Smoking Elevates Risk Factors in Rheumatoid Arthritis

Smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.

New findings reveal an association between smoking and the concurrent presence of multiple rheumatoid arthritis (RA)-related autoantibodies, rather than only anti-citrullinated protein antibodies (ACPA).

In a study published in Arthritis Research & Therapy, investigators sought to determine whether association of smoking with RA was limited only to anti-citrullinated protein antibodies (ACPA), or there was an association with several other autoantibodies.

The investigators examined the association of smoking with rheumatoid factor (RF) and anti-CCP2 in a population-based cohort of health individuals; the association of smoking and anti-cyclic citrullinated peptide antibodies (anti-CCP2), IgM-RF, and anti-carbamylated protein antibodies (anti-CarP); and whether smoking was associated with the breadth of the autoimmune response.

Additionally, the investigators examined anti-nuclear antibodies (ANA) to determine whether the association between smoking and autoantibodies was specific to RA-related autoantibodies or autoantibodies in general.

For the study, investigators used a population-based Japanese cohort (n=9575) to examine the association between smoking with RF and anti-CCP2 in individuals without RA. Data for patients with RA were obtained from 3 early arthritis cohorts from the United Kingdom (n=678), the Netherlands (n=769), and Sweden (n=795).

The investigators calculated the total score of autoantibodies. Logistic regression was used to calculate ORs and 95% CIs. Data on smoking, RF, anti-CCP2, and anti-CarP were available.

Of the 9575 participants in the study, 35% had smoked, 1.7% were anti-CCP2-positive, and 5.3% were RF-positive. The results of the study showed no association between smoking and the presence of anti-CCP2 or RF in the healthy participants.

However, smoking was significantly associated with the presence of both anti-CCP2 and RF. According to the authors, the findings suggest that smoking may lead to the development of multiple autoantibodies, as opposed to 1 specific autoantibody.

When the investigators examined the association between smoking and RF, anti-CCP2, and anti-CarP, irrespective of the presence of other autoantibodies in patients with RA, they found a significant association for each autoantibody in all of the cohorts.

Based on the findings, the investigators calculated the total number of autoantibodies per patient to determine whether smoking is associated with the number of autoantibodies present. The results of the study revealed no association of smoking with either 1 or 2 autoantibodies. However, there was a significant association with triple-autoantibody positivity.

“Ordinal regression analysis showed a significant association between smoking and the number of autoantibodies in all cohorts, indicating a significantly stronger association in patients with many versus few autoantibodies,” the authors wrote.

The investigators conducted a pooled analysis of the 3 early arthritis cohorts. Although there was no association detected between ever smoking and single seropositivity, never smoking was associated with double-autoantibody-positive RA and triple-autoantibody-positive RA.

“When comparing double-positive patients with triple-positive patients, there was a trend towards a stronger association in the triple-positive patients, although this did not reach statistical significance.

Limitations to the study were some of the heterogeneity between the cohorts with regard to patient recruitment; the small patient numbers in the single autoantibody-positive groups may have caused a lack of power to detect associations; there was only available data on every smoking versus never smoking; the study was performed in European and Asian populations, and therefore replication in different ethnicities is warranted; and one could argue that preferably healthy controls should be used as the reference category instead of autoantibody-negative RA patients, according to the study.

The authors noted that one of the strengths of the study was the use of a unique healthy cohort, as well as several disease cohorts, which allowed investigators to capture the entire spectrum of disease development.

“Smoking is not only associated with the presence of ACPA, but rather with the concurrent presence of several autoantibodies in RA,” the authors concluded. “These findings shed new light on the important role of smoking in disease-specific immunomodulation in RA.”