ObjectivesTofacitinib 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.MethodsData 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.Results6194 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.ConclusionThis 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.

Background Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA). Methods Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators’ discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients’ average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy. Results Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained. Conclusions Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions. Trial registration NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006) Electronic supplementary material The online version of this article (10.1186/s13075-019-1866-2) contains supplementary material, which is available to authorized users.

Objective. To determine the rate of infection and all-cause mortality across tofacitinib phase II, phase III, and long-term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA).Methods. Conclusion. The overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time. 550) is an oral JAK inhibitor used for the treatment of rheumatoid arthritis (RA) and has a novel mechanism of action. The JAK family of tyrosine kinases includes JAK-1, JAK-2, JAK-3, and Tyk-2. Tofacitinib preferentially inhibits signaling by heterodimeric receptors associated with JAK-3 and/or JAK-1, with functional selectivity over receptors that signal in pairs of JAK-2 (1). Common ␥-chaincontaining receptors using JAK-1 and JAK-3 include

ObjectivesEvaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.MethodsPatients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis).ResultsRisk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07).ConclusionsThis post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low.Trial registration numberNCT02092467.

Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.