Interfering with interferons: targeting the JAK-STAT pathway in complications of systemic juvenile idiopathic arthritis (SJIA)

Verweyen, Emely; Schulert, Grant S.

doi:10.1093/rheumatology/keab673

Cited by 29 publications

(23 citation statements)

References 96 publications

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“…82,83 Individuals with A-DS present with more small joints involvement, but lower levels of inflammatory markers including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), than euploid individuals with JIA. 83 Cases with interferon-induced arthritis have been reported, together with a type I IFN signature in rheumatoid arthritis, 84,85 but the contribution of IFN to A-DS remains unclear. Early screening and interventions are the key preventive approaches for A-DS.…”

Section: Arthropathy and Alzheimer's Disease In Dsmentioning

confidence: 99%

Interferon-Driven Immune Dysregulation in Down Syndrome: A Review of the Evidence

Chung¹,

Green²,

Wang³

et al. 2021

JIR

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Down syndrome (DS) is a unique genetic disease caused by the presence of an extra copy of chromosome 21, which carries four of the six interferon receptor (IFN-R) genes on its long arm. Recent studies reporting higher levels of interferon-stimulated gene (ISG) expression in primary immune cells studied ex vivo have suggested that the additional copies of the IFN-R genes in DS result in mild interferonopathy. In this review, we analyze the potential clinical and immunological impacts of this interferonopathy in DS. We performed a literature review to explore the epidemiology and risks of celiac disease, type 1 diabetes, thyroid dysfunction, mucocutaneous manifestations, infectious diseases (including COVID-19), and Alzheimer's disease in individuals with DS relative to the general population with or without iatrogenic exposure to interferons. We analyzed immunophenotyping data and the current experimental evidence concerning IFN-R expression, constitutive JAK-STAT activation, and ISG overexpression in DS. Despite the lack of direct evidence that implicating this mild interferonopathy directly in illnesses in individuals with DS, we highlight the challenges ahead and directions that could be taken to determine more clearly the biological impact of interferonopathy on various immune-related conditions in DS.

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Section: Arthropathy and Alzheimer's Disease In Dsmentioning

confidence: 99%

Interferon-Driven Immune Dysregulation in Down Syndrome: A Review of the Evidence

Chung¹,

Green²,

Wang³

et al. 2021

JIR

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“…JAK inhibitors look promising as these drugs may be active on both SJIA activity and MAS [ 54 , 55 , 56 ]. In particular, in patients with remitting–relapsing MAS, we would at the moment privilege this treatment.…”

Section: Resultsmentioning

confidence: 99%

Systemic Juvenile Idiopathic Arthritis/Pediatric Still’s Disease, a Syndrome but Several Clinical Forms: Recent Therapeutic Approaches

Quartier

2022

JCM

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Background: Systemic Juvenile Idiopathic Arthritis (SJIA)/Pediatric Still’s disease is associated with different phenotypes and outcomes from currently available treatments. Methods: A review of opinion, based on personal experience in a reference pediatric rheumatology center and key publications, to explore the most important questions regarding disease heterogeneity and treatment approaches. Results: A few situations deserve particular attention: 1/patients with recent-onset SJIA who may benefit from a treat-to-target approach with a key place for interleukin (IL)-1 inhibition; 2/SJIA patients refractory to Il-1 and IL-6 antagonists in whom several options may be discussed, including thalidomide or allogeneic hematopoietic stem cell transplantation; 3/SJIA patients with macrophage activation syndrome who may benefit from both well-used classical treatment and innovative approaches, such as anti-interferon gamma therapy or Janus Kinase (JAK) inhibitors; 4/SJIA with severe lung involvement, 5/SJIA patients who achieve complete remission on treatment, with some recent evidence that treatment may be reduced in intensity but not so easily withdrawn. Conclusions: a case-by-case discussion with expert teams is recommended in this heterogeneous, often difficult-to-treat population of patients.

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“…A few such cytokines are IFN-γ and IL-6, which as previously mentioned are important in the pathophysiology of SJIA. An in depth review regarding the theoretic benefits of Jakinibs in SJIA is detailed in a recent review by Verweyen and Schulert [ 78 ]. There is currently a clinical trial using tofacitinib for treatment of children with SJIA with active systemic features (NCT03000439).…”

Section: Treatment Options For Refractory Sjiamentioning

confidence: 99%

“…While mechanistically Jakinibs are intriguing, there are only few case reports published of their use in the treatment of SJIA. One case report from China describes a 13-year-old girl with recalcitrant systemic and arthritic manifestations of SJIA despite long term glucocorticoids, methotrexate, and TNF-α inhibition [ 78 ]. The patient suffered significant glucocorticoid toxicity with vertebral compression fractures and growth retardation.…”

Section: Treatment Options For Refractory Sjiamentioning

confidence: 99%

Refractory systemic onset juvenile idiopathic arthritis: current challenges and future perspectives

et al. 2022

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Systemic juvenile idiopathic arthritis (SJIA) is a rare disease with distinct features not seen in other categories of juvenile idiopathic arthritis. In recent years, advances in the understanding of disease immunopathogenesis have led to improved targeted therapies with significant improvement in patient outcomes. Despite these advances, there remain subsets of SJIA with refractory disease and severe disease-associated complications. This review highlights existing options for treatment of refractory SJIA and explores potential future therapeutics for refractory disease. Key Points: Despite targeted Interleukin IL-1 and IL-6 inhibitors a subset of SJIA remains refractory to therapy. About 1 in 7 SJIA patients will be refractory to targeted IL-1 or IL-6 therapy. There is no current agreed upon definition for refractory SJIA and we propose in this review that refractory SJIA is presence of active systemic or arthritic features despite treatment with anti-IL-1 or anti-IL-6 therapy or disease requiring glucocorticoids for control beyond 6 months. SJIA disease associated complications include presence of associated macrophage activation syndrome (MAS), interstitial lung disease (ILD) or amyloidosis and management of each differs. Refractory SJIA treatment options currently include additional conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS), biologic (bDMARDS), combination biologic therapy, targeted synthetic (tsDMARDS) or other immunomodulatory therapies.

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Interfering with interferons: targeting the JAK-STAT pathway in complications of systemic juvenile idiopathic arthritis (SJIA)

Cited by 29 publications

References 96 publications

Interferon-Driven Immune Dysregulation in Down Syndrome: A Review of the Evidence

Interferon-Driven Immune Dysregulation in Down Syndrome: A Review of the Evidence

Systemic Juvenile Idiopathic Arthritis/Pediatric Still’s Disease, a Syndrome but Several Clinical Forms: Recent Therapeutic Approaches

Refractory systemic onset juvenile idiopathic arthritis: current challenges and future perspectives

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