Frequency and Duration of Early Non-serious Adverse Events in Patients with Rheumatoid Arthritis and Psoriatic Arthritis Treated with Tofacitinib
Ara Dikranian, David Gold, Louis Bessette, Peter Nash, Valderilio F Azevedo, Lisy Wang, John Woolcott, Andrea B Shapiro, Annette Szumski, Dona Fleishaker, Jürgen Wollenhaupt, Ara Dikranian, David Gold, Louis Bessette, Peter Nash, Valderilio F Azevedo, Lisy Wang, John Woolcott, Andrea B Shapiro, Annette Szumski, Dona Fleishaker, Jürgen Wollenhaupt
Abstract
Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This post hoc analysis assessed frequency or duration of early select non-serious adverse events (AEs; excluding infections), and their impact on treatment discontinuation, in patients with RA or PsA treated with tofacitinib 5 or 10 mg twice daily, or placebo.
Methods: Data were pooled from five phase 3 and one phase 3b/4 studies in patients with moderate-to-severe RA, and two phase 3 studies in patients with active PsA. Select all-causality, non-serious AEs, reported to month 3 (placebo-controlled period), were headache, diarrhea, nausea, vomiting, and gastric discomfort (including dyspepsia, gastritis, epigastric discomfort, and abdominal discomfort or pain); incidence rates (unique patients with events per 100 patient-years of follow-up), duration of, and discontinuations due to these non-serious AEs were reported.
Results: We analyzed 3871 and 710 patients with RA and PsA, respectively. Incidence of non-serious AEs to month 3 was generally similar with tofacitinib and placebo. The most frequent non-serious AEs were headache and diarrhea with tofacitinib, and dyspepsia, nausea, and headache with placebo. Most events were mild or moderate in severity, lasting ≤ 4 weeks. Permanent discontinuations due to non-serious AEs were not observed in patients with PsA, and were < 1.0% in patients with RA across treatment groups. The most frequent cause of temporary discontinuation across all groups was gastric discomfort (0.3-0.8%).
Conclusions: Non-serious AE incidence was generally similar in patients with RA or PsA receiving tofacitinib or placebo. Most events were mild or moderate and generally resolved within 4 weeks.
Trial registration: ClinicalTrials.gov identifiers: NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01877668; NCT01882439; NCT02187055.
Keywords: Adverse event; Antirheumatic agents; Autoimmune diseases; Psoriatic arthritis; Rheumatoid arthritis; Tofacitinib; Tolerability.
© 2021. The Author(s).
Figures
References
- Singh JA, Guyatt G, Ogdie A, et al. Special article: 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis. Arthritis Rhematol. 2019;71:5–32.
- Singh JA, Saag KG, Bridges SL, Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1–26.
- Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75:499–510.
- Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79:685–699.
- Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012;64:617–629.
- Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60:1895–1905.
- Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012;64:970–981.
- Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH, Tofacitinib Study Investigators Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res. 2011;63:1150–1158.
- Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol. 2015;25:514–521.
- Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381:451–460.
- Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495–507.
- Kremer J, Li Z-G, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159:253–261.
- Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370:2377–2386.
- van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65:559–570.
- van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508–519.
- Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet. 2017;390:457–468.
- Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41:837–852.
- Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther. 2016;18:34.
- Wollenhaupt J, Lee EB, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res Ther. 2019;21:89.
- Mease P, Hall S, FitzGerald O, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377:1537–1550.
- Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med. 2017;377:1525–1536.
- Nash P, Coates LC, Fleishaker D, et al. Safety and efficacy of tofacitinib up to 48 months in patients with active psoriatic arthritis: final analysis of the OPAL Balance long-term extension study. Lancet Rheumatol. 2021;3:e270–e283.
- US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry: E9 statistical principles for clinical trials. 1998. . Accessed 10 Sept 2021.
- European Medicines Agency. ICH topic E9: Statistical principles for clinical trials. 1998. . Accessed 10 Sept 2021.
- US Food and Drug Administration. What is a serious adverse event? 2016. . Accessed 10 Sept 2021.
- European Medicines Agency. Guideline on good pharmacovigilance practices (GVP): Annex I - Definitions (Rev 4). 2017. . Accessed 10 Sept 2021.
- Ferrari A, Spaccapelo L, Gallesi D, Sternieri E. Focus on headache as an adverse reaction to drugs. J Headache Pain. 2009;10:235–239.
- Cohen S, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the RA clinical development program [abstract] Arthritis Rheumatol. 2018;70(Suppl 10):963.
- Burmester GR, Curtis JR, Yun H, et al. 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. Drug Saf. 2020;43:379–392.
- Cohen S, Curtis JR, DeMasi R, et al. Worldwide, 3-year, post-marketing surveillance experience with tofacitinib in rheumatoid arthritis. Rheumatol Ther. 2018;5:283–291.
- Cohen SB, Tanaka Y, Mariette X, et al. 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. Ann Rheum Dis. 2017;76:1253–1262.
- Kivitz AJ, Cohen S, Keystone E, et al. A pooled analysis of the safety of tofacitinib as monotherapy or in combination with background conventional synthetic disease-modifying antirheumatic drugs in a phase 3 rheumatoid arthritis population. Semin Arthritis Rheum. 2018;48:406–415.
- Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324.
- Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569–2581.
- Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665–2673.
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723–1736.
- US Food and Drug Administration. Methotrexate tablets, USP. 2018. . Accessed 10 Sept 2021.
- Ma SN, Zaman Huri H, Yahya F. Drug-related problems in patients with rheumatoid arthritis. Ther Clin Risk Manag. 2019;15:505–524.
- Mueller RB, Hasler C, Popp F, et al. Effectiveness, tolerability, and safety of tofacitinib in rheumatoid arthritis: a retrospective analysis of real-world data from the St. Gallen and Aarau cohorts. J Clin Med. 2019;8:1548.
- Kavanaugh A, Gladman DD, Edwards CJ, et al. Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1–3 pooled analysis. Arthritis Res Ther. 2019;21:118.
- Wells AF, Edwards CJ, Kivitz AJ, et al. Apremilast monotherapy in DMARD-naive psoriatic arthritis patients: results of the randomized, placebo-controlled PALACE 4 trial. Rheumatology. 2018;57:1253–1263.
- Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:2503–2512.
- Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018;391:2513–2524.
- Rubbert-Roth A, Enejosa J, Pangan AL, et al. Trial of upadacitinib or abatacept in rheumatoid arthritis. N Engl J Med. 2020;383:1511–1521.
- Smolen JS, Pangan AL, Emery P, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet. 2019;393:2303–2311.
- Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376:652–662.
- Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76:88–95.
- Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374:1243–1252.
- Wells RE, Kaptchuk TJ. To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent. Am J Bioeth. 2012;12:22–29.
- Barnes K, Faasse K, Geers AL, et al. Can positive framing reduce nocebo side effects? Current evidence and recommendation for future research. Front Pharmacol. 2019;10:167.
Source: PubMed