JAK inhibitors hold promise for severe sclerosis

The Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) was shown in the first clinical series to alleviate the severe inflammatory and cutaneous manifestations of disabling pansclerotic morphea (DPM).

Critically ill patient 2 after a series of basic science and in vitro experiments revealed a genetic basis and pointed to the inflammatory cytokine interleukin-6 (IL-6) as a key culprit in a rare condition. reported that they received oral medication with good results.Lori Broderick, MD, University of California, San Diego, and his colleagues New England Journal of Medicine.

One patient reported near-clearance of DPM-induced chest rash and oral ulcers after 11 months of treatment, and by 18 months the lesions on her arms and legs had largely disappeared, and she had fully recovered without the need for other medications. improved clinical symptoms.

Other patients who started medication more recently showed improvement in pulmonary hypertension, less frequent IV immune globulin, resolution of neutropenia, normalization of inflammatory markers, decreased anemia, and thrombocytopenia was found to stabilize.

No side effects were seen in patients receiving either treatment.

“Given the multiple systemic systems and body surface areas affected, oral systemic rather than topical JAK inhibitor therapy would be appropriate for patients with DPM,” Broderick and team wrote. ing. “We propose that this immunomodulatory approach may hold promise for patients with intractable diseases.”

It may also offer hope for other sclerosing diseases.

“The results of this study open the door to the potential of JAK inhibitors as a treatment for other inflammatory skin diseases and diseases associated with tissue scarring, such as lung, liver and bone marrow scarring. said co-author Dan Kastner. M.D., Division of Inflammatory Diseases, National Human Genome Institute, Bethesda, Maryland. Statement from NIH.

DPM is the most severe subtype of deep morphea within juvenile focal scleroderma, with rapidly progressive deep fibrosis involving all layers of skin, fascia, muscle and bone. Although systemic inflammation is clearly behind poor wound healing leading to contractures, musculoskeletal atrophy and ankylosis, speculation of a genetic cause has not been proven.

Broderick’s group studied four patients from three separate families with the disease. They are, STAT4 A gene that promotes the production of a protein essential for IL-6 receptor signaling and transcription. IL-6, in turn, participates in the activation of the JAK/STAT signaling pathways that regulate cytokine responses, affecting immune responses, cell growth and differentiation, cell survival, apoptosis, and carcinogenesis.

“Researchers had previously believed that the disease was caused by the immune system attacking the skin,” said co-author, former postdoctoral fellow in the Division of Inflammatory Diseases at the National Human Genome Institute and medical student at the University of South Dakota. Sarah Blackstone says In Vermilion, in an NIH statement. “However, this is an oversimplification and we found that both the skin and the immune system play an active role in counteracting pansclerotic morphea.”

When the researchers studied cells cultured from diseased patients, unstimulated skin fibroblasts secreted 12 times more IL-6 than fibroblasts from healthy donors.

When healthy donor fibroblasts were exposed to IL-6 for the duration of the scratch assay, they showed many problems with healing, similar to DPM patient fibroblasts. reduced migration, failure to close wounds, and reduced transforming growth factor beta. Contraction was induced and cell size increased.

“Together, these data suggest that gain of function STAT4 The A635V mutant triggers an autoinflammatory loop mediated primarily by interleukin-6, which drives the fibroblast phenotype,” Broderick et al.

In vitro administration of anti-IL-6 to cells from affected patients only modestly improved their function, suggesting that upstream targets of this molecular pathway are important for clinical suppression of autoinflammation. The researchers added that this suggests that a modification may be necessary.

Treatment of the patient’s primary dermal fibroblasts with ruxolitinib significantly reduced IL-6 secretion and nearly normalized scratch test closure.Activity of genes controlling inflammatory pathways — etc. IFNGMore, Ifna, TNF, IL6and STAT1 — This also decreased with treatment.

“we, STAT4 “Gain-of-function mutations are dependent on JAK activity and we considered the use of the clinically available JAK inhibitor ruxolitinib in patients from the most severely affected families. , we observed a majority of normalization of immunological function,” the researchers wrote. Allows fluctuation and resolution of systemic symptoms without adverse effects. “

Apart from ruxolitinib, anti-IL-6 monoclonal antibodies such as tocilizumab (Actemra), which are currently approved for interstitial lung disease in systemic sclerosis, have the potential to be an alternative therapy and/or JAK inhibitors in patients. may be useful in combination with We used DPM,” said Broderick and the team.