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Autoimmune polyendocrine syndrome type 1 (APS-1) responded to ruxolitinib (Jakafi) in a small study, researchers said, offering hope that one drug can relieve most of the symptoms of this rare but devastating disorder.

Five patients with APS-1 went into remission after starting the Janus kinase (JAK) inhibitor, with tests affirming that the treatment normalized interferon-γ, a defining biomarker in the condition, reported Michail Lionakis, MD, ScD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and colleagues in the .

Ruxolitinib was chosen somewhat arbitrarily for this pioneering study, as any of the eight approved JAK inhibitors would be expected to dampen interferon-γ, and other classes of immunomodulatory drugs may have similar effects. Consequently, Lionakis and colleagues didn't push ruxolitinib specifically as a promising APS-1 treatment. Rather, they concluded that the new study merely "provides the foundation for therapies that affect interferon-γ-mediated disease."

In an accompanying "Science Behind the Study" commentary, a researcher from the University of California Los Angeles agreed. "These results support the testing of JAK inhibitors as potential first-line immunotherapies for APS-1 in clinical trials," wrote Maureen Su, MD.

Indeed, the researchers' main goal was to elucidate more fully the pathophysiology of APS-1, a genetic disease in which, as the researchers explained, "self-reactive T cells escape to the periphery, infiltrate organs, and drive autoimmune damage." Almost any organ system may be affected: in the five patients treated in this study, symptoms included alopecia, thrush, malformed nails, gastrointestinal issues and nutrient malabsorption, arthritis, thyroiditis, urticaria, and anemia, and the specific constellation differed from one patient to another.

have showed mortality rates in APS-1 of up to 30%, and treatment heretofore has focused on the specific symptoms. As Su explained in her commentary, "the [current] goals of medical management center on regular screening for the development of new clinical manifestations, hormone replacement for endocrine disease, and immunotherapies targeted at specific non-endocrine autoimmune conditions (i.e., hepatitis, pneumonitis, and pancreatitis). However, an immunotherapeutic approach is not yet available that broadly treats the many disease manifestations associated with [APS-1]."

Although the specific genetic defect underlying the disorder was known -- expressed as -- the exact steps by which it produces autoimmune pathology and organ involvement were not. Lionakis and colleagues first performed studies in AIRE-knockout mice, from which the group determined that excessive interferon-γ release was a critical driver. Knowing that interferon-γ expression is mediated by JAK activity, the researchers turned to ruxolitinib, a JAK inhibitor available from the NIH Clinical Center's pharmacy, to test first in their mouse model and then in patients.

The five patients included two middle-age U.S. adults (one man, one woman) and three adolescents from Europe (a boy and two girls). All suffered from bowel dysfunction, although in two patients it manifested as severe constipation while others had diarrhea. Beyond that, as noted earlier, their symptom sets differed considerably. But they all showed high levels of interferon-γ.

Ruxolitinib was started at 5 mg twice daily in four of the patients; for reasons not explained in the published paper, the fifth (the American man) received a starting dose of 5 mg three times weekly. Patients were followed for 8 to 12 months while on the drug. Notably, these doses were far less than allowed under the drug's FDA-approved label, which carries a maximum of 25 mg twice daily.

In all cases, their symptoms resolved, though not always right away, and some patients needed higher doses to reach full remission. The American man, for example, eventually took the drug at 15 mg three times weekly, and a 12-year-old boy had his dose raised to 10 mg twice daily before his diarrhea finally normalized. Interferon-γ was normalized in all patients.

APS-1 had left the adolescents undersized. A 12-year-old boy and a 15-year-old girl each weighed less than 30 kg when starting treatment, while an 11-year-old girl weighed about 36 kg. Once on the drug, all three showed marked gains, reaching nearly 60 kg in the boy's case.

Future research should examine other JAK inhibitors such as tofacitinib (Xeljanz), Lionakis and colleagues wrote, as well as the that neutralizes interferon-γ directly. The investigators also noted that dosing might be further optimized.

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