Advanced therapies in US veterans with rheumatoid arthritis-associated interstitial lung disease: a retrospective, active-comparator, new-user, cohort study

Abstract

Background: Uncertainty exists regarding patient outcomes when using TNF inhibitors versus other biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis-associated interstitial lung disease (ILD). We compared survival and respiratory hospitalisation outcomes following initiation of TNF-inhibitor or non-TNF inhibitor biological or targeted synthetic DMARDs for treatment of rheumatoid arthritis-associated ILD.

Methods: We did a retrospective, active-comparator, new-user, observational cohort study with propensity score matching following the target trial emulation framework using US Department of Veterans Affairs (VA) electronic and administrative health records. VA health-care enrollees with rheumatoid arthritis-associated ILD and no previous receipt of ILD-directed therapies (eg, antifibrotics) who initiated a TNF inhibitor or non-TNF inhibitor between Jan 1, 2006, and Dec 31, 2018, were included. Propensity score matching was performed using demographics, health-care use, health behaviours, comorbidity burden, rheumatoid arthritis-related severity factors, and ILD-related severity factors, including baseline forced vital capacity. Study outcomes were respiratory hospitalisation, all-cause mortality, and respiratory-related death over follow-up of up to 3 years, from VA, Medicare, and National Death Index data. People with lived experience of rheumatoid arthritis-associated ILD were not involved in the design or conduct of this study.

Findings: Of 1047 patients with rheumatoid arthritis-associated-ILD who initiated biological or targeted synthetic DMARDs, we matched 237 patients who had initiated TNF inhibitors and 237 who had initiated non-TNF inhibitors (mean age 68 years [SD 9]); 434 (92%) of 474 were male and 40 (8%) were female. Death and respiratory hospitalisation did not significantly differ between groups (adjusted hazard ratio 1·21 [95% CI 0·92-1·58]). Respiratory hospitalisation (1·27 [0·91-1·76]), all-cause mortality (1·15 [0·83-1·60]), and respiratory mortality (1·38 [0·79-2·42]) did not differ between groups. Secondary, sensitivity, and subgroup analyses supported the primary findings.

Interpretation: In US veterans with rheumatoid arthritis-associated ILD, no difference in outcomes were seen between those who started TNF inhibitors compared to those starting non-TNF biological or targeted synthetic DMARDs. These data do not support systematic avoidance of TNF inhibitors in all people with rheumatoid arthritis-associated ILD. Comparative efficacy trials in patients with rheumatoid arthritis-associated ILD are needed given the potential for residual confounding and selection bias in observational studies.

Funding: US Department of Veterans Affairs.

Figure 1.. Graphical depiction of study design.

Study design is graphically depicted illustrating the evaluation of eligibility criteria and covariable assessment prior to biologic or targeted-synthetic disease-modifying anti-rheumatic (b/tsDMARD) drug start date. Study outcomes of death and respiratory hospitalization were ascertained after b/tsDMARD start date. Graphical depiction template adapted from Wang SV & Schneeweiss S, Clin Epidemiol 2022; 14:601-608. Abbreviations: bDMARD, biologic disease-modifying anti-rheumatic drug; CMS, Centers for Medicare Services; CTD, connective tissue disease; ILD; interstitial lung disease; MS, multiple sclerosis; NDI, National Death Index; RA, rheumatoid arthritis; tsDMARD, targeted-synthetic disease-modifying anti-rheumatic drug; VA, Veterans Health Administration.

Figure 2.. Distribution of propensity scores and variable balance before and after matching in primary cohort.

Panel A, Kernal density plots of propensity score (PS) distributions before and after matching in the primary cohort. Panel B, Standardized differences before and after propensity score matching in the primary cohort. Variables with standardized difference >0·1 are bolded. Abbreviations: CCP, cyclic-citrullinated peptide; CRP, C-reactive protein; DMARDs, disease-modifying anti-rheumatic drugs; Elev, elevated; ESR, erythrocyte sedimentation rate; FVC, forced vital capacity; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate; Pos, positive; RF, rheumatoid factor; SSZ, sulfasalazine; Supp, supplemental.

Figure 2.. Distribution of propensity scores and variable balance before and after matching in primary cohort.

Panel A, Kernal density plots of propensity score (PS) distributions before and after matching in the primary cohort. Panel B, Standardized differences before and after propensity score matching in the primary cohort. Variables with standardized difference >0·1 are bolded. Abbreviations: CCP, cyclic-citrullinated peptide; CRP, C-reactive protein; DMARDs, disease-modifying anti-rheumatic drugs; Elev, elevated; ESR, erythrocyte sedimentation rate; FVC, forced vital capacity; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate; Pos, positive; RF, rheumatoid factor; SSZ, sulfasalazine; Supp, supplemental.

Figure 3.. Kaplan-Meier curves among RA-ILD patients initiating TNFi or non-TNFi b/tsDMARDs in the primary cohort.

Kaplan-Meier curves show outcome free survival amongst propensity score (PS)-matched RA-ILD patients (n=474) initiating either TNFi or non-TNFi b/tsDMARDs. Panel A shows the composite outcome of death or respiratory hospitalization, panel B shows respiratory hospitalization, panel C shows all-cause mortality, and panel D shows respiratory mortality. Abbreviations: b/tsDMARDs, biologic or targeted-synthetic disease-modifying anti-rheumatic drugs; RA-ILD, rheumatoid arthritis-associated interstitial lung disease; TNFi, tumor necrosis factor inhibitor.

Figure 4.. Forest plot of results from primary analysis, secondary analyses, and sensitivity analyses over up to 3-years of follow-up.

Adjusted hazard ratios depicting risk of study outcomes in non-TNFi vs. TNFi initiators for the composite outcome of death or respiratory hospitalization as well as the individual outcomes of respiratory hospitalization and all-cause mortality over up to 3-years of follow-up. Standardized differences are provided in the Appendix p. 6-7 and a full listing of these results is provided in the Appendix p. 10-14. Abbreviations: aHR, adjusted hazard ratio; b/tsDMARD, biologic/targeted-synthetic disease-modifying anti-rheumatic drug; CI, confidence interval; FVC, forced vital capacity; ILD, interstitial lung disease; RTX, rituximab; TNFi, tumor necrosis factor inhibitor