JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency

Alsohime, Fahad; Martín-Fernández, Marta; Temsah, Mohamad-Hani; Alabdulhafid, Majed; Voyer, Tom Le; Alghamdi, Malak; Qiu, Xueer; Alotaibi, Najla; Alkahtani, Areej; Buta, Sofija; Jouanguy, Emmanuelle; Al‐Eyadhy, Ayman; Gruber, Conor; Hasan, Gamal; Bashiri, Fahad A.; Halwani, Rabih; Hassan, Hamdy H.; Al‐Muhsen, Saleh; Alkhamis, Nouf; Alsum, Zobaida; Casanova, Jean‐Laurent; Bustamante, Jacinta; Bogunovic, Dusan; Alangari, Abdullah

doi:10.1056/nejmoa1905633

Cited by 79 publications

(75 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…89 Other indications for which JAKi are being evaluated include non-infectious uveitis, CANDLE syndrome and other interferonopathies, including USP18 deficiency. [90][91][92] The reader is referred to the SLR manuscript. 43…”

Section: Other Diseasesmentioning

confidence: 99%

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement

et al. 2020

View full text Add to dashboard Cite

ObjectivesJanus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.MethodsExisting data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.ResultsThe Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.ConclusionThe consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

show abstract

Section: Other Diseasesmentioning

confidence: 99%

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement

et al. 2020

View full text Add to dashboard Cite

show abstract

“…STAT2 deficiency, alongside ISG15 and USP18 deficiencies, now constitutes a third genetic etiology leading to inadequate control of late cellular responses to IFN-I. Of note, this novel disease largely phenocopies USP18 deficiency in clinical presentation and molecular mechanism ( Alsohime et al, 2020 ; Meuwissen et al, 2016 ). Clearly, tight control of IFNAR is essential for viability.…”

Section: Resultsmentioning

confidence: 99%

“…Clearly, tight control of IFNAR is essential for viability. If diagnosed and treated rapidly, as was the case in a recent USP18-deficient child, perhaps JAK inhibitor therapy would have rescued the life of this unfortunate child and his deceased siblings ( Alsohime et al, 2020 ). This possibility is further substantiated by several recent studies that successfully introduced JAK inhibitors in a diverse range of genetic etiologies of type I interferonopathies ( Sanchez et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

Gruber

Martín-Fernández

Ailal

et al. 2020

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I–stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.

show abstract

“…These patients suffer from severe acute respiratory distress, cytopenia, hemorrhage, and septic shock (Dauphinee et al, 2014; Lindner et al, 2007) with the majority succumbing to the condition in late gestation or early infancy. Despite the increased levels of ISGylation observed in these patients, their disease was primarily attributed to elevated IFN-I signaling and the resultant interferonopathy (Alsohime et al, 2020; Meuwissen et al, 2016). Data presented herein suggests that dysregulated ISGylation/deISGylation in the absence of USP18 can be causal in aberrant immune inflammation in the lung.…”

Section: Discussionmentioning

confidence: 95%

“…Humans with recessive mutations in USP18 display severe pathological manifestations with heightened innate inflammation, neurological abnormalities, respiratory failure and thrombocytopenia, and, as a result, all known patients have succumbed shortly after birth (Alsohime et al, 2020; Meuwissen et al, 2016). Pathological manifestations in USP18 -deficient humans are associated with heightened IFN-I signaling, however, the contribution of dysregulated deISGylation in USP18 -deficient patients remains unclear.…”

Section: Introductionmentioning

confidence: 99%

ISG15 drives immune pathology and respiratory failure during viral infection

Shaabani

Zak

Johnson

et al. 2020

Preprint

View full text Add to dashboard Cite

Cytokine storm during respiratory viral infection is an indicator of disease severity and poor prognosis. Type 1 interferon (IFN-I) production and signaling has been reported to be causal in cytokine storm-associated pathology in several respiratory viral infections, however, the mechanisms by which IFN-I promotes disease pathogenesis remain poorly understood. Here, using Usp18-deficient, USP18 enzymatic-inactive and Isg15-deficient mouse models, we report that lack of deISGylation during persistent viral infection leads to severe immune pathology characterized by hematological disruptions, cytokine amplification, lung vascular leakage and death. This pathology requires T cells but not T cell-intrinsic deletion of Usp18. However, lack of Usp18 in myeloid cells mimicked the pathological manifestations observed in Usp18 -/or Usp18 C61A mice which were dependent on Isg15. We further mechanistically demonstrate that interrupting the ISGylation/deISGylation circuit increases extracellular levels of ISG15 which is accompanied by inflammatory neutrophil accumulation to the lung. Importantly, neutrophil depletion reversed morbidity and mortality in Usp18 C61A mice. In summary, we reveal that the enzymatic function of Usp18 is crucial for regulating extracellular release of ISG15. This is accompanied by altered neutrophil differentiation, cytokine amplification and mortality following persistent viral infection. Moreover, our results suggest that extracellular ISG15 may drive the inflammatory pathology observed and could be both a prospective predictor of disease outcome and a therapeutic target during severe respiratory viral infections. was not certified by peer review)

show abstract

JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency

Cited by 79 publications

References 21 publications

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement

Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

ISG15 drives immune pathology and respiratory failure during viral infection

Contact Info

Product

Resources

About