Tofacitinib is an oral, small molecule inhibitor of Janus kinases that is used to treat moderate-to-severe rheumatoid arthritis. Tofacitinib is associated with transient and usually mild elevations in serum aminotransferase levels during therapy, but has yet to be linked to cases of clinically apparent acute liver injury.
Tofacitinib (tow" fa sye' ti nib) is an orally available, specific inhibitor of Janus-associated kinases (mainly JAK1 and JAK3) that is used to treat moderate-to-severe rheumatoid arthritis. The Janus kinases are critical steps in immune activation as well as in hematopoiesis. The immunomodulatory effects of tofacitinib led to its evaluation in several autoimmune conditions including rheumatoid arthritis and psoriasis. In multiple, randomized controlled trials, tofacitinib was found to improve symptoms and signs of severe rheumatoid arthritis when used alone or in combination with other disease modifying antirheumatologic drugs (DMARDs). Tofacitinib was approved for use in the United States in 2012. Current indications are limited to moderate-to-severe rheumatoid arthritis after failure or intolerance to methotrexate or other non-biological DMARDs. Tofacitinib is available in tablets of 5 mg under the brand name Xeljanz. The recommended dose is 5 mg twice daily. More recently, an extended release formulation of tofacitinib (Xeljanz XR, 11 mg tablets) that allows for once daily dosing has been made available. Common side effects of tofacitinib are neutropenia, headaches, diarrhea, fatigue, hypertension and symptoms of upper respiratory tract infection. Severe adverse events may include severe infections, reactivation of latent tuberculosis, gastrointestinal perforation and de novo malignancies including Epstein-Barr virus related lymphoproliferative disorder.
In the large registration clinical trials, serum aminotransferase elevations occurred in 28% to 34% of tofacitinib treated subjects compared to 25% in comparator arms and 10% in placebo recipients. These elevations were typically mild and transient, but values above 3 times the upper limit of normal (ULN) occurred in 1% to 2% of patients on tofacitinib compared to <1% on placebo. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to tofacitinib. Since approval and more wide scale availability of tofacitinib, there have been no published reports of hepatotoxicity or reactivation of hepatitis B associated with its use. Thus, clinically apparent liver injury from tofacitinib must be rare if it occurs at all.
Likelihood score: E* (suspected but unproven rare cause of clinically apparent liver injury).
Mechanism of Injury
The causes of serum enzyme elevations during tofacitinib therapy are not known. Tofacitinib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic or immunogenic intermediate. Because it is a substrate for CYP 3A4, tofacitinib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity.
Outcome and Management
Monitoring of serum aminotransferase levels is recommended for patients starting tofacitinib. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There are no data to suggest a cross reactivity in risk for hepatic injury between tofacitinib and other kinase inhibitors or biologic or nonbiologic DMARDs.
REPRESENTATIVE TRADE NAMES
Tofacitinib – Xeljanz®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 22 June 2018
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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 (Hoboken) 2011; 63: 1150-8. PubMed Citation (Among 140 patients with rheumatoid arthritis receiving methotrexate treated with tofacitinib [1, 3, 5 or 10 mg] or placebo twice daily for 12 weeks, ALT elevations occurred in 19% of patients on tofacitinib [vs 4% on placebo], but levels were above 3 times ULN in only 3% and no patient developed clinically apparent liver injury).
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van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, García Meijide JA, Wagner S, Forejtova S, et al.; ORAL Standard Investigators. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367: 508-19. PubMed Citation (Among 717 patients with rheumatoid arthritis on methotrexate treated with tofacitinib [5 or 10 mg] or adalimumab or placebo for 52 weeks, clinical response rates were higher for tofacitinib [52-53%] than placebo [28%] and adverse events were more common [with two cases of pulmonary tuberculosis]; ALT elevations during the first 3 months occurred in 26% on tofacitinib vs 17% on placebo).
Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, Gruben D, et al.; ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367: 495-507. PubMed Citation (Among 611 patients with rheumatoid arthritis treated with tofacitinib [5 or 10 mg] or placebo twice daily for 3 months, clinical response rates were higher with tofacitinib, and adverse events included headache, infections, neutropenia and increases in serum cholesterol; ALT elevations above 3 times ULN occurred during the first 3 months in <1% of both groups).
Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, Isaacs JD, 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: 253-61. PubMed Citation (Among 795 patients with rheumatoid arthritis [and an inadequate response to DMARDs] treated with tofacitinib [5 or 10 mg] or placebo twice daily for 3 months with extension of active treatment for 1 year, 3 tofacitinib treated patients stopped therapy early because of ALT or AST elevations, but there were no reports of clinically apparent liver injury).
Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, Gruben D, et al.; ORAL Step investigators. 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 (9865): 451-60. PubMed Citation (Among 399 patients with rheumatoid arthritis [and an inadequate response to antitumor necrosis factor agents] treated with tofacitinib [5 or 10 mg] or placebo twice daily for 3 months, ALT elevations occurred in 17% on tofacitinib vs 13% on placebo, but were above 3 times ULN in 0.8% vs 0% and no patient developed clinically apparent liver injury).
Tofacitinib (Xeljanz) for rheumatoid arthritis. Med Lett Drugs Ther 2013; 55 (1407); 1-3. PubMed Citation (Concise review of the mechanism of action, pharmacology, efficacy, safety and costs of tofacitinib shortly after its approval for in the US, mentions that elevations in ALT and AST have occurred with therapy and that “liver enzymes should be monitored regularly”).
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Strategy investigators. Efficacy and safety of tofacitinib monotherapy,
tofacitinib with methotrexate, and adalimumab with methotrexate in patients with
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randomised controlled trial. Lancet 2017; 390 (10093): 457-68. PubMed Citation (Among 1146 patients with rheumatoid arthritis treated with tofacitinib alone or with methotrexate or adalimumab for 1 year, response rates were slightly higher with addition of methotrexate [46%] and adalimumab [44%] compared to tofacitinib alone, as were ALT elevations above 3 times ULN [4% and 4% vs 2%], and 2 patients developed "drug-induced liver injury").
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randomized, double-blind, placebo-controlled study. J Dermatol Sci 2017; 88: 36-45. PubMed Citation (Among 266 Asian patients with plaque psoriasis treated with tofacitinib or placebo for 16 weeks and then "advanced" to tofacitinib, only 3 patients had ALT elevations above 3 times ULN and none developed symptoms or jaundice).
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rheumatoid arthritis. Rheumatol Ther 2018; 5: 283-91. PubMed Citation (Postmarketing reports of adverse events over a 3 year period identified 4352 serious adverse events, the most frequent of which were infections [n=827, 2.6 per 100 patient-yrs] and hepatobiliary disorders were rare [n=41, 0.12 per 100 patient-yrs], but no details provided).
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