Publications by authors named "Randy Q Cron"

146 Publications

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children.

Curr Opin Pediatr 2021 Sep 15. Epub 2021 Sep 15.

Division of Rheumatology, Cincinnati Children's Hospital Medical Center Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio Division of Rheumatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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.
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http://dx.doi.org/10.1097/MOP.0000000000001061DOI Listing
September 2021

Calming the cytokine storm in COVID-19.

Nat Med 2021 Sep 3. Epub 2021 Sep 3.

Division of Clinical Immunology and Rheumatology, University of Alabama School of Medicine, Birmingham, AL, USA.

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http://dx.doi.org/10.1038/s41591-021-01500-9DOI Listing
September 2021

Performance of Cytokine Storm Syndrome Scoring Systems in Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children.

ACR Open Rheumatol 2021 Aug 25. Epub 2021 Aug 25.

University of Alabama at Birmingham.

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.
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http://dx.doi.org/10.1002/acr2.11331DOI Listing
August 2021

Hyperferritinemia Wins Again: Defining Macrophage Activation Syndrome in Pediatric Systemic Lupus Erythematosus.

J Rheumatol 2021 Sep 15;48(9):1355-1357. Epub 2021 Jun 15.

E.A. Smitherman, MD, MS, Assistant Professor, R.Q. Cron, MD, PhD, Professor, Division of Pediatric Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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http://dx.doi.org/10.3899/jrheum.210024DOI Listing
September 2021

Thrombotic Microangiopathy Associated with Macrophage Activation Syndrome: A Multinational Study of 23 Patients.

J Pediatr 2021 Aug 7;235:196-202. Epub 2021 Apr 7.

IRCCS Istituto Giannina Gaslini, Genoa, Italy; Università degli Studi di Genova, Genoa, Italy; Sechenov First Moscow State Medical University, Moscow, Russian Federation.

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.
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http://dx.doi.org/10.1016/j.jpeds.2021.04.004DOI Listing
August 2021

The role of antirheumatics in patients with COVID-19.

Lancet Rheumatol 2021 Jun 30;3(6):e447-e459. Epub 2021 Mar 30.

Danish Hospital for Rheumatic Diseases, University of Southern Denmark, Sønderborg, Danmark.

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.
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http://dx.doi.org/10.1016/S2665-9913(21)00062-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009617PMC
June 2021

Recent progress in the treatment of non-systemic juvenile idiopathic arthritis.

Fac Rev 2021 26;10:23. Epub 2021 Feb 26.

Children's of Alabama/University of Alabama at Birmingham, Birmingham, Alabama, USA.

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.
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http://dx.doi.org/10.12703/r/10-23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946384PMC
February 2021

Management of juvenile idiopathic arthritis: Preliminary qualitative findings from the National Dental Practice-Based Research Network.

J World Fed Orthod 2021 Jun 5;10(2):70-73. Epub 2021 Mar 5.

Department of Clinical and Community Sciences.

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic arthritis in childhood and represents a series of chronic inflammatory arthritides that develop before 16 years of age.

Methods: In 2020, investigators with an interest in the management of JIA engaged the National Dental Practice-Based Research Network by conducting a preliminary qualitative questionnaire ("Quick Poll") that comprised 6 questions about JIA management.

Results: A total of 604 persons responded. Results suggested that there was an interest in the management of JIA, but many clinicians did not feel that they had the necessary knowledge or experience to treat these patients.

Conclusions: The study clearly highlights a distinct gap in awareness and understanding of JIA among clinicians polled. Future work in this area should focus on education and awareness across multiple specialties, clinical guidelines for the management of JIA, and a data repository of long-term outcomes.
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http://dx.doi.org/10.1016/j.ejwf.2021.01.003DOI Listing
June 2021

COVID-19 cytokine storm: targeting the appropriate cytokine.

Authors:
Randy Q Cron

Lancet Rheumatol 2021 Apr 3;3(4):e236-e237. Epub 2021 Feb 3.

Randy Cron, Children's of Alabama, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USA.

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http://dx.doi.org/10.1016/S2665-9913(21)00011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906730PMC
April 2021

Distinguishing active pediatric COVID-19 pneumonia from MIS-C.

Pediatr Rheumatol Online J 2021 Feb 24;19(1):21. Epub 2021 Feb 24.

Division of Rheumatology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave. S., CPPN #G10, Birmingham, AL, 35233-1711, USA.

Importance: Active pediatric COVID-19 pneumonia and MIS-C are two disease processes requiring rapid diagnosis and different treatment protocols.

Objective: To distinguish active pediatric COVID-19 pneumonia and MIS-C using presenting signs and symptoms, patient characteristics, and laboratory values.

Design: Patients diagnosed and hospitalized with active COVID-19 pneumonia or MIS-C at Children's of Alabama Hospital in Birmingham, AL from April 1 through September 1, 2020 were identified retrospectively. Active COVID-19 and MIS-C cases were defined using diagnostic codes and verified for accuracy using current US Centers for Disease Control case definitions. All clinical notes were reviewed for documentation of COVID-19 pneumonia or MIS-C, and clinical notes and electronic medical records were reviewed for patient demographics, presenting signs and symptoms, prior exposure to or testing for the SARS-CoV-2 virus, laboratory data, imaging, treatment modalities and response to treatment.

Findings: 111 patients were identified, with 74 classified as mild COVID-19, 8 patients as moderate COVID-19, 8 patients as severe COVID-19, 10 as mild MIS-C and 11 as severe MIS-C. All groups had a male predominance, with Black and Hispanic patients overrepresented as compared to the demographics of Alabama. Most MIS-C patients were healthy at baseline, with most COVID-19 patients having at least one underlying illness. Fever, rash, conjunctivitis, and gastrointestinal symptoms were predominant in the MIS-C population whereas COVID-19 patients presented with predominantly respiratory symptoms. The two groups were similar in duration of symptomatic prodrome and exposure history to the SARS-CoV-2 virus, but MIS-C patients had a longer duration between presentation and exposure history. COVID-19 patients were more likely to have a positive SAR-CoV-2 PCR and to require respiratory support on admission. MIS-C patients had lower sodium levels, higher levels of C-reactive protein, erythrocyte sedimentation rate, d-dimer and procalcitonin. COVID-19 patients had higher lactate dehydrogenase levels on admission. MIS-C patients had coronary artery changes on echocardiography more often than COVID-19 patients.

Conclusions And Relevance: This study is one of the first to directly compare COVID-19 and MIS-C in the pediatric population. The significant differences found between symptoms at presentation, demographics, and laboratory findings will aide health-care providers in distinguishing the two disease entities.
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http://dx.doi.org/10.1186/s12969-021-00508-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903373PMC
February 2021

Discrete Choice Experiment on a Magnetic Resonance Imaging Scoring System for Temporomandibular Joints in Juvenile Idiopathic Arthritis.

Arthritis Care Res (Hoboken) 2021 Feb 8. Epub 2021 Feb 8.

The Hospital for Sick Children, Toronto, ON, Canada.

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 temporomandibular joints (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 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 non-linear 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 rho of 0.92 (intra-quartile range: 0.87-0.95) for the inflammation and 0.93 (0.90-0.94) for the damage domain.

Conclusions: 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.
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http://dx.doi.org/10.1002/acr.24577DOI Listing
February 2021

Effect of COVID-19 on anakinra-induced remission in homozygous STX11 hemophagocytosis lymphohistiocytosis.

Pediatr Blood Cancer 2021 06 14;68(6):e28897. Epub 2021 Jan 14.

Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, New York.

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http://dx.doi.org/10.1002/pbc.28897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995056PMC
June 2021

Severe Neonatal Coronavirus Disease 2019 Presenting as Acute Respiratory Distress Syndrome.

Pediatr Infect Dis J 2020 11;39(11):e367-e369

From the Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.

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.
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http://dx.doi.org/10.1097/INF.0000000000002864DOI Listing
November 2020

Defining the scourge of COVID-19 hyperinflammatory syndrome.

Lancet Rheumatol 2020 Dec 29;2(12):e727-e729. Epub 2020 Sep 29.

Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.

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http://dx.doi.org/10.1016/S2665-9913(20)30335-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524518PMC
December 2020

Highways to hell: Mechanism-based management of cytokine storm syndromes.

J Allergy Clin Immunol 2020 11 29;146(5):949-959. Epub 2020 Sep 29.

University of Alabama, Birmingham/Children's of Alabama, Birmingham, Ala.

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.
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http://dx.doi.org/10.1016/j.jaci.2020.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522622PMC
November 2020

Intravenous anakinra for cytokine storm syndromes - Authors' reply.

Lancet Rheumatol 2020 Sep 21;2(9):e522-e523. Epub 2020 Jul 21.

Department of Rheumatology, Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.

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http://dx.doi.org/10.1016/S2665-9913(20)30215-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373390PMC
September 2020

Coronavirus is the trigger, but the immune response is deadly.

Authors:
Randy Q Cron

Lancet Rheumatol 2020 Jul 29;2(7):e370-e371. Epub 2020 May 29.

Children's of Alabama, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35233-1711, USA.

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http://dx.doi.org/10.1016/S2665-9913(20)30165-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259908PMC
July 2020

Multidisciplinary Guidance Regarding the Use of Immunomodulatory Therapies for Acute Coronavirus Disease 2019 in Pediatric Patients.

J Pediatric Infect Dis Soc 2020 Dec;9(6):716-737

Division of Infectious Diseases, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1093/jpids/piaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454742PMC
December 2020

One-two punch of cytokine storm syndrome.

Authors:
Randy Q Cron

Blood 2020 08;136(6):645-646

University of Alabama at Birmingham.

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http://dx.doi.org/10.1182/blood.2020007159DOI Listing
August 2020

The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis.

Pediatr Blood Cancer 2020 11 29;67(11):e28581. Epub 2020 Jul 29.

Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, New York.

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 /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.
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http://dx.doi.org/10.1002/pbc.28581DOI Listing
November 2020

Drs. Cron and Chatham reply.

J Rheumatol 2020 11 8;47(11):1723. Epub 2020 Jun 8.

University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, Birmingham, Alabama, USA.

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http://dx.doi.org/10.3899/jrheum.200744DOI Listing
November 2020

Drs. Cron and Chatham reply.

J Rheumatol 2020 10 25;47(10):1590-1591. Epub 2020 May 25.

Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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http://dx.doi.org/10.3899/jrheum.200679DOI Listing
October 2020

Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.

Lancet Rheumatol 2020 Jun 4;2(6):e358-e367. Epub 2020 May 4.

Department of Rheumatology, Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children's Hospital NHS Foundation trust, Sheffield, UK.

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.
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http://dx.doi.org/10.1016/S2665-9913(20)30096-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198216PMC
June 2020

Drs. Cron and Chatham reply.

J Rheumatol 2021 Aug 25;48(8):1345-1346. Epub 2020 Apr 25.

University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, Birmingham, Alabama, USA.

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http://dx.doi.org/10.3899/jrheum.200492DOI Listing
August 2021

On the Alert for Cytokine Storm: Immunopathology in COVID-19.

Arthritis Rheumatol 2020 07 10;72(7):1059-1063. Epub 2020 May 10.

Boston Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/art.41285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262347PMC
July 2020

The genetics of macrophage activation syndrome.

Genes Immun 2020 05 15;21(3):169-181. Epub 2020 Apr 15.

Division of Rheumatology, Children's of Alabama and Department of Pediatrics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.

Macrophage activation syndrome (MAS), or secondary hemophagocytic lymphohistiocytosis (HLH), is a cytokine storm syndrome associated with multi-organ system dysfunction and high mortality rates. Laboratory and clinical features resemble primary HLH, which arises in infancy (1 in 50,000 live births) from homozygous mutations in various genes critical to the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. MAS/secondary HLH is about ten times more common and typically presents beyond infancy extending into adulthood. The genetics of MAS are far less defined than for familial HLH. However, the distinction between familial HLH and MAS/secondary HLH is blurred by the finding of heterozygous perforin-pathway mutations in MAS patients, which may function as hypomorphic or partial dominant-negative alleles and contribute to disease pathogenesis. In addition, mutations in a variety of other pathogenic pathways have been noted in patients with MAS/secondary HLH. Many of these genetically disrupted pathways result in a similar cytokine storm syndrome, and can be broadly categorized as impaired viral control (e.g., SH2P1A), dysregulated inflammasome activity (e.g., NLRC4), other immune defects (e.g., IKBKG), and dysregulated metabolism (e.g., LIPA). Collectively these genetic lesions likely combine with states of chronic inflammation, as seen in various rheumatic diseases (e.g., still disease), with or without identified infections, to result in MAS pathology as explained by the threshold model of disease. This emerging paradigm may ultimately support genetic risk stratification for high-risk chronic and even acute inflammatory disorders. Moving forward, continued whole-exome and -genome sequencing will likely identify novel MAS gene associations, as well as noncoding mutations altering levels of gene expression.
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http://dx.doi.org/10.1038/s41435-020-0098-4DOI Listing
May 2020

The Rheumatologist's Role in COVID-19.

J Rheumatol 2020 05 24;47(5):639-642. Epub 2020 Mar 24.

University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, Birmingham, Alabama, USA.

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http://dx.doi.org/10.3899/jrheum.200334DOI Listing
May 2020

Adolescent Sjogren's syndrome presenting as psychosis: a case series.

Pediatr Rheumatol Online J 2020 Feb 11;18(1):15. Epub 2020 Feb 11.

Department of Pediatrics, Division of Rheumatology at Rady Children's Hospital, 3020 Childrens Way, San Diego, Ca, 92123, USA.

Background: Neurological involvement has been reported in up to 80% of adults with Primary Sjogren's syndrome (pSS) with psychiatric abnormalities including anxiety, depression, and cognitive dysfunction being common. Psychosis due to pSS has been reported in adult patients but has never been previously reported in the adolescent/pediatric literature. Here we describe for the first time four cases of adolescent Sjogren's syndrome that presented with psychotic symptoms. Rituximab treatment was followed by improvement of psychiatric symptoms in all patients.

Case Presentation: 1: 16 year old female without significant past medical history presented to the emergency department with 4 days of abnormal behavior, tremors, insomnia, polyphagia, polyuria, and suicidal ideation. 2: 16 year old female with a 4 year history of severe anxiety, OCD, and tic disorder treated with fluoxetine with partial benefit presented with an abrupt and severe worsening of anxiety, OCD and new auditory hallucinations. 3: 19 year old female without significant past medical history presented with a 3 day history of progressively altered behavior, incoherent speech, insomnia, headache, and tangential thoughts. 4: 17 year old female without significant past medical history presented with new onset suicidal ideation, paranoia, confusion, and emotional lability.

Conclusion: Psychosis is more common in autoimmune disease than previously known. To our knowledge, the four teenage women described above are the first reported patients with adolescent pSS manifesting as psychosis. pSS should be considered in the differential diagnosis of young patients with new psychiatric disorders, even in the absence of sicca symptoms. Psychiatric symptoms improved with rituximab infusions in all 4 of our patients, which suggests rituximab may be an effective treatment option that should be considered early after the diagnosis of pSS-associated psychiatric disturbance.
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http://dx.doi.org/10.1186/s12969-020-0412-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014743PMC
February 2020

Successful treatment of pediatric Tolosa-Hunt syndrome with adalimumab.

Eur J Rheumatol 2019 Dec 3:1-3. Epub 2019 Dec 3.

Department of Pediatrics, University of Alabama, Birmingham, Alabama, USA.

Objective: Tolosa-Hunt syndrome (THS) is a rare disease characterized by painful unliteral ophthalmoplegia and headache. THS is caused by granulomatous inflammation of the cavernous sinus, and its diagnosis is typically made by elimination and exclusion. The characteristic pain can typically be managed with steroid therapy, but relapses are common. Additional therapy is needed for refractory or recurrent cases.

Methods: Herein, using the electronic medical record with institutional review board approval, we report a case of a pediatric patient diagnosed with corticosteroid-dependent THS. The child was effectively treated with the tumor necrosis factor inhibitor (TNFi), adalimumab. We have reviewed the THS literature, including 2 adult THS patients who have been successfully treated with intravenous TNFi, infliximab.

Results: This is the first report in the scientific literature to effectively treat pediatric THS, and also the first such case to use adalimumab to successfully treat THS.

Conclusion: Adalimumab, a subcutaneous TNFi, appears to be an effective treatment for corticosteroid-dependent THS.
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http://dx.doi.org/10.5152/eurjrheum.2019.19149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004262PMC
December 2019
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