Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi‐Goutières Syndrome, a Type I Interferonopathy

Meesilpavikkai, Kornvalee; Dik, Willem A.; Schrijver, Benjamin; Helden-Meeuwsen, Cornelia G van; Versnel, Marjan A.; Hagen, P. Martin van; Bijlsma, Emilia K.; Ruivenkamp, Claudia; Oele, Margreet J.; Dalm, Virgil A. S. H.

doi:10.1002/art.40805

Cited by 48 publications

(40 citation statements)

References 10 publications

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“…34). Clinical benefit in patients treated with JAK inhibitors who have CAN-DLE (11), SAVI (11,35,36), or AGS (37,38) are encouraging, and the correlation of treatment responses with suppression of the IRG-S (34) suggests that the IRG-S is useful in diagnosis and as tial leveraging of the diversity in IRG regulation for diagnostic purposes. Though all disease groups had elevated IRG-S compared with negative controls (healthy controls and NOMID), the mean IRG-S elevation was significantly lower in patients with IL-18PAP-MAS (G1), LRBA deficiency (G2), NEMO-NDAS (G3), and SAMD9L-SAAD (G4).…”

Section: Discussionmentioning

confidence: 99%

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Jesus¹,

Hou²,

Brooks³

et al. 2020

Journal of Clinical Investigation

167

173

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onset in infancy (SAVI), and another by additive loss-of-function mutations in proteasome genes causing the proteasome-associated autoinflammatory syndromes (PRAAS) (also, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures [CANDLE]), presented with chronically elevated interferon (IFN) signatures, suggesting a pathogenic role for type-I IFN in autoinflammatory diseases (2, 3). Type-I IFN was first discovered as a soluble antiviral factor over 50 years ago, and a role in sterile inflammation was proposed in patients with systemic lupus erythematosus (4). However, the discovery of genetic mutations that cause the autoinflammatory type-I interferonopathies CANDLE (2, 5), SAVI (3, 6-8), and Aicardi-Goutières syndrome (AGS) (9, 10) have shed light on pathomechanisms that drive chronic IFN signaling, and recent studies blocking IFN signaling validate a critical role for type-I IFNs (11). AGS-causing loss-of-function mutations in nucleases impair self-nucleic acid homeostasis, SAVI-causing

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Section: Discussionmentioning

confidence: 99%

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Jesus¹,

Hou²,

Brooks³

et al. 2020

Journal of Clinical Investigation

167

173

View full text Add to dashboard Cite

show abstract

“…Ruxolitinib has reduced neuroin ammation in a patient with a heterozygous mutation in IFIH1 [17]. Baricitinib could alleviate chilblain lesions in a patient with AGS5 [18]. Tofacitinib ameliorated aortic valve calci cation in a patient with Singleton-Merten syndrome (SMS) [19].…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Xia

Yang

2020

Preprint

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Introduction: Aicardi-Goutières (AGS) is a rare immune dysregulated disease due to mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1. Clinical features include basal ganglia calcifications, white matter abnormalities, and cerebral atrophy. Severe systemic inflammation and chronic kidney disease (CKD) are extremely rare in AGS. Herein, we report a patient presenting with systemic inflammation and CKD to broaden the clinical phenotype spectrum of the RNASEH2B defect. Methods: All testing and molecular genetic analysis were performed after obtaining the informed consent of the parents. Demographic, clinical, and laboratory findings were abstracted from outpatient and inpatient encounters. Cerebral magnetic resonance imaging (MRI), computed tomography (CT) scans, and renal biopsy histopathology reports were reviewed and summarized. Whole exome sequencing (WES) was performed on peripheral blood cells. After exposure to cGAMP in vitro for 24 hours, mRNA expression of twelve IFN-stimulated cytokine genes in PBMCs was assessed. Serum cytokine levels were detected by Milliplex. Results: A 11-year-old girl presented with recurrent aseptic fever, arthritis, chilblains, failure to thrive, mild hearing loss, and neurological manifestations. Laboratory and immunologic findings demonstrated lymphopenia, low complement levels, positive autoantibodies, elevated levels of acute-phase reactants and inflammatory cytokines. Cerebral imaging showed cerebral atrophy, white matter abnormalities, and intracranial calcification. Renal biopsy showed glomerular sclerosis in three of fourteen glomeruli, infiltration of lymphocytes and other mononuclear cells. WES revealed a homozygous and heterozygous mutations in RNASEH2B . Over-expression of IFN-stimulated cytokine genes was observed, including IFI44, IFI27, IFIT1, IFIT2, IFIT3, ISG15, OAS1, and SIGLEC1. Conclusions: To date, only two cases with AGS have been reported to have renal disease. Here, we describe a patient with both homozygous and heterozygous variants in RNASEH2B, presenting with neurological manifestations, persistently systemic autoinflammation, and CKD. CKD has never been reported in patients with AGS due to the RNASEH2B defect .

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“…Belimumab demonstrated efficacy versus placebo in reducing SLE disease activity and the time to lupus flares in addition to standard care in two phase III RCTs (BLISS-52 and BLISS-76 [132,133] [140]. However, familial chilblain lupus associated with three prime repair exonuclease 1 (TREX1) mutation and Aicardi-Goutières syndrome was significantly improved with baricitinib 4 and 2 mg/day, respectively [141,142]. Filgotinib is an oral selective JAK1 inhibitor that has shown promising results in two-phase II studies of active ankylosing spondylitis and psoriatic arthritis with acceptable safety profile [143,144].…”

Section: Belimumabmentioning

confidence: 99%

Current Concepts and Future Approaches in the Treatment of Cutaneous Lupus Erythematosus: A Comprehensive Review

Chasset

Françès

2019

Drugs

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Standard treatment of cutaneous lupus erythematosus (CLE) includes preventive measures such as smoking cessation and photoprotection associated with topical therapies and antimalarial agents, which are recommended as first-line systemic treatment. In more severe disease, alternative therapeutic options include immunosuppressive and immunomodulatory drugs. Recently, the development of specific tools to assess CLE activity and the publication of European CLE guidelines have improved the management of CLE. Moreover, several biologic agents are currently studied specifically in CLE or in systemic lupus erythematosus with assessment of skin involvement and may be promising therapies. However, improvement of the management of CLE remains a major unmet need. In this review, we summarize current concepts in the management of CLE as well as future approaches for more targeted treatments. Key points:  Some targeted agents that have shown some promise in skin manifestations with systemic lupus erythematosus.  Future studies are needed specifically for cutaneous lupus erythematosus (CLE), with responses for each of the CLE subtypes reported separately.

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Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi‐Goutières Syndrome, a Type I Interferonopathy

Cited by 48 publications

References 10 publications

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Current Concepts and Future Approaches in the Treatment of Cutaneous Lupus Erythematosus: A Comprehensive Review

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