Study of Tofacitinib in Refractory Dermatomyositis: An Open-Label Pilot Study of Ten Patients.

OBJECTIVE: This open-label 12-week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment-refractory active dermatomyositis (DM). METHODS: Tofacitinib in extended-release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid-sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety. RESULTS: At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin. CONCLUSION: This is the first prospective, open-label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan-JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.

Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis.

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor-ß2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFß2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.