First JAK inhibitor approved as second-line RA treatment


Tofacitinab approved for 5-mg tablets for the treatment of adult patients with moderately to severely active rheumatoid arthritis unhealed by methotrexate


In November 2012, FDA approved tofacitinib (Xeljanz, Pfizer) 5-mg tablets for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have not shown an adequate response to methotrexate or who are intolerant to methotrexate. Tofacitinib, an oral nonbiologic disease-modifying antirheumatic drug (DMARD), can be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs. It is contraindicated for use with biologic DMARDs or with immunosuppressive agents, such as azathioprine and cyclosporine.

Tofacitinib is the first treatment for RA with a new class of drugs, Janus kinase (JAK) inhibitors. JAKs are enzymes that transmit signaling from cytokines and growth-factor receptors involved in hematopoiesis and immune function. Tofacitinib inhibits JAKs; this in turn blocks the signaling of several cytokines and interleukins involved in lymphocyte function. 

Tofacitinib was approved with a Risk Evaluation and Mitigation Strategy (REMS), including a Medication Guide for patients, a communication plan for healthcare providers and pharmacists, and periodic submissions of assessments of the REMS. The manufacturer will also be conducting post-marketing clinical trials to evaluate long-term safety of tofacitinib and to determine its efficacy and safety in children with polyarticular juvenile idiopathic arthritis.


FDA approved tofacitinib on the basis of two six-month dose-ranging studies and five confirmatory studies, which evaluated approximately 5,000 patients with RA. Based on two dose-finding studies, tofacitinib 5 mg and 10 mg twice daily were evaluated in five confirmatory trials. Trials evaluated patients with moderate-to-severe RA in addition to one of the following characteristics: inadequate DMARD response, inadequate nonbiologic DMARD response, inadequate methotrexate response, or inadequate tumor necrosis factor inhibitor response.  Tofacitinib was used either alone or in addition to a nonbiologic DMARD, often methotrexate. In the trial evaluating patients with inadequate response to methotrexate, adalimumab was also used as a comparator. Primary end points of the trials included the American College of Rheumatology 20 (ACR20), change in Health Assessment Questionnaire–Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28–4 (ESR) less than 2.6.

In all the studies, patients treated with tofacitinib at either 5 mg or 10 mg twice daily had a higher ACR20 response rate than that of the placebo group, regardless of background DMARD therapy. In patients with inadequate response to methotrexate, addition of tofacitinib 5 mg or 10 mg twice daily increases achievement of a Disease Activity Score of DAS28-4 (ESR) less than 2.6 (1% in methotrexate plus placebo, 6% in methotrexate plus tofacitinib 5 mg, and 13% in methotrexate plus tofacitinib 10 mg groups).

Physical function as measured by the HAQ-DI improved from baseline to 3 months in patients who inadequately responded to methotrexate when tofacitinib 5 mg or 10 mg twice daily was added to methotrexate. The mean differences in both tofacitinib groups were significant [-0.22 (-0.35 to -0.10) in patients taking tofacitinib 5 mg and -0.32 (-0.44 to -0.19) in tofacitinib 10-mg groups]. The manufacturer reports that similar findings were noted in the other trials as well.


Tofacitinib carries a boxed warning of risk for serious infections, lymphoma, and other malignancies. The most common adverse event observed in the clinical trial program was serious infection, although the difference in risk was not significant when tofacitinib was compared to placebo, using data at 3 months [risk difference 1.1 (-0.4 to 2.5) events per 100 patient years]. Longer-term data compared to placebo is not yet available. The most common serious infections were pneumonia, cellulitis, herpes zoster, and urinary tract infections. Although no cases of tuberculosis (TB) were reported at 3 months, by 12 months 6 patients in the tofacitinib 10-mg group had TB. Patients must be tested for latent TB before initiation of treatment with tofacitinib, and if the test results are positive, should be treated for TB before initiation of tofacitinib therapy. All patients should be monitored for active TB as well as for other infections during treatment, since infections that have led to hospitalization or death have been observed during tofacitinib therapy. Because of the lack of data, live vaccines should not be administered to patients taking tofacitinib, and immunizations should be updated before initiation of therapy.

Patients who have had a malignancy previous to tofacitinib treatment or develop a malignancy during tofacitinib treatment need to consider the risk and benefits of tofacitinib. Of the 3,328 patients in the clinical trial program who received tofacitinib with or without a DMARD, there have been 11 solid tumors and one lymphoma case at 12 months. No malignancies have been reported in the 809 patients treated with placebo. In a small trial of renal transplant patients, five of 218 patients treated with tofacitinib developed Epstein Barr Virus-associated post-transplant lymphoproliferative disorder, compared with none in the 11 cyclosporine-treated patients.

Other safety findings included gastrointestinal perforations, lymphocytosis, neutropenia, decreased hemoglobin, liver enzyme elevations, and lipid elevations. The most commonly reported side effects were upper respiratory tract infections, headache, diarrhea, hypertension, and nasopharyngitis.


The recommended dose of tofacitinib is 5 mg twice daily. In the following patients, tofacitinib should not be initiated: those with severe hepatic impairment, a lymphocyte count less than 500 cells/mm3, an absolute neutrophil count less than 1000 cells/mm3, or hemoglobin levels less than 9 g/dL. Tofacitinib should be interrupted for the management of lymphopenia, neutropenia, and anemia, either by reducing the dose to 5 mg daily or holding the dose until lab values have normalized. There are also recommendations to reduce the dose to 5 mg daily in patients who have moderate-to-severe renal insufficiency or moderate hepatic impairment; or who are receiving potent inhibitors of cytochrome P450 3A4, such as ketoconazole, and receiving one or more concomitant medications that can result in moderate inhibition of CYP3A4 and potent inhibition of CYP2C19. Patients taking potent CYP3A4 inducers may have a reduced response to tofacitinib.

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