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Objective: To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice., Methods: A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure., Results: Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS., Conclusion: High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Current HLH-2004-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here we performed a case-control study to test and possibly improve these clinical criteria. We also developed two complementary expert opinion-based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (n=366) were children <16 years with verified familial and/or genetic FHL (n=341) or Griscelli syndrome type 2 (GS2) (n=25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329+361 children in two cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on the number of diagnostic criteria fulfilled from 17 variables studied, reveled almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%). Notably, assessment of the original HLH-2004 criteria revealed accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Since cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without NK-cell function was also studied which showed accuracy 99.0% (sensitivity 96.2%; specificity 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis., (Copyright © 2024 American Society of Hematology.)

The coronavirus disease 2019 (COVID-19) pandemic emerged just months after the publication of the first ever textbook devoted to cytokine storm syndromes (CSSs). The severe disease caused by COVID-19 and the intersection between immune responses and their pathologies played out before the world in media reports, in scientific publications, and through the personal narratives of millions of people's experiences. An entirely new immune-mediated disease, multisystem inflammatory disease in children (MISC), was described. Cytokines played a role in all of these areas, bringing the idea of a cytokine storm squarely to the front and center of the public eye. At the same time, science continued to progress in the lab and in the clinic, thus illuminating our understanding of CSSs both old and new since the publication of the first edition of this book. It was clear that a new edition was needed to keep up with these changes., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Interleukin-1 is a prototypic proinflammatory cytokine that is elevated in cytokine storm syndromes (CSSs), such as secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS). IL-1 has many pleotropic and redundant roles in both innate and adaptive immune responses. Blockade of IL-1 with recombinant human interleukin-1 receptor antagonist has shown efficacy in treating CSS. Recently, an IL-1 family member, IL-18, has been demonstrated to be contributory to CSS in autoinflammatory conditions, such as in inflammasomopathies (e.g., NLRC4 mutations). Anecdotally, recombinant IL-18 binding protein can be of benefit in treating IL-18-driven CSS. Lastly, another IL-1 family member, IL-33, has been postulated to contribute to CSS in an animal model of disease. Targeting of IL-1 and related cytokines holds promise in treating a variety of CSS., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Familial forms of hemophagocytic lymphohistiocytosis (HLH) are caused by loss-of-function mutations in genes encoding perforin as well as those required for release of perforin-containing cytotoxic granule constituent. Perforin is expressed by subsets of CD8 + T cells and NK cells, representing lymphocytes that share mechanism of target cell killing yet display distinct modes of target cell recognition. Here, we highlight recent findings concerning the genetics of familial HLH that implicate CD8 + T cells in the pathogenesis of HLH and discuss mechanistic insights from animal models as well as patients that reveal how CD8 + T cells may contribute to or drive disease, at least in part through release of IFN-γ. Intriguingly, CD8 + T cells and NK cells may act differentially in severe hyperinflammatory diseases such as HLH. We also discuss how CD8 + T cells may promote or drive pathology in other cytokine release syndromes (CSS). Moreover, we review the molecular mechanisms underpinning CD8 + T cell-mediated lymphocyte cytotoxicity, key to the development of familial HLH. Together, recent insights to the pathophysiology of CSS in general and HLH in particular are providing promising new therapeutic targets., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

While viruses are considered the most common infectious triggers for cytokine storm syndromes (CSS), a growing list of bacterial pathogens, particularly intracellular organisms, have been frequently reported to be associated with this syndrome. Both familial and sporadic cases of CSS are often precipitated by acute infections. It is also important to note that an underlying precipitating infection might not be clinically obvious as the CSS clinical picture can mimic an infectious process or an overwhelming septicemia. It is important to detect such an underlying treatable condition. In addition, infections can also be acquired during the course of CSS due to the concurrent immune suppression with treatment. Optimal CSS outcomes require treating bacterial infections when recognized.CSS should always be suspected in patients presenting with a sepsis-like or multi-organ dysfunction picture. There are many criteria proposed to diagnose CSS in general, with HLH-2004 being the most commonly used. Alternatively, criteria have been proposed for CSS occurring in specific underlying conditions such as systemic lupus erythematosus (SLE) or systemic juvenile idiopathic arthritis (sJIA). However, waiting for many of these criteria to be fulfilled could lead to significant delay in diagnosis, and the physician needs a high index of suspicion for CSS in critically ill febrile hospitalized patients in order to properly recognize the condition. Thus, there should be diagnostic equipoise between CSS and infections, including bacterial, in this population. In this chapter, we discuss the more common bacterial precipitants of CSS with many of the cases being discussed in the pediatric age group., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Natural killer (NK) cells are innate immune lymphocytes that rapidly produce cytokines upon activation and kill target cells. NK cells have been of particular interest in primary hemophagocytic lymphohistiocytosis (pHLH) since all of the genetic defects associated with this disorder cause diminished cytotoxic capacity of NK cells and T lymphocytes, and assays of NK cell killing are used clinically for the diagnosis of HLH. Herein, we review human NK cell biology and the significance of alterations in NK cell function in the diagnosis and pathogenesis of HLH., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Competing Interests: RQC declares consulting fees for Sobi in regard to the use of anakinra in clinical trials to treat macrophage activation syndrome; textbook royalties from Springer; speaker fees from Lilly, Sobi, MedStudy, and Arthros Rheum; and consulting or advisory fees from Sironax and CareerPhysician. RQC also serves on adjudication committees and has received personal fees to establish episodes of macrophage activation syndrome among patients enrolled in clinical trials (funded by Pfizer and AbbVie) for therapeutics used to treat juvenile idiopathic arthritis. RQC holds a patent on detecting rare long non-coding RNA mutations in people with COVID-19 unrelated to the content of this Comment. ECR declares no competing interests.

Cytokine storm syndrome (CSS) is a serious and potentially life-threatening condition caused by severe systemic inflammation, immune activation, and a positive feedback loop of cytokine release. Typically triggered by systemic infection, malignancy, monogenic or rheumatic disease, similar patterns of hyper-inflammation have been seen in patients undergoing cardiopulmonary bypass (CPB) and in patients treated with extracorporeal membrane oxygenation (ECMO). Typical treatments used for the prevention and treatment of CPB/ECMO-induced hyper-inflammation have not been shown to be substantially effective. Two patients suffering from ECMO-related CSS were identified by their severe hyper-inflammatory profile and life-threatening sequelae of vasodilatory shock and respiratory failure. Anakinra, an interleukin-1 receptor antagonist, was employed as specific cytokine-directed therapy for the treatment of CSS in these two patients to good effect, with significant improvement in hyper-inflammation and cardiorespiratory status. The use of cytokine-directed therapies in CPB/ECMO-related CSS has great potential to improve the treatment and outcomes of this serious condition.

Cytokine storm syndromes (CSSs) are potentially fatal hyperinflammatory states that share the underpinnings of persistent immune cell activation and uninhibited cytokine production. CSSs can be genetically determined by inborn errors of immunity (i.e., familial hemophagocytic lymphohistiocytosis) or develop as a complication of infections, chronic inflammatory diseases (e.g., Still disease), or malignancies (e.g., T cell lymphoma). Therapeutic interventions that activate the immune system such as chimeric Ag receptor T cell therapy and immune checkpoint inhibition can also trigger CSSs in the setting of cancer treatment. In this review, the biology of different types of CSSs is explored, and the current knowledge on the involvement of immune pathways and the contribution of host genetics is discussed. The use of animal models to study CSSs is reviewed, and their relevance for human diseases is discussed. Lastly, treatment approaches for CSSs are discussed with a focus on interventions that target immune cells and cytokines., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Cytokine storm syndrome (CSS), which is frequently fatal, has garnered increased attention with the ongoing coronavirus pandemic. A variety of hyperinflammatory conditions associated with multiorgan system failure can be lumped under the CSS umbrella, including familial hemophagocytic lymphohistiocytosis (HLH) and secondary HLH associated with infections, hematologic malignancies, and autoimmune and autoinflammatory disorders, in which case CSS is termed macrophage activation syndrome (MAS). Various classification and diagnostic CSS criteria exist and include clinical, laboratory, pathologic, and genetic features. Familial HLH results from cytolytic homozygous genetic defects in the perforin pathway employed by cytotoxic CD8 T lymphocytes and natural killer (NK) cells. Similarly, NK cell dysfunction is often present in secondary HLH and MAS, and heterozygous mutations in familial HLH genes are frequently present. Targeting overly active lymphocytes and macrophages with etoposide and glucocorticoids is the standard for treating HLH; however, more targeted and safer anticytokine (e.g., anti-interleukin-1, -6) approaches are gaining traction as effective alternatives.

Involvement of the temporomandibular joint (TMJ) is common in juvenile idiopathic arthritis (JIA). TMJ arthritis can lead to orofacial symptoms, orofacial dysfunction, and dentofacial deformity with negative impact on quality of life. Management involves interdisciplinary collaboration. No current recommendations exist to guide clinical management. We undertook this study to develop consensus-based interdisciplinary recommendations for management of orofacial manifestations of JIA, and to create a future research agenda related to management of TMJ arthritis in children with JIA. Recommendations were developed using online surveying of relevant stakeholders, systematic literature review, evidence-informed generation of recommendations during 2 consensus meetings, and Delphi study iterations involving external experts. The process included disciplines involved in the care of orofacial manifestations of JIA: pediatric rheumatology, radiology, orthodontics, oral and maxillofacial surgery, orofacial pain specialists, and pediatric dentistry. Recommendations were accepted if agreement was >80% during a final Delphi study. Three overarching management principles and 12 recommendations for interdisciplinary management of orofacial manifestations of JIA were outlined. The 12 recommendations pertained to diagnosis (n = 4), treatment of TMJ arthritis (active TMJ inflammation) (n = 2), treatment of TMJ dysfunction and symptoms (n = 3), treatment of arthritis-related dentofacial deformity (n = 2), and other aspects related to JIA (n = 1). Additionally, a future interdisciplinary research agenda was developed. These are the first interdisciplinary recommendations to guide clinical management of TMJ JIA. The 3 overarching principles and 12 recommendations fill an important gap in current clinical practice. They emphasize the importance of an interdisciplinary approach to diagnosis and management of orofacial manifestations of JIA., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background : Multisystem inflammatory syndrome in children (MIS-C) is a severe, postinfectious manifestation of coronavirus disease 2019 (COVID-19) in the pediatric population. The disease is manifested by hyperinflammation and can result in cardiac dysfunction, coronary changes, and end-organ damage. Adequate timely treatment can prevent poor outcomes in the short term, but long-term data is lacking. Methods : A large single center MIS-C cohort was followed longitudinally after treatment with intravenous immunoglobulin (IVIG) ± glucocorticoids to determine the natural history of the disease and to describe improvement in laboratory markers and cardiac outcomes. Patient were stratified by disease severity and compared. Results : 137 patients were identified with demographics similar to previously described cohorts. Regardless of disease severity, when adequately treated, initial lab abnormalities rapidly improved by the 6-8 month follow-up period, with some resolved in as little as 1-2 weeks. Similarly, cardiac abnormalities improved quickly after treatment; all abnormalities resolved in this cohort by 1-2 months post-hospitalization. Conclusions : Although MIS-C is a serious sequela of COVID-19, when identified quickly and treated aggressively, laboratory abnormalities, coronary dilatation, and systolic dysfunction rapidly improve with minimal long-term morbidity or mortality.

Purpose of Review: Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affecting children. MIS-C shares features with Kawasaki disease (KD) and cytokine storm syndrome (CSS) frequently requiring intensive care support. Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). Understanding the clinical features, inflammatory cytokines, and genetic associations provides rationale for bDMARD in treating severe MIS-C., Recent Findings: Children with MIS-C have clinical KD features and often present in hypovolemic and cardiogenic shock requiring volume repletion (gastrointestinaI losses) and cardiac pressor support (epinephrine). Investigation of MIS-C serum reveals elevated pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18, interferon gamma (IFNγ), tumor necrosis factor (TNF)], but to a lesser extent than other established CSS. Gene sequencing of MIS-C children identifies heterozygous mutations in CSS associated genes. Treatment of refractory (IVIg and GC) MIS-C with bDMARDs to IL-1, IL-6, and TNF is efficacious for survival as well as resolving cardiac and coronary artery inflammation., Summary: MIS-C is a postinfectious complication of SARS-CoV-2 resembling KD and CSS, both genetically and by pro-inflammatory cytokines. MIS-C that is refractory to IVIg and GC is routinely responsive to bDMARDs targeting IL-1, IL-6, and TNF., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Macrophage activation syndrome (MAS) is a life-threatening, potentially fatal condition associated with systemic juvenile idiopathic arthritis (sJIA). Interleukin-1 (IL-1) is a key cytokine in the pathogenesis of sJIA MAS. Many cases of MAS are medically refractory to traditional doses of biologic cytokine inhibitors and may require increased dosing. When MAS occurs in the setting of sJIA treated with the IL-1 receptor antagonist (IL-1Ra), anakinra, increased anakinra dosing may be beneficial. Increased dosing of another IL-1 inhibitor, canakinumab, a monoclonal antibody to IL-1β, has not been reported to treat refractory MAS in the setting of sJIA., Methods: Retrospective data collection extracted from the electronic medical record focused on canakinumab usage and dosing in 8 children with sJIA who developed MAS at a single academic center from 2011 to 2020., Results: Eight sJIA children (five girls) with median age 8.5 years (range, 0.9-14.2 years) were included in the present study. Five children developed MAS at disease onset and three during ongoing canakinumab therapy. MAS resolved in all eight children with canakinumab treatment. When the canakinumab dosing was insufficient or MAS developed during canakinumab therapy, the dosing was temporally up-titrated (four patients, maximum 300 mg per dose) without observed side effects., Conclusion: This report provides evidence for the efficacy and safety of short-term increased doses (2-3-times normal) of canakinumab in treating sJIA associated MAS. Further study of the efficacy and safety of increased doses of canakinumab for treatment of MAS in children with sJIA is warranted., Competing Interests: Author RC has served as a consultant to SOBI, Novartis, Pfizer, and Sironax, and has received grant support from SOBI. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kostik, Isupova, Belozerov, Likhacheva, Suspitsin, Raupov, Masalova, Chikova, Dubko, Kalashnikova, Chasnyk and Cron.)

Recent development of new medications has changed the juvenile idiopathic arthritis (JIA) treatment goal to inactive disease. With numerous options, how does a clinician choose which medication to use? Treatment options may depend on the clinical classification and a new paradigm considers the JIA subtypes in reference to categories of adult inflammatory arthritis; poligo JIA, spondyloarthritis JIA, and systemic JIA that can help guide a clinician in determining treatment options. Treatment strategies such as consensus treatment plans can provide guidance on treatment escalation. However, a treat-to-target strategy using frequent standardized disease activity measurements, shared decision making with the patient, and treatment escalation to achieve the disease activity target can provide a personalized approach to managing JIA., Competing Interests: Conflict of interest statement Melissa L. Mannion – none. Randy Q. Cron - Tofacitinib for sJIA Adjudication of MAS Committee Chair, Pfizer, 2017-Present., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: I report grants and personal fees from Sobi, and personal fees from Novartis and Pfizer, outside the submitted work.

Objective: To provide updated guidelines for pharmacologic management of juvenile idiopathic arthritis (JIA), focusing on treatment of oligoarthritis, temporomandibular joint (TMJ) arthritis, and systemic JIA with and without macrophage activation syndrome. Recommendations regarding tapering and discontinuing treatment in inactive systemic JIA are also provided., Methods: We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations., Results: Similar to those published in 2019, these JIA recommendations are based on clinical phenotypes of JIA, rather than a specific classification schema. This guideline provides recommendations for initial and subsequent treatment of JIA with oligoarthritis, TMJ arthritis, and systemic JIA as well as for tapering and discontinuing treatment in subjects with inactive systemic JIA. Other aspects of disease management, including factors that influence treatment choice and medication tapering, are discussed. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional., Conclusion: This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis. It serves as a tool to support clinicians, patients, and caregivers in decision-making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision-making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver., (© 2022 American College of Rheumatology.)

Objective: To determine the relative importance weights of items and grades of a newly developed additive outcome measure called the juvenile idiopathic arthritis (JIA) magnetic resonance imaging (MRI) scoring system for the temporomandibular joint (TMJ) (JAMRIS-TMJ)., Methods: An adaptive partial-profile, discrete choice experiment (DCE) survey using the 1000Minds platform was independently completed by members of an expert group consisting of radiologists and non-radiologist clinicians to determine the group-averaged relative weights for the JAMRIS-TMJ. Subsequently, an image-based vignette ranking exercise was done, during which experts individually rank ordered 14 patient vignettes for disease severity while blinded to the weights and unrestricted to JAMRIS-TMJ assessment criteria. Validity of the weighted JAMRIS-TMJ was tested by comparing the consensus-graded, DCE-weighted JAMRIS-TMJ score of the vignettes with their unrestricted image-based ranks provided by the experts., Results: Nineteen experts completed the DCE survey, and 21 completed the vignette ranking exercise. Synovial thickening and joint enhancement showed higher weights per raw score compared to bone marrow items and effusion in the inflammatory domain, while erosions and condylar flattening showed nonlinear and higher weights compared to disk abnormalities in the damage domain. The weighted JAMRIS-TMJ score of the vignettes correlated highly with the ranks from the unrestricted comparison method, with median Spearman's ρ of 0.92 (interquartile range [IQR] 0.87-0.95) for the inflammation and 0.93 (IQR 0.90-0.94) for the damage domain., Conclusion: A DCE survey was used to quantify the importance weights of the items and grades of the JAMRIS-TMJ. The weighted score showed high convergent validity with an unrestricted, holistic vignette ranking method., (© 2021, American College of Rheumatology.)

Background: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene STXBP2 , and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo., Methods: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient's STXBP2 mutation and wild-type (WT) STXBP2 were separately transduced into the NK-92 human NK cell line. The WT and mutant STXBP2 transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively., Results: Compared to WT STXBP2, the patient's STXBP2 mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro., Conclusion: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.

Competing Interests: RQC reports grants and personal fees from Sobi, personal fees from Novartis, personal fees from Pfizer during the conduct of the study. DAK declares no competing interests.

Purpose of Review: Multisystem inflammatory disease in children (MIS-C) is a novel post-infectious phenomenon following coronavirus disease-19 (COVID-19). Herein, we present an in-depth review of the latest MIS-C literature related to clinical findings, pathophysiology, imaging and laboratory studies, treatment algorithms, and disease outcomes., Recent Findings: With its non-specific presentation of fever, gastrointestinal symptoms, cardiovascular injury and shock, systemic inflammation, and Kawasaki disease (KD)-like features, MIS-C can be a diagnostic challenge, overlapping with KD and active COVID-19 infection. However, common laboratory features, imaging findings, and historical clues can lead to accurate diagnosis and allow for appropriate treatment with a variety of immunomodulatory therapies, including intravenous immunoglobulin (IVIG). Aggressive treatment of MIS-C leads to good outcomes. Longitudinal studies continue to illuminate long-term cardiac sequelae and recovery. MIS-C presents with fever, KD features, gastrointestinal symptoms, cardiac inflammation, and shock. Early recognition and prompt institution of IVIG and glucocorticoids provide for rapid improvement., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: This review is meant to describe the genetic associations with pediatric severe COVID-19 pneumonia and the postinfectious complication of the multisystem inflammatory syndrome in children (MIS-C). Multiple genetic approaches have been carried out, primarily in adults with extrapolation to children, including genome-wide association studies (GWAS), whole exome and whole genome sequencing (WES/WGS), and target gene analyses., Recent Findings: Data from adults with severe COVID-19 have identified genomic regions (human leukocyte antigen locus and 3p21.31) as potential risk factors. Genes related to viral entry into cells (ABO blood group locus, ACE2, TMPRS22) have been linked to severe COVID-19 patients by GWAS and target gene approaches. Type I interferon (e.g. IFNAR2) and antiviral gene (e.g. TLR7) associations have been identified by several genetic approaches in severe COVID-19. WES has noted associations with several immune regulatory genes (e.g. SOCS1). Target gene approaches have identified mutations in perforin-mediated cytolytic pathway genes in children and adults with severe COVID-19 and children with MIS-C., Summary: Several genetic associations have been identified in individuals with severe COVID-19 and MIS-C via various genetic approaches. Broadly speaking, COVID-19 genetic associations include genes involved with antiviral functions, viral cell entry, immune regulation, chemotaxis of white blood cells, and lymphocyte cytolytic function., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The objective of this study is to evaluate pediatric patients using existing macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) scoring systems to determine how these systems identify patients with cytokine storm syndrome (CSS) in the setting of a multisystem inflammatory syndrome in children (MIS-C) and active coronavirus disease 2019 (COVID-19) infection., Methods: Hospitalized pediatric patients with MIS-C and active COVID-19 infection at a single institution were identified. Infectious data, clinical findings, and laboratory values were collected, and patients were stratified by disease severity. Eight historically used scoring systems for MAS, HLH, and CSS were examined in the cohort of patients with MIS-C and pediatric COVID-19., Results: The HLH-2004 criteria and HScore did not identify any patients as having CSS on admission, with only one patient with COVID-19 meeting criteria at peak disease severity. The 2016 systemic juvenile idiopathic arthritis (sJIA)/MAS criteria, ferritin/erythrocyte sedimentation rate (ESR) ratio, and COVID-19 CSS Quick Score most frequently identified CSS in this population and distinguished between COVID-19 and MIS-C hyperinflammation. The 2019 MAS/sJIA (MS) score and the COVID-19-associated hyperinflammatory syndrome (cHIS) criteria were less likely to identify CSS, as the MS score overestimated CSS and the cHIS resulted in similar scores regardless of severity or disease type. The Caricchio COVID-Cytokine Storm (COVID-CS) criteria identified patients with COVID-19 frequently but was less useful in MIS-C because of its COVID-19-specific criteria., Conclusion: MIS-C and pediatric COVID-19 result in relatively unique CSSs and patterns of inflammation. Existing scoring systems for CSSs likely do not capture the full breadth of this disease process in MIS-C and pediatric COVID-19., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The introduction of disease-modifying anti-rheumatic drug therapies for treating children and adolescents with chronic arthritis (ie, juvenile idiopathic arthritis [JIA]) has revolutionised care and outcomes. The biologic revolution continues to expand, with ever-changing immunological targets coming to market after basic research and clinical trials. The first class of biologics that was beneficial for children with JIA was tumour necrosis factor (TNF) inhibitors. If used early and aggressively, TNF inhibitors are capable of inducing disease remission for most of the seven subtypes of JIA, with the exception of systemic JIA (which more frequently responds to interleukin [IL]-1 or IL-6 inhibition). Nevertheless, there are still subsets of patients with JIA with disease that is difficult to treat or who develop extra-articular features that require a different therapeutic approach. Although finding an effective biological therapy for individual children with JIA can be trial and error, ongoing research and clinical trials are providing insight into a more personalised approach to care. In addition, redefining the JIA classification, in part based on shared similarities with various adult arthritides, could allow for extrapolation of knowledge from studies in adults with chronic arthritis., Competing Interests: Declaration of interests RQC is on the Swedish Orphan Biovitrum advisory board for macrophage activation syndrome as a paid speaker and moderator for MEDSCAPE and WebMD and investigator initiating a clinical trial of anakinra to treat MAS; consults for Novartis and Sironax; and is working for Pfizer on a clinical trial of MAS as an adjudication committee chair., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA)., Study Design: International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS., Results: Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab., Conclusions: The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has resulted in more than 2 million deaths globally. Two interconnected stages of disease are generally recognised; an initial viral stage and a subsequent immune response phase with the clinical characteristics of hyperinflammation associated with acute respiratory distress syndrome. Therefore, many immune modulators and immunosuppressive drugs, which are widely used in rheumatological practice, have been proposed as treatments for patients with moderate or severe COVID-19. In this Review, we provide an overview of what is currently known about the efficacy and safety of antirheumatic therapies for the treatment of patients with COVID-19. Dexamethasone has been shown to reduce COVID-19 related mortality, interleukin-6 inhibitors to reduce risk of cardiovascular or respiratory organ support, and baricitinib to reduce time to recovery in hospitalised patients requiring oxygen support. Further studies are needed to identify whether there is any role for glucocorticoids in patients with less severe COVID-19. Although evidence on the use of other antirheumatic drugs has suggested some benefits, results from adequately powered clinical trials are urgently needed. The heterogeneity in dosing and the absence of uniform inclusion criteria and defined stage of disease studied in many clinical trials have affected the conclusions and comparability of trial results. However, after the success of dexamethasone in proving the anti-inflammatory hypothesis, the next 12 months will undoubtedly bring further clarity about the clinical utility and optimal dose and timing of other anti-rheumatic drugs in the management of COVID-19., Competing Interests: INB reports grants and speaker fees from GlaxoSmithK, line grants from Sanofi Genzyme, and consulting fees, speaker fees, or both (paid to his institution) from AstraZeneca, UCB, Bristol Myers Squibb, Eli Lilly, ILTOO Pharma, and Merck Serono, outside the submitted work. RQC reports grants and personal fees from Swedish Orphan Biovitrum and personal fees from Sironax, Novartis, and Pfizer, outside the submitted work. KSta reports personal fees from Amgen, Sanofi, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Vifor Pharma, and Berlin Chemie, outside the submitted work. All other authors declare no competing interests., (© 2021 Elsevier Ltd. All rights reserved.)

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease affecting the joints and other organs that occurs in 1 in 1,000 children in the United States. Given the various categories of JIA, interpretation of the literature can be difficult. In this review, new developments in understanding non-systemic JIA and its treatment will be covered. Recent advances in the journey toward personalized treatment in JIA will be highlighted, including a review of currently available biologic modifiers. Uveitis and the temporomandibular joint will be discussed as particularly challenging treatment issues. Recent guideline updates and literature-guided treatment decisions will be reviewed., Competing Interests: The authors declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2021 Cron RQ et al.)

Background: Immune-mediated lung injury and systemic hyperinflammation are characteristic of severe and critical coronavirus disease 2019 (COVID-19) in adults. Although the majority of severe acute respiratory syndrome coronavirus 2 infections in pediatric populations result in minimal or mild COVID-19 in the acute phase of infection, a small subset of children develop severe and even critical disease in this phase with concomitant inflammation that may benefit from immunomodulation. Therefore, guidance is needed regarding immunomodulatory therapies in the setting of acute pediatric COVID-19. This document does not provide guidance regarding the recently emergent multisystem inflammatory syndrome in children (MIS-C)., Methods: A multidisciplinary panel of pediatric subspecialty physicians and pharmacists with expertise in infectious diseases, rheumatology, hematology/oncology, and critical care medicine was convened. Guidance statements were developed based on best available evidence and expert opinion., Results: The panel devised a framework for considering the use of immunomodulatory therapy based on an assessment of clinical disease severity and degree of multiorgan involvement combined with evidence of hyperinflammation. Additionally, the known rationale for consideration of each immunomodulatory approach and the associated risks and benefits was summarized., Conclusions: Immunomodulatory therapy is not recommended for the majority of pediatric patients, who typically develop mild or moderate COVID-19. For children with severe or critical illness, the use of immunomodulatory agents may be beneficial. The risks and benefits of such therapies are variable and should be evaluated on a case-by-case basis with input from appropriate specialty services. When available, the panel strongly favors immunomodulatory agent use within the context of clinical trials. The framework presented herein offers an approach to decision-making regarding immunomodulatory therapy for severe or critical pediatric COVID-19 and is informed by currently available data, while awaiting results of placebo-controlled randomized clinical trials., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hemophagocytic lymphohistiocytosis (HLH) can be familial or secondary, which is often triggered by infection or malignancy. HLH therapy includes dexamethasone and etoposide. However, therapy is associated with significant morbidity and mortality. Anakinra, a recombinant interleukin-1 receptor antagonist, has been reported to treat macrophage activation syndrome (MAS), rheumatic sHLH. We report our experience with anakinra to treat patients with nonrheumatic secondary HLH (sHLH)., Procedure: Six children were diagnosed with HLH from December 2014 to August 2016 and were treated with subcutaneous anakinra (6-10 mg/kg/day divided over four doses) with or without dexamethasone (10 mg/m 2 /day). Therapy was either escalated or weaned based on clinical and laboratory response., Results: Five of six patients were treated with anakinra and dexamethasone, and one with anakinra alone due to active cytomegalovirus (CMV) pneumonitis. The median age of diagnosis was 1.8 years (range 0.8-14.9 years). No pathogenic mutations associated with HLH were identified, but three of six possessed genetic variants of unknown significance. Infectious triggers were identified for four patients and two patients had malignancies. The average treatment duration was 8 weeks with 3.5-5.5 years of follow up. No patient needed escalation of therapy to include etoposide. All patients achieved remission. Anakinra was well tolerated without significant adverse effects., Conclusion: Initial treatment with anakinra (with or without dexamethasone) is a feasible treatment alternative for patients with secondary HLH and may allow for avoidance of etoposide. We recommend early initiation of anakinra when HLH is suspected. A broader investigation of the use of anakinra as a first-line agent for HLH is ongoing., (© 2020 Wiley Periodicals LLC.)

Since initial identification of severe acute respiratory syndrome coronavirus 2 in 2019, the virus has proved to be highly transmissible, resulting in a global pandemic with emerging reports of infected neonates. This report highlights a severe case of neonatal coronavirus disease 2019 with acute respiratory distress syndrome.

Since the first textbook devoted to cytokine storm syndromes (CSSs) was published in 2019, the world has changed dramatically and the term's visibility has broadened. Herein, we define CSSs broadly to include life/organ-threatening systemic inflammation and immunopathology regardless of the context in which it occurs, recognizing that the indistinct borders of such a definition limit its utility. Nevertheless, we are focused on the pathomechanisms leading to CSSs, including impairment of granule-mediated cytotoxicity, specific viral infections, excess IL-18, and chimeric antigen receptor T-cell therapy. These mechanisms are often reflected in distinct clinical features, functional tests, and/or biomarker assessments. Moreover, these mechanisms often indicate specific, definitive treatments. This mechanism-focused organization is vital to both advancing the field and understanding the complexities in individual patients. However, increasing evidence suggests that these mechanisms interact and overlap. Likewise, the utility of a broad term such as "cytokine storm" is that it reflects a convergence on a systemic inflammatory phenotype that, regardless of cause or context, may be amenable to "inflammo-stabilization." CSS research must improve our appreciation of its various mechanisms and their interactions and treatments, but it must also identify the signs and interventions that may broadly prevent CSS-induced immunopathology., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19., (© 2020, American College of Rheumatology.)

The term cytokine storm syndromes describes conditions characterised by a life-threatening, fulminant hypercytokinaemia with high mortality. Cytokine storm syndromes can be genetic or a secondary complication of autoimmune or autoinflammatory disorders, infections, and haematological malignancies. These syndromes represent a key area of interface between rheumatology and general medicine. Rheumatologists often lead in management, in view of their experience using intensive immunosuppressive regimens and managing cytokine storm syndromes in the context of rheumatic disorders or infection (known as secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome [sHLH/MAS]). Interleukin (IL)-1 is pivotal in hyperinflammation. Anakinra, a recombinant humanised IL-1 receptor antagonist, is licenced at a dose of 100 mg once daily by subcutaneous injection for rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and cryopyrin-associated periodic syndromes. In cytokine storm syndromes, the subcutaneous route is often problematic, as absorption can be unreliable in patients with critical illness, and multiple injections are needed to achieve the high doses required. As a result, intravenous anakinra is used in clinical practice for sHLH/MAS, despite this being an off-licence indication and route of administration. Among 46 patients admitted to our three international, tertiary centres for sHLH/MAS and treated with anakinra over 12 months, the intravenous route of delivery was used in 18 (39%) patients. In this Viewpoint, we describe current challenges in the management of cytokine storm syndromes and review the pharmacokinetic and safety profile of intravenous anakinra. There is accumulating evidence to support the rationale for, and safety of, intravenous anakinra as a first-line treatment in patients with sHLH/MAS. Intravenous anakinra has important clinical relevance when high doses of drug are required or if patients have subcutaneous oedema, severe thrombocytopenia, or neurological involvement. Cross-speciality management and collaboration, with the generation of international, multi-centre registries and biobanks, are needed to better understand the aetiopathogenesis and improve the poor prognosis of cytokine storm syndromes., (© 2020 Elsevier Ltd. All rights reserved.)