Genetic variants in STAT4 linked to disabling pansclerotic morphea: JAK inhibition shows promise

Hratch Baghdassarian, graduate, PhD candidate

Credit: Google Scholar

A collaborative effort involving 14 institutions sought to examine genetic variants in STAT4 that correlate with disabling pansclerotic morphea (PMD), a rare systemic inflammatory disease. The study results 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 PMD in the 4 patients evaluated, and intervention with the JAK inhibitor ruxolitinib showed favorable outcomes by attenuating the dermatological and inflammatory phenotype in vitro and in affected patients.

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

Deaths are high in these patients and have mainly been attributed to complications including squamous cell carcinoma, restrictive lung disease, sepsis and gangrene which contribute to a post-diagnosis survival time of less than 10 years.

The standard treatment approach involves 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 research has found they have demonstrated limited efficacy and no adverse.

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

The intervention and the analysis

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

Patients were diagnosed with PMD 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.

Sequencing identified 3 novel heterozygous missense gain-of-function variants identified in signal transducer and activator transcription gene 4 (STAT4). In vitro experiments using primary skin fibroblasts have shown increased interleukin-6 secretion, impaired wound healing, collagen matrix contraction, and matrix secretion.

The intervention involved initiation of oral ruxolitinib treatment in patients 1 and 2 after gain-of-function STAT4 variants were identified. 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 that control inflammatory pathways in these cell types.

Furthermore, ruxolitinib treatment improved the hyperinflammatory fibroblast phenotype in vitro and led to resolution of inflammatory markers and clinical symptoms in treated patients, without any adverse effects.

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

The patients

All 4 patients had disease onset before the age of 5 and showed signs of mucosal ulcerations and cutaneous sclerosis. Hematoxylin and eosin staining of skin biopsy specimens confirmed the presence of morphea. Musculoskeletal imaging revealed deep tissue inflammation and sclerosis, indicating the presence of MPD in affected individuals.

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

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

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

In Patient 2, improvement in pulmonary hypertension was observed after initiation of treatment. She continued to receive intravenous immunoglobulin infusions for low IgG levels, but the investigators reported the possibility of extending the infusion intervals up to 2 months.

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

According to the study, these data provide valuable insight into the pathogenesis of DPM and suggest that targeting JAK-STAT signaling may have therapeutic potential for managing this debilitating disorder. The researchers recognized the need for further investigations and clinical trials to validate these findings and explore the efficacy of JAK inhibitors in a larger cohort of PMD patients.

References:

  1. Baghdassarian H, Blackstone SA, Clay OS, et al. Variant STAT4 and response to ruxolitinib in an autoinflammatory syndrome. N English J Med. 2023

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