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Tofacitinib Monotherapy for RA versus Risk of Adverse Events
Results of a phase 3, double-blind, placebo-controlled study [N Engl J Med. 2012;367(6):495-507] show that tofacitinib monotherapy is associated with a reduction in signs and symptoms of rheumatoid arthritis (RA) and improvement in physical function in patients with active RA who failed to achieve an adequate response with prior disease-modifying drugs. However, these benefits must be weighed against the risk of adverse effects associated with tofacitinib.
Despite improved outcomes for patients with RA with the emergence of nonbiologic disease-modifying drugs and biologic agents, the need for additional types of agents to treat RA are needed. Prior proof-of-concept and phase 2 studies have shown that tofacitinib, a novel oral Janus kinase (JAK) inhibitor, is safe and effective in patients with RA who have had an inadequate response to disease-modifying drugs.
In the current phase 3 study, sponsored by Pfizer between February 2009 through June 2010, investigators assessed the efficacy and safety of tofacitinib in 610 patients with RA randomly assigned to 1 of 4 regimens: (1) 5 mg of tofacitinib (twice daily) (n=243) for 6 months; (2) 10 mg of tofacitinib (twice daily) (n=245) for 6 months; (3) placebo (n=122) for 3 months followed by 5 mg of tofacitinib (twice daily) for 3 months; or (4) placebo for 3 months followed by 10 mg of tofacitinib (twice daily) for 3 months.
All patients in the trial were at least 18 years of age diagnosed with RA based on revised criteria of the American College of Rheumatology (ACR), had active disease, and had had an inadequate response to at least one nonbiologic or biologic disease-modifying drug.
Patients were excluded from the trial if they had received prior treatment with lymphocyte-depleting therapies or alkylating agents, had a hemoglobin level of less than 9.0 g per deciliter, a hematocrit of less than 30%, a white blood cell count of less than 3.0x109 per liter, a platelet count of less than 100x109 per liter, an estimated glomerular filtration rate of 40 ml per minute or less, a total bilirubin, aspartate aminotransferase or alanine aminotransferase level higher than 1.5 times the upper limit of normal range, or a history of various disorders including other autoimmune rheumatic diseases, recent or current infections, history of a lymphoproliferative disorder, or cancers other than adequately treated nonmetastatic basal-cell or squamous-cell skin cancer or cervical cancer in situ.
There were 3 primary end points of the study comparing tofacitinib monotherapy at 5 or 10 mg twice daily to placebo at 3 months: (1) the percentage of patients who met the criteria for ACR 20 response, defined as at least a 20% reduction from baseline in the number of tender and swollen joints as well as at least 20% improvement in 3 or more of the patient’s assessment of pain, the level of disability, C-reactive protein level, and global assessment of disease by the patient and physician; (2) change from baseline in physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI), and (3) percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of < 2.6.
The study found that significantly more patients treated with tofacitinib at 5 and 10 mg met the criteria for an ACR 20 response at 3 months compared with those who received placebo (59.8% and 65.7%, respectively, vs 26.7%; P<.001 for both comparisons). Reductions from baseline in HAQ-DI scores were also significantly greater in the patients treated with tofacitinib at 5 and 10 mg compared with placebo (-0.50 and -0.57 points, respectively, vs -0.19 points; P<.001).
According to the study’s investigators, the clinical benefits seen with tofacitinib need to be weighed against the risk of serious infections and adverse events on lipid, aminotransferase, and serum creatinine levels. Further study on the safety of tofacitinib is needed in a larger number of patients treated for longer periods of time, they added.
