Rheumatoid Factor Positive Disease Research Articles

Association Study of PTPN22 (rs2476601) and PADI4 (rs2240340) Polymorphisms with Rheumatoid Arthritis in Algerian Population

An association between protein tyrosine phosphatase 22 (PTPN22) and Peptidylarginine deiminase 4 (PADI4) genes with rheumatoid arthritis (RA) has been demonstrated in several populations. The present study investigated whether PTPN22 and PADI4 genes polymorphisms were involved in the genetic predisposition to RA in the Algerian patients. Materials and methods: The PADI4_94 (rs2240340) and the PTPN22 (rs2476601) Single Nucleotide Polymorphisms (SNPs) were genotyped in 300 RA patients and 306 healthy controls by real time polymerase chain reaction method (TaqMan Assays). The relationships between Anti-Citrullinated Peptide Antibody (ACPA) positivity, Rheumatoid Factor (RF) positivity and genotypes were statistically analyzed. Results: There was no significant association between the PTPN22, PADI4 SNP and RA susceptibility in our population (p>0.05). No association with ACPA profile with either PTPN22 or PADI4 was detected (p>0.05). However, our results showed a strong association of PTPN22 minor T allele with RF positive disease (OR=8.53 (95% CI 1.34-354.9), p=0.013); also, a significant association was shown between CT genotype of PTPN22 SNP and RF positive RA (OR=8.01 (95% CI 1.22-336.5), p=0.018). Conclusion: Our findings indicated that PTPN22 and PADI4 polymorphisms were unlikely to play an important role in the susceptibility to RA in Algerian population but PTPN22 polymorphism T allele may predispose individuals to RF positive RA.

Confirmation of association ofFCGR3Bbut notFCGR3Acopy number with susceptibility to autoantibody positive rheumatoid arthritis

The FCGR locus encoding the low-affinity Fcγ receptors (FcγR) for immunoglobulin G has largely been missed by genome-wide association studies due to complications with structural variation and segmental duplication. Recently identified copy number variants (CNVs) affecting FCGR3A and FCGR3B have been linked to a number of autoimmune disorders. We have developed and validated a novel quantitative sequence variant assay in combination with an adapted paralogue ratio test to examine independent CNVs carrying FCGR3A and FCGR3B in rheumatoid arthritis (RA) compared with healthy volunteers (n = 1,115 and 654, respectively). Implementation of a robust statistical analysis framework (CNVtools) allowed for systematic batch effects and for the inherent uncertainty of copy number assignment, thus avoiding two major sources of false positive results. Evidence for association with neither duplications nor deletions of FCGR3A was found; however, in line with previous studies, there was evidence of overrepresentation of FCGR3B deletions in RA (odds ratio [OR] 1.50, P = 0.028), which was more apparent in rheumatoid factor positive disease (OR 1.61, P = 0.011). The level of FcγRIIIb, encoded by FCGR3B, expression on neutrophils was shown to correlate with gene copy number. Thus, our results may highlight an important role for neutrophils in the pathogenesis of RA, potentially through reduced FcγRIIIb-mediated immune complex clearance.

Cerebral vasculitis in a patient with rheumatoid arthritis

Inflammatory vasculitis of the central nervous system is exceedingly rare in patients with rheumatoid arthritis (RA). The symptoms may be misleading. Most of the reported cases occurred in males with long-standing, nodular, destructive, rheumatoid factor-positive disease. Severe constitutional symptoms and prominent extraarticular manifestations of vasculitis were usually present. We report a case of cerebral vasculitis in a 59-year-old woman with a 20-year history of destructive rheumatoid factor-positive RA that was well controlled by methotrexate. Headache that was unresponsive to symptomatic treatment developed abruptly, together with gait disorders. Magnetic resonance imaging of the brain showed dot-like areas of high-signal in a periventricular subcortical distribution on both sides. Magnetic resonance angiography visualized a long tight stenosis of the right internal carotid artery and a string-of-beads stenosis of the left internal carotid artery suggesting vasculitis. Pulse therapy with methylprednisolone (1 g/d for 3 days) and cyclophosphamide (1 g) once a month ensured resolution of the neurological symptoms and laboratory evidence of inflammation. There was no evidence of a relapse at last follow-up after 5 months. Cerebral vasculitis is usually treated with monthly glucocorticoid and cyclophosphamide boluses separated by continuous glucocorticoid therapy. TNFα antagonists may be effective in patients who fail to respond to conventional treatment. However, other vasculitides such as giant cell arteritis and Wegener's granulomatosis must be ruled out, as they are refractory to TNFα antagonist therapy.

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46-2.10, P=1.3 x 10(-9)). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92-1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35-8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.

Association of rheumatoid arthritis with an amino acid allelic variation of the T cell receptor.

To investigate allelic variations of T cell receptor residues for a contribution to rheumatoid arthritis (RA) susceptibility. We conducted an RA case-control study involving 1,579 northwest Europeans: 766 patients with erosive and rheumatoid factor-positive disease and 813 control subjects. Productive changes of segments TCRAV6S1, TCRAV7S1, TCRAV8S1, TCRAV10S2, and TCRBV6S1, TCRBV6S7 were investigated by single-strand conformation polymorphisms. The TCRAV8S1 association was confirmed by restriction fragment length polymorphism. In the systematic study (77 patients and 119 controls), an increase in 1 TCRAV8S1 genotype was found in the RA patients (P = 0.0004). This finding was replicated in 2 further populations, one from France (212 patients and 254 controls) and the other from Britain (477 patients and 440 controls), with a similar odds ratio (OR), which allowed pooling of the data and confirmation of the association (OR 1.3 [95% confidence interval 1.1-1.7], P = 0.008). These findings show evidence that TCRA is an RA susceptibility locus.

Rheumatoid arthritis: Relationship with HLA-D

Understanding of the genetic component of rheumatoid arthritis has been greatly enhanced by the discovery of the association of risk for development of this disease with certain histocompatibility antigens. The HLA-D region, at the centromeric end of the HLA gene complex, on the short arm of chromosome number 6, is concerned with important functions in the regulation of the Immune response. The products of the HLA-D region (DR, SB, MT, and the like) function as “restriction elements” for antigen presentation, mediators of immune response and immune suppressor genes, stimulators of graft rejection, and of other allogenic effects. Rheumatoid arthritis is associated with Dw4 and DR4 in Caucasians. The association with DR4 has been observed also in Blacks and Orientals. HLA-DR4 is associated with more severe, rheumatoid factor-positive disease. Clinical and genetic heterogeneity has been revealed by studies of patients with juvenile arthritis. Conditions often associated with rheumatoid arthritis and also thought to have an immunologic basis, such as Sjögren's syndrome, Felty's syndrome, and rheumatoid vasculitis, and reactions to medications, such as gold and penicillamine, reveal an interesting spectrum of immunogenetic relationships. Thus, HLA studies have shed light on the classification of patients with rheumatoid diseases. In view of the role of HLA-D in the immune response, these studies are expected to further our understanding of the mechanism underlying predisposition for development of rheumatoid arthritis and related conditions.