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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03002649.

Figure 1.. Key Outcome Measures including the Total Improvement Score and CDASI.

(a) The median improvement score of all 10 subjects demonstrates that the TIS improved over the 12 week study period; (b) Graphical representation of the TIS of each individual subject in the study and (c) Boxplot demonstrates total CDASI activity scores from baseline to week 12 with the median shown as the line in the box. The whiskers of each boxplot represent the spread of the scores.

Figure 2.. Cutaneous improvement after treatment with tofacitinib.

Improvement in Skin Disease with Treatment at Baseline, 4 weeks and 12 weeks in study subjects enrolled in the study.

Figure 3.. Median Serum Chemokine (CXCL 9 and 10) from baseline (0 weeks) to 12 weeks with 95% confidence intervals for the median.

Levels of both are in pg/mL (Y-axis). *CXCL10: Wilcoxon rank sum test for difference between median at 12 weeks and median at baseline, p = 0.013; ** (CXCL9 (pg/mL)) Wilcoxon rank sum test for difference between median at 12 weeks and median at baseline, p=0.049

Figure 4.. STAT1 immunostaining staining is downregulated in skin biopsies from baseline to 12 weeks.

Skin paraffin sections from affected skin biopsied at baseline and 12 weeks after starting treatment were stained for STAT1.

Figure 5.. Tofacitinib suppresses IFN target gene expression in skin biopsies.

(A) Volcano plots of differentially expressed genes (dots) between baseline and 12 weeks of tofacitinib treatment. (B) Top Ingenuity Pathway Analysis predictions of upstream regulators of differentially expressed genes assessed by RNA-seq. Adjusted p value < 0.05. Upstream regulators were predicted as inhibited (yellow) or activated (blue). (C) Table shows differentially expressed genes targeted by each upstream regulator.