Format

Send to

Choose Destination
J Clin Invest. 2018 Jul 2;128(7):3041-3052. doi: 10.1172/JCI98814. Epub 2018 Jun 11.

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

Author information

1
Translational Autoinflammatory Disease Section, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2
Faculty of Physicians of the University of Nebraska Medical Center, College of Medicine, Omaha, Nebraska, USA.
3
IWK Health Centre, Halifax, Nova Scotia, Canada.
4
Department of Pediatric Rheumatology and Immunology, University Children's Hospital, Muenster, Germany.
5
Shaare-Zedek Medical Center, Jerusalem, Israel.
6
Hadassah Hebrew University Medical Center, Jerusalem, Israel.
7
Hauner Children's Hospital LMU, Munich, Germany.
8
Hospital Infantil La Paz, Madrid, Spain.
9
University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
10
Children's Hospital Los Angeles, Los Angeles, California, USA.
11
National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
12
Riley Hospital for Children, Indianapolis, Indiana, USA.
13
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA.
14
Clinical Center, NIH, Bethesda, Maryland, USA.
15
National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA.
16
National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
17
National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
18
Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
19
NIAID, NIH, Bethesda, Maryland, USA.
20
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA.
21
University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
22
Eli Lilly and Company, Indianapolis, Indiana, USA.
23
Hacettepe University Faculty of Medicine, Ankara, Turkey.
24
Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, Maryland, USA.
25
University College London (UCL) Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation, London, United Kingdom.

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.

KEYWORDS:

Immunology; Innate immunity; Monogenic diseases; Therapeutics; Translation

Comment in

PMID:
29649002
PMCID:
PMC6026004
DOI:
10.1172/JCI98814
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center