Prediction of Survival by IL-6 in a Randomized Placebo-Controlled Trial of Anakinra in COVID-19 Cytokine Storm.

(1) Background: Some severe COVID-19 patients develop hyperinflammatory cytokine storm syndrome (CSS). We assessed the efficacy of anakinra added to standard of care (SoC) in hospitalized COVID-19 CSS patients. (2) Methods: In this single-center, randomized, double-blind, placebo-controlled trial (NCT04362111), we recruited adult hospitalized patients with SARS-CoV-2 infection, evidence of pneumonia, new/increasing oxygen requirement, ferritin ≥ 700 ng/mL, and at least three of the following indicators: D-dimer ≥ 500 ng/mL, platelet count < 130,000/mm3, WBC < 3500/mm3 or lymphocyte count < 1000/mm3, AST or ALT > 2X the upper limit of normal (ULN), LDH > 2X ULN, C-reactive protein > 100 mg/L. Patients were randomized (1:1) to SoC plus anakinra (100 mg subcutaneously every 6 h for 10 days) or placebo. All received dexamethasone. The primary outcome was survival and hospital discharge without need for intubation/mechanical ventilation. The data were analyzed according to the modified intention-to-treat approach. (3) Results: Between August 2020 and January 2021, 32 patients were recruited, of which 15 were assigned to the anakinra group, and 17 to the placebo group. Two patients receiving the placebo withdrew within 48 h and were excluded. The mean age was 63 years (SD 10.3), 20 (67%) patients were men, and 20 (67%) were White. At Day 10, one (7%) patient receiving anakinra and two (13%) patients receiving the placebo had died (p = 1.0). At hospital discharge, four (27%) patients receiving anakinra and four (27%) patients receiving the placebo had died. The IL-6 level at enrollment was predictive of death (p < 0.01); anakinra use was associated with decreases in CXCL9 levels. (4) Conclusions: Anakinra added to dexamethasone did not significantly impact the survival of COVID-19 pneumonia patients with CSS. Additional studies are needed to assess patient selection and the efficacy, timing, and duration of anakinra treatment for COVID-19 CSS.

Majority of new patient referrals to a large pediatric rheumatology center result in non-rheumatic diagnosis.

OBJECTIVE: Pediatric rheumatology faces a looming supply-demand crisis. While strategies have been proposed to address the supply shortfall, investigation into the increased demand for pediatric rheumatic care has been limited. Herein, we analyze new patient visits to a large tertiary care pediatric rheumatology center to identify emerging trends in referrals and areas for potential intervention to meet this increased demand. METHODS: All patients referred to and seen by the University of Alabama at Birmingham Pediatric Rheumatology Division between January 2019 and December 2021 for a new patient evaluation were identified. Patient data was retrospectively abstracted, de-identified, and analyzed to develop trends in referrals and frequency of rheumatic disease, non-rheumatic disease, and specific diagnoses. RESULTS: During the study period, 2638 patients were referred to and seen in by the pediatric rheumatology division. Six hundred and ten patients (23.1%) were diagnosed with rheumatic disease. The most common rheumatic disease was juvenile idiopathic arthritis (JIA) at 45.6%, followed by primary Raynaud phenomenon (7.4%), recurrent fever syndromes (6.9%), vasculitides (6.7%), and inflammatory eye disease (6.2%). Of the 2028 patients (76.9%) diagnosed with a non-rheumatic condition, benign musculoskeletal pain was the most common (61.8%), followed by a combination of somatic conditions (11.6%), and non-inflammatory rash (7.7%). CONCLUSION: In this analysis of new patient referrals to a large pediatric rheumatology center, the majority of patients were diagnosed with a non-rheumatic condition. As a worsening supply-demand gap threatens the field of pediatric rheumatology, increased emphasis should be placed on reducing non-rheumatic disease referrals.

The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS).

OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.

The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.

Cytokine Storm Syndrome Triggered by Extracorporeal Membrane Oxygenation in Pediatric Patients.

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.

The Multifaceted Immunology of Cytokine Storm Syndrome.

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.

DOCK2 Mutation and Recurrent Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome resulting from uncontrolled hyper-inflammation, excessive immune system activation, and elevated levels of inflammatory cytokines. HLH can be caused by the inability to downregulate activated macrophages by natural killer (NK) and CD8 cytotoxic T cells through a process reliant on perforin and granzyme B to initiate apoptosis. Homozygous genetic mutations in this process result in primary HLH (pHLH), a disorder that can lead to multi-system organ failure and death in infancy. Heterozygous, dominant-negative, or monoallelic hypomorphic mutations in these same genes can cause a similar syndrome in the presence of an immune trigger, leading to secondary HLH (sHLH). A genetic mutation in a potential novel HLH-associated gene, dedicator of cytokinesis 2 (DOCK2), was identified in a patient with recurrent episodes of sHLH and hyperinflammation in the setting of frequent central line infections. He required baseline immune suppression for the prevention of sHLH, with increased anti-cytokine therapies and corticosteroids in response to flares and infections. Using a foamy-virus approach, the patient's DOCK2 mutation and wild-type (WT) control DOCK2 cDNA were separately transduced into a human NK-92 cell line. The NK-cell populations were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro and degranulation and cytolysis were measured using CD107a expression and live/dead fixable cell dead reagent, respectively. Compared to WT, the patient's DOCK2 mutation was found to cause significantly decreased NK cell function, degranulation, and cytotoxicity. This study speaks to the importance of DOCK2 and similar genes in the pathogenesis of sHLH, with implications for its diagnosis and treatment.

Cytokine Storm Syndrome.

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.

Management of Orofacial Manifestations of Juvenile Idiopathic Arthritis: Interdisciplinary Consensus-Based Recommendations.

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.

Standard and increased canakinumab dosing to quiet macrophage activation syndrome in children with systemic juvenile idiopathic arthritis.

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-1ß, 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.

Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children.

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.

Therapeutic strategies for treating juvenile idiopathic arthritis.

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.

2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging.

OBJECTIVE: To provide recommendations for the management of juvenile idiopathic arthritis (JIA) with a focus on nonpharmacologic therapies, medication monitoring, immunizations, and imaging, irrespective of JIA phenotype. 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: Recommendations in this guideline include the use of physical therapy and occupational therapy interventions; a healthy, well-balanced, age-appropriate diet; specific laboratory monitoring for medications; widespread use of immunizations; and shared decision-making with patients/caregivers. Disease management for all patients with JIA is addressed with respect to nonpharmacologic therapies, medication monitoring, immunizations, and imaging. 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, and a concurrent 2021 guideline on oligoarthritis, temporomandibular arthritis, and systemic JIA. 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.

Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) affects few children previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In 2020, 45 children admitted to our hospital for MIS-C underwent genetic screening with a commercial 109-immune-gene panel. Thirty-nine children were diagnosed with MIS-C, and 25.4% of the 39 MIS-C patients harbored rare heterozygous missense mutations either in primary hemophagocytic lymphohistiocytosis (pHLH) genes (LYST, STXBP2, PRF1, UNC13D, AP3B1) or the HLH-associated gene DOCK8 (four variants). We demonstrate that foamy virus introduction of cDNA for the four DOCK8 variants into human NK-92 natural killer (NK) cells led to decreased CD107a expression (degranulation) and decreased NK cell lytic function in vitro for each variant. Heterozygous carriers of missense mutations in pHLH genes and DOCK8 may serve as risk factors for development of MIS-C among children previously infected with SARS-CoV-2.