Incidence Rates of Interstitial Lung Disease Events in Tofacitinib-Treated Rheumatoid Arthritis Patients: Post Hoc Analysis From 21 Clinical Trials

Gustavo Citera, Eduardo Mysler, Hugo Madariaga, Mario H Cardiel, Oswaldo Castañeda, Aryeh Fischer, Pascal Richette, Sandra Chartrand, Jin Kyun Park, Sander Strengholt, Jose L Rivas, Amit V Thorat, Tanya Girard, Kenneth Kwok, Lisy Wang, Dario Ponce de Leon, Gustavo Citera, Eduardo Mysler, Hugo Madariaga, Mario H Cardiel, Oswaldo Castañeda, Aryeh Fischer, Pascal Richette, Sandra Chartrand, Jin Kyun Park, Sander Strengholt, Jose L Rivas, Amit V Thorat, Tanya Girard, Kenneth Kwok, Lisy Wang, Dario Ponce de Leon

Abstract

Background/objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD.

Methods: This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as "probable" (supportive clinical evidence) or "possible" (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events.

Results: Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13-5.21]), current smokers (2.89 [1.33-6.26]), and Disease Activity Score in 28 joints-erythrocyte sedimentation rate score (1.30 [1.04-1.61]) as significant risk factors for ILD events.

Conclusions: Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

Conflict of interest statement

This study was sponsored by Pfizer Inc. G.C. has received research grants from Novartis and Pfizer Inc. and is a speaker, advisor and/or consultant to AbbVie, Bristol-Myers Squibb, Eli Lilly, Genzyme, Janssen, Novartis, Pfizer Inc., and Roche. E.M. has received research grants from Eli Lilly, Pfizer Inc., and Roche and is a member of the speakers' bureaus for AbbVie, Bristol-Myers Squibb, Eli Lilly, Pfizer Inc., Roche, and Sanofi. M.H.C. has received research grants from Gilead, Pfizer Inc., and Roche; and is a consultant and member of the speakers' bureaus for Eli Lilly and Pfizer Inc. A.F. has received research grants from Boehringer Ingelheim and Corbus and is a consultant to Boehringer Ingelheim and Roche. A.F. is a former employee of the University of Colorado and is currently employed by Bristol-Myers Squibb. P.R. is a consultant to Pfizer Inc. S.C. is a consultant to AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Novartis, and Pfizer Inc. J.L.R., A.V.T., T.G., K.K., L.W., and D.P.L., are employees and shareholders of Pfizer Inc. S.S. is a former employee of Pfizer Inc., Capelle aan den IJssel, the Netherlands. J.K.P., H.M., and O.C. declare no conflict of interest.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1
FIGURE 1
Incidence rates for ILD events in patients receiving (A) all tofacitinib doses or tofacitinib 5 or 10 mg BID in the overall cohort, and (B) all tofacitinib doses, tofacitinib 5 or 10 mg BID, or placebo in the randomized controlled cohort. *Data for the overall cohort are derived based on the average dose of tofacitinib received. †The all-tofacitinib group in the randomized controlled cohort comprised all patients who had ever received tofacitinib, including patients who switched from placebo or adalimumab to tofacitinib. ‡Includes patients randomized to receive tofacitinib 5 mg BID. §Includes patients randomized to receive tofacitinib 10 mg BID. ¶Includes patients randomized to receive placebo.
FIGURE 2
FIGURE 2
Incidence rates for ILD events in the overall cohort (all tofacitinib doses) by 6-month time interval.
FIGURE 3
FIGURE 3
Incidence rates for ILD events in patients receiving monotherapy, combination therapy, or mixed therapy in the overall cohort. Background therapy groups were assigned based on the patient's exposure to monotherapy or combination therapy for ≥80% of the patient's tofacitinib exposure. If a patient was not on either monotherapy or combination therapy for ≥80% of the time, the patient was assigned to the mixed group.

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