Psoriasis is a chronic inflammatory disease that predominantly affects the skin and may affect other organ systems, particularly the joints. About one third of patients with psoriasis have psoriatic arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the recommended first-line therapy for patients with mild disease.
For patients with more-severe disease, treatment with disease-modifying anti-rheumatic drugs (DMARDs) is recommended. DMARDs are classified as conventional synthetic DMARDS (methotrexate, sulfasalazine, leflunomide), targeted synthetic DMARDs (e.g. phosphodiesterase-4 inhibitors; apremilast), and biologic DMARDs (e.g. tumor necrosis factor inhibitors, IL-12/23 inhibitors, IL-17 inhibitors).
For patients with severe disease, enthesitis (inflammation around the insertion site of tendons, ligaments, or fascia to the bone), and axial disease who have had inadequate responses to conventional synthetic DMARDs, tumor necrosis factor (TNF) inhibitors are the current standard of care. However, limitations of TNF inhibitors include loss of efficacy resulting from the development of antibodies against biologic agents and increased risk of hypersensitivity reactions or drug-related adverse events.
What is tofacitinib?
Tofacitinib is an oral Janus kinase (JAK) inhibitor that affects both the innate and adaptive immune responses. Tofacitinib blocks the production of cytokines that are directly and indirectly regulated by the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway, leading to the down regulation of TNF and IL-17, the two inflammatory cytokines implicated in psoriatic arthritis.
What is this study about?
In this multicenter, double-blind, placebo-controlled, phase 3 trial, 395 patients with active psoriatic arthritis and inadequate responses to one or more TNF inhibitors were randomized to receive tofacitinib (5 mg or 10 mg twice daily) or placebo. At 3 months, the placebo arms were switched to tofacitinib treatment.
The primary outcomes were the percentage of patients at 3 months who had an American College of Rheumatology 20 (ACR20) response and the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score. The ACR20 response is ≥20% improvement from baseline in the number of tender and swollen joints and in three of the following domains: patient’s assessment of disease activity, patient’s assessment of pain, physician’s assessment of disease activity, disability, or acute-phase response (C-reactive protein level). The HAQ-DI is a measure of physical function., based on the patients’ responses to 20 questions about their ability to perform activities of daily living.
What are the results?
At 3 months, a significantly higher percentage of patients treated with tofacitinib had ACR20 responses, compared with placebo (50% and 47% with 5 and 10 mg tofacitinib, respectively vs. 24% with placebo; P<0.001 for both comparisons). Tofacitinib-treated patients also had improved physical function as measured by the change in the mean HAQ-DI score (-0.39 and -0.35 vs. -0.14, respectively; P<0.001 for both comparisons).
However, during 3 months of treatment, the rate of adverse events (including lipid profile and liver enzyme elevations, serious infections, and herpes zoster) was higher among patients who received tofacitinib (5 mg, 55% and 10 mg, 53%) than among those who received placebo (44%). Serious adverse event rates were 1% and 2% in the tofacitinib groups, respectively, and 2% in the placebo group.
Editorialists Robert A. Colbert and Michael M. Ward from the National Institutes of Health state: “Comparisons of tofacitinib with other biologic DMARDs will inform its place in the treatment algorithm of psoriatic arthritis.” Because tofacitinib appears to carry an additional risk for herpes zoster infection, they add, “differences in safety will also inform the choice of treatments.” Whether lipid profile elevations associated with tofacitinib treatment have long-term cardiovascular consequences also remains uncertain.
What is my take-away?
Tofacitinib, an oral JAK inhibitor, is beneficial in patients with psoriatic arthritis who previously had inadequate responses to one or more TNF inhibitors, but questions about its safety profile and durability of response will require longer trials.
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James was a 2015-2016 NEJM Editorial Fellow. He recently completed fellowship in General Internal Medicine at Brigham and Women’s Hospital. He is interested in evidence-based medicine, medical education, knowledge translation, and pharmacoepidemiology.