Ruxolitinib Rescues Multiorgan Clinical Autoimmunity in Patients with APS-1

**Background:** Autoimmune polyendocrine syndrome type-1 (APS-1) is a monogenic inborn error of immunity caused by loss-of-function variants in the AIRE gene, leading to defective central tolerance and widespread autoimmunity. Patients develop multiple endocrinopathies, chronic mucocutaneous candidiasis, and other autoimmune manifestations. Management is symptomatic, with no curative or preventive strategies. JAK inhibitors (JAKi) have shown efficacy in other immune dysregulatory disorders, but their use in APS-1 had not been reported.

**Methods:** This was a pilot, longitudinal observational study conducted at Necker Children's Hospital (Paris, France). Three adolescents with genetically confirmed APS-1 were treated off-label with ruxolitinib. Patient 1 (17-year-old male) had alopecia areata, autoimmune hepatitis, keratitis, exocrine pancreatic insufficiency, and severe abdominal pain. Patient 2 (18-year-old female) had alopecia, diabetes insipidus, renal potassium wasting, hypoparathyroidism, and chronic mucocutaneous candidiasis. Patient 3 (21-year-old male, brother of patient 2) had alopecia universalis and hypoparathyroidism. Ruxolitinib was initiated at 10–20 mg twice daily (12–25 mg/m²/day), with dose adjustments based on comedications (e.g., fluconazole). Clinical and biological data were collected before and during treatment (follow-up: 25–31 months).

**Key Results:** All three patients showed marked improvement across multiple organ systems. Patient 1 achieved complete remission of autoimmune hepatitis (steroids and azathioprine discontinued after 6 and 20 months, respectively), keratitis (topical cyclosporine stopped after 13 months), and exocrine pancreatic insufficiency (steatorrhea decreased from 103 to 6 g/day; stool elastase normalized from 186 to 719 μg/day; pancreatic enzymes stopped after 24 months). Abdominal pain resolved, and pain medications were discontinued. His medication burden decreased from 12 drugs (>30 pills/day) to 5 drugs (10 pills/day). Patient 2 experienced complete hair regrowth after 24 months of ruxolitinib (Fig. 1). Diabetes insipidus resolved: natremia decreased from a mean of 144.1±1.18 mmol/L to 139.3±0.83 mmol/L (p=0.0011), allowing desmopressin discontinuation. Renal potassium wasting improved: potassium supplements reduced from 3 g/day to 0.5 g/day. Hypoparathyroidism partially remitted: serum phosphate decreased from 1.78±0.42 to 1.20±0.18 mmol/L, and alfacalcidol dose was tapered from 1.9±0.5 to 1.7±0.4 μg/day. Mucosal candidiasis did not recur. Patient 3 showed complete resolution of alopecia universalis after 12 months (Fig. 3). Hypoparathyroidism improved: PTH infusion requirements decreased from 42.4±0.7 μg/day to 21.2±0.7 μg/day (p<0.0001). Adrenal insufficiency was the only manifestation that did not respond in any patient. Safety was acceptable: no infectious adverse events, no herpes zoster reactivation, no significant laboratory abnormalities except transient anemia in patient 2 (which resolved after switching to baricitinib and back). All patients had mild COVID-19 while on ruxolitinib.

**Clinical Implications:** This first report of ruxolitinib in APS-1 demonstrates broad and sustained efficacy across multiple autoimmune manifestations, including endocrine components (hypoparathyroidism, diabetes insipidus) that are typically considered irreversible. The treatment dramatically improved quality of life and reduced polypharmacy. The lack of response in adrenal insufficiency suggests that complete tissue destruction may preclude recovery. The favorable safety profile in this small series is encouraging, but caution is warranted given the risk of infections (especially in APS-1 patients with functional asplenia and anti-type I IFN autoantibodies). The authors recommend ensuring up-to-date vaccinations (SARS-CoV-2, influenza, meningococcus, pneumococcus) before initiating JAKi. Larger prospective trials are needed to confirm efficacy, determine optimal dosing, and identify which JAK/STAT pathways are most relevant in APS-1.