Individuals at risk of seropositive rheumatoid arthritis: the evolving story.

The aetiology of the autoimmune disease rheumatoid arthritis (RA) involves a complex interplay between genetic and environmental factors that initiate many years before the onset of clinical symptoms. These interactions likely include both protective and susceptibility factors which together determine the risk of developing RA. More than 100 susceptibility loci have been linked to RA. The strongest association is with HLA-DRB1 alleles encoding antigen presenting molecules containing a unique sequence in the peptide-binding grove called the 'shared epitope'. Female sex, infections during childhood, lifestyle habits (e.g. smoking and diet) and distinct microbial agents, amongst many others, are interacting risk factors thought to contribute to RA pathogenesis by dysregulating the immune system in individuals with genetic susceptibility. Interestingly, patients with RA develop autoantibodies many years before the clinical onset of disease, providing strong evidence that the lack of tolerance to arthritogenic antigens is amongst the earliest events in the initiation of seropositive RA. Here, we will discuss the clinical and mechanistic evidence surrounding the role of different environmental and genetic factors in the phases leading to the production of autoantibodies and the initiation of symptomatic RA. Understanding this complexity is critical in order to develop tools to identify drivers of disease initiation and propagation and to develop preventive therapeutics.

Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review.

Three important factors, including genetics, environment factors and autoimmunity play a role in the pathogenesis of rheumatoid arthritis (RA). The heritability of RA has been accounted to be 50-60%, while the HLA involvement in heritability of the disease has been accounted to be 10-40%. It has been documented that shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, some HLA alleles like HLA-DRB1*13 and DRB1*15 are connected to RA susceptibility. An advanced classification of SE categorizes SE alleles into four main groups namely, S1, S2, S3D, and S3P. The S2 and S3P groups have been linked to susceptibility of seropositive RA. Various genome-wide association studies (GWAS) have discovered many susceptibility loci implicated in pathogenesis of RA. Some of the important single nucleotide polymorphisms (SNPs) linked to RA are TRAF1, STAT4, CTLA4, IRF5, CCR6, PTPN22, IL23R, and PADI4. HLA and non-HLA genes may discriminate anti-cyclic citrullinated peptide (anti-CCP) antibody-positive and anti-CCP-negative RA groups. Furthermore, risk of the disease has also been linked to environmental agents, mainly cigarette smoking. Pharmacogenomics has also confirmed SNPs or genetic patterns that might be linked to drugs responses. Different aspects of genetic involvement in the pathogenesis, etiology, and RA complications are reviewed in this article.

Associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis.

OBJECTIVE: To investigate the associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis (RA). METHODS: We conducted a prospective study consisting of 662 patients with RA who were followed up to 7 years from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study. Smoking and alcohol consumption were assessed through yearly questionnaires. The disease activity and functional status were measured annually by the Disease Activity Score examined in 28 commonly affected joints using C-reactive protein (DAS28-CRP3) and the Modified Health Assessment Questionnaire (MHAQ). Linear mixed models were developed to assess the longitudinal effects of smoking and alcohol consumption on DAS28-CRP3 and MHAQ after adjustment for potential confounders. The HLA-DRB1 shared epitope (HLA-SE) by smoking and alcohol interactions were also evaluated in the analysis. RESULTS: The median followup time of the cohort was 4 years. Current smoking was not associated with DAS28-CRP3 in our study, but was associated with a higher MHAQ than nonsmokers with seropositive RA (p = 0.05). Alcohol consumption showed an approximate J-shaped relationship with MHAQ, with the minima occurring at 5.1-10.0 g/day. Compared to no alcohol use, alcohol consumption of 5.1-10.0 g/day was associated with a significant decrease of MHAQ (p = 0.02). When stratified by HLA-SE, the effect of alcohol consumption appeared to be stronger in HLA-SE-positive RA than HLA-SE-negative RA. CONCLUSION: We found that current smoking was associated with a worse functional status, while moderate alcohol consumption was associated with a better functional status in RA. Replications of these findings in other prospective studies are needed.