Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease

Rice, Gillian I.; Melki, Isabelle; Frémond, Marie-Louise; Briggs, Tracy A; Rodero, Mathieu P; Kitabayashi, Naoki; Oojageer, Anthony; Bader-Meunier, Brigitte; Belot, Alexandre; Bodemer, Christine; Quartier, Pierre; Crow, Yanick J.

doi:10.1007/s10875-016-0359-1

Cited by 164 publications

(150 citation statements)

References 45 publications

(43 reference statements)

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“…In our study, galectin‐9 was a specific biomarker for inflammatory myopathies. In patients with juvenile DM, high circulating interferon‐α levels have been found, and in one group of patients with juvenile DM, more than 75% of patients had a positive interferon signature . Circulating galectin‐9 and CXCL10 levels could therefore be a direct reflection of active, interferon‐driven inflammation, which is supported by a recent study in which galectin‐9 was demonstrated to be a marker for the interferon signature in SLE and antiphospholipid syndrome .…”

Section: Discussionmentioning

confidence: 66%

Galectin‐9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation

Wienke

Enders

Lim

et al. 2019

Arthritis & Rheumatology

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Objective Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (DM) due to a lack of reliable biomarkers, but it is crucial to avoid both under‐ and overtreatment of patients. Recently, we identified 2 proteins, galectin‐9 and CXCL10, whose levels are highly correlated with the extent of juvenile DM disease activity. This study was undertaken to validate galectin‐9 and CXCL10 as biomarkers for disease activity in juvenile DM, and to assess their disease specificity and potency in predicting the occurrence of flares. Methods Levels of galectin‐9 and CXCL10 were measured by multiplex immunoassay in serum samples from 125 unique patients with juvenile DM in 3 international cross‐sectional cohorts and a local longitudinal cohort. The disease specificity of both proteins was examined in 50 adult patients with DM or nonspecific myositis (NSM) and 61 patients with other systemic autoimmune diseases. Results Both cross‐sectionally and longitudinally, galectin‐9 and CXCL10 outperformed the currently used laboratory marker, creatine kinase (CK), in distinguishing between juvenile DM patients with active disease and those in remission (area under the receiver operating characteristic curve [AUC] 0.86–0.90 for galectin‐9 and CXCL10; AUC 0.66–0.68 for CK). The sensitivity and specificity for active disease in juvenile DM was 0.84 and 0.92, respectively, for galectin‐9 and 0.87 and 1.00, respectively, for CXCL10. In 10 patients with juvenile DM who experienced a flare and were prospectively followed up, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before the onset of symptoms, even in the absence of elevated CK levels. Galectin‐9 and CXCL10 distinguished between active disease and remission in adult patients with DM or NSM (P = 0.0126 for galectin‐9 and P < 0.0001 for CXCL10) and were suited for measurement in minimally invasive dried blood spots (healthy controls versus juvenile DM, P = 0.0040 for galectin‐9 and P < 0.0001 for CXCL10). Conclusion In this study, galectin‐9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in juvenile DM. Implementation of these biomarkers into clinical practice as tools to monitor disease activity and guide treatment might facilitate personalized treatment strategies.

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Section: Discussionmentioning

confidence: 66%

Galectin‐9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation

Wienke

Enders

Lim

et al. 2019

Arthritis & Rheumatology

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“…20,21 We emphasize that the interferon signature remains elevated many years after disease onset, providing evidence of ongoing pathology. ADAR1 is expressed throughout the brain including the basal ganglia (http://www.brain-map.org), and it has been shown that a loss of ADAR1 renders cells more susceptible to apoptosis following stress, including infection.…”

Section: Discussionmentioning

confidence: 94%

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

et al. 2017

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We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

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“…Overexpression of a set of interferon-stimulated genes (ISGs) in peripheral blood has consistently been found in all reported patients with SAVI syndrome [6,14,15]. Modulation of IFN signature following treatment may represent a surrogate biomarker.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

et al. 2019

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Objectives Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. Methods We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. Results We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid Stefano Volpi and Antonella Insalaco contributed equally.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00645-0) contains supplementary material, which is available to authorized users. treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. Conclusions We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

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Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease

Cited by 164 publications

References 45 publications

Galectin‐9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation

Galectin‐9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

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