Specific anticitrullinated protein antibodies (ACPAs) and antinative protein antibodies improve the prediction of rheumatoid arthritis–associated interstitial lung disease
(RA-ILD), according to study findings published in The Lancet Rheumatology.
RA-ILD is a leading cause of death among patients with RA therefore, improved prediction of RA-ILD is critical for early diagnosis and treatment.
In a nested case-control study conducted within the prospective Brigham Rheumatoid Arthritis Sequential Study (BRASS), researchers sought to identify fine-specificity ACPAs and antinative protein antibodies related to RA-ILD.
Patients with incident RA-ILD diagnosed between March 2003 and 2016 were matched with control patients with RA without ILD, based on the time of blood collection, sex, age, duration of RA, and rheumatoid factor status.
RA-ILD was defined as interstitial changes on clinically indicated chest computed tomography following BRASS study enrollment, which were confirmed by 2 attending thoracic radiologists and 1 attending pulmonologist, with use of a validated sequential reading method. ACPAs and antinative protein antibodies were measured by a multiplex assay on stored serum collected prior to the onset of RA-ILD.
A total of 84 patients with incident RA-ILD (mean age, 67 years; 77% men; 90% White) and 233 control participants with RA without ILD (mean age, 66 years; 20% men; 94% White) were included in the study.
The researchers identified 6 fine-specificity antibodies that were linked to RA-ILD. The antibody isotypes and targeted proteins included immunoglobulin A2 (IgA2) to citrullinated histone 4 (adjusted odds ratio [aOR], 0.08; 95% CI, 0.03-0.22 per log-transformed unit); IgA2 to citrullinated histone 2A (aOR, 4.03; 95% CI, 2.03-8.00); IgG to cyclic citrullinated filaggrin (aOR, 3.47; 95% CI, 1.71-7.01); IgA2 to native cyclic histone 2A (aOR, 5.52; 95% CI, 2.38-12.78); IgA2 to native histone 2A (aOR, 4.60; 95% CI, 2.18-9.74); and IgG to native cyclic filaggrin (aOR, 2.53; 95% CI, 1.47-4.34).
The predictive value of the 6 antibodies was superior to that of all clinical factors combined (optimism-corrected area under the curve [AUC], 0.84 vs 0.73). Thus, the researchers developed a risk score for RA-ILD by combining the 6 antibodies and clinical factors (ie, smoking, obesity, disease activity, and glucocorticoid use). At 50% predicted probability of developing RA-ILD, the risk scores both without and with antibody biomarkers (2.6 and 5.9, respectively) attained a specificity of at least 93% for RA-ILD.
Study limitations included that ACPA fine-specificities that vary in different populations was not accounted for; the results may not be generalizable to the entire population with RA-ILD; and that some control participants might have had subclinical RA-ILD.
According to the study authors, “These findings implicate synovial protein antibodies in the pathogenesis of [RA-ILD] and, once validated in external studies, suggest that these antibodies might have clinical utility in predicting the development of ILD in patients with [RA].”
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Kronzer VL, Hayashi K, Yoshida K, et al. Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: a nested case control study. Lancet Rheumatol. 2023;5:e77-e87. doi:10.1016/S2665-9913(22)00380-0