Background/Purpose: Interstitial lung disease (ILD) mortality is reported to be increased in RA (Bongartz T et al. A&R 2010; 62: 1583-91). However, non-malignant respiratory mortality has not been reported in population-based RA and CN subjects.  This study aimed to analyze predictors of non-malignant respiratory cause mortality in a community-based cohort of incident RA vs non-RA control (CN) subjects as well as the relation of higher baseline levels of immunological biomarkers.   

Methods: Total incident cases (n = 54) had onset of ACR-positive RA, 3 to 20 (mean 12) years, after cohort entry (n = 21,061 adults) in 1974. Cases were matched at entry with 203 CN by age, gender, and race (all Caucasian). All subjects (n=257) had baseline data on: demographic, cigarette smoking, and inflammatory or cytokine biomarkers (n = 7) tested on stored (-70˚C) sera. A total of 113 deaths were identified from 1992 to 2013, and 100 of them had completed death certificates retrieved. Two investigators independently determined underlying causes of death from the completed certificate codes, without knowledge of RA vs CN status. The few differences in interpretation were also “blindly” resolved. Multiple imputation and aggregate methods were used to enter values for a minority of randomly missing test results on the analyzed biomarkers: acute serum amyloid A (ASAA); C-reactive protein (CRP);  IL-1β; IL-1ra; TNFα; sTNF-R1, and sIL-2Rα. Biomarker values were normalized using z-scores within sexes to adjust for any dimorphic differences.  Critical limits of biomarker levels were searched to identify associations with total mortality, e.g., 0.50+SE for sIL-2Rα. Non-malignant respiratory diseases included ICD-9 codes, 460-519, and ICD-10 codes, J00-J99.  Cox regression models were used to estimate hazard ratios (HRs) for respiratory causes of death vs remaining subjects, adjusting for covariates.   

Results: Non-malignant respiratory deaths occurred in 8 (14.8%) of 54 RA vs 5 (2.5%) of 203 CN, p = 0.001 by Fisher’s exact test. The HR for respiratory deaths was 14.3 (95% CI 3.07-66.82), p = 0.001, in RA vs CN, after adjusting for cohort entry age, cigarette smoking, years of education, and the 7 immunological biomarkers.  Respiratory death was independently predicted by: RA vs CN; entry age, and higher levels (0.50+SE) of sIL-2Rα, as shown in the below Cox survival model, adjusted for 9 additional covariates.

Conclusion: Respiratory deaths were significantly (p = 0.001) greater in incident RA (14.8%) than CN (2.5%), with an HR of 14.3 (3.07-66.82), and higher sIL-2Rα levels significantly (p = 0.001) predicted respiratory cause mortality, which deserve further investigation.