Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. In this case series, ruxolitinib was associated with improved inflammatory markers in patients with disabling pansclerotic morphea (DPM).

2. Ruxolitinib use was also associated with improved clinical symptoms in treated patients with DPM.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

DPM is a severe autoinflammatory disorder characterized by poor wound healing with rapidly progressive deep fibrosis. DPM is often refractory to systemic steroids, immunosuppression, and autologous stem-cell transplantation therapies. DPM is also associated with a substantially increased risk of squamous cell carcinoma. Ruxolitinib has been proposed to improve outcomes in patients with DPM with monoallelic gain-of-function variants in the gene encoding Signal Transducer and Activator of Transcription 4 (STAT 4). However, there is a gap in knowledge as to understanding the effect of ruxolitinib on DPM and whether it would appropriately inhibit the Janus Kinase (JAK)-STAT signaling pathway responsible for the manifestations of DPM. Overall, this study found that Ruxolitinib provided some benefit in improving the inflammatory markers and clinical symptoms in patients with gain-of-function variants in STAT4 caused by DPM. This study was limited by the small sample size of patients and patient families tested. Nevertheless, these study’s findings are significant, as they demonstrate that the JAK inhibitor ruxolitinib was associated with improvement in clinical symptoms and laboratory results in patients with STAT4 gain-of-function mutations caused by DPM.

Relevant Reading: Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease

In-Depth [case series]:

This case series studied the disease course of four patients in three independent families with DPM. These patients had monoallelic gain-of-function variants in the gene encoding STAT4. Patients with this mutation were eligible for the study. The primary outcome measured was evaluated using patients’ blood samples. These samples were used to perform a host of laboratory tests such as flow cytometry, fluorescence imaging, wound-healing assays, and enzyme-linked immunosorbent assays. The clinical course of DPM in these patients was monitored, as well. Outcomes in the primary analysis were assessed via either the Student’s t-Test or the Kruskal-Wallis test. Based on the primary analysis, inhibition of Janus kinase (JAK)–STAT signaling with ruxolitinib led to an improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that was appropriately modified through JAK inhibition via ruxolitinib. In summary, this case series demonstrates that JAK inhibition via Rruxolitinib may provide improved dermatologic and inflammatory symptoms in patients with gain-of-function variants in STAT4 caused by DPM.

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