Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity

Hadjadj, Jérôme; Frémond, Marie-Louise; Neven, Bénédicte

doi:10.3389/fimmu.2021.717388

Cited by 30 publications

(23 citation statements)

References 106 publications

(133 reference statements)

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“…JAK inhibitors (JAKinibs) are small molecules interfering with the process of cytokine-dependent JAK activation. In patients with STAT1 GOF, ruxolitinib®, as well as baricitinib®, have been used [ 13 , 14 ]. However, the clinical experience with these drugs in the field of inborn errors of immunity (IEI) is still limited and important questions including indications, dosing, and monitoring remain, especially in pediatric patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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, 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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…The type of organ involvement must also be taken into account as, for example, JAK inhibitors do not fully pass the blood-brain barrier [98]. Finally, our experience tends to favor the use of JAK1/2 inhibitors, such as ruxolitinib or baracitinib, over JAK1/3 inhibitors [99]. In SAVI, the main reported side effects were infectious (shingles, viral respiratory infections, rotavirus enteritidis, and aspergilloma in lung cavities).…”

Section: Jak Inhibitorsmentioning

confidence: 99%

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

David

Frémond

2022

Cells

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STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans.

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“…Differently, autoimmune cytopenia is less common (< 10%) in STAT1 GOF, in which the clinical spectrum is dominated by susceptibility to infections and endocrinopathy ( 24 ). Although the definitive treatment of STAT-related disorders is represented by hematopoietic stem cell transplantation (HSCT), the use of JAK inhibitors (ruxolitinib and baricitinib) has proven efficacy in the management of immune dysregulation in this condition ( 8 , 25 ). However, the overall number of patients with STAT-related disorders treated with JAK inhibitors is still low.…”

Section: Immune Dysregulation Disorders Associated With Immune Thromb...mentioning

confidence: 99%

“…However, the overall number of patients with STAT-related disorders treated with JAK inhibitors is still low. Indeed, the administration of JAK inhibitors has been reported only in 18 patients with STAT1 GOF and 13 patients with STAT3 GOF (27 receiving ruxolitinib, 3 tofactinib, and 1 baricitinib, respectively) with a high response rate but a reported short duration of follow-up ( 25 ).…”

Section: Immune Dysregulation Disorders Associated With Immune Thromb...mentioning

confidence: 99%

“…Finally, as the activation of STAT3 is also triggered by interleukin (IL)-6, the anti-IL-6 antibody tocilizumab is a promising alternative for patients with severe disease and multisystemic involvement and its use has been described only in less than 10 patients with STAT3 GOF so far ( 25 ).…”

Section: Immune Dysregulation Disorders Associated With Immune Thromb...mentioning

confidence: 99%

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