An Integrated Analysis of the Safety of Tofacitinib in Psoriatic Arthritis across Phase III and Long-Term Extension Studies with Comparison to Real-World Observational Data

Abstract

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA).

Objective: Our objective was to compare the incidence rates (IRs) of adverse events in tofacitinib clinical trials and real-world observational data for alternative treatments.

Methods: The tofacitinib "dose-comparison cohort" included months 0-12 of two phase III studies (tofacitinib 5 [n = 238] and 10 [n = 236] mg twice daily [BID]); the "all-tofacitinib comparison cohort" (n = 783) included two phase III and one ongoing long-term extension study (data cutoff May 2016). An "observational comparison cohort" (n = 5799) comprised patients initiating a conventional synthetic disease-modifying antirheumatic drug (DMARD), biologic DMARD, or apremilast in the US Truven MarketScan database from 2010 to 2015. IRs for serious infections (SIEs; requiring hospitalization), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, and major adverse cardiovascular events (MACE) across cohorts were qualitatively compared.

Results: IRs (patients with events/100 patient-years) for SIEs were similar between the tofacitinib dose-comparison cohort (5 mg BID: 1.3; 10 mg BID: 2.0) and the observational comparison cohort (1.1-7.9; treatment dependent). The tofacitinib dose-comparison cohort had a higher rate of HZ (5 mg BID: 2.0; 10 mg BID: 2.7) than did the observational comparison cohort (0.8-2.0). IRs for NMSC were generally lower in the all-tofacitinib comparison cohort (0.5) than in the observational comparison cohort (0.4-6.0). IRs for MACE, malignancies excluding NMSC, and NMSC were similar between cohorts.

Conclusion: In patients with PsA, tofacitinib had a safety profile similar to that of other systemic therapies in real-world settings, except for the risk of HZ, a known risk of tofacitinib.

Trial registration: ClinicalTrials.gov: NCT01877668; NCT01882439; NCT01976364.

Fig. 1

Schematic of clinical trial cohorts. ^aAll patients received tofacitinib 5 mg BID upon entry into OPAL Balance; the tofacitinib dose could be increased to 10 mg BID at the investigator’s discretion if it was believed that a patient would benefit from a higher dose and was not experiencing any tofacitinib-related AEs, including abnormalities in laboratory test results that were judged to be related to tofacitinib. The dose could be decreased from 10 to 5 mg BID for safety reasons at any time. AEs adverse events, BID twice daily, LTE long-term extension, Q2W every 2 weeks

Fig. 2

IRs for SIEs a resulting in hospitalization or b requiring parenteral antimicrobials in an emergency department setting or resulting in hospitalization over 12 months across cohorts. The tofacitinib dose-comparison cohort included patients who were randomized to receive either tofacitinib 5 mg BID or 10 mg BID (n = 474) in the two phase III studies (12 or 6 months’ duration). For the observational comparison cohort, follow-up was truncated at 1 year because of the possible time-varying hazard between PsA treatments and infections to ensure equal follow-up time. Observational comparison cohort outcomes were weighted based on previous TNFi use (identified using all available data: TNFi naïve vs. TNFi experienced), concomitant MTX use (identified using data from the index date to 90 days before the index date: MTX only vs. no MTX or with other csDMARDs), and concomitant steroid use (identified on the index date: steroid use vs. no steroid use); the weights were derived using the all-tofacitinib comparison cohort data. For bDMARD, bDMARD + csDMARD, TNFi, and TNFi + csDMARD, n refers to “treatment episodes” rather than patients, as the patients in these groups may have initiated more than one drug in the given class. bDMARD biologic DMARD, BID twice daily, CI confidence interval, csDMARD conventional synthetic DMARD, DMARD disease-modifying antirheumatic drug, IR incidence rate (patients with event/100 PY), MTX methotrexate, PsA psoriatic arthritis, PY patient-years, SIEs serious infections, TNFi tumor necrosis factor inhibitor, tofa tofacitinib

Fig. 3

IRs for a HZ and b OI over 12 months across cohorts. The tofacitinib dose-comparison cohort included patients who were randomized to receive either tofacitinib 5 mg BID or 10 mg BID (n = 474) in the two phase III studies (12 or 6 months’ duration). OI included HZ and excluded tuberculosis. Observational comparison cohort outcomes were weighted based on previous TNFi use (identified using all available data: TNFi naïve vs. TNFi experienced), concomitant MTX use (identified using data from the index date to 90 days before the index date: MTX only vs. no MTX or with other csDMARDs), and concomitant steroid use (identified on the index date: steroid use vs. no steroid use); the weights were derived using the all-tofacitinib comparison cohort data. For bDMARD, bDMARD + csDMARD, TNFi, and TNFi + csDMARD, n refers to “treatment episodes” rather than patients, as the patients in these groups may have initiated more than one drug in the given class. bDMARD biologic DMARD, BID twice daily, CI confidence interval, csDMARD conventional synthetic DMARD, DMARD disease-modifying antirheumatic drug, HZ herpes zoster, IR incidence rate (patients with event/100 PY), MTX methotrexate, OI opportunistic infection, PY patient-years, TNFi tumor necrosis factor inhibitor, tofa tofacitinib

Fig. 4

IRs for a MACE, b malignancies (excluding NMSC), and c NMSC across cohorts. The all-tofacitinib comparison cohort included patients who received at least one dose of either tofacitinib 5 mg BID or 10 mg BID (n = 783) in either of the two phase III studies or the LTE. Observational comparison cohort outcomes were weighted based on previous TNFi use (identified using all available data: TNFi naïve vs. TNFi experienced), concomitant MTX use (identified using data from the index date to 90 days before the index date: MTX only vs. no MTX or with other csDMARDs), and concomitant steroid use (identified on the index date: steroid use vs. no steroid use); the weights were derived using the all-tofacitinib comparison cohort data. For bDMARD, bDMARD + csDMARD, TNFi, and TNFi + csDMARD, n refers to “treatment episodes” rather than patients, as the patients in these groups may have initiated more than one drug in the given class. bDMARD biologic DMARD, BID twice daily, CI confidence interval, csDMARD conventional synthetic DMARD, DMARD disease-modifying antirheumatic drug, IR incidence rate (patients with event/100 PY), LTE long-term extension, MACE major adverse cardiovascular event, MTX methotrexate, NMSC non-melanoma skin cancer, PY patient-years, TNFi tumor necrosis factor inhibitor, tofa tofacitinib