Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program

Arthritis Care Res (Hoboken). 2018 May;70(5):685-694. doi: 10.1002/acr.23421. Epub 2018 Apr 2.


Objective: Tofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). We characterized lymphoma events in the tofacitinib RA clinical development program.

Methods: Lymphoma events (up to March 2015) were identified from 19 tofacitinib studies (2 phase I, 9 phase II, 6 phase III, and 2 long-term extension) of patients with moderate to severe RA. Patients in these studies received tofacitinib dosed at 1-30 mg twice daily or 20 mg once daily, as monotherapy or with conventional synthetic disease-modifying antirheumatic drugs. Lymphoma incidence rates (IRs; number of patients with events/100 patient-years) and standardized incidence ratios (SIRs) were calculated. A descriptive case-matched control analysis (1:4) was performed to identify potential risk factors for lymphoma.

Results: A total of 6,194 patients received tofacitinib (19,406 patient-years of exposure, 3.4 years median treatment duration). Nineteen lymphomas occurred (IR 0.10 [95% confidence interval (95% CI) 0.06-0.15]), with no increase observed with time of exposure. The age- and sex-adjusted SIR of lymphoma was 2.62 (95% CI 1.58-4.09) (Surveillance, Epidemiology, and End Results [SEER] program database). The clinical characteristics of the 19 lymphomas were typical for the RA population. Three lymphomas were positive for Epstein-Barr virus, 8 were negative, 2 were equivocal, and 6 were untested. Numerically, more lymphoma cases had a history of Sjögren's syndrome and were positive for anti-cyclic citrullinated protein and rheumatoid factor at baseline versus matched controls. The mean corticosteroid dose was higher for lymphoma cases versus controls.

Conclusion: In the tofacitinib RA clinical development program, lymphoma rates were stable over time and there were minimal differences in the baseline characteristics of patients with and without lymphoma.

Trial registration: NCT00147498 NCT00413699 NCT00413660 NCT00960440 NCT00550446 NCT00603512.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / complications*
  • Arthritis, Rheumatoid / drug therapy
  • Case-Control Studies
  • Female
  • Humans
  • Janus Kinase 3 / antagonists & inhibitors*
  • Lymphoma / epidemiology*
  • Lymphoma / etiology
  • Male
  • Middle Aged
  • Piperidines / adverse effects*
  • Pyrimidines / adverse effects*
  • Pyrroles / adverse effects*


  • Piperidines
  • Pyrimidines
  • Pyrroles
  • tofacitinib
  • Janus Kinase 3

Associated data