Abstract
Objective
We aimed to evaluate lung cancer risk in patients with rheumatoid arthritis (RA) and RA‐interstitial lung disease (ILD).
Methods
We performed a retrospective, matched cohort study of RA and RA‐ILD within the Veterans Health Administration (VA) between 2000 and 2019. Patients with RA and RA‐ILD were identified with validated administrative‐based algorithms, then matched (up to 1:10) on age, gender, and VA enrollment year to individuals without RA. Lung cancers were identified from a VA oncology database and the National Death Index. Conditional Cox regression models assessed lung cancer risk adjusting for race, ethnicity, smoking status, Agent Orange exposure, and comorbidity burden among matched individuals. Several sensitivity analyses were performed.
Results
We matched 72,795 patients with RA with 633,937 patients without RA (mean age 63 years; 88% male). Over 4,481,323 patient‐years, 17,099 incident lung cancers occurred. RA was independently associated with an increased lung cancer risk (adjusted hazard ratio [aHR] 1.58 [95% confidence interval (CI) 1.52–1.64]), which persisted in never smokers (aHR 1.65 [95% CI 1.22–2.24]) and in those with incident RA (aHR 1.54 [95% CI 1.44–1.65]). Compared to non‐RA controls, prevalent RA‐ILD (n = 757) was more strongly associated with lung cancer risk (aHR 3.25 [95% CI 2.13–4.95]) than RA without ILD (aHR 1.57 [95% CI 1.51–1.64]). Analyses of both prevalent and incident RA‐ILD produced similar results (RA‐ILD vs non‐RA aHR 2.88 [95% CI 2.45–3.40]).
Conclusion
RA was associated with a >50% increased risk of lung cancer, and those with RA‐ILD represented a particularly high‐risk group with an approximate three‐fold increased risk. Increased lung cancer surveillance in RA, and especially RA‐ILD, may be a useful strategy for reducing the burden posed by the leading cause of cancer death.
INTRODUCTION
Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily manifesting as an inflammatory arthritis that can result in extra‐articular manifestations, particularly in the lungs. 1 Interstitial lung disease (ILD) clinically affects approximately 10% of people with RA causing substantial morbidity and mortality. 2 , 3 , 4 People with RA are also more susceptible to the development of airway diseases, such as chronic obstructive pulmonary disease and bronchiectasis. 5 , 6 Beyond these parenchymal and airway diseases, prior meta‐analyses have estimated an approximately 40%–60% increased risk of lung cancer in those with RA. 7 , 8 , 9 Consistent with the general population, lung cancer is the most frequent cause of cancer deaths among people with RA. 10 , 11
The reasons for an increased risk of lung cancer in RA are not well understood. Prior studies have often lacked adjustment for cigarette smoking, a shared risk factor for RA and lung cancer, 7 , 8 although recent studies have observed a higher lung cancer risk in RA despite cigarette smoking history. 12 , 13 Chronic inflammation accompanying RA may contribute to lung cancer risk, with studies among people with RA demonstrating associations between pro‐inflammatory cytokines and lung cancer risk independent of cigarette smoking. 14 , 15 In contrast, a recent Mendelian randomization study did not show a causal link between RA‐related genes and lung cancer risk. 9 However, the single‐nucleotide polymorphisms selected only accounted for 7% of the genetic variation in RA, and these single‐nucleotide polymorphisms are not specific to RA. 9 Moreover, RA genes and cigarette smoking are known to interact, 16 and people with RA experience premature mortality that may be a competing risk to developing lung cancer. In the general population, there is a growing body of evidence supporting the role of inflammation in tumor initiation and progression. 17 Further, inhibiting the pro‐inflammatory cytokine interleukin 1β with canakinumab was associated with a reduced lung cancer risk in the canakinumab antiinflammatory thrombosis outcome study (CANTOS) trial. 18
Recent studies investigating survival in patients with RA with ILD have identified malignancies, specifically lung cancer, as a common cause of death. 4 , 10 Although cigarette smoking is also a shared risk factor for RA‐ILD and lung cancer, these findings raise the possibility that the chronic inflammatory and fibrotic processes occurring within the lungs in RA‐ILD may predispose to the development of lung cancer. Indeed, idiopathic pulmonary fibrosis (IPF), which closely resembles RA‐ILD in a usual interstitial pneumonia pattern, has been identified as an independent risk factor for lung cancer in epidemiologic studies. 19 , 20 To date, there have not been studies that specifically evaluated the risk of incident lung cancer in RA‐ILD.
Understanding whether RA predisposes to the development of lung cancer independent of other risk factors and whether people with RA‐ILD represent a uniquely high‐risk group could inform cancer‐screening strategies. The objective of this study was to determine the risk of lung cancer in those with RA and RA‐ILD compared with the risk in matched non‐RA controls. We hypothesized that people with RA would have a higher risk of lung cancer than matched non‐RA controls and that this risk would be further increased among those with RA‐ILD.
PATIENTS AND METHODS
Study design
We conducted a retrospective matched cohort study of patients with RA and without RA within the Veterans Health Administration (VA) from January 2000 to December 2019. Data were obtained from the VA Corporate Data Warehouse (CDW) and linked external datasets within the VA Informatics and Computing Infrastructure. This study received institutional review board approval.
Patient selection and matching
Patients with RA were identified by applying an administrative‐based algorithm requiring at least two International Classification of Diseases, Ninth (ICD‐9) and Tenth Revision (ICD‐10) codes (ICD‐9: 714.0, 714.1, 714.2, and 714.81; ICD‐10: M05.x and M06.x excluding M06.1 and M06.4) ≥30 days apart, a rheumatologist diagnosis of RA, and either receipt of a disease‐modifying antirheumatic drug (DMARD) or seropositivity (rheumatoid factor [RF] or anti–cyclic citrullinated peptide [anti‐CCP]). DMARD use was identified via the presence of a prescription filled for either conventional synthetic DMARD (csDMARD) or biologic/targeted synthetic DMARD (b/tsDMARD) within pharmacy records. Autoantibody status was determined from laboratory data within the CDW. We excluded individuals with diagnostic codes for psoriatic arthritis (ICD‐9: 696.0 and ICD‐10: L40.5), ankylosing spondylitis (ICD‐9: 720.0 and ICD‐10: M45.x), myositis (ICD‐9: 710.3 and 710.4 and ICD‐10: M33.x), systemic sclerosis (ICD‐9: 517.2 and 710.1 and ICD‐10: M34.x), systemic lupus erythematosus (ICD‐9: 710.0 and ICD‐10: M32.x), inflammatory polyarthropathy (ICD‐10: M06.4), or adult‐onset Still disease (ICD‐10: M06.1) entered by a rheumatologist. Such algorithms have a >90% positive predictive value for RA. 21 Among patients with RA, RA‐ILD was identified by applying a validated administrative‐based ILD algorithm requiring at least two diagnostic ICD‐9/10 codes for ILD and either a pulmonologist diagnosis of ILD or ILD diagnostic testing through computed tomography (CT) scans, pulmonary function tests, or lung biopsy. This algorithm has a >75% positive predictive value for RA‐ILD. 22
Patients with RA were matched with up to 10 randomly selected individuals without RA diagnostic codes on year of birth, gender, and VA enrollment year (non‐RA). The cohort entry date (ie, beginning of follow‐up) was the date patients with RA (or RA‐ILD) fulfilled RA (or RA‐ILD) algorithm requirements. Non‐RA controls were assigned the same calendar date for the cohort entry date as the matched patient with RA. RA‐ILD was considered prevalent if the ILD algorithm was fulfilled at or before the RA algorithm and incident if fulfilled following the RA algorithm. We excluded patients with and without RA with a history of lung cancer before the cohort entry date based on records in VA oncology databases or the presence of diagnostic codes for lung cancer (ICD‐9: 162.xx and ICD‐10: C33.xx–C34.xx) from inpatient or outpatient encounters. In sensitivity analyses, we excluded non‐RA controls with diagnostic codes for IPF. 23
Study outcome
The primary outcome in this study was incident lung cancer, determined from the VA Oncology Raw Domain and the National Death Index (NDI). The VA Oncology Raw Domain is a cancer registry by the VA and includes detailed characteristics of cancers. Approximately 90% of cancer diagnoses are estimated to be captured in VA cancer registries. 24 From this database, the date of lung cancer diagnosis, histologic subtype, grade, primary site, location of metastasis, and Surveillance, Epidemiology, and End Result (SEER) stage were collected. The histologic subtype was categorized as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, or other. Lung cancers with histologic subtypes that suggested alternative primary cancer sites were censored. Additional lung cancers and lung cancer deaths were obtained from the NDI based on the presence of ICD‐10 codes (C33.xx–C34.xx).
Study covariates and descriptive variables
Demographic and health behavior data were obtained from the VA CDW and included age, gender, race, ethnicity, and Agent Orange exposure. Smoking status (current, former, and never categories) was obtained from “health factors,” clinical reminders recorded in the electronic medical record that have demonstrated substantial agreement with survey data. 25 The Rheumatic Disease Comorbidity Index (RDCI) score (without lung disease for RA‐ILD analyses) was calculated from diagnostic codes for included comorbidities within the VA CDW before cohort entry. 26 Performance of chest CT scans in the 12 months before cohort entry was collected, and a history of malignancy (nonlung cancer) before cohort entry was collected from the VA Oncology Raw Domain. RA treatments during the 12 months before cohort entry were obtained from pharmacy dispensing data within the CDW and included prednisone, methotrexate, other csDMARDs (leflunomide, sulfasalazine, hydroxychloroquine, or azathioprine), and b/tsDMARDs (tumor necrosis factor inhibitors [TNFis], abatacept, tocilizumab, sarilumab, rituximab, and JAK inhibitors).
RA‐related factors were obtained from the VA CDW and included serostatus and elevated markers of inflammation. Serostatus was determined by having either an elevated anti‐CCP antibody or RF. Elevated markers of inflammation were defined as erythrocyte sedimentation rate (ESR) ≥20 mm/hour or C‐reactive protein (CRP) >1.0 mg/dL, respectively.
Statistical analysis
Participants were observed from cohort entry until incident lung cancer, death, end of study period (December 31, 2019), or 365 days without VA care. Crude rates for the development of lung cancer were calculated for RA overall, prevalent RA‐ILD, and non‐RA. We then compared the risk of lung cancer between RA and non‐RA matched sets by constructing conditional Cox regression models first accounting only for matched factors and then adjusting for prehypothesized baseline confounders including race, ethnicity, smoking status, Agent Orange exposure, and RDCI score.
Sensitivity analyses were performed restricting the study population to (1) individuals who were never smokers and (2) incident patients with RA and their matched non‐RA controls. Incident RA was defined as 365 days of enrollment in the VA without an RA diagnosis by a provider or prescription of RA medication. 27 Furthermore, sensitivity analyses were performed comparing the incidence of lung cancer within the VA Oncology Raw domain and the NDI independently. Secondary analyses were performed that stratified patients with RA by (1) RF/anti‐CCP seropositivity and (2) high versus normal markers of inflammation. Lung cancer mortality in RA versus non‐RA was evaluated using similar models as the primary analyses.
We subsequently evaluated lung cancer risk in RA‐ILD by performing stratified analyses by prevalent RA‐ILD status at the cohort entry date. Because ILD could also occur during follow‐up, in a separate model we compared the incidence of lung cancer in RA‐ILD versus non‐RA including both prevalent and incident RA‐ILD. In this analysis, the cohort entry date for both RA‐ILD and matched patients without RA was the calendar date when the RA‐ILD algorithm was fulfilled, and individuals (RA‐ILD and non‐RA) who either died or developed lung cancer before this cohort entry date were excluded.
The proportional hazards assumptions were assessed through log‐log plots and testing of Schoenfeld residuals. A potential violation by RA status was identified from Schoenfeld residuals and log‐log plots. However, on further investigation, the violation was restricted to <15 days early in the follow‐up period when minimal failure events had occurred. No further violations were appreciated; therefore, Cox models were considered appropriate for analyses. Missing covariates were modeled using the missing indicator method. All analyses were completed in Stata v17 (StataCorp).
RESULTS
Baseline patient characteristics
We identified 72,795 patients with RA and matched them with 633,937 patients without RA. Our RA cohort was predominantly male (87.6%) and White (81.8%) and had a mean (SD) age of 63.0 (11.9) years (Table 1). Of the patients with RA, 84.7% had a smoking history at baseline, 15.3% had Agent Orange exposure, and 68.8% were seropositive. Methotrexate and b/tsDMARDs were used by 37.5% and 19.2% (TNFi by 16.9%), respectively. Few patients had a chest CT scan before cohort entry (8.6%).
Table 1.
Baseline characteristics of patients with RA and RA‐ILD and of patients without RA*
| RA vs non‐RA | RA‐ILD vs non‐RA | |||
|---|---|---|---|---|
| RA (n = 72,795) | Non‐RA (n = 633,937) | RA‐ILD (n = 757) a | Non‐RA (n = 5,931) | |
| Demographics and health indicators | ||||
| Age, mean (SD), y | 63.0 (11.9) | 61.9 (11.7) | 67.4 (10.2) | 65.8 (10.0) |
| Male gender, % | 87.6 | 86.7 | 89.3 | 87.6 |
| White/Caucasian race, % | 81.8 | 76.4 | 79.3 | 79.2 |
| Non‐Hispanic ethnicity, % | 94.8 | 95.5 | 93.6 | 95.9 |
| Smoking status, % | ||||
| Current smoker | 49.9 | 46.6 | 51.7 | 46.4 |
| Former smoker | 34.8 | 31.8 | 36.5 | 32.9 |
| Never smoker | 15.3 | 21.6 | 11.9 | 20.7 |
| Agent Orange exposure, % | 15.3 | 12.6 | 19.6 | 14.5 |
| RDCI score, mean (SD) | 1.7 (1.6) | 1.2 (1.4) | – | – |
| RDCI score (no lung disease), mean (SD) | – | – | 2.2 (1.4) | 1.4 (1.3) |
| Chest CT before cohort entry date, % | 8.6 | 2.5 | 63.9 | 4.0 |
| Cancer (other site) history, % | 4.9 | 3.6 | 8.4 | 5.1 |
| RA‐related factors | ||||
| Anti‐CCP or RF seropositive, % | 68.8 | – | 80.1 | – |
| Elevated ESR, % | 51.8 | – | 69.6 | – |
| Elevated CRP, % | 41.5 | – | 52.7 | – |
| Nonmethotrexate csDMARDs, % | 35.1 | – | 52.0 | – |
| Methotrexate, % | 37.5 | – | 18.0 | – |
| b/tsDMARDs, % | 19.2 | – | 23.5 | – |
| Prednisone, % | 42.5 | – | 67.5 | – |
Missingness: race, (n = 8,428 in RA, n = 127,853 in non‐RA, n = 77 in RA‐ILD, and n = 1,069 in non‐RA); ethnicity, (n = 6,943 in RA, n = 111,048 in non‐RA, n = 57 in RA‐ILD, and n = 869 in non‐RA); smoking status, (n = 3,366 in RA, n = 87,510 in non‐RA; n = 41 in RA‐ILD, and n = 687 in non‐RA); seropositivity (n = 11,632 in RA and n = 73 in RA‐ILD); ESR (n = 12,994 in RA and n = 49 in RA‐ILD); and CRP (n = 32,163 in RA and n = 154 in RA‐ILD). Anti‐CCP, anticyclic citrullinated peptide antibody; b/tsDMARD, biologic or targeted synthetic disease‐modifying antirheumatic drug; CRP, C‐reactive protein; csDMARD, conventional synthetic disease‐modifying antirheumatic drug; CT, computerized tomography; DMARD, disease‐modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; ILD, interstitial lung disease; RA, rheumatoid arthritis; RDCI, Rheumatic Disease Comorbidity Index; RF, rheumatoid factor.
Prevalent RA‐ILD at the cohort entry date.
Among these patients with RA, 757 had prevalent RA‐ILD and they were matched to 5,931 patients without RA. The mean (SD) age was older in the RA‐ILD cohort (67.4 [10.2] years) and there was a higher comorbidity burden (mean [SD] RDCI score 2.2 [1.4]), even with exclusion of lung disease from the RDCI score (Table 1). The majority of the RA‐ILD cohort had a smoking history (88.2%) and were seropositive (80.1%). The most commonly used DMARDs were nonmethotrexate csDMARDs (52.0%) and b/tsDMARDs (23.5%; TNFi 17.0%). Patients with RA‐ILD frequently had a chest CT scan before cohort entry date (63.9%).
Incidence of lung cancer in RA
Over 4,481,323 patient‐years (mean follow‐up 6.3 years), 17,099 incident lung cancers occurred (n = 2,974 in RA; n = 14,125 in non‐RA). A higher proportion of patients with lung cancer were identified through the VA Oncology Raw Domain in RA (62.9%) than in non‐RA (51.6%). Lung cancers among patients with RA were most commonly squamous cell carcinoma (35.9%) compared with adenocarcinoma in non‐RA (33.9%) (Table 2). SEER stage, grade of differentiation, and metastatic disease were similar between RA and non‐RA. Patients with RA had a higher rate of incident lung cancer than those without RA (adjusted hazard ratio [aHR] 58.4 [95% confidence interval (CI) 56.4–60.6] vs 35.6 [35.0–36.1] per 10,000 patient‐years). After adjusting for potential confounders, RA was associated with an increased risk of lung cancer (aHR 1.58 [95% CI 1.52–1.64]) (Figure 1A; Table 3). The association persisted when analyses were restricted to never smokers (aHR 1.65 [95% CI 1.22–2.24]) and incident RA cases (aHR 1.54 [95% CI 1.44–1.65]) and when controls with codes for IPF were excluded (aHR 1.61 [95% CI 1.55–1.68]). In subgroup analyses, seropositive patients with RA had an increased risk of lung cancer compared with those without RA (aHR 1.65 [95% CI 1.57–1.74]), but no increased lung cancer risk was observed among the seronegative patients (aHR 0.95 [95% CI 0.86–1.05]). Furthermore, patients with RA with an elevated ESR or CRP at baseline had a higher risk of lung cancer (aHR 1.74 [95% CI 1.65–1.84]) compared with non‐RA controls than patients with RA with a normal ESR or CRP (aHR 1.29 [95% CI 1.19–1.39]) versus non‐RA.
Table 2.
Lung cancer characteristics in patients with RA and RA‐ILD and in patients without RA*
| RA vs non‐RA, n (%) | RA‐ILD vs non‐RA, n (%) | |||
|---|---|---|---|---|
| RA | Non‐RA | RA‐ILD a | Non‐RA | |
| Total lung cancers, N | 2,974 | 14,125 | 34 | 96 |
| Source | ||||
| VA Oncology Raw Domain | 1,871 (62.9) | 7,292 (51.6) | 21 (61.8) | 49 (51.0) |
| NDI | 1,103 (37.1) | 6,833 (48.4) | 13 (38.2) | 47 (49.0) |
| Lung cancer characteristics for those identified in VA Oncology Database | ||||
| Histology | ||||
| Adenocarcinoma | 565 (30.2) | 2,475 (33.9) | 6 (29.0) | 21 (43.0) |
| Large cell carcinoma | 34 (1.8) | 126 (1.7) | 0 (0.0) | 0 (0.0) |
| Small cell carcinoma | 225 (12.0) | 884 (12.1) | 5 (24.0) | 3 (6.0) |
| Squamous cell carcinoma | 671 (35.9) | 2,103 (28.8) | 6 (29.0) | 14 (29.0) |
| Other | 369 (19.7) | 1,680 (23.0) | 4 (19.0) | 11 (22.0) |
| Unknown | 7 (0.4) | 24 (0.3) | 0 (0) | 0 (0.0) |
| SEER staging | ||||
| In situ | 5 (0.1) | 5 (0.1) | 0 (0) | 0 (0.0) |
| Localized | 475 (25.4) | 1,593 (21.8) | 2 (10.0) | 10 (20.0) |
| Regional | 476 (25.4) | 1,891 (25.9) | 3 (14.0) | 13 (27.0) |
| Distant | 611 (32.7) | 2,525 (34.6) | 8 (38.0) | 15 (31.0) |
| Unknown | 307 (16.4) | 1,278 (17.5) | 8 (38.0) | 11 (22.0) |
| Graded differentiation | ||||
| Grade I | 58 (3.1) | 200 (2.7) | 0 (0.0) | 1 (2.0) |
| Grade II | 310 (16.6) | 991 (13.6) | 1 (5.0) | 6 (12.0) |
| Grade III | 363 (19.4) | 1,474 (20.2) | 2 (10.0) | 10 (20.0) |
| Grade IV | 36 (1.9) | 160 (2.2) | 0 (0.0) | 0 (0.0) |
| Unknown | 1,104 (59.0) | 4,467 (61.3) | 18 (86.0) | 32 (65) |
| Primary site | ||||
| Lower lobe | 464 (24.8) | 1,819 (24.9) | 3 (14.0) | 13 (27.0) |
| Middle lobe | 89 (4.8) | 307 (4.2) | 0 (0.0) | 0 (0.0) |
| Upper lobe | 1,052 (56.2) | 3,989 (54.7) | 10 (48.0) | 29 (59.0) |
| Main bronchus | 41 (2.2) | 235 (3.2) | 0 (0.0) | 3 (6.0) |
| Overlap | 26 (1.4) | 89 (1.2) | 0 (0.0) | 0 (0.0) |
| NOS | 199 (10.6) | 853 (11.7) | 8 (33.0) | 4 (8.0) |
| Metastasis site | ||||
| Bone | 147 (7.9) | 547 (7.5) | 1 (2.0) | 1 (2.0) |
| CNS | 55 (2.9) | 302 (4.1) | 0 (0.0) | 3 (6.0) |
| Distant lymph nodes | 32 (1.7) | 146 (2.0) | 1 (5.0) | 1 (2.0) |
| Liver | 124 (6.6) | 455 (6.2) | 2 (10.0) | 3 (6.0) |
| Lung | 125 (6.7) | 502 (6.9) | 3 (14.0) | 4 (8.0) |
| Peritoneum | 0 (0.0) | 17 (0.2) | 0 (0.0) | 0 (0.0) |
| Pleura | 28 (1.5) | 129 (1.8) | 1 (5.0) | 0 (0.0) |
| Skin | 1 (0.1) | 12 (0.2) | 0 (0.0) | 0 (0.0) |
| Other | 50 (2.7) | 252 (3.5) | 0 (0.0) | 1 (2.0) |
| None | 1,011 (54.0) | 3,777 (51.8) | 5 (24.0) | 26 (53) |
| Missing | 298 (15.9) | 1,153 (15.8) | 8 (23.5) | 10 (10.4) |
CNS, central nervous system; ILD, interstitial lung disease; NDI, National Death Index; NOS, not otherwise specified; RA, rheumatoid arthritis; SEER, Surveillance, Epidemiology, and End Result; VA, Veterans Health Administration.
Prevalent RA‐ILD at the index date.
Figure 1.
Cumulative hazard of lung cancer in RA and RA‐ILD versus matched non‐RA controls. Cumulative hazard of incident lung cancer in (A) RA versus matched non‐RA controls and (B) RA‐ILD versus matched non‐RA controls. Non‐RA comparators were matched on age, gender, and Veterans Health Administration enrollment year. All models were adjusted for race, ethnicity, smoking status, Agent Orange exposure, and Rheumatic Disease Comorbidity Index (lung disease was not included in the Rheumatic Disease Comorbidity Index score in RA‐ILD analyses). aHR, adjusted hazard ratio; ILD, interstitial lung disease; RA, rheumatoid arthritis.
Table 3.
Associations of RA with lung cancer risk*
| n | IR/10,000 PY (95% CI) | HR (95% CI) | aHR (95% CI) a | |
|---|---|---|---|---|
| Primary results | ||||
| RA | 72,795 | 58.4 (56.4–60.6) | 1.63 (1.57–1.70) | 1.58 (1.52–1.64) |
| Non‐RA | 633,937 | 35.6 (35.0–36.1) | Ref | Ref |
| Restricted to never smokers | ||||
| RA | 10,635 | 14.3 (11.7–17.4) | 1.78 (1.33–2.40) | 1.65 (1.22–2.24) |
| Non‐RA | 21,137 | 7.8 (6.3–9.7) | Ref | Ref |
| Restricted to incident RA | ||||
| RA | 32,227 | 58.9 (55.5–62.4) | 1.78 (1.67–1.90) | 1.54 (1.44–1.65) |
| Non‐RA | 261,762 | 32.8 (31.9–33.8) | Ref | Ref |
aHR, adjusted hazard ratio; CI, confidence interval; HR, hazard ratio; IR, incidence rate; PY, patient‐years; RA, rheumatoid arthritis; Ref, reference.
In addition to matching on age, gender, and Veterans Health Administration enrollment year, the models were adjusted for race, ethnicity, smoking status, Agent Orange exposure, and Rheumatic Disease Comorbidity Index score.
A total of 13,288 lung cancer deaths occurred over 4,500,671 patient‐years of follow‐up. Lung cancer mortality rates were higher in those with RA (43.6 per 10,000 patient‐years) than in non‐RA controls (27.7 per 10,000 patient‐years). After adjustment, there was a >50% increase in lung cancer–related mortality among patients with RA (aHR 1.58 [95% CI 1.51–1.66]) (Figure 2A). The mean (SD) survival time following lung cancer diagnosis was similar between those with RA (7.0 [5.1] years) and those without RA (6.3 [5.2] years).
Figure 2.
Cumulative hazard of lung cancer death in RA and RA‐ILD versus matched non‐RA controls. Cumulative hazard of lung cancer death in (A) RA versus matched non‐RA controls and (B) RA‐ILD versus matched non‐RA controls. Non‐RA comparators were matched on age, gender, and Veterans Health Administration enrollment year. All models were adjusted for race, ethnicity, smoking status, Agent Orange exposure, and Rheumatic Disease Comorbidity Index (lung disease was not included in the Rheumatic Disease Comorbidity Index score in RA‐ILD analyses). aHR, adjusted hazard ratio; ILD, interstitial lung disease; RA, rheumatoid arthritis. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42961/abstract.
Incidence of lung cancer in RA‐ILD
Among individuals with prevalent RA‐ILD, 130 incident lung cancers occurred over 33,268 patient‐years (mean follow‐up 5.0 years). As for RA, a higher proportion of the identified lung cancers were identified through the VA Oncology Raw Domain in RA‐ILD (61.8%) compared with non‐RA (51.0%). Lung cancers among those with RA‐ILD were most commonly squamous cell carcinoma (29.0%) or adenocarcinoma (29.0%) compared with the lung cancers in the non‐RA cohort, which were most commonly adenocarcinomas (43.0%). The SEER stage and grade of differentiation were similar between those with RA‐ILD and those without RA (Table 2).
Patients with prevalent RA‐ILD had a higher rate of incident lung cancer than non‐RA controls (aHR 109.3 [95% CI 78.1–153.0] vs aHR 31.8 [95% CI 26.1–38.9] per 10,000 patient‐years). When adjusted for potential confounders, the risk of lung cancer in prevalent RA‐ILD was more than three times higher than for non‐RA controls (aHR 3.25 [95% CI 2.13–4.95]) (Table 4). This was substantially higher than for patients with RA without ILD at baseline than for non‐RA controls (aHR 1.57 [95% CI 1.51–1.64] vs non‐RA). Analyses of patients with prevalent and incident RA‐ILD showed a similar increased lung cancer risk for RA‐ILD versus non‐RA (aHR 2.88 [95% CI 2.45–3.40]) (Figure 1B). Stratification by seropositivity or elevated ESR/CRP did not meaningfully alter these estimates (data not shown) and excluding controls with ILD produced similar findings (aHR 2.99 [95% CI 2.53–3.53]).
Table 4.
Associations of RA‐ILD with lung cancer risk*
| n | IR/10,000 PY (95% CI) | HR (95% CI) | aHR (95% CI) a | |
|---|---|---|---|---|
| Analyses stratified by prevalent RA‐ILD status | ||||
| RA‐ILD | 757 | 109.3 (78.1–153.0) | 3.43 (2.32–5.06) | 3.25 (2.13–4.95) |
| Non‐RA | 5,931 | 31.8 (26.1–38.9) | Ref | Ref |
| RA‐no ILD | 72,038 | 58.1 (56.1–60.3) | 1.62 (1.56–1.69) | 1.57 (1.51–1.64) |
| Non‐RA | 628,006 | 35.6 (35.0–36.2) | Ref | Ref |
| Prevalent and incident RA‐ILD | ||||
| RA‐ILD | 4,206 | 127.2 (110.7–146.2) | 3.17 (2.71–3.71) | 2.88 (2.45–3.40) |
| Non‐RA | 32,045 | 41.0 (37.9–44.3) | Ref | Ref |
aHR, adjusted hazard ratio; CI, confidence interval; HR, hazard ratio; ILD, interstitial lung disease; IR, incidence rate; PY, patient‐years; RA, rheumatoid arthritis; Ref, reference.
In addition to matching on age, gender, and Veterans Health Administration enrollment year, the models were adjusted for race, ethnicity, smoking status, Agent Orange exposure, and Rheumatic Disease Comorbidity Index score (lung disease was not included in the Rheumatic Disease Comorbidity Index score in RA‐ILD analyses).
Lung cancer deaths occurred in 100 patients over 33,409 patient‐years of follow‐up. Lung cancer mortality rates were higher in prevalent RA‐ILD than non‐RA (82.7 vs 24.5 per 10,000 patient‐years). There was a greater than three‐fold increase in lung cancer mortality in patients with prevalent RA‐ILD compared with those without RA (aHR 3.46 [95% CI 2.17–5.52]) in multivariable analyses. The mean (SD) survival time following lung cancer diagnosis was 4.2 (3.4) years in prevalent RA‐ILD compared with 5.1 (4.3) years in non‐RA. The increased lung cancer mortality risk persisted in analyses of prevalent and incident RA‐ILD (aHR 3.17 [95% CI 2.62–3.82]) (Figure 2B).
DISCUSSION
ILD is a common extra‐articular manifestation in RA that is recognized to dramatically impact survival. 1 Whether a portion of the heightened mortality in RA‐ILD may be related to the development of lung cancer is poorly understood. In this study, we aimed to determine the incidence of lung cancer in RA and RA‐ILD. By using national VA data and linkage to cancer databases and death records, we found that individuals with RA and RA‐ILD experienced an increased risk of lung cancer. The risk of lung cancer was >50% higher in patients with RA and, notably, 2.5‐ to three‐fold higher for patients with RA‐ILD when compared with non‐RA controls. Our results highlight those with RA and RA‐ILD as high‐risk populations that may benefit from enhanced lung cancer screening.
Consistent with previous epidemiologic studies, patients with RA in our study had a >50% increased risk of incident lung cancer. 7 , 8 Although some prior studies were limited by their inability to account for smoking status, 7 , 8 , 28 our estimates are in agreement with others that accounted for higher prevalence of current or former smoking history in RA. 12 , 13 Furthermore, analyses restricted to never smokers produced similar risk estimates. Together, this suggests that the shared risk factor of cigarette smoking does not fully explain the heightened lung cancer risk in RA. Supporting that RA‐related factors may drive lung cancer risk, 29 patients with RA who were seropositive and had elevated inflammatory measures at baseline had a greater risk of incident lung cancer in stratified analyses. This builds on prior findings of pro‐inflammatory serum cytokines/chemokines being associated with cancer incidence and mortality, particularly lung cancers, in RA 14 , 15 as well as lower lung cancer risk with interleukin 1β inhibition in the CANTOS trial. 18 Chatzidionysiou et al also recently found seropositivity to be associated with lung cancer risk. 12 RA disease activity measures were not available, and future studies should investigate disease activity and lung cancer risk. Squamous cell carcinoma was the most common lung cancer histology in RA compared with adenocarcinoma in non‐RA, a difference that may be explained by differences in smoking history given the association between squamous cell carcinoma and smoking. 30
We tested and confirmed our hypothesis that RA‐ILD accentuates the risk of lung cancer in RA. Patients with prevalent or incident RA‐ILD were at 2.5‐ to three‐fold higher risk of developing lung cancer. Although this was independent of smoking status, we were insufficiently powered to perform analyses restricted to never smokers to remove any residual confounding related to smoking duration or intensity. Cho et al also found patients with RA‐ILD to have a higher incidence rate of lung cancer (8.89 per 1,000 person‐years) than RA alone (1.86 per 1,000 person‐years) or non‐RA controls (1.25 per 1,000 person‐years). 13 The mechanisms for the increased risk of RA‐ILD–associated lung cancer will need to be elucidated in future translational studies. Injury and activation of inflammatory and fibrotic processes within the lungs of people with RA‐ILD are possible mechanisms, as hypothesized in IPF, a disease that closely resembles RA‐ILD. 19 , 31 Importantly, in stratified analyses, patients with RA without ILD still had a higher risk of lung cancer, although the estimate was attenuated. Additionally, given the reliance on administrative algorithms for identifying patients with RA‐ILD, our estimates are most pertinent for clinical RA‐ILD rather than subclinical RA‐ILD. Future studies are needed to explore whether ILD severity is related to lung cancer risk, with ILD‐related death being a potential competing event. It is possible that surveillance bias caused by more frequent chest imaging being performed in patients with RA‐ILD contributed to our findings. However, the higher lung cancer mortality risk and the similar survival after lung cancer diagnosis observed between RA‐ILD and non‐RA controls argues against this. Whether increased lung cancer surveillance and early intervention in RA‐ILD could help address a persistent mortality gap in this population will require future study. 32
The current recommendations for lung cancer screening by the United States Preventive Services Task Force (USPSTF) use the patient's age and smoking pack‐years to guide the recommendation for annual low‐dose chest CT scans. Lung cancer screening is recommended in all adults between the ages of 50 and 80 years old who have a 20 pack‐year smoking history and currently smoke or have quit smoking within the past 15 years. 33 Discontinuation of lung cancer screening is recommended when the patient has a health problem that substantially increases their mortality or if the patient is unable to have curative lung surgery or has abstained from smoking for >15 years. Importantly, the USPSTF recognizes many risk factors for the development of lung cancer, including race, gender, education level, environmental exposures, prior radiation therapy, other lung diseases, and family history. 33 , 34 However, because of insufficient evidence on the mortality and morbidity benefits of incorporating these risk factors in screening guidelines, the USPSTF does not recommend incorporating these into models for the risk stratification of patients. The results of our study suggest that RA, and particularly RA‐ILD, may warrant incorporation in prediction models to determine eligibility for lung cancer screening. Providers should recognize that many people with RA‐ILD will already fulfill USPSTF criteria for annual low‐dose chest CT scans.
Limitations to the study include the predominantly male population, which could impact generalizability. However, men more frequently develop extra‐articular manifestations of RA, including RA‐ILD. 35 Although we incorporated smoking status into our analyses, measures of cigarette smoking duration and intensity were not available. Smoking duration and intensity, often evaluated as pack‐years, are more closely associated with lung cancer risk. 36 To address resulting residual confounding, we performed analyses of patients with RA and without RA restricted to never smokers. Because of the insufficient sample sizes, the restriction to never smokers was unable to be completed in RA‐ILD versus non‐RA comparisons. Because of missing data on the characteristics of lung cancer for cases obtained from the NDI, definitive conclusions regarding lung cancer characteristics (eg, histology and stage) could not be established. Detection bias caused by patients with RA preferentially remaining within the VA health care system was considered. In addition to censoring patients if they discontinued VA care, we also performed analyses of lung cancer mortality using only NDI data. These analyses produced similar RA‐ and RA‐ILD–related risks as the primary analyses. Although the recent oral rheumatoid arthritis trial Surveillance trial highlights the potential differences in cancer risk between different DMARDs, 37 alternative pharmacoepidemiologic study designs will be required to evaluate the effects of DMARDs (and antifibrotic agents) on the development of lung cancer in those with RA and RA‐ILD. Because RA and RA‐ILD classification was based on administrative data, there may be misclassification that would likely bias findings toward the null. ILD‐related factors (eg, ILD pattern, ILD severity, and indications for chest imaging), lung cancer treatments, socioeconomic status, and pollutant measures were not available, and there were missing covariate data for some patients.
In summary, both RA and RA‐ILD were associated with an increased risk of lung cancer independent of other lung cancer risk factors. Smoking status, a shared risk factor for RA/RA‐ILD and lung cancer, did not fully explain the heightened risk of lung cancer observed in RA/RA‐ILD. Because patients with RA and RA‐ILD represent high‐risk populations for developing lung cancer, enhanced screening may be warranted to achieve earlier diagnoses and reduce mortality in RA‐ and RA‐ILD–associated lung cancer.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr England confirms that all authors have provided the final approval of the version to be published, and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Helsinki Declaration requirements.
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ACKNOWLEDGMENTS
This work was supported by the Center of Excellence for Suicide Prevention, Joint Department of Veterans Affairs and Department of Defense Mortality Data Repository – National Death Index.
The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the US Department of Veterans Affairs (VA) or the United States government.
Dr Johnson's work was supported by the Rheumatology Research Foundation. Dr Ganti's work was supported by the VA Biomedical Laboratory Research and Development (BLRD) (grant I01‐BX‐004676) and the VA Lung Precision Oncology Program (grant I50‐CU‐000163‐01). Dr Singh's work was supported by the Rheumatology Research Foundation and the American Heart Association. Dr Baker's work was supported by the VA Clinical Science Research and Development (CSRD) (grant I01‐CX‐001703). Dr Mikuls’ work was supported by the VA BLRD (grants I01‐BX‐004660 and I01‐BX‐003635), the Department of Defense (grant PR200793), the Rheumatology Research Foundation, and the National Institute of General Medical Sciences (grant U54‐GM‐115458). Dr England's work was supported by the VA CSRD (grant IK2‐CX‐002203), the Rheumatology Research Foundation, and the National Institute of General Medical Sciences (grant U54‐GM‐115458) which funds the Great Plains IDeA‐CTR Network.
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/art.42961.
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