseline and after 4 years of followup. MMP-1 polymorphism genotyping was analyzed using a fluorescent-based polymerase chain reaction (PCR). HLA-DRB1 genotypes were determined by PCR sequence-specific oligonucleotide probes. One hundred and thirty-three healthy individuals were used as controls. RESULTS: MMP-1 allele and genotype frequencies did not differ between RA patients and controls. The radiographic damage or its progression over the 4 years of followup did not differ across MMP-1 genotypes. The radiographic damage score and its progression over the 4 years of followup differed across HLA-DRB1 genotypes. The HLA-DRB I shared epitope +/+ genotype was associated with the highest radiographic damage score and the highest progression, while the shared epitope -/- genotype was associated with the lowest. CONCLUSION: Our results do not support the hypothesis of an association between this particular polymorphism in the MMP-1 gene promoter and susceptibility to, or severity of, RA. This study confirms the previous reports of an association between the HLA-DRB1 gene polymorphism and severity of RA.

Constantin A, Navaux F, Lauwers-Cancès V, Abbal M, van Meerwijk JP, Mazières B, Cambon-Thomsen A, Cantagrel A. · No affiliation provided · Lancet. · Pubmed #11755617 No free full text.

Abstract: A strong association between an interferon gamma (IFN-gamma) gene polymorphism and rheumatoid arthritis susceptibility and severity has been reported in a case-control study. We investigated this polymorphism in 103 patients with early rheumatoid arthritis and 130 controls. Severity of rheumatoid arthritis was measured after 4-year follow-up with a validated radiographic score. The median radiographic score in patients increased from 1 (IQR 0-4) to 11.5 (2-35) over the 4-year follow up. The distribution of IFN-gamma alleles did not differ between patients and controls, and the distribution of radiographic scores did not differ among patients carrying the different IFN-gamma alleles. We have failed to confirm the association between the IFN-gamma gene polymorphism and rheumatoid arthritis susceptibility or severity.