Ruxolitinib Response in an Infant With Very‐early‐onset Inflammatory Bowel Disease and Gain‐of‐function <i>STAT1</i> Mutation

Acker, Karen P.; Borlack, Rachel; Iuga, Alina; Remotti, Helen; Soderquist, Craig; Okada, Satoshi; Tsumura, Miyuki; Casanova, Jean‐Laurent; Picoraro, Joseph A.; Puel, Anne; Kinberg, Sivan; Demirdağ, Yeşim Yılmaz

doi:10.1097/mpg.0000000000002854

Cited by 15 publications

(23 citation statements)

References 7 publications

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“…Infections were common in our cohort, correlating well with previous reports [3,8,9,10,16,17]. Before starting JAKinibs, most infections had been controlled; only P3 suffered fromCMV stomatitis.…”

Section: Disease Manifestationssupporting

confidence: 91%

“…Collectively, CMC was the most prevalent disease manifestation (n=23) and JAKinib treatment was effective in almost all patients (overall response rate 20/22, Figure 1) within 2-8 weeks of treatment.Contrastingly, Acker et al recently described a patient with only transient responses to JAKinib, administeredfor CMC, enteropathy and cytopenia [17].Importantly, in our cohort, the only patient receiving baricitinib did not show clinical improvement resulting in its discontinuation and switch to ruxolitinib.…”

Section: Treatment Dosing and Treatment Responsecontrasting

confidence: 84%

“…Reasons to start JAKinibs stated by the attendingphysicians of our cohort were similar to previous reports [3,8,9,10,16,17]. Beyond CMC, these included refractory autoimmune complications, progressive vasculopathy and lung disease (Table 1, Table S1).…”

Section: Indicationssupporting

confidence: 82%

“…In addition, these patients had also received other immunosuppressive drugs.Thus, in most of themJAKinibs were not used as " rst-line" therapy. In our series, JAKinibs were initiated at earlier disease stages, possiblyre ecting the positive experiences reported in the previous studies [3,8,9,10,16,17].…”

Section: Disease Manifestationssupporting

confidence: 74%

“…In contrast, keratitis, autoimmune hepatitis or pulmonary hypertension required prolonged treatment (4-8 months) and cerebral aneurysms did not show any treatment responses.In the reviewed cases from the literaturethe variable "time to response"was not consistently reported [Table S-2]. In those cases where speci c information was available,hemolytic autoimmune anemia (n=1) responded after 1 month of treatment initiation [16], enteropathy improved between2 weeksto2 months in three patients [8],whereas a singular more severe case required up to 12 monthsof therapy [17]. Resolution of diabetes mellitus was observedafter 12 months ofruxolitinib treatment in 1 case [10].…”

Section: Jakinib Treatment Responsesmentioning

confidence: 99%

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Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain-of-Function (GOF) Mutations – 10 Children and Review of the Literature

Deyà‐Martínez

Riviere²,

Roxo-Junior³

et al. 2022

Preprint

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Introduction. Since the first description of gain of function (GOF) mutations in Signal Transducer and Activator of Transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, its indications, dosing and monitoring remain to be established. Methods. A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results. Ten children (median age 8.5y (3-18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18m (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p=0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patient; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre HSCT and absence of response. Conclusions. Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

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Section: Disease Manifestationssupporting

confidence: 91%

Section: Treatment Dosing and Treatment Responsecontrasting

confidence: 84%

Section: Indicationssupporting

confidence: 82%

Section: Disease Manifestationssupporting

confidence: 74%

Section: Jakinib Treatment Responsesmentioning

confidence: 99%

See 3 more Smart Citations

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain-of-Function (GOF) Mutations – 10 Children and Review of the Literature

Deyà‐Martínez

Riviere²,

Roxo-Junior³

et al. 2022

Preprint

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Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

et al. 2020

Self Cite

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Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.

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Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature

et al. 2022

View full text Add to dashboard Cite

Introduction Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. Methods A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

show abstract

Ruxolitinib Response in an Infant With Very‐early‐onset Inflammatory Bowel Disease and Gain‐of‐function STAT1 Mutation

Cited by 15 publications

References 7 publications

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain-of-Function (GOF) Mutations – 10 Children and Review of the Literature

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain-of-Function (GOF) Mutations – 10 Children and Review of the Literature

Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature

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