A medicine that inhibits the enzyme Janus kinase (JAK) benefits children and young adults with too much interferon due to different genetic variants
Date of publication:
24/2/26
Author:
Roger Brooks
Category:
SAVI treatment
Article body content:
Plain Language Some rare genetic conditions cause the immune system to become overactive from birth. In these disorders — such as CANDLE and SAVI — the body produces too much interferon (a powerful immune signalling protein), leading to ongoing inflammation, fevers, skin problems, lung disease, poor growth, and organ damage.
In this study, 18 children and young adults with these conditions were treated with a medication called baricitinib, which blocks signals that interferon uses to cause inflammation.
Over several years of treatment:
· Symptoms improved significantly
· Many children were able to reduce or stop steroid treatment
· Growth and bone strength improved
· Lung disease stabilised in SAVI patients
· Laboratory markers of inflammation decreased
Some infections occurred as side effects, so careful monitoring is needed. Overall, the treatment showed meaningful and lasting benefits for many patients.
Why it Matters This study provided the first long-term evidence that targeting JAK1/2 can meaningfully reduce disease activity in monogenic interferonopathies.
It demonstrated:
· A direct pathogenic role for type I interferon signalling
· That interferon blockade can induce durable remission
· That steroid-sparing therapy is achievable
· That growth impairment can partially reverse
· It also established interferon biomarkers (e.g., IFN gene signature, IP-10) as useful disease activity markers.
Hope for the Future
This work:
· Validates JAK inhibition as a treatment strategy
· Opens the door for earlier intervention
· Suggests biomarker-guided treatment approaches
· Supports the development of more selective interferon pathway inhibitors
· Provides a model for precision therapy in rare genetic immune diseases
· Long-term monitoring of infection risk and viral reactivation will remain important.
Read More:
Background Monogenic type I interferonopathies such as CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) and SAVI (STING-associated vasculopathy with onset in infancy) are characterized by:
· Constitutive type I interferon pathway activation
· Elevated interferon response gene signatures (IRS)
· Severe systemic inflammation beginning in infancy
· High morbidity and mortality
CANDLE is caused by loss-of-function mutations in proteasome subunits, leading to impaired protein degradation and enhanced IFN production. SAVI is caused by gain-of-function mutations in TMEM173 (STING), leading to constitutive interferon-β production.
Conventional biologic therapies targeting interleukin-1 (IL-1), interleukin 6 (IL-6), or tumour necrosis factor (TNF) have shown limited efficacy.
The JAK/STAT pathway mediates signalling downstream of type I and II interferon receptors. Baricitinib, a selective JAK1/JAK2 inhibitor, reduces signal transducer and activator of transcription (STAT1) phosphorylation and interferon signalling in vitro, providing a mechanistic rationale for therapeutic use in interferonopathies.
What the Study Found Eighteen patients (10 CANDLE, 4 SAVI, 4 other interferonopathies) were treated under an expanded access program for a mean of ~3 years.
Clinical Outcomes
· Median daily symptom score decreased significantly (P < 0.0001)
· 71% of steroid-treated patients reduced corticosteroid doses
· 50% of CANDLE patients achieved sustained remission
· SAVI patients showed reduced vasculitis severity and stabilization of interstitial lung disease
· Growth parameters and bone mineral density improved significantly
Biomarker Outcomes
· Decrease in CRP
· Reduction in 25-gene interferon signature
· Reduction in serum IP-10
· Reduced STAT1 phosphorylation
Safety
· Common adverse events: upper respiratory infections, gastroenteritis
· BK viremia observed in several patients
· Two deaths occurred (related to disease complications)
The drug exposure required to control disease was higher than standard rheumatoid arthritis dosing.
Citation Sanchez GAM et al., J Clin Invest. 2018 128(7):3041-52.
Authors Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, Schalm S, Murias S, Dare JA, Brown D, Stone DL, Gao L, Klausmeier T, Foell D, de Jesus AA, Chapelle DC, Kim H, Dill S, Colbert RA, Failla L, Kost B, O’Brien M, Reynolds JC, Folio LR, Calvo KR, Paul SM, Weir N, Brofferio A, Soldatos A, Biancotto A, Cowen EW, Digiovanna JJ, Gadina M, Lipton AJ, Hadigan C, Holland SM, Fontana J, Alawad AS, Brown RJ, Rother KI, Heller T, Brooks KM, Kumar P, Brooks SR, Waldman M, Singh HK, Nickeleit V, Silk M, Prakash A, Janes JM, Ozen S, Wakim PG, Brogan PA, Macias WL, Goldbach-Mansky R.
Date of publication 1/7/18 Link 10.1172/JCI98814