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Off-label use of JAK inhibitors: Promising efficacy in dermatomyositis, but not always safe

Natalia Reoutova
28 Dec 2019
Prof Kunihiro Yamaoka

Janus kinase (JAK) inhibitors have shown promising efficacy in dermatomyositis (DM) with interstitial lung disease (ILD) but are not without risks, according to Professor Kunihiro Yamaoka of Kitasato University School of Medicine, Tokyo, Japan, who discussed off-label use of some JAK inhibitors at the International Conference of Chinese Rheumatologists (ICCR) 2019 held in Hong Kong.

Rapidly progressive ILD is frequently associated with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) DM and amyopathic DM. [Arthritis Rheum 2005;52:1571-1576] Overproduction of multiple cytokines plays a crucial role in the development of anti-MDA5 Ab+ DM and accompanying ILD. [Rheumatology 2014;53:2196-2203] “Therefore, blocking of multiple cytokines, such as types I and II interferons [IFNs] and interleukin [IL]-6, with a JAK inhibitor could represent a new therapeutic approach for this condition,” suggested Yamaoka.

The effectiveness of JAK inhibitor therapy in DM was first reported as early as 2014, in a case with refractory DM and concomitant myelofibrosis, both of which were successfully treated with ruxolitinib, a JAK1/2 inhibitor. [N Engl J Med 2014;371:2537-2538] The effectiveness of tofacitinib, another JAK inhibitor, was later reported in three cases of DM with refractory cutaneous manifestations and a case of DM with cutaneous, articular, and muscular manifestations. [JAMA Dermatol 2016;152:944-945; Semin Arthritis Rheum 2017;46:e19]

Adding tofacitinib to triple therapy with high-dose glucocorticoids, cyclosporin A and cyclophosphamide was subsequently shown to control refractory anti-MDA5 Ab+ ILD in a small group of Japanese patients (n=5). The survival rate of patients who received tofacitinib was considerably higher than that of historical controls treated with immunosuppressive therapy. However, patients treated with the combination therapy became susceptible to infections and experienced cytomegalovirus reactivation. [Rheumatology 2018;57:2114-2119]

A Chinese single-centre, open-label clinical study evaluated the efficacy of tofacitinib in 18 patients with early-stage anti-MDA5 Ab+ DM and associated ILD against 32 historical controls who received conventional treatments. Survival at 6 months after ILD onset was significantly higher among patients in the prospective group (18 of 18; 100 percent) vs the control group (25 of 32; 78 percent) (p=0.04). Ferritin level, forced vital capacity, single-breath carbon monoxide diffusing capacity, and findings on high-resolution CT were also considerably improved over time in the tofacitinib group. In addition, most of the adverse events AEs in patients who received tofacitinib were of low grade. [N Engl J Med 2019;381:291-293]

“However, a review by the European Medicines Agency [EMA] Pharmacovigilance Risk Assessment Committee [PRAC] has concluded that tofacitinib could increase the risk of blood clots in the lungs and in deep veins in patients who are already at high risk, such as those with heart failure or prior MI, cancer, inherited blood clotting disorders or a history of blood clots, as well as patients on combined hormonal contraceptives or hormone replacement therapy, those undergoing major surgery, or those who are immobile. Tofacitinib should be used with caution in such patients,” Yamaoka cautioned. “Doctors should also consider other factors that may increase the risk of blood clots, including age, obesity, diabetes, hypertension or smoking.”

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