Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials

Stanley B Cohen, Yoshiya Tanaka, Xavier Mariette, Jeffrey R Curtis, Eun Bong Lee, Peter Nash, Kevin L Winthrop, Christina Charles-Schoeman, Krishan Thirunavukkarasu, Ryan DeMasi, Jamie Geier, Kenneth Kwok, Lisy Wang, Richard Riese, Jürgen Wollenhaupt, Stanley B Cohen, Yoshiya Tanaka, Xavier Mariette, Jeffrey R Curtis, Eun Bong Lee, Peter Nash, Kevin L Winthrop, Christina Charles-Schoeman, Krishan Thirunavukkarasu, Ryan DeMasi, Jamie Geier, Kenneth Kwok, Lisy Wang, Richard Riese, Jürgen Wollenhaupt

Abstract

Objectives: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA.

Methods: Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest.

Results: 6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure.

Conclusion: This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports.

Trial registration numbers: NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.

Keywords: Cardiovascular Disease; Infections; Rheumatoid Arthritis; Treatment; Tuberculosis.

Conflict of interest statement

Competing interests: SBC, KLW, CC-S and JW have served as consultants for, and have received speaker fees and honoraria from, Pfizer Inc. YT has served as a consultant for, and has received speaker fees and honoraria from, AbbVie, Asahi-kasei, Astellas Pharma, BMS, Chugai Pharma, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Pfizer Inc, Sanofi, Takeda, Teijin and YL Biologics. XM has served as a consultant for, and has received speaker fees and honoraria from, BMS, GlaxoSmithKline, Pfizer Inc and UCB. EBL has served as a consultant for Pfizer Inc. KT, RDM, JG, KK and LW are employees and shareholders of Pfizer Inc. RR was an employee of Pfizer Inc at the time these analyses were conducted and holds stock/stock options in Pfizer Inc.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
IRs for (A) SIE, (B) HZ (non-serious and serious) and (C) OI (excluding tuberculosis) over time for all tofacitinib doses. HZ, herpes zoster; IR, incidence rate; OI, opportunistic infection; SIE, serious infection event.
Figure 1
Figure 1
Continued
Figure 2
Figure 2
HRs of potential risk factors for events of serious infection (A), herpes zoster (B) and opportunistic infections excluding tuberculosis (C)—results from multivariable Cox regression models in the phases I–III and LTE studies *Medical history and/or complication of COPD. †In Unit=x, ‘x’ is the change in the continuous variable corresponding to which the change in hazards is observed. ‡Based on exposure period before lymphopenia <500 cells/µL versus exposure period after lymphopenia <500 cells/µL. COPD, chronic obstructive pulmonary disease; HAQ-DI, Health Assessment Questionnaire-Disability Index; LA, Latin America; LTE, long-term extension.
Figure 3
Figure 3
IRs for malignancies excluding NMSC (A) and (B) NMSC over time for all tofacitinib doses. IR, incidence rate; NMSC, non-melanoma skin cancer.

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