Ruxolitinib Rescues Multiorgan Clinical Autoimmunity in Patients with APS-1

Abstract

Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by mono- or biallelic loss-of-function variants of the autoimmune regulator gene AIRE underlying early-onset multiorgan autoimmunity and the production of neutralizing autoantibodies against cytokines, accounting for mucosal candidiasis and viral diseases. Medical intervention is essential to prevent or attenuate autoimmune manifestations. Ruxolitinib is a JAK inhibitor approved for use in several autoimmune conditions. It is also used off-label to treat autoimmune manifestations of a growing range of inborn errors of immunity. We treated three APS-1 patients with ruxolitinib and followed them for at least 30 months. Tolerance was excellent, with no medical or biological adverse events. All three patients had remarkably positive responses to ruxolitinib for alopecia, nail dystrophy, keratitis, mucosal candidiasis, steroid-dependent autoimmune hepatitis, exocrine pancreatic insufficiency, renal potassium wasting, hypoparathyroidism, and diabetes insipidus. JAK inhibitors were therefore considered an effective treatment in three patients with APS-1. Our observations suggest that JAK/STAT pathways are involved in the pathogenesis of APS-1 autoimmune manifestations. They also suggest that JAK inhibitors should be tested in a broader range of APS-1 patients.

Keywords: AIRE; APS-1; Jak inhibitor; Ruxolitinib.

Fig. 1

Course of alopecia in Patient 2 Photographs before the introduction of ruxolinitib (A) and after 12 (B) and 24 (C) months of treatment in patient 2

Fig. 2

Course of the disease in Patient 2 (A-B) Course of natremia. Diabetes insipidus was treated by substitution with desmopressin; the treatment and dose are indicated by the green bars (right y axis). Note the sodium concentration above or at the upper limit of the normal range (mean ± SD: 144.1 ± 1.18 mmol/L; n = 16) before ruxolinitib treatment (black bars) and the recurrent episodes of hyponatremia during the course of ruxolinitib treatment (A), suggesting an excess of desmopressin and leading to a gradual decrease of desmopressin dose and the discontinuation of this treatment at the most recent follow-up visit (B). Na (blood sodium determination); the reference range is 136–146 mmol/L; the red asterisk indicates the period during which the patient received baricitinib. Follow-up spans of 3.5 years and 2.5 years before and after the initiation of ruxolinitib (R), respectively. (C-D) Renal potassium wasting was suspected when serum potassium concentration fell below the normal range despite adrenal insufficiency, a condition associated with hyperkalemia. Potassium supplements were prescribed at a dose of up to 3 g/day (empty bars) leading to a slow, but steady increase in blood potassium concentration and a decrease in potassium supplement intake. K (blood potassium determination); the reference range is 3.5–4.5 mmol/L. Follow-up spans of 3.5 years and 2.5 years before and after of the initiation of ruxolinitib, respectively. (E–F) Hypoparathyroidism was treated with alfacalcidol; treatment and dose are indicated by the blue bars (right y axis). Blood phosphate levels decreased on ruxolinitib treatment, from 1.78 ± 0.42 to 1.20 ± 0.18 mmol/L, this decrease being associated with an increase in the percentage of measurements within the normal range from 30 to 91%. Concomitantly, the requirement for alfacalcidol to sustain blood calcium level (calcium 2.35 ± 0.29 and 2.25 ± 0.21 mmol/L; 56 and 62% of measurements in the normal range before and during ruxolinitib treatment, respectively) decreased from 1.9 ± 0.5 to 1.7 ± 0.4 µg/day. Ca (blood calcium determination); the reference range is 2.2–2.6 mmol/L; Pi (blood phosphate determination); the reference range is 0.95–1.45 mmol/L. Follow-up spans of 3.5 years and 2.5 years before and after the initiation of ruxolinitib, respectively

Fig. 3

Course of the disease in patient 3 Photographs before the initiation of ruxolinitib (A) and after 12 (B) and 24 (C) months of treatment. (D-E) Hypoparathyroidism was treated by subcutaneous PTH¹⁻³⁴ infusion; the treatment and dose are shown by the blue bars (right y axis). While on subcutaneous PTH¹⁻³⁴ infusion, the patient experienced several episodes of hypo- and hypercalcemia. Over a period of about two years before the initiation of ruxolinitib, blood calcium levels were adequately maintained within the reference range. Upon ruxolinitib therapy, the PTH¹⁻³⁴ requirements for sustaining balanced blood calcium levels decreased from 42.4 ± 0.7 to 21.2 ± 0.7 µg/day. Ca (blood calcium determination); the reference range is 2.2–2.6 mmol/L