Background/Purpose: RA-associated interstitial lung disease (RA-ILD) is a heterogenous condition encompassing multiple subtypes with varying histopathology, prognosis, and potential treatment options. The most common RA-ILD subtypes are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). RA-UIP is characterized by fibrosis and portends the worst prognosis but may be treated with antifibrotic therapy. RA-NSIP is more likely to have inflammatory features on lung imaging. Despite these differences, most prior research studied RA-ILD as a single entity rather than examining individual subtypes. Therefore, we investigated differences in demographic, serologic, and lifestyle risk factors for RA-ILD and major RA-ILD subtypes.

Methods: We systematically identified RA-ILD cases and RA-noILD controls from two established RA cohorts. RA-ILD and subtypes (including UIP, NSIP, and other/indeterminate) were determined by clinical imaging reports and research review of clinically-indicated chest high-resolution computed tomography (HRCT) by at least two thoracic radiologists using a sequential reader method. RA-ILD cases met criteria for definite/probable RA-ILD (Bongartz, A&R, 2010). RA-noILD controls had no evidence of ILD on clinical review of medical records AND research HRCT review. Demographics, RA-related autoantibody testing, and smoking were extracted from study questionnaires or electronic health records. We investigated associations between RA-ILD and subtypes with demographic, serologic, and lifestyle factors using multivariable logistic regression, pooling both cohorts due to limited sample size.

Results: From 3328 RA patients, we identified 201 RA-ILD cases (mean age 51 years, 66.2% female) and 547 RA-noILD controls (mean age 49 years, 78.1% female). Of the RA-ILD cases, 69 (34.3%) had RA-UIP, 34 (16.9%) had RA-NSIP, and 98 (48.8%) had other subtypes or were indeterminate (Table 1). RA-ILD was associated with male sex (OR 1.63, 95%CI 1.12 to 2.37), seropositivity for RF and/or anti-CCP (OR 2.23, 95%CI 1.52 to 3.28) and ever smoking (OR 1.71, 95%CI 1.19 to 2.45, Table 2). Having all three risk factors (male, seropositive, smoking) was strongly associated with RA-ILD (OR 6.09, 95%CI 2.95 to 12.58, Table 3) and particularly with RA-UIP (OR 12.8, 95%CI 3.50 to 46.8) compared to RA-NSIP (OR 2.96 95%CI 0.77 to 11.56). RA-UIP was associated with male sex (OR 2.69, 95%CI 1.56 to 4.67) and positive anti-CCP (OR 2.23, 95%CI 1.52 to 3.28, Table 2). RA-NSIP was associated with positive RF (OR 3.21 95%CI 1.46 to 7.07) but not male sex (OR 1.21, 95%CI 0.53 to 2.74).

Conclusion: In this study comparing systematically phenotyped RA-ILD cases with RA-noILD controls confirmed by HRCT, we found distinct risk factor profiles for RA-UIP and RA-NSIP. Male sex and elevated anti-CCP were strongly associated with RA-UIP, the most severe RA-ILD subtype. The combination of male sex, seropositivity, and smoking conferred nearly 13-fold increased risk of RA-UIP. These findings suggest that RA-ILD sex differences are specific to RA-UIP and may help clarify RA-ILD heterogeneity to optimize screening and treatment approaches.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-impact-of-sex-serostatus-and-smoking-on-risk-for-rheumatoid-arthritis-associated-interstitial-lung-disease-subtypes/