Kawasaki disease (KD) is a common vasculitis of childhood, typically affecting children under the age of five. Despite many aspects of its presentation that bear resemblence to acute infection, no ...causative infectious agent has been identified despite years of intense scrutiny. Unlike most infections, however, there are significant differences in racial predilection that suggest a strong genetic influence. The inflammatory response in KD specifically targets the coronary arteries, also unusual for an infectious condition. In this review, we discuss recent hypotheses on KD pathogenesis as well as new insights into the innate immune response and mechanisms behind vascular damage. The pathogenesis is complex, however, and remains inadequately understood.
•Genetic, environmental, and infectious factors contribute to Kawasaki disease pathogenesis.•The innate immune response plays a prominent role in KD systemic and vascular inflammation.•No single causative infectious agent has yet been identified, but unbiased sequencing approaches may yield new insights.•Epidemiology of disease clusters may give clues into environmental factors influencing KD development.
Current understanding of the pathophysiology of systemic lupus erythematosus has expanded rapidly over the past few decades. These advances have been driven in part by advances in sequencing ...technology allowing better insights into the genetic underpinnings of the disease, but also by recognition that the inherent heterogeneity of lupus permits detailed study of various aspects of autoimmune physiology. This review outlines some of the lessons learned over time from the study of SLE across different age groups and different phenotypes.
•Clinical differences in SLE suggests the contribution of different mechanisms in pathogenesis.•The study of monogenic lupus has led to new insights into the pathophysiology and inheritance of typical, polygenic lupus.•The female sex predominance in lupus can be explained by hormonal, epigenetic, and X chromosome-related differences.
BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic ...spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.
The aetiology of systemic lupus erythematosus (SLE) is multifactorial, and includes contributions from the environment, stochastic factors, and genetic susceptibility. Great gains have been made in ...understanding SLE through the use of genetic variant identification, mouse models, gene expression studies, and epigenetic analyses. Collectively, these studies support the concept that defective clearance of immune complexes and biological waste (such as apoptotic cells), neutrophil extracellular traps, nucleic acid sensing, lymphocyte signalling, and interferon production pathways are all central to loss of tolerance and tissue damage. Increased understanding of the pathogenesis of SLE is driving a renewed interest in targeted therapy, and researchers are now on the verge of developing targeted immunotherapy directed at treating either specific organ system involvement or specific subsets of patients with SLE. Accordingly, this Review places these insights within the context of our current understanding of the pathogenesis of SLE and highlights pathways that are ripe for therapeutic targeting.
The pathophysiology of systemic lupus erythematosus (SLE) has been intensely studied but remains incompletely defined. Currently, multiple mechanisms are known to contribute to the development of ...SLE. These include inadequate clearance of apoptotic debris, aberrant presentation of self nucleic antigens, loss of tolerance, and inappropriate activation of T and B cells. Genetic, hormonal, and environmental influences are also known to play a role. The study of lupus in children, in whom there is presumed to be greater genetic influence, has led to new understandings that are applicable to SLE pathophysiology as a whole. In particular, characterization of inherited disorders associated with excessive type I interferon production has elucidated specific mechanisms by which interferon is induced in SLE. In this review, we discuss several monogenic forms of lupus presenting in childhood and also review recent insights gained from cytokine and autoantibody profiling of pediatric SLE.
Monogenic Lupus Lo, Mindy S.
Current rheumatology reports,
12/2016, Letnik:
18, Številka:
12
Journal Article
Recenzirano
Purpose of Review
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease known for its clinical heterogeneity. Over time, new insights into the complex genetic origin of SLE have ...started to explain some of this clinical variability. These findings, reviewed here, have also yielded important understanding in the immune mechanisms behind SLE pathogenesis.
Recent Findings
Several new monogenic disorders with lupus-like phenotype have been described. These can be organized into physiologic pathways that parallel mechanisms of disease in SLE. Examples include genes important for DNA damage repair (e.g.,
TREX1
), nucleic acid sensing and type I interferon overproduction (e.g.,
STING, TREX1
), apoptosis (
FASLG
), tolerance (
PRKCD
), and clearance of self-antigen (
DNASE1L3
).
Summary
Further study of monogenic lupus may lead to better genotype/phenotype correlations in SLE. Eventually, the ability to understand individual patients according to their genetic profile may allow the development of more targeted and personalized approaches to therapy.
Intravenous immunoglobulin (IVIg) is a purified plasma product that is used for many immune‐deficient conditions and autoimmune conditions. Use of IVIg for treatment for Kawasaki disease (KD) is ...critical for control of inflammation. The American Heart Association (AHA) recommends a single infusion of 2 g/kg preferably given during the first 10 days of illness. In this review, we have discussed the possible mechanisms of action of IVIg in KD and its clinical usage in this condition.
Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in ...overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS.
We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis.
ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes.
These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.
Objective
Systemic immunosuppressive treatment of pediatric chronic anterior uveitis (CAU), both juvenile idiopathic arthritis–associated and idiopathic anterior uveitis, varies, making it difficult ...to identify best treatments. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for CAU for the purpose of reducing practice variability and allowing future comparison of treatments using comparative effectiveness analysis techniques.
Methods
A core group of pediatric rheumatologists, ophthalmologists with uveitis expertise, and a lay advisor comprised the CARRA uveitis workgroup that performed a literature review on pharmacologic treatments, held teleconferences, and developed a case‐based survey administered to the CARRA membership to delineate treatment practices. We held 3 face‐to‐face consensus meetings using nominal group technique to develop CTPs.
Results
The survey identified areas of treatment practice variability. We developed 2 CTPs for the treatment of CAU, case definitions, and monitoring parameters. The first CTP is directed at children who are naive to steroid‐sparing medication, and the second at children initiating biologic therapy, with options for methotrexate, adalimumab, and infliximab. We defined a core data set and outcome measures, with data collection at 3 and 6 months after therapy initiation. The CARRA membership voted to accept the CTPs with a >95% approval (n = 233).
Conclusion
Using consensus methodology, 2 standardized CTPs were developed for systemic immunosuppressive treatment of CAU. These CTPs are not meant as treatment guidelines, but are designed for further pragmatic research within the CARRA research network. Use of these CTPs in a prospective comparison effectiveness study should improve outcomes by identifying best practice options.
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