One patient in the 3 mg bid (twice daily) group experienced 3 of these serious adverse events (AEs) (pneumonia, respiratory failure, and cardiac failure); all other patients with a serious AE had 1 serious AE only. No serious AEs were reported in the placebo group or in the groups initially receiving tofacitinib 3 mg twice daily, tofacitinib 20 mg once daily, or placebo who were reassigned after week 12 to tofacitinib 5 mg bid. UTI = urinary tract infection; LRTI = lower respiratory tract infection; qd = once daily.
Article first published online: 27 AUG 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 9, pages 3056–3057, September 2012
How to Cite
Kremer, J. M., Cohen, S., Wilkinson, B. E., Connell, C. A., Gruben, D., Kanik, K. S. and Zwillich, S. H. (2012), Reply. Arthritis & Rheumatism, 64: 3056–3057. doi: 10.1002/art.34563
- Issue published online: 27 AUG 2012
- Article first published online: 27 AUG 2012
- Accepted manuscript online: 5 JUN 2012 10:40AM EST
To the Editor:
We would like to thank Dr. Leonardi for his letter concerning our article, and we appreciate the opportunity to expand on this important topic. We can confirm that evaluation of safety and tolerability in all tofacitinib groups versus placebo was an objective of this study, and that all AEs, their seriousness, severity, and the investigators' and sponsor's opinion of their relationship to the study drug were recorded.
A serious AE was predefined as any AE at any dose that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent or significant disability/incapacity, or resulted in a congenital anomaly. A serious infectious event was any infection (bacterial, viral, or fungal) that required hospitalization or required treatment with parenteral antimicrobial agents; all serious infections were reported as serious AEs in this study. Other AEs and infectious events could have been reported as serious even if they did not meet these criteria, if it was considered that the event was an important medical event.
As described in the article, 21 patients experienced serious AEs, including 5 patients who experienced serious infectious events. Serious infectious events and the one death that occurred during the study are detailed in the original article. Herein, we provide further details on the remaining serious AEs.
The serious AEs, including infections, are listed in Table 1. Among the serious AEs, there was 1 malignancy, a stage II malignant melanoma, in patients receiving tofacitinib at dosages of 5 mg twice daily. The patient was taking leflunomide and MTX prior to the discovery of the nevus, and this serious AE was considered to be unrelated to the study drug. The event occurred on day 86 of the study; it is possible that melanoma was present, even in microscopic form, before the start of the study. However, an association between tofacitinib and this event cannot be ruled out. Congestive heart failure and blindness, also occurring in the 5 mg twice daily treatment group, were considered to be unrelated to the study drug following review of the medical history. The patient who developed blindness in the right eye had undergone a corneal transplant in 2002, ∼6 years before entering the study. No opportunistic infections were reported. There were no apparent relationships between the type of serious AE and the dose of tofacitinib (Table 1). Five serious AEs were considered to be related to the study drug (Table 1).
|Serious AE||Tofacitinib dose|
|1 mg bid (n = 49)||1 mg bid (n = 21)†||3 mg bid (n = 55)||5 mg bid (n = 71)||10 mg bid (n = 74)||15 mg bid (n = 75)||20 mg qd (n = 67)|
|Congestive heart failure||–||–||–||1||–||–||–|
We trust that this information provides a more complete picture of this study to readers. However, we believe that the safety profile of tofacitinib is more fully understood in view of the phase III and long-term extension studies (1–6).
- 1Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with methotrexate, in patients with active rheumatoid arthritis with an inadequate response to tumor necrosis factor-inhibitors: a 6-month Phase 3 study [abstract]. Arthritis Rheum 2011; 63 Suppl: S279., , , , , , et al.
- 2Phase 3 study of oral JAK inhibitor tasocitinib (CP-690,550) monotherapy in patients with active rheumatoid arthritis [abstract]. Arthritis Rheum 2010; 62: 3841., , , , , , et al.
- 3Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with traditional DMARDS: a phase 3 efficacy and safety study in patients with active rheumatoid arthritis with an inadequate response to DMARDs [abstract]. Ann Rheum Dis 2011; 70: 170., , , , , , et al.
- 4Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with methotrexate reduced the progression of structural damage in patients with rheumatoid arthritis: a 24-month phase 3 study [abstract]. Arthritis Rheum 2011; 63 Suppl: S1017–8., , , , , , et al.
- 5Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, or adalimumab versus placebo in patients with rheumatoid arthritis on background methotrexate: a phase 3 study [abstract]. Arthritis Rheum 2011; 63 Suppl: S153., , , , , , et al.
- 6Tofacitinib (CP-690,550), an oral Janus kinase inhibitor: analysis of infections and all-cause mortality across phase 3 and long-term extension studies in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2011; 63 Suppl: S153., , , , , , et al.
Joel M. Kremer MD*, Stanley Cohen MD, Bethanie E. Wilkinson PhD, Carol A. Connell PhD, David Gruben PhD, Keith S. Kanik MD, Samuel H. Zwillich MD, * Albany Medical College, Albany, NY, Metroplex Clinical Research Center, Dallas, TX, Pfizer, Groton, CT.