Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a chronic inflammatory arthritis that affects multiple synovial lined joints. The natural history of the condition is one of progressive articular damage leading to joint deformation and disabilities. Rheumatoid Arthritis is associated with a number of co-morbidities particularly in the cardiovascular system. The onset of RA is preceded by a prearticular autoimmune phase, the presence of antibodies against citrullinated (deaminated) protein and the presence of rheumatoid factor. Autoimmunity to citrullinated protein appears to be highly specific for Rheumatoid Arthritis with anti – citrullinated protein antibodies detected in approximately 70% of Rheumatoid Arthritis patients.

The prevalence of RA seems to be relatively uniform around the world though prevalence is low in sub Saharan Africa. This might reflect underreporting. The risk of developing RA does however vary between ethnic populations in the same global region, demonstrating a genetic component to this disease. The prevalence of Rheumatoid Arthritis in the general population is less than 1% but rises to between 2 – 4% in siblings of RA patients. This is confirmed by studies in monozygotic twins.

Multiple genetic loci have been shown to contribute to the risk of developing RA. Of these, the HLA class II DRB1 is the most important and contributes 30 – 50% of the overall genetic susceptibility risk. The association was initially thought to be with HLA-DR4 but subsequent studies have shown an association between RA and multiple HLA-DRB1 alleles not all of them DR4. These alleles did however share common sequences at positions 70 – 74 in the sequence. This has lead to the shared epitope hypothesis. Amino acids in these positions influence both peptide binding and contact between MHC and T cell receptor. HLA-DRB1 alleles associated with RA, more specifically with anti – citrullinated protein antibodies RA, were shown to have the sequence Arg-Ala-Ala (RAA) at positions 72–74. Gln (Q) or Arg (R) at position 70 carries a higher risk than Asp (D) whilst Lys (K) or Arg (R) at position 71 carry a higher risk than Ala (A) or Glu (Q). The shared epitopes that carry an increased risk are therefore QKRAA, QRRAA, RKRAA and RRRAA. HLA-DRB1 alleles with one of these sequences include HLA-DRB1*01:01, HLA-DRB1*01:02, HLA-DRB1*04:01, HLA-DRB1*04:04, HLA-DRB1*04:05, HLA-DRB1*04:08, HLA-DRB1*10:01, HLA-DRB1*13:03, HLA-DRB1*14:02 and HLA-DRB1*14:06. There is a gene additive effect such that patient’s homozygous or compound heterozygosity for the disease susceptibility alleles are at increased relative risk. Alleles which do not share any of these sequences and may be protective for RA are HLA-DRB1*03, HLA-DRB1*04:03, HLA-DRB1*04:07, HLA-DRB1*07, HLA-DRB1*08 and HLA-DRB1*09.

The shared HLA-DRB1 epitope does not explain the full RA genetic heritability. Genome wide association studies have led to recognition of an association between RA and the Arg620 to Trp polymorphism in the Protein tyrosine Phosphatase, non-receptor type-22 (PTPN22) gene, which codes for a powerful inhibitor of T-cell activation. A number of other candidate genes which have a much smaller effect than HLA-DRB1 and PTPN22 have also been described.


Do you or someone you know suffer from Rheumatoid Arthritis or are you a researcher working in this area? Please join the conversation. Leave a comment. Thanks.

 


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