Utility of Ruxolitinib in a Child with Chronic Mucocutaneous Candidiasis Caused by a Novel STAT1 Gain-of-Function Mutation
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu kazuistiky, časopisecké články, práce podpořená grantem
PubMed
29934865
DOI
10.1007/s10875-018-0519-6
PII: 10.1007/s10875-018-0519-6
Knihovny.cz E-zdroje
- Klíčová slova
- Chronic mucocutaneous candidiasis, Janus kinase inhibitor, candida, ruxolitinib, signal transducer and activator of transcription 1,
- MeSH
- aktivační mutace * MeSH
- biologické markery MeSH
- CD4-pozitivní T-lymfocyty imunologie metabolismus MeSH
- cytokiny metabolismus MeSH
- dítě MeSH
- fosforylace MeSH
- genetická predispozice k nemoci MeSH
- imunofenotypizace MeSH
- inhibitory proteinkinas aplikace a dávkování terapeutické užití MeSH
- Janus kinasy antagonisté a inhibitory MeSH
- kandidóza chronická mukokutánní diagnóza farmakoterapie genetika metabolismus MeSH
- lidé MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- nitrily MeSH
- pyrazoly aplikace a dávkování terapeutické užití MeSH
- pyrimidiny MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- transkripční faktor STAT1 genetika metabolismus MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- biologické markery MeSH
- cytokiny MeSH
- inhibitory proteinkinas MeSH
- Janus kinasy MeSH
- nitrily MeSH
- pyrazoly MeSH
- pyrimidiny MeSH
- ruxolitinib MeSH Prohlížeč
- STAT1 protein, human MeSH Prohlížeč
- transkripční faktor STAT1 MeSH
PURPOSE: Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We aim to report the effect of oral ruxolitinib, the Janus kinase (JAK) family tyrosine kinase inhibitor, on clinical and immune status of a 12-year-old boy with severe CMC due to a novel STAT1 GOF mutation. METHODS: Clinical features and laboratory data were analyzed, particularly lymphocyte subsets, ex vivo IFNγ- and IFNα-induced STAT1, 3, 5 phosphorylation dynamics during the course of JAK1/2 inhibition therapy, and Th17-related, STAT1- and STAT3-inducible gene expression before and during the treatment. Sanger sequencing was used to detect the STAT1 mutation. Literature review of ruxolitinib in treatment of CMC is appended. RESULTS: A novel STAT1 GOF mutation (c.617T > C; p.L206P), detected in a child with recalcitrant CMC, was shown to be reversible in vitro with ruxolitinib. Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo. Clinical relapse and spike of all monitored phosphorylated STAT activity was registered shortly after unplanned withdrawal, decreasing again after ruxolitinib reintroduction. No increase of peripheral CD4+ IL17+ T cells was detected after 4 months of therapy. No adverse effects were noted. CONCLUSION: JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation.
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