Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis

Abstract

Background: Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults.

Methods: We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between -600 and -250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking.

Results: In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected.

Conclusions: RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers.

Keywords: Clinical Epidemiology; Connective tissue disease associated lung disease; Interstitial Fibrosis; Rheumatoid lung disease.

Figure 1

Continuous relationships of RF IgM (A and D), RF IgA (B and E), and CCP (C and F) with predicted (adjusted) high attenuation area volume (A, B, C) and the predicted probability of interstitial lung abnormalities (D, E, F). A, B, and C: Smoothed regression lines (solid line: all subjects, dashed line: ever smokers, dotted line: never smokers) are adjusted for age, sex, race, study site, BMI, total volume of imaged lung, percent emphysema, and tube current. The solid line is also adjusted for pack-years of smoking and current smoking status. D, E, F: Smoothed regression lines (solid line: all subjects, dashed line: ever smokers, dotted line: never smokers) are adjusted for age, sex, and race. The solid line is also adjusted for pack-years of smoking and current smoking status. Each vertical tick mark on the rug plot running along the internal border of the x-axis represents one study participant. P-values shown are for the multivariable-adjusted associations between each autoantibody and HAA or ILA in the overall cohort and for interactions between each autoantibody and ever smoking status.

Figure 2

Forest plots showing associations between smoking status and high attenuation areas (left panel) and smoking status and interstitial lung abnormalities (right panel), stratified by quartiles of RF IgM, RF IgA, and anti-CCP. Boxes are point estimates. Horizontal lines are 95% confidence intervals. P-values for interaction are shown.