Tofacitinib for dermatomyositis: A potential belle of the ball?
By Warren R. Heymann, MDAug. 23, 2016
JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling plays a role in the development of several malignancies including leukemias, lymphomas, and myeloproliferative neoplasms. Tofacitinib (Xeljans) is a pan-JAK inhibitor that is approved by the FDA for the treatment of rheumatoid arthritis and ruxolitinib (Jakafi) is a JAK1/2 inhibitor approved for the treatment of polycythemia vera and myelofibrosis (1).
We have previously discussed the expanding use of JAK inhibitors, notably ruxolitinib for chilblain lupus erythematosus, and anticipated further reports for other collagen vascular disorders, such as dermatomyositis. Kurtzman et al, who demonstrated impressive cutaneous improvement in 3 patients utilizing tofacitinib for recalcitrant, multidrug-resistant cutaneous dermatomyositis, have now reported this, utilizing the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). Two patients improved from moderate-to-severe to mild disease using tofacitinib as monotherapy; a third patient improved to a lesser degree, while also receiving hydroxychloroquine. The authors suggested that JAK inhibitors may be valuable for dermatomyositis and recommended further studies. Importantly, they stated: “Because each patient had dermatomyositis for more than 3 years before starting tofacitinib, these patients were past the high-risk period in which adult-onset dermatomyositis is associated with malignancy” (2).
What is the actual malignant risk for patients receiving tofacitinib? Curtis et al studied 5671 tofacitinib-treated patients with rheumatoid arthritis. 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardized incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA. The authors concluded that “The overall rates and types of malignancies observed in the tofacitinib clinical program remained stable over time with increasing tofacitinib exposure. Continued longer-term surveillance is necessary to further evaluate any potential malignancy risk during tofacitinib treatment” (3).
JAK inhibitors will play an increasingly important role in the management of recalcitrant, severe inflammatory diseases, including connective tissue disease. Despite its impressive debut in treating recalcitrant dermatomyositis, because of the malignant risk, this debutante should not be the first to attend the ball. Should the other suitors (hydroxycholoroquine, methotrexate, mycophenolate mofetil, IVIG) fall by the wayside, and associated malignancies are ruled out beyond the high-risk time frame, that would be an appropriate time for tofacitinib to be at the center of the dance.
1. Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res 2016; 111: 784-803.
2. Kurtzman DJB, et al. Tofacitinib citrate for refractory cutaneous dermatomyositis: An alternative treatment. JAMA Dermatology 2016; 152: 944-5.
3. Curtis JR, et al. Tofacitinib, an oral Janus kinase inhibitor: Analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis 2016; 75: 831-841.
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