HLA-SE Alleles, Smoking Exert Effects on RA Development

Older woman holding cigarette
cigarette, smoking, RA
A meta-analyses of studies evaluating associations of smoking and HLA-SE with ACPAs in asymptomatic patients with rheumatoid arthritis is conducted.

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

Few research studies have identified at which pre-arthritis stage (ie, asymptomatic vs symptomatic) smoking and HLA-SE alleles exert their effects on the development of RA.

To address this knowledge gap, a team of UK and Dutch researchers conducted meta-analyses of studies evaluating associations of smoking and HLA-SE with ACPAs in asymptomatic patients with RA. The investigators also examined associations of smoking and HLA-SE with autoantibody positivity at the onset of clinically suspect arthralgia (CSA) and with progression of RA to clinical IA.

Although the meta-analyses showed no association between HLA-SE and ACPA positivity in asymptomatic patients (odds ratio [OR], 1.06; 95% CI, 0.69-1.64), the researchers did find an association between smoking and ACPA positivity (OR, 1.37; 95% CI, 1.15-1.63). 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, 1.24-3.49).

The median time for patients in the follow-up analyses 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 was 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 a multivariable Cox regression analysis, AAPA was associated with the development of IA independent from rheumatoid factor and ACPA (HR, 1.79; 95% CI, 1.02-3.16; P =.043).

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

The researchers added that the findings “on smoking not only imply that cessation of smoking might be able to influence the risk of ACPA development and/or symptom onset but also imply 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. Determining in which pre-arthritis stage HLA-shared epitope alleles 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