JAK inhibitor ruxolitinib promising in reducing severity of rare form of sclerosis: NEJM

The present study evaluated four patients from three unrelated families (autosomal dominant pattern DPM inheritance). Genomic sequencing independently identified three heterozygous variants in genes-specific region encoding for signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays defined the functional nature of the genetic defect.

The results of the study are:

• The three novel heterozygous missense gain-of-function variants in STAT4 were revealed by Genome sequencing.
• In vitro, primary skin fibroblasts presented enhanced secretion of interleukin-6, with impaired wound healing, contraction of the collagen matrix, and matrix secretion.
• Inhibition of Janus kinase (JAK)–STAT signalling with ruxolitinib improved hyperinflammatory fibroblast phenotype.
• Using JAK inhibitors led to the resolution of inflammatory markers and clinical symptoms. One patient had near resolution of the chest rash and oral ulcers following 11 months of therapy. By 18 months, lesions were cleared on the patient's arms and legs.

• Other patients showed improvement in pulmonary hypertension, reduced frequency of IV immunoglobulin, and neutropenia resolution. There was a reduction in inflammatory markers and anaemia.

• No adverse events were reported.
• Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that was appropriately modified through JAK inhibition.

This study identified genetic basis and inflammatory cytokine interleukin-6 (IL-6) as the main culprits in this rare condition.

They said, “Gain-of-function variants in STAT4 caused DPM in the families we studied.”

Ruxolitinib attenuated dermatologic and inflammatory phenotype (in vitro and affected family members).

As acknowledged, the study received funding from the American Academy of Allergy, Asthma, and Immunology Foundation and others.

Further reading:

https://www.nejm.org/doi/full/10.1056/NEJMoa2202318