Comparative cancer risk associated with methotrexate, other non-biologic and biologic disease-modifying anti-rheumatic drugs

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Abstract

Objective

There is little information comparing the potential risk of cancer across conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Methotrexate has not been the focus of most contemporary pharmacoepidemiologic studies of cancer.

Methods

We conducted a comparative effectiveness study with cancer as the outcome. A large observational cohort of RA was followed up from 2001 to 2010. Reports of any cancer prompted a confirmation process that included adjudication of the primary cancer records. We used a propensity score (PS) with relevant covariates and cohort trimming to improve the balance between DMARD cohorts. Cox proportional hazard regression models were constructed to estimate the risk of cancer with various DMARDs, all compared with methotrexate.

Results

We identified 6806 DMARD courses for analysis (1566 methotrexate; 904 nbDMARDs; 3761 TNF antagonists; 408 abatacept; and 167 rituximab). Non-biologic DMARDs (HR 0.17, 95% CI 0.05–0.65) and TNF antagonists (HR 0.29, 95% CI 0.05–0.65) were associated with a reduced adjusted risk of cancer compared with methotrexate. Abatacept (HR 1.55, 95% CI 0.40–5.97) and rituximab (HR 0.42, 95% CI 0.07–2.60) were similar in risk of cancer with methotrexate. These results were robust to sensitivity analyses. After controlling for DMARD exposures, risk factors for cancer included male gender, age, and alcohol consumption.

Conclusions

Cancer risk was elevated for methotrexate users compared with nbDMARDs and TNF antagonists.

Introduction

Patients with rheumatoid arthritis (RA) suffer from a higher risk of certain malignancies, such as non-Hodgkin’s lymphoma [1], [2]. This risk is likely related to the immune dysregulation associated with RA [3]. Methotrexate, the most common treatment for RA, has been linked to some cancers but is also used, in higher doses, as chemotherapy for other cancers [4], [5]. This background of increased cancer risk related to RA itself, and methotrexate use provides a complex setting to assess relative cancer risk associated with other disease-modifying anti-rheumatic drugs (DMARDs).

Biologic DMARDs, such as tumor necrosis factor (TNF) antagonists, abatacept, tocilizumab, and rituximab, target specific aspects of the immune system and are efficacious in RA patients with an inadequate response to methotrexate [6], [7], [8]. Possible cancer risks for several of these agents have prompted regulators to mandate warnings [9]. Such warnings generate concerns for patients and providers as RA is a chronic disease, requiring long-term therapy. However, it is not clear how the potential cancer risk associated with these newer drugs compares with methotrexate.

Several studies support the possible risk of cancer associated with some of these agents, specifically TNF antagonists. A meta-analysis of randomized trials found that two monoclonal antibodies to TNF were associated with a 3.3-fold elevated cancer risk [10]. A meta-analysis of etanercept trials found an approximate doubling of the cancer risk [11]. Other meta-analyses of trials and observational studies have not found any substantial increase in overall cancer risk associated with TNF antagonists [12], [13], [14]. However, there have been concerns raised about skin cancer risk associated with TNF antagonists [15], [16]. There are few studies, other than the relatively short-term randomized trials, regarding cancer risk of abatacept, tocilizumab, or rituximab in RA [17], [18], [19].

It is unlikely that randomized controlled trials will directly compare methotrexate with newer DMARDs in large-enough samples for long-enough periods to estimate comparative cancer risk. Observational drug studies have well-described and important limitations with respect to confounding bias [20]; however, this issue is more critical when examining a drug’s potential benefits than risks. Unintended treatment effects, such as cancer, can be well studied in observational settings.

We undertook a study of the comparative risk of malignancy associated with DMARDs, comparing different agents with methotrexate, a treatment that most clinicians are comfortable using in routine practice and is a first-line therapy for most patients with RA. This study was carried out using the Consortium of Rheumatology Researchers of North America (CORRONA) registry.

Section snippets

Study cohort and data source

We examined data from the CORRONA registry covering the period 10/01/2001 to 11/30/2010. This cohort has been described in detail previously [21]. It is based in 132 rheumatology practices throughout the US. Subjects and rheumatologists complete questionnaires at study visits approximately every four months. Patients enter at different times in their treatment course, depending upon when they are first enrolled in the registry. Data are entered online via an electronic data capture system for

Results

After applying the inclusion and exclusion criteria, the study cohort consisted of 15,659 subjects who contributed 17,393 exposure periods (see Fig. 1). The propensity scores were calculated comparing each exposure to methotrexate, and the cohorts were trimmed to reduce non-overlap. The trimmed cohorts are shown in Table 1 (all of the different methotrexate propensity cohorts are shown in Supplementary Table 1) and show good balance across most baseline patient characteristics. However, even

Discussion

The advent of newer DMARDs and combination therapy has allowed more RA patients to lead more functional lives. With this improvement in therapy, more attention is focused on the comparative risks and benefits of treatment. Research into this area is not straightforward and, because of the scarcity of comparative randomized controlled clinical trials, requires epidemiologic methods applied to observational data. We examined the comparative risk of cancer associated with methotrexate compared

Conclusion

We studied a large RA cohort based in the United States to estimate the comparative risk of cancer across different DMARD groups compared with methotrexate. We found no important increase in cancer risk for the different biologic DMARDs compared with methotrexate. Rather, we found a reduced risk of cancer among users of TNF antagonists and nbDMARD users compared with methotrexate. The heightened risk associated with methotrexate compared with several other DMARDs is plausible and worthy of

Acknowledgment

Competing interests: Dr. Solomon has received research grants in the last three years from Amgen, Abbott Immunology, and Eli Lilly. He serves as a paid consultant to CORRONA. He has served in unpaid roles on two Pfizer sponsored trials regarding pain medications. Dr. Kremer owns shares in the CORRONA registry. Dr. Hochberg serves as a consultant to Abbott Laboratories, Amgen, Bristol Meyers Squibb, Genentech–Roche and UCB, Inc. Dr. Curtis has received research grants and consulting for

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  • Cited by (0)

    Role of funding source: There was no specific support for these analyses. CORRONA has received general support in the last 2 years from Abbott, Amgen, Astra Zeneca, Genentech, Janssen (Centocor), Lilly, and Pfizer. Dr. Solomon receives salary support from research grants from the NIH (AR AR055989 and AR 047782), AHRQ, Amgen, and Lilly. Jeffrey Curtis receives salary support from NIH (AR053351). Dr. Harrold was supported by K23AR053856 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and holds a research grant from CORRONA. Dr. Greenberg receives salary support from the NIH (K23AR054412) and AHRQ (R01HS018517).

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