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JAK Inhibitor Shows Promise in Severe Type of Sclerosis

— Study finds genetic basis long sought in disabling pansclerotic morphea, leading to effective tx

MedpageToday
A photo of bottles of varying doses of Jakafi.

The Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) eased the severe inflammatory and dermatologic symptoms of disabling pansclerotic morphea (DPM), an initial clinical series showed.

After a series of basic science and in vitro experiments uncovered a genetic basis and pointed to the inflammatory cytokine interleukin-6 (IL-6) as a key culprit in the rare condition, two severely affected patients received the oral medication with good results, reported Lori Broderick, MD, PhD, of the University of California San Diego, and colleagues in the .

One had near resolution of the chest rash and oral ulcers caused by DPM after 11 months of therapy, with substantial clearing of lesions on his arms and legs by 18 months, as well as global clinical improvement without need for any other medications.

The other patient who started the medication more recently had improvement in pulmonary hypertension, a reduction in frequency of IV immunoglobulin, resolution of neutropenia, normalization of inflammatory markers, decreased anemia, and stabilized thrombocytopenia.

No adverse effects were seen in either treated patient.

"Given the multiple systems and body-surface area affected, we expect that oral systemic therapy, rather than topical JAK inhibitor therapy, would be appropriate in patients with DPM," Broderick and team wrote. "We propose that this immunomodulatory approach may be promising for patients with refractory disease."

It might also offer hope for other sclerotic conditions.

"The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver, or bone marrow," said co-author Dan Kastner, MD, PhD, of the National Human Genome Research Institute's Inflammatory Disease Section in Bethesda, Maryland, in a .

DPM is the most severe subtype of deep morphea within the spectrum of juvenile localized scleroderma, with rapidly progressive deep fibrosis in all layers of the skin, fascia, muscle, and bone. While it has been clear that systemic inflammation is behind the poor wound healing that leads to contractures, musculoskeletal atrophy, and articular ankylosis, speculations of a genetic cause hadn't been proven.

Broderick's group studied four patients in three separate families affected by the condition. They found variants in the STAT4 gene that boost protein production essential for IL-6 receptor signaling and transcription. IL-6, in turn, is involved in activating the JAK/STAT signaling pathway that regulates cytokine responses and acts in immune responses, cell growth and differentiation, cell survival, apoptosis, and oncogenesis.

"Researchers previously thought that this disorder was caused by the immune system attacking the skin," said co-author Sarah Blackstone, BS, a predoctoral fellow with the National Human Genome Research Institute's Inflammatory Disease Section and a medical student at the University of South Dakota in Vermillion, in the NIH statement. "However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea."

When the researchers studied cells cultured from the affected patients, their unstimulated skin fibroblasts secreted 12 times as much IL-6 as seen with fibroblasts from healthy donors.

When healthy donors' fibroblasts were exposed to IL-6 through the duration of a scratch assay, they showed many of the same problems with healing as did fibroblasts from DPM patients: reduced migration, failure to close the wound, reduced transforming growth factor beta-induced contraction, and increased cell size.

"Together, these data suggest that the gain-of-function STAT4 A635V variant causes an autoinflammatory loop, largely mediated by interleukin-6, which drives the fibroblast phenotype," Broderick and colleagues noted.

Giving affected patients' cells anti-IL-6 in vitro improved their function only modestly, which suggested that inhibiting autoinflammation in the clinic might require upstream targeting of this molecular pathway, they added.

When patient's primary skin fibroblasts were treated with ruxolitinib, IL-6 secretions dropped significantly and scratch test closure nearly normalized. Activity of genes controlling inflammatory pathways -- such as IFNG, IFNA, TNF, IL6, and STAT1 -- also decreased with treatment.

"We speculated that the STAT4 gain-of-function mutations were dependent on JAK activity and explored the use of the clinically available JAK inhibitor ruxolitinib for patients in the most severely affected family," the researchers wrote. "In the patient receiving consistent therapy, we observed normalization of most immunologic variables and resolution of systemic symptoms, without adverse effects."

Aside from ruxolitinib, anti-IL-6 monoclonal antibodies -- such as tocilizumab (Actemra), "which is currently approved for interstitial lung disease in systemic sclerosis -- may be an alternative therapy or may be useful in combination with JAK inhibitors in patients with DPM," Broderick and team noted.

Disclosures

The study was supported by grants from the American Academy of Allergy, Asthma, and Immunology Foundation, the Ludwig Institute for Cancer Research, the University of California San Diego, and the Novo Nordisk Foundation. Additional support came from Deutsche Forschungsgemeinschaft, the NIH, the National Institute of General Medical Sciences, the California Institute for Regenerative Medicine, the Hydrocephalus Association, and the Scleroderma Research Foundation.

Broderick disclosed grant funding from the American Academy of Allergy, Asthma, and Immunology and the University of California San Diego Department of Pediatrics, along with funds from Novartis related to a separate phase II trial.

Primary Source

New England Journal of Medicine

Baghdassarian H, et al "Variant STAT4 and response to ruxolitinib in an autoinflammatory syndrome" N Engl J Med 2023; DOI: 10.1056/NEJMoa2202318.