HLA-SE alleles, smoking affects the development of RA



Human leukocyte antigen (HLA-SE) shared epitope alleles and smoking represent 2 predominant genetic and environmental risk factors for rheumatoid arthritis (RA), respectively. While smoking increases the risk of anti-citrullinated protein antibodies (ACPA) and confers the development of joint symptoms, HLA-SE mediates symptom development and progression to clinical inflammatory arthritis (IA), according to the findings of ” a study published in the Annals of Rheumatic Diseases.

Few research studies have identified at what pre-arthritic stage (i.e. asymptomatic vs symptomatic) smoking and HLA-SE alleles exert their effects on the development of RA.

To fill this knowledge gap, a team of British and Dutch researchers conducted meta-analyzes of studies evaluating associations between smoking and HLA-SE with ACPA in asymptomatic patients with RA. The researchers also examined the associations between smoking and HLA-SE with the positivity of autoantibodies at the onset of clinically suspicious arthralgia (CSA) and with the progression of RA in clinical IA.

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Although meta-analyzes showed no association between HLA-SE positivity and ACPA in asymptomatic patients (odds ratio [OR], 1.06; 95% CI 0.69-1.64), researchers found an association between smoking and ACPA positivity (OR, 1.37; 95% CI, 1.15 to 1.63) . In addition, the likelihood of ACPA positivity was higher in patients who smoked (OR, 2.41; 95% CI, 1.31-4.43) and those who were HLA-SE positive (OR, 2 , 08; 95% CI, 1.24 to 3.49).

The median time for patients in follow-up analyzes to develop IA was 16 weeks; patients who did not progress were followed for a median of 109 weeks. In all patients with CSA, the presence of HLA-SE has been associated with the development of IA (hazard ratio [HR], 1.86; 95% CI, 1.23-2.82). In a meta-analysis of ACPA positive patients from 2 studies, HLA-SE was also significantly associated with the development of IA (HR, 1.52; 95% CI, 1.08-2.15).

In multivariate Cox regression analysis, AAPA was associated with the development of IA independent of rheumatoid factor and ACPA (RR: 1.79; 95% CI: 1.02-3.16; P = .043).

“Even though the underlying time-specific biological pathways require further exploration, these data improve our understanding of the timing of major genetic and environmental risk factors in the development of RA,” the researchers wrote.

The researchers added that the findings “on smoking imply not only that smoking cessation could influence the risk of ACPA development and / or the appearance of symptoms, but also implies that it may not be effective in reducing. the risk of progression from CSA to clinical arthritis. “


Wouters F, Maurits MP, van Boheemen L, et al. To determine the pre-arthritic stage at which alleles of shared HLA epitopes and smoking exert their effect on the development of rheumatoid arthritis. Ann Rheum Dis. Published online July 20, 2021. doi: 10.1136 / annrheumdis-2021-220546


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