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

Gerd R Burmester, Jeffrey R Curtis, Huifeng Yun, Oliver FitzGerald, Kevin L Winthrop, Valderilio F Azevedo, William F C Rigby, Keith S Kanik, Cunshan Wang, Pinaki Biswas, Thomas Jones, Niki Palmetto, Thijs Hendrikx, Sujatha Menon, Ricardo Rojo, Gerd R Burmester, Jeffrey R Curtis, Huifeng Yun, Oliver FitzGerald, Kevin L Winthrop, Valderilio F Azevedo, William F C Rigby, Keith S Kanik, Cunshan Wang, Pinaki Biswas, Thomas Jones, Niki Palmetto, Thijs Hendrikx, Sujatha Menon, Ricardo Rojo

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.

Conflict of interest statement

Gerd R. Burmester has received consulting fees from AbbVie, Gilead, Lilly, and Pfizer Inc and lecture fees from AbbVie, Lilly, and Pfizer Inc. Jeffrey R. Curtis has received research grants and consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Eli Lilly, Janssen, Myriad, Pfizer Inc, Regeneron, Roche, and UCB. Huifeng Yun has received grant/research support from Pfizer Inc. Oliver FitzGerald has received research grants and honoraria from AbbVie, Celgene, Janssen, Lilly, Novartis, Pfizer Inc, and UCB. Kevin L. Winthrop has received consulting fees from AbbVie, Galapagos, Gilead, GSK, Lilly, Pfizer Inc, Roche, and UCB. Valderilio F. Azevedo has received grant/research support and consulting fees from AbbVie, Lilly, Novartis, and Pfizer Inc and lecture fees from AbbVie, Boehringer Ingelheim, Celltrion, Janssen, Lilly, Novartis, and Pfizer Inc. William F.C. Rigby has received consulting fees for work unrelated to this manuscript. Keith S. Kanik, Cunshan Wang, Pinaki Biswas, Thomas Jones, Thijs Hendrikx, and Ricardo Rojo are shareholders and employees of Pfizer Inc. Sujatha Menon is an employee of Pfizer Inc. Niki Palmetto was an employee of Pfizer Inc at the time of the analysis.

Figures

Fig. 1
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
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
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
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

References

    1. Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Acosta-Felquer ML, Armstrong AW, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol. 2016;68(5):1060–1071.
    1. Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75(3):499–510.
    1. Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58(5):851–864.
    1. Mease PJ, Armstrong AW. Managing patients with psoriatic disease: the diagnosis and pharmacologic treatment of psoriatic arthritis in patients with psoriasis. Drugs. 2014;74(4):423–441.
    1. Nadarajan P, Fabre A, Kelly E. Sulfasalazine: a rare cause of acute eosinophilic pneumonia. Respir Med Case Rep. 2016;18:35–36.
    1. Ceponis A, Kavanaugh A. Use of methotrexate in patients with psoriatic arthritis. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S132–S137.
    1. Sevilla-Mantilla C, Ortega L, Agúndez JA, Fernández-Gutiérrez B, Ladero JM, Díaz-Rubio M. Leflunomide-induced acute hepatitis. Dig Liver Dis. 2004;36(1):82–84.
    1. Krathen MS, Gottlieb AB, Mease PJ. Pharmacologic immunomodulation and cutaneous malignancy in rheumatoid arthritis, psoriasis, and psoriatic arthritis. J Rheumatol. 2010;37(11):2205–2215.
    1. Minozzi S, Bonovas S, Lytras T, Pecoraro V, González-Lorenzo M, Bastiampillai AJ, et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis. Expert Opin Drug Saf. 2016;15(sup1):11–34.
    1. Mease P, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila-Zapata F, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377(16):1537–1550.
    1. Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med. 2017;377(16):1525–1536.
    1. Nash P, Coates LC, Kivitz AJ, Mease PJ, Gladman DD, Covarrubias-Cobos JA, et al. Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, up to 24 months in patients with active psoriatic arthritis: interim data from OPAL Balance, an open-label, long-term extension study. Ann Rheum Dis. 2017;76:682.
    1. Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen P, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 2015;74(12):2107–2116.
    1. Daly L. Simple SAS macros for the calculation of exact binomial and Poisson confidence limits. Comput Biol Med. 1992;22(5):351–361.
    1. Baddley JW, Winthrop KL, Chen L, Liu L, Grijalva CG, Delzell E, et al. Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic ThERapy (SABER) study. Ann Rheum Dis. 2014;73(11):1942–1948.
    1. Bharat A, Xie F, Baddley JW, Beukelman T, Chen L, Calabrese L, et al. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthritis Care Res (Hoboken). 2012;64(4):612–615.
    1. Curtis JR, Chen SY, Werther W, John A, Johnson DA. Validation of ICD-9-CM codes to identify gastrointestinal perforation events in administrative claims data among hospitalized rheumatoid arthritis patients. Pharmacoepidemiol Drug Saf. 2011;20(11):1150–1158.
    1. Curtis JR, Lanas A, John A, Johnson DA, Schulman KL. Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(12):1819–1828.
    1. Curtis JR, Sarsour K, Napalkov P, Costa LA, Schulman KL. Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor alpha agents, a retrospective cohort study. Arthritis Res Ther. 2015;17:319.
    1. Haynes K, Beukelman T, Curtis JR, Newcomb C, Herrinton LJ, Graham DJ, et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum. 2013;65(1):48–58.
    1. Kiyota Y, Schneeweiss S, Glynn RJ, Cannuscio CC, Avorn J, Solomon DH. Accuracy of Medicare claims-based diagnosis of acute myocardial infarction: estimating positive predictive value on the basis of review of hospital records. Am Heart J. 2004;148(1):99–104.
    1. Kumamaru H, Judd SE, Curtis JR, Ramachandran R, Hardy NC, Rhodes JD, et al. Validity of claims-based stroke algorithms in contemporary Medicare data: reasons for geographic and racial differences in stroke (REGARDS) study linked with medicare claims. Circ Cardiovasc Qual Outcomes. 2014;7(4):611–619.
    1. Patkar NM, Curtis JR, Teng GG, Allison JJ, Saag M, Martin C, et al. Administrative codes combined with medical records based criteria accurately identified bacterial infections among rheumatoid arthritis patients. J Clin Epidemiol. 2009;62(3):321–327.
    1. Scott FI, Mamtani R, Brensinger CM, Haynes K, Chiesa-Fuxench ZC, Zhang J, et al. Risk of nonmelanoma skin cancer associated with the use of immunosuppressant and biologic agents in patients with a history of autoimmune disease and nonmelanoma skin cancer. JAMA Dermatol. 2016;152(2):164–172.
    1. Setoguchi S, Solomon DH, Glynn RJ, Cook EF, Levin R, Schneeweiss S. Agreement of diagnosis and its date for hematologic malignancies and solid tumors between medicare claims and cancer registry data. Cancer Causes Control. 2007;18(5):561–569.
    1. Winthrop KL, Baxter R, Liu L, McFarland B, Austin D, Varley C, et al. The reliability of diagnostic coding and laboratory data to identify tuberculosis and nontuberculous mycobacterial disease among rheumatoid arthritis patients using anti-tumor necrosis factor therapy. Pharmacoepidemiol Drug Saf. 2011;20(3):229–235.
    1. Winthrop KL, Neal J, Hrycaj P, Soma K, Wilkinson B, Hodge J, et al. Evaluation of influenza and pneumococcal vaccine responses in rheumatoid arthritis patients using tofacitinib. Ann Rheum Dis. 2013;72:A107–A108.
    1. Xie F, Yun H, Bernatsky S, Curtis JR. Brief report: risk of gastrointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or other biologic treatments. Arthritis Rheumatol. 2016;68(11):2612–2617.
    1. Yawn BP, Wollan P, St Sauver J. Comparing shingles incidence and complication rates from medical record review and administrative database estimates: how close are they? Am J Epidemiol. 2011;174(9):1054–1061.
    1. Yun H, Xie F, Delzell E, Chen L, Levitan EB, Lewis JD, et al. Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease-modifying therapy. Arthritis Care Res (Hoboken). 2015;67(5):731–736.
    1. Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, 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(7):1253–1262.
    1. Papp KA, Krueger JG, Feldman SR, Langley RG, Thaci D, Torii H, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study. J Am Acad Dermatol. 2016;74(5):841–850.
    1. Sandborn WJ, Ghosh S, Panés J, Vranic I, Su C, Rousell S, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616–624.
    1. Ramiro S, Sepriano A, Chatzidionysiou K, Nam JL, Smolen JS, van der Heijde D, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1101–1136.
    1. Desai RJ, Thaler KJ, Mahlknecht P, Gartlehner G, McDonagh MS, Mesgarpour B, et al. Comparative risk of harm associated with the use of targeted immunomodulators: a systematic review. Arthritis Care Res (Hoboken). 2016;68(8):1078–1088.
    1. Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66(Suppl 10):2675–2684.
    1. Winthrop KL, Lebwohl M, Cohen AD, Weinberg JM, Tyring SK, Rottinghaus ST, et al. Herpes zoster in psoriasis patients treated with tofacitinib. J Am Acad Dermatol. 2017;77(2):302–309.
    1. Winthrop KL, Curtis JR, Lindsey S, Tanaka Y, Yamaoka K, Valdez H, et al. Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol. 2017;69(10):1960–1968.
    1. Winthrop KL, Park SH, Gul A, Cardiel MH, Gomez-Reino JJ, Tanaka Y, et al. Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75(6):1133–1138.
    1. Leiter U, Garbe C. Epidemiology of melanoma and nonmelanoma skin cancer–the role of sunlight. Adv Exp Med Biol. 2008;624:89–103.
    1. Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis. 2013;72(4):517–524.
    1. Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et al. Safety of abatacept administered intravenously in treatment of rheumatoid arthritis: integrated analyses of up to 8 years of treatment from the abatacept clinical trial program. J Rheumatol. 2013;40(6):787–797.
    1. Bykerk VP, Cush J, Winthrop K, Calabrese L, Lortholary O, de Longueville M, et al. Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials. Ann Rheum Dis. 2015;74(1):96–103.
    1. Gladman DD, Ang M, Su L, Tom BD, Schentag CT, Farewell VT. Cardiovascular morbidity in psoriatic arthritis. Ann Rheum Dis. 2009;68(7):1131–1135.
    1. Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis. 2015;74(2):326–332.
    1. Polachek A, Touma Z, Anderson M, Eder L. Risk of cardiovascular morbidity in patients with psoriatic arthritis: a meta-analysis of observational studies. Arthritis Care Res (Hoboken). 2017;69(1):67–74.
    1. Charles-Schoeman C, Wicker P, Gonzalez-Gay MA, Boy M, Zuckerman A, Soma K, et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin Arthritis Rheum. 2016;46(3):261–271.
    1. Wu JJ, Strober BE, Hansen PR, Ahlehoff O, Egeberg A, Qureshi A, et al. Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis. J Am Acad Dermatol. 2016;75(5):897–905.
    1. Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2019;71(7):1042–1055.
    1. Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, 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(10139):2513–2524.
    1. US Food and Drug Administration. XELJANZ® (tofacitinib): Highlights of prescribing information. 2019. . Accessed 29 Oct 2019.
    1. European Medicines Agency. EMA confirms Xeljanz to be used with caution in patients at high risk of blood clots. 2019. . Accessed 15 Nov 2019.
    1. Matsui D. Strategies to measure and improve patient adherence in clinical trials. Pharm Med. 2009;23(5–6):289–297.

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