JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

Abstract

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595.FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Relapsing–remitting clinical course expands the phenotype of Aicardi–Goutières syndrome

“…Type I interferon upregulation in AGS is not limited to the initial encephalopathic disease stage and may be a lifelong phenomenon. Therapies to block interferon signaling may therefore be of utility in patients exhibiting recurrent symptomatology, and several Janus kinase inhibitors have shown early promise in several type I interferonopathies . Additionally, patients with mutations in the RNASE H2 complex in particular exhibited reductions in interferon signaling following treatment with a combination of anti‐human immunodeficiency virus‐1 reverse transcriptase inhibitors (abacavir, lamivudine, and zidovudine) .…”

Treatments in Aicardi–Goutières syndrome

“…). Of note, a handful of recent reports suggest encouraging results with the use of Janus kinase (JAK) inhibition in several distinct type I interferonopathies, with JAK1 comprising an essential component of the type I interferon receptor complex. We have seen definite improvement in TREX1‐related skin disease and IFIH1‐determined systemic inflammation with the JAK1/2 inhibitor, ruxolitinib.…”

Monogenic autoinflammatory disorders: beyond the periodic fever

“…Since this time, several reports published suggest that the phenotypic spectrum is broad, and the penetrance of disease is variable, with cytopenias, lymphoproliferative disease and immune deficiencies being reported. [113][114][115] Interestingly, some clinical manifestations persist despite treatment. 112 Gain-of-function mutations in TMEM137 encoding the cytosolic innate immune sensor STING result in an autoinflammatory disease characterised by peripheral vascular inflammation, nail dystrophy and interstitial lung disease termed STING associated vasculopathy with onset in infancy (SAVI).…”