Genetic Variants in STAT4 Linked to Disabling Pansclerotic Morphea: JAK Inhibition Shows Promising Results

Hratch Baghdassarian, BS, PhD Candidate

Credit: Google Scholar

A collaborative effort involving 14 institutions sought to examine the genetic variants in STAT4 that are correlated with disabling pansclerotic morphea (DPM), a rare systemic inflammatory disorder. The study findings revealed the therapeutic potential of Janus kinase (JAK) inhibition.

The investigators observed that gain-of-function variants in STAT4 were associated with the development of DPM in the 4 patients evaluated and intervention with JAK inhibitor ruxolitinib displayed favorable outcomes by attenuating the dermatologic and inflammatory phenotype in vitro and in affected patients.

Based on previous evidence, the pathogenesis of the disease has been linked to abnormal synthesis and deposition of collagen, vascular damage, and altered immunoregulation, similar to other forms of scleroderma. Despite extensive research, the genetic etiology remains unidentified.

Mortalities are high in these patients and have primarily been attributed to complications including squamous-cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene which contribute to a postdiagnosis survival time of less than 10 years.

The standard treatment approach includes a combination of various pharmaceutical and ancillary therapies: methotrexate, mycophenolate mofetil, and ultraviolet A light therapy. These treatments aim to halt the progression of the disease but the research noted they have demonstrated limited efficacy and adverse events.

In this study, Hratch Baghdassarian, BS, PhD Candidate, Bioinformatics and Systems Biology, University of California San Diego, and an extension team of investigators aimed to examine the genetic basis of DPM and explore the therapeutic potential of the JAK inhibitor ruxolitinib.

The Intervention and Analysis

The population consisted of 4 individuals from 3 different families with an autosomal dominant pattern of inheritance and presented with early-onset DPM characterized by a range of symptoms: mucosal lesions, joint swelling, contractures, progressive skin ulcerations, and muscle wasting.

Patients were diagnosed with DPM based on clinical evaluations, skin biopsies, and imaging studies, which confirmed the presence of morphea and associated tissue changes. Genomic sequencing was performed to identify potential genetic variants associated with the condition.

The sequencing identified 3 novel heterozygous missense gain-of-function variants were identified in the signal transducer and activator of transcription 4 (STAT4) gene. In vitro experiments using primary skin fibroblasts showed enhanced interleukin-6 secretion, impaired wound healing, collagen matrix contraction, and matrix secretion.

The intervention involved initiating oral ruxolitinib treatment in Patients 1 and 2 after identifying gain-of-function STAT4 variants. Single-cell RNA sequencing was performed on peripheral-blood samples to analyze cell types and differential gene expression in specific cell types, such as natural killer cells and T cells known to express STAT4.

Pathway analysis revealed that ruxolitinib treatment reduced the activity of genes controlling inflammatory pathways in these cell types.

Additionally, treatment with ruxolitinib ameliorated the hyperinflammatory fibroblast phenotype in vitro and resulted in the resolution of inflammatory markers and clinical symptoms in the treated patients, without any adverse effects.

Investigators also reported an analysis of single-cell RNA sequencing data indicated an immunodysregulatory phenotype that was appropriately modified by JAK inhibition.

The Patients

All 4 patients experienced disease onset before the age of 5 and exhibited signs of mucosal ulcerations and skin sclerosis. Hematoxylin and eosin staining of skin biopsy samples confirmed the presence of morphea. Musculoskeletal imaging revealed deep-tissue inflammation and sclerosis, indicating the presence of DPM in the affected individuals.

The pair of related patients were diagnosed with DPM via skin biopsy at the University of California, San Diego. Patient 1 developed mucosal lesions at the age of 3, while Patient 2 experienced polyarthritis as the initial symptom. Both patients exhibited inflammation, ulcerative lesions of the skin, joint swelling, and contractures.

With the initiation of oral ruxolitinib, Patient 1 experienced significant improvement in dermatologic symptoms and laboratory evaluations showed stable leukocyte counts, normal levels of inflammatory markers, and normal IgG and IgM levels (with persistent IgA deficiency). No adverse events were reported during ruxolitinib treatment.

After 18 months of treatment, Patient 1 discontinued all other medications, with complete resolution of the chest rash, substantial clearing on the arms and legs, and overall clinical improvement.

Improvement in pulmonary hypertension was observed in Patient 2 following treatment initiation. He continued to receive intravenous immunoglobulin infusions for low IgG levels but investigators reported the ability to extend the infusion intervals to up to 2 months.

The patient’s neutropenia also resolved, inflammatory markers normalized, anemia decreased, and thrombocytopenia stabilized.

According to the study, these data provide valuable insights into the pathogenesis of DPM and suggest that targeting JAK-STAT signaling may hold therapeutic potential for managing this debilitating disorder. Investigators acknowledged the need for further investigation and clinical trials to validate these findings and explore the efficacy of JAK inhibitors in a larger cohort of DPM patients.

References:

1. Baghdassarian H, Blackstone SA, Clay OS, et al. Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome. N Engl J Med. 2023