Rheumatoid Arthritis: Navaux F

Godinho F, Godfrin B, El Mahou S, Navaux F, Zabraniecki L, Cantagrel A. · Department of Rheumatology, Rangueil Hospital, Toulouse, France. · Clin Exp Rheumatol. · Pubmed #15144127 No free full text.

Abstract: OBJECTIVE: To analyse the safety of leflunomide plus infliximab combination therapy, in adult rheumatoid arthritis (RA) patients. PATIENTS: A retrospective study of 17 adult patients with active RA (DAS 28 = 5.94 +/- 0.88 at baseline) who were treated with a combination of leflunomide plus infliximab after failure of treatment with other DMARDs. 13 patients were treated for a minimum of 3 months with leflunomide without toxicity before beginning infliximab. Treatment was begun simultaneously with both drugs in 4 patients. Side effects (clinical and biological) and efficacy (DAS 28) were evaluated at each infliximab infusion (3 mg/kg at week 0, 2, 6 and then every 8 weeks). RESULTS: Thirteen patients experienced 20 types of side effects and 8 of them stopped the combination therapy. The causes of discontinuation were congestive heart failure (1 case), hypertension with thoracic pain (2 cases), eczematous skin patches (2 cases) and neutropenia (3 cases). No death was registered. Nine RA patients continuted the therapy with a median follow-up of 22 weeks. Only 4 of them experienced no side effects. Eight patients were positive for antinuclear antibodies (ANA) and 1 for double-stranded DNA (dsDNA) antibodies at study entry. After treatment, 13 and 5 patients tested positive respectively for ANAs and dsDNA antibodies. There was no relationship between discontinuation and ANA/dsDNA positivity. CONCLUSION: In this cohort, adverse events were not very different from those seen in patients on either treatment alone and the combination of leflunomide plus infliximab did not appear to be as badly tolerated as described in a previous study.

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.

Cantagrel A, Navaux F, Loubet-Lescoulié P, Nourhashemi F, Enault G, Abbal M, Constantin A, Laroche M, Mazières B. · Service de Rhumatologie, Hôpital Rangueil, Toulouse, France. · Arthritis Rheum. · Pubmed #10366101 links to  free full text

Abstract: OBJECTIVE: To test if interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-4, or IL-10 gene polymorphisms could be used as markers of susceptibility or severity in rheumatoid arthritis (RA). METHODS: The study included 108 patients with early RA followed up for 2 years and 128 healthy controls. From genomic DNA, 6 polymorphisms in genes for IL-1beta, IL-1Ra, IL-10, and IL-4 were typed. Allelic frequencies and carriage rates were compared between RA patients and controls, between patients with erosive and nonerosive RA, and between patients with or without sustained remission. RESULTS: The RP1 allele of the IL-4 gene was found with a significantly higher frequency in RA patients compared with controls. The combination of an RA-related HLA-DR allele expressing shared epitope and the presence of allele E2 in IL-1beta exon 5 was found to expose patients to an increased risk of erosive disease, with an odds ratio of 8.20 (95% confidence interval 2.59-25.84, P < 0.0001). No significant association was observed between polymorphisms and the occurrence of sustained remission. CONCLUSION: This report, for the first time, indicates an association between RA and a polymorphic IL-4 gene sequence located in 5q31-33. In addition, the results show the prognostic value of a polymorphism in IL-1beta exon 5, which allowed prediction of erosive disease with a specificity of 91.8% in 42.1% of patients. Although these observations are very interesting, they have to be considered preliminary and will need to be confirmed.

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.