Patients with systemic rheumatic diseases, particularly rheumatoid arthritis (RA), systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myopathies, are at increased risk of developing malignancies. This risk is related to the pathobiology of the underlying rheumatic diseases including the inflammatory burden, immunological defects, and personal and environmental exposure such as smoking and some viral infections [
A number of studies have shown RA and RA diseases activity as pathogenic factors in the development of lymphoma [
This retrospective, population-based study was conducted using the resources of the Rochester Epidemiology Project, a medical records linkage system that allows ready access to the complete (inpatient and outpatient) medical records from all community medical providers [
For both the RA and comparator cohorts, cancer diagnoses were retrieved from the Mayo Clinic Cancer Registry (all malignancies except NMSC) and NMSC were abstracted from the medical charts using a standardized abstraction form. Cancer diagnoses from both before and after RA diagnosis were collected. Cancer categories included head/neck, gastric, pancreatic, liver, colon/rectal, other digestive, lung, other thorax, bone, soft tissue, skin (subdivided into melanoma and NMSC), breast, ductal carcinoma in situ, ovarian, other gynecologic, prostate, kidney, bladder, other genitourinary, ophthalmic, central nervous system, lymphoma, leukemia, multiple myeloma, myeloproliferative syndrome, myelodysplastic syndrome, and other.
The information on RA characteristics included RF status, erythrocyte sedimentation rate (ESR) at RA incidence, large joint swelling, joint erosions/destructive changes on radiographs, joint surgeries (i.e., arthroplasty and synovectomy), and extra-articular manifestations of RA (ExRA). ExRA were classified according to the criteria used in our previous studies [
Descriptive statistics were used to summarize data of the RA and comparator groups. The cumulative incidence of malignancy adjusted for the competing risk of death was estimated for both cohorts. This method, although similar to the Kaplan-Meier method, better accounts for patients who die before experiencing malignancy. Patients and comparator subjects with previous malignancy were excluded from analysis. These analyses were completed both as an overall estimate and by cancer type. Cox proportional hazard models were used to examine the differences between cohorts, as well as the association between patient characteristics (age, time since RA diagnosis, etc.) and the rate of development of malignancy within the RA cohort, and to assess trends in malignancy over time. Time-dependent covariates were used to model risk factors that develop over time. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria).
There were 813 incident cases of RA identified. The mean age of diagnosis was 55.9 (SD: 15.7) years with 42 (68.4%) females. The mean length of follow-up after diagnosis was 14.1 (SD: 7.7) years. The majority of the patients in this study were Caucasian, 93.6% in the RA group and 94.8 in the non-RA group. In the non-RA comparator cohort the number of patients and mean age at index date were the same as for the RA cohort. The mean length of follow-up in the non-RA cohort was 14.9 (SD: 8.1) years. There were 21.9% and 17.7% current smokers in the RA and non-RA cohort, respectively. Prior to RA incidence/index date, 52 patients with RA and 66 non-RA subjects had malignancies excluding NMSC (
A total of 143 patients with malignancies excluding NMSC were detected in the RA cohort, compared with 118 patients experiencing malignancies in the general population comparator cohort. The hazard ratio (HR) of any malignancy excluding NMSC was 1.32 (95% confidence interval
Cumulative incidence rates of malignancy in 813 patients with rheumatoid arthritis in 1980–2007 compared to 813 subjects without rheumatoid arthritis.
Malignancy site/type |
Number of events after incidence/index in RA/non-RA | Cumulative incidence at 10 years for RA patients (± SE) | Cumulative incidence at 10 years for non-RA subjects (± SE) | Hazard ratio |
---|---|---|---|---|
Any malignancy excluding NMSC | 143/118 | 11.8 ± 1.2 | 9.3 ± 1.1 | 1.32 (1.03, 1.68) |
Any malignancy including NMSC | 194/179 | 15.6 ± 1.4 | 14.3 ± 1.4 | 1.13 (0.92, 1.38) |
Any solid malignancy | 116/113 | 10.3 ± 1.1 | 8.8 ± 1.1 | 1.11 (0.85, 1.44) |
Hematologic | 28/9 | 1.5 ± 0.4 | 0.6 ± 0.3 | 3.58 (1.69, 7.60) |
Head/neck | 11/9 | 0.9 ± 0.3 | 0.9 ± 0.3 | 1.41 (0.58, 3.42) |
Colon/rectal | 9/9 | 0.8 ± 0.3 | 0.8 ± 0.3 | 1.08 (0.43, 2.72) |
Lung | 29/17 | 2.1 ± 0.5 | 1.1 ± 0.4 | 1.97 (1.08, 3.59) |
Breast (among females) | 24/29 | 1.8 ± 0.6 | 3.5 ± 0.8 | 0.95 (0.55, 1.63) |
Bladder | 4/10 | 0.4 ± 0.2 | 0.6 ± 0.3 | 0.46 (0.14, 1.49) |
Melanoma | 11/13 | 1.2 ± 0.4 | 0.8 ± 0.3 | 0.90 (0.40, 2.00) |
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NMSC | 86/109 | 6.3 ± 0.9 | 7.5 ± 1.0 | 0.83 (0.63, 1.10) |
Basal cell carcinoma | 57/75 | 3.3 ± 0.7 | 5.0 ± 0.7 | 0.81 (0.57, 1.14) |
Squamous cell carcinoma | 56/69 | 4.2 ± 0.7 | 4.3 ± 0.7 | 0.90 (0.63, 1.29) |
NMSC = nonmelanoma skin cancer; RA = rheumatoid arthritis; SE = standard error; CI = confidence interval.
Cumulative incidence of any malignancy excluding nonmelanotic skin cancers among Olmsted County, Minnesota, residents with rheumatoid arthritis (solid line) compared to those without rheumatoid arthritis (dashed line).
The incidence of hematologic cancers in patients with RA was increased compared to the general population (HR 3.58; 95% CI: 1.69, 7.60). Of solid malignancies, lung cancer was diagnosed in 29 patients in the RA cohort; the incidence was increased compared to the non-RA cohort with HR 1.97 (95% CI: 1.08, 3.59).
Characteristics associated with a high risk of any malignancy included smoking (HR: 1.60; CI: 1.09, 2.34) and erosions/destructive joint changes (HR: 1.47; 95% CI: 1.04, 2.09; Table
Risk factors for malignancy in 813 patients with rheumatoid arthritis (RA) at RA incidence and during follow-up.
Characteristic | Value |
Hazard ratio |
Hazard ratio |
Hazard ratio |
---|---|---|---|---|
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Age, mean (± SD) | 55.9 (± 15.7) | 1.64 |
1.98 |
1.91 |
Female sex | 556 (68.4%) | 0.70 (0.50, 0.99) | 0.89 (0.39, 2.01) | 0.61 (0.28, 1.30) |
Calendar year of RA incidence, mean (± SD) | 1995.6 (± 7.9) | 1.06 |
1.64 |
1.06 |
ESR at index, mean (± SD) | 24.8 (± 20.5) | 0.99 |
0.89 |
1.05 |
Highest ESR in 1st year, mean (± SD) | 32.7 (± 25.7) | 1.00 |
0.93 |
1.03 |
Rheumatoid factor positive | 539 (66%) | 0.91 (0.64, 1.30) | 0.79 (0.35, 1.77) | 3.59 (1.23, 10.48) |
Current smoker | 178 (22%) | 1.60 (1.09, 2.34) | 0.38 (0.09, 1.63) | 22.40 (8.48, 59.21) |
Former smoker | 271 (33%) | 0.91 (0.63, 1.31) | 1.60 (0.72, 3.56) | 0.42 (0.17, 1.06) |
Body mass index, kg/m2 | 27.7 (± 5.9) | 1.00 (0.97, 1.03) | 0.95 (0.88, 1.04) | 0.95 (0.87, 1.03) |
Obesity (body mass index ≥ 30 kg/m2) | 244 (30.0%) | 0.75 (0.50, 1.13) | 0.81 (0.32, 2.05) | 0.77 (0.31, 1.92) |
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BMI ≥ 30 kg/m2, ever | 391 (48%) | 1.03 (0.73, 1.45) | 0.89 (0.40, 1.98) | 0.61 (0.27, 1.36) |
BMI < 20 kg/m2, ever | 196 (24%) | 0.83 (0.51, 1.34) | 0.66 (0.19, 2.28) | 3.12 (1.29, 7.55) |
Alcohol abuse | 69 (8%) | 1.82 (1.07, 3.10) | — | 7.89 (3.41, 18.22) |
Rheumatoid nodules | 272 (33%) | 1.20 (0.83, 1.73) | 1.95 (0.87, 4.37) | 2.49 (1.14, 5.40) |
Erosions/destructive changes | 459 (56%) | 1.47 (1.04, 2.09) | 1.88 (0.81, 4.34) | 2.65 (1.14, 6.16) |
Severe extra-articular manifestation of RA | 94 (12%) | 1.41 (0.84, 2.35) | 0.79 (0.19, 3.38) | 1.99 (0.75, 5.29) |
Large joint swelling | 648 (80%) | 1.06 (0.70, 1.60) | 0.85 (0.33, 2.17) | 3.42 (0.81, 14.54) |
Joint synovectomy | 89 (11%) | 1.53 (0.93, 2.52) | 0.69 (0.16, 2.98) | 1.06 (0.31, 3.61) |
Joint arthroplasty | 174 (21%) | 0.96 (0.61, 1.49) | 0.27 (0.06, 1.18) | 1.21 (0.50, 2.96) |
Ever 3 ESR ≥ 60 mm/1 hr | 114 (14%) | 1.29 (0.78, 2.14) | 0.62 (0.15, 2.67) | 0.55 (0.13, 2.33) |
Methotrexate | 495 (61%) | 1.04 (0.72, 1.50) | 0.74 (0.31, 1.73) | 1.49 (0.66, 3.39) |
Other DMARD | 580 (71%) | 1.29 (0.88, 1.90) | 1.35 (0.55, 3.31) | 2.38 (0.91, 6.22) |
Biologics | 175 (22%) | 0.69 (0.36, 1.35) | 1.16 (0.32, 4.14) | 0.34 (0.04, 2.61) |
Glucocorticoids | 650 (80%) | 1.57 (1.04, 2.39) | 0.87 (0.34, 2.22) | 1.39 (0.54, 3.62) |
COX-2 inhibitor | 393 (48%) | 1.09 (0.74, 1.60) | 1.52 (0.65, 3.55) | 1.10 (0.47, 2.58) |
ASA (≥1950 mg/day; ≥3 mo) | 338 (42%) | 0.76 (0.51, 1.13) | 0.53 (0.21, 1.34) | 0.63 (0.26, 1.52) |
NSAIDs for RA | 738 (91%) | 0.67 (0.40, 1.10) | 1.17 (0.27, 5.04) | 0.48 (0.18, 1.29) |
ASA = acetylated salicylate; BMI = body mass index; CI = confidence interval; ESR = erythrocyte sedimentation rate; COX2 = cyclooxygenase 2; DMARD = disease modifying antirheumatic drugs; NSAID = nonsteroidal anti-inflammatory drug; RA = rheumatoid arthritis.
There were no apparent calendar time trends in the occurrence of malignancies among the RA or non-RA cohorts.
The use of glucocorticoids in patients with RA was associated with increased malignancy risk (HR 1.57; 95% CI: 1.04, 2.39). This association between glucocorticoid use and development of any malignancy persisted after additional adjustment for ESR at RA incidence, rheumatoid factor positivity, and current smoking (HR: 3.59; 95% CI: 1.03, 2.40).
Methotrexate use was not associated with overall increased malignancy risk in patients with RA (HR: 1.04; 95% CI: 0.72, 1.50). Other DMARDs as a group were not associated with an increased risk for malignancy, although the risk of lung cancer was numerically but not significantly increased (HR: 2.38; 95%; CI: 0.91, 6.22). As well, malignancy risk was not associated with use of biologics (primarily antitumor necrosis factor agents), glucocorticoids or anti-inflammatory analgesics (Table
This retrospective population-based cohort study examined the incidence of malignancy in a nonreferral community-based population with RA and the risk for individual malignancies, including specific solid tumors, lymphomas, leukemias, and skin cancers (NMSC and melanoma). Excluding NMSC in the risk estimation revealed an increased risk of cancer in patients with RA; however, when NMSC were included, the overall cancer risk was not increased.
In this study, the overall risk of malignancy in patients with RA was not associated with DMARDs or biologic response modifiers, principally TNF inhibitors. The use of glucocorticoids was associated with increased risk of any malignancy, but there was no apparent association between glucocorticoids and hematologic cancers or lung cancers. The association between glucocorticoid use and development of any malignancy persisted after additional adjustment for ESR at RA incidence, rheumatoid factor positivity, and current smoking. The reason for this association is not certain. However, given the observational nature of our study, glucocorticoid use may be confounded with more severe disease and increased inflammatory burden, which may be associated with malignancy risk.
The overall increased risk of cancer was largely driven by the increased risk of hematologic cancers. A link between lymphoma and RA was first reported from a medical record linkage study in 1978 [
Pooled data from 74 randomized controlled trials showed that TNF inhibitors were associated with an increase in risk of NMSC beyond the risk associated with RA alone [
One of the studies conducted among 13,001 patients using the US National Cancer Institute SEER (Surveillance, Epidemiology, and End Results) database revealed increased risk for skin cancers with biologic therapy, but not for solid tumors or lymphoproliferative malignancies. These associations were consistent across different biologic therapies [
The risk for lung cancer was increased in the current study. An increased risk of lung cancer has been reported in individual studies [
Strengths of this study include its population-based design and complete medical record review. The Rochester Epidemiology project affords the ability to include both patients with RA and age- and sex-matched comparator subjects living within the same community, reducing biases of referral populations. The average follow-up of 14 years in this study is much longer than the majority of other retrospective studies [
Limitations may include the fact that the population of Olmsted County is predominately Caucasian; however results of REP studies are generally applicable to other population cohorts [
There was a small to moderately increased risk of malignancies excluding NMSC in RA patients; the risk was highest for hematologic cancers. Risk for lung cancer was also increased. The overall risk of malignancy in patients with RA was not associated with DMARDs or biologic response modifiers, principally TNF inhibitors. Cancer surveillance is imperative in all patients with RA.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors declare that they have no competing interests.
This work was funded by a grant from the National Institutes of Health, NIAMS (R01 AR46849). Research reported in this paper was supported by the National Institute on Aging of the National Institutes of Health under Award no. R01AG034676.