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Original Investigation
November 2017

Malignant Neoplasms in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors, Tocilizumab, Abatacept, or Rituximab in Clinical PracticeA Nationwide Cohort Study From Sweden

Hjalmar Wadström, MD1; Thomas Frisell, PhD1; Johan Askling, MD, PhD1,2; et al for the Anti-Rheumatic Therapy in Sweden (ARTIS) Study Group
Author Affiliations
  • 1Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, 171 76 Stockholm, Sweden
  • 2Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
JAMA Intern Med. 2017;177(11):1605-1612. doi:10.1001/jamainternmed.2017.4332
Key Points

Question  Does treatment with tocilizumab, abatacept, rituximab, or tumor necrosis factor (TNF) inhibitors affect the risk of malignant neoplasms among patients with rheumatoid arthritis?

Findings  In this register-based cohort study, the risk of malignant neoplasms did not differ between patients treated with a first anti-TNF drug, a second anti-TNF drug, tocilizumab, abatacept, rituximab, or conventional synthetic disease-modifying antirheumatic drugs, with the possible exception of an increased risk of squamous cell skin cancer risk in patients treated with abatacept.

Meaning  Short- to medium-term use of tocilizumab, abatacept, rituximab, or anti-TNF drugs seems to be safe with regard to risks of incident cancer.


Importance  Considering the widespread and increasing use of biological immunomodulators (biological disease-modifying antirheumatic drugs [bDMARDs]) to treat chronic inflammatory conditions, and the concern that immunomodulation may alter cancer risk and progression, the limited available data on use of these therapies as used in clinical practice and cancer risks are a concern.

Objective  To assess the risk of incident malignant neoplasms in patients with rheumatoid arthritis (RA) treated with bDMARDs.

Design, Setting, and Participants  This was a national register–based prospective cohort study of the public health care system in Sweden from 2006 to 2015. Cohorts of patients with RA initiating treatment with tocilizumab (n = 1798), abatacept (n = 2021), and rituximab (n = 3586), a tumor necrosis factor inhibitor (TNFi) as first-ever (n = 10 782) or second-ever (n = 4347) bDMARD, a biologics-naive cohort treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (n = 46 610), and a general population comparator cohort (n = 107 491).

Exposures  Treatment with tocilizumab, abatacept, rituximab, or TNFi.

Main Outcomes and Measures  Outcomes included a first invasive solid or hematologic malignant neoplasm, or skin cancer. Hazard ratios were calculated using Cox-regression, adjusted for age, sex, disease and treatment characteristics, and educational level.

Results  We identified a total of 15 129 initiations of TNFi as the first or second bDMARD, 7405 initiations of other bDMARDs, and 46 610 csDMARD users. The mean age varied from 58 to 64 years, and the proportion of female patients varied from 71% to 80%, across the 7 cohorts under study. The observed numbers of events (crude incidence per 100 000 person-years) for a first invasive solid or hematologic malignant neoplasm were 50 (959) for tocilizumab, 61 (1026) for abatacept, 141 (1074) for rituximab, 478 (978) for initiators of TNFi as first bDMARD, and 169 (917) for TNFi as second bDMARD. There were no statistically significant differences between initiators of a first or second TNFi, or other bDMARDs, and bDMARD-naive RA for any of a total of 25 drug- and outcome-specific comparisons, with 1 exception (abatacept and increased risk of squamous cell skin cancer).

Conclusions and Relevance  The overall risk of cancer among patients with RA initiating TNFi as first or second bDMARD, tocilizumab, abatacept, or rituximab does not differ substantially from that of biologic drug–naive, csDMARD-treated patients with RA, although altered risks for specific cancer types, or those with longer latency, cannot be excluded.