A large retrospective cohort study of U.S. veterans found that rheumatoid arthritis (RA) and rheumatoid arthritis–associated interstitial lung disease (RA-ILD) were independently associated with an increased risk of lung cancer.
The study, published in Arthritis & Rheumatology, revealed that patients with RA had a 58% higher risk of developing lung cancer compared to matched controls without RA. Notably, patients with RA-ILD faced an even greater risk—with a nearly threefold increase in lung cancer incidence.
Researchers analyzed data from 72,795 patients with RA and 633,937 matched non-RA controls treated within the Veterans Health Administration (VA) between 2000 and 2019. Among the RA cohort, 757 patients had prevalent RA-ILD at baseline. The study utilized validated administrative algorithms to identify RA and RA-ILD cases, with lung cancer diagnoses obtained from VA oncology databases and the National Death Index.
Key Findings
Patients with RA had an adjusted hazard ratio (aHR) of 1.58 (95% confidence interval [CI] = 1.52-1.64) for developing lung cancer compared to non-RA controls. Patients with RA-ILD exhibited a substantially higher risk, with an aHR of 2.88 (95% CI = 2.45-3.40) for lung cancer incidence.
The increased risk persisted in never-smokers with RA (aHR = 1.65; 95% CI = 1.22-2.24) and in incident RA cases (aHR = 1.54; 95% CI = 1.44-1.65).
Seropositive RA patients had a higher lung cancer risk (aHR = 1.65; 95% CI = 1.57-1.74) compared to seronegative patients (aHR = 0.95; 95% CI = 0.86-1.05).
RA patients with elevated inflammatory markers at baseline showed an increased lung cancer risk (aHR = 1.74; 95% CI = 1.65-1.84) compared to those with normal markers (aHR = 1.29; 95% CI = 1.19-1.39).
Lung cancer mortality was significantly higher in both RA (aHR = 1.58; 95% CI = 1.51-1.66) and RA-ILD patients (aHR = 3.17; 95% CI = 2.62-3.82) compared to non-RA controls.
Over 4,481,323 patient-years of follow-up (mean = 6.3 years), 17,099 incident lung cancers occurred (2,974 in RA cohort; 14,125 in non-RA cohort). The crude incidence rate of lung cancer was higher in RA patients (58.4 per 10,000 patient-years; 95% CI = 56.4-60.6) compared to non-RA controls (35.6 per 10,000 patient-years; 95% CI = 35.0-36.1). Prevalent RA-ILD patients demonstrated an even higher incidence rate of 109.3 per 10,000 patient-years (95% CI = 78.1-153.0) compared to 31.8 per 10,000 patient-years (95% CI = 26.1-38.9) in matched non-RA controls.
Baseline characteristics of the study population revealed important differences between groups. The mean age was 63.0 years (standard deviation [SD] = 11.9) for patients with RA and 67.4 years (SD = 10.2) for patients with RA-ILD. The cohorts were predominantly male (87.6% in RA, 89.3% in RA-ILD). Smoking status in the RA cohort showed that 49.9% of patients were current smokers, 34.8% were former smokers, and 15.3% were never smokers, while in the RA-ILD cohort, 51.7% were current smokers, 36.5% were former smokers, and 11.9% were never smokers.
Agent Orange exposure was noted in 15.3% of patients in the RA cohort and 19.6% of those in the RA-ILD cohort.
The mean Rheumatic Disease Comorbidity Index score was 1.7 (SD = 1.6) in the RA cohort and 2.2 (SD = 1.4) in the RA-ILD cohort (excluding lung disease). Seropositivity was observed in 68.8% of those in the RA cohort and 80.1% of those in the RA-ILD cohort. Elevated erythrocyte sedimentation rate was found in 51.8% of RA patients and 69.6% of RA-ILD patients, while elevated C-reactive protein was noted in 41.5% of RA patients and 52.7% of RA-ILD patients.
Treatment patterns varied between groups. Non-methotrexate conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were used in 35.1% of RA patients and 52.0% of RA-ILD patients. Methotrexate was used by 37.5% of patients in the RA cohort, but only 18.0% of those in the RA-ILD cohort. Biologic or targeted synthetic DMARDs were used in 19.2% of RA patients and 23.5% of RA-ILD patients. Prednisone use was notably higher in the RA-ILD cohort (67.5%) compared to the RA cohort (42.5%).
Histological analysis revealed that squamous cell carcinoma was the most common lung cancer subtype in RA patients (35.9%), while adenocarcinoma was more prevalent in non-RA controls (33.9%). RA-ILD patients showed equal prevalence of squamous cell carcinoma and adenocarcinoma (29.0% each). Small cell carcinoma was more common in RA-ILD patients (24.0%) compared to RA patients (12.0%).
SEER staging in the RA cohort showed 25.4% localized, 25.4% regional, and 32.7% distant lung cancers. In contrast, the RA-ILD cohort had 10.0% localized, 14.0% regional, and 38.0% distant disease, suggesting more advanced-stage disease at lung cancer diagnosis.
Lung cancer mortality rates were higher in patients with RA (43.6 per 10,000 patient-years) and RA-ILD (82.7 per 10,000 patient-years) compared to non-RA controls (27.7 and 24.5 per 10,000 patient-years, respectively). The mean survival time following lung cancer diagnosis was 7.0 years (SD = 5.1 years) in RA patients, compared to 4.2 years (SD = 3.4 years) in RA-ILD patients.
Sensitivity analyses reinforced the primary findings. When controls with IPF codes were excluded, the aHR for lung cancer in RA patients was 1.61 (95% CI = 1.55-1.68). For prevalent RA-ILD, the risk of lung cancer remained high, with an aHR of 3.25 (95% CI = 2.13-4.95).
The authors acknowledged several limitations of the study, including the predominantly male population, potential residual confounding from smoking intensity and duration, and the reliance on administrative data for disease classification. Additionally, the study lacked information on RA disease activity measures and specific ILD-related factors.
Disclosures can be found in the study.