BACKGROUND. Monogenic Interferon (IFN)-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN-response-gene-signature (IRS), inflammatory organ damage and high mortality. We used the janus kinase (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 with SAVI (Stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an Expanded Access Program. Patients underwent dose-escalation, 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. 18 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 (IQR 0.93–1.78) to 0.25 (IQR 0.1-0.63) (P < 0.0001). In 14 patients receiving steroids 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); 5 of 10 CANDLE patients achieved lasting clinical remission. Quality of life, height and bone mineral density Z-scores significantly improved, and IFN biomarkers decreased. Three patients discontinued, two with genetically undefined conditions due to lack of efficacy, and one CANDLE patient due to BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, BK viruria and viremia. CONCLUSION. On baricitinib treatment, clinical manifestations, inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies, CANDLE, SAVI and 2 other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING. NIH, NIAID, NIAMS, NIDDK, NHLBI, NINDS, and the Clinical Center. Baricitinib was provided by Eli Lilly. Eli Lilly is the sponsor of the compassionate use program.
Gina A. Montealegre Sanchez, Adam Reinhardt, Suzanne Ramsey, Helmut Wittkowski, Philip J. Hashkes, Yackov Berkun, Susanne Schalm, Sara Murias, Jason A. Dare, Diane Brown, Deborah L. Stone, Ling Gao, Thomas Klausmeier, Dirk Foell, Adriana A. de Jesus, Dawn C. Chapelle, Hanna Kim, Samantha Dill, Robert Colbert, Laura Failla, Bahar Kost, Michelle O'Brien, James C. Reynolds, Les R. Folio, Katherine R. Calvo, Scott M. Paul, Nargues Weir, Alessandra Brofferio, Ariane Soldatos, Angélique Biancotto, Edward W. Cowen, John G. Digiovanna, Massimo Gadina, Andrew J. Lipton, Colleen Hadigan, Steven M. Holland, Joseph Fontana, Ahmad S. Alawad, Rebecca J. Brown, Kristina I. Rother, Theo Heller, Kristina M. Brooks, Parag Kumar, Stephen R. Brooks, Meryl Waldman, Harsharan K. Singh, Volker Nickeleit, Maria Silk, Apurva Prakash, Jonathan M. Janes, Seza Ozen, Paul G. Wakim, Paul A. Brogan, William L. Macias, Raphaela Goldbach-Mansky