Objective
To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests ...late in the course of severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) infection. Recommendations are also provided for children with hyperinflammation during coronavirus disease 2019 (COVID‐19), the acute, infectious phase of SARS–CoV‐2 infection.
Methods
The Task Force was composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS‐C and hyperinflammation in COVID‐19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9‐point scale was used to determine the appropriateness of each statement (median scores of 1–3 for inappropriate, 4–6 for uncertain, and 7–9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting.
Results
The first version of the guidance was approved in June 2020, and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS‐C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS‐C was added.
Conclusion
Our understanding of SARS–CoV‐2–related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.
Objective
To provide guidance on the management of multisystem inflammatory syndrome in children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests ...late in the course of severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID‐19), the acute, infectious phase of SARS–CoV‐2 infection.
Methods
A multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS‐C associated with SARS–CoV‐2 and hyperinflammation in COVID‐19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS‐C and hyperinflammation in COVID‐19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9‐point scale was used to determine the appropriateness of each statement (median scores of 1–3 for inappropriate, 4–6 for uncertain, and 7–9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting.
Results
The ACR task force approved a total of 128 guidance statements addressing the management of MIS‐C and hyperinflammation in pediatric COVID‐19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS‐C.
Conclusion
Our understanding of SARS–CoV‐2–related syndromes in the pediatric population continues to evolve. The guidance provided in this “living document” reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available.
Objective
To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests ...late in the course of SARS–CoV‐2 infection. Recommendations are also provided for children with hyperinflammation during COVID‐19, the acute, infectious phase of SARS–CoV‐2 infection.
Methods
The Task Force is composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS‐C and hyperinflammation in COVID‐19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9‐point scale was used to determine the appropriateness of each statement (median scores of 1–3 for inappropriate, 4–6 for uncertain, and 7–9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting.
Results
The guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS‐C and recommendations for initial immunomodulatory treatment of MIS‐C.
Conclusion
Our understanding of SARS–CoV‐2–related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.
Systemic autoinflammatory diseases (SAIDs) are characterized by unprovoked exaggerated inflammation on a continuum from benign recurrent oral ulceration to life-threatening strokes or amyloidosis, ...with renal failure as a potential sequela. The ability to discriminate these diagnoses rests on the genetic and mechanistic defect of each disorder, considering potential overlapping autoinflammation, autoimmunity, and immune deficiency. A comprehensive and strategic genetic investigation influences management as well as the consequential expected prognoses in these subsets of rare diseases. The ever-expanding therapeutic armamentarium reflects international collaborations, which will hasten genetic discovery and consensus-driven treatment.
Objective
To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness ...treatment studies.
Methods
Virtual and face‐to‐face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions.
Results
Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response.
Conclusion
Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is considered the most common periodic fever syndrome of childhood. Although it was first described three ...decades ago, the pathogenesis has been poorly understood. Recent studies on the heritability and immunology of the disorder have begun to shed light into the mechanisms of this autoinflammatory disorder. This review will focus on the pathogenesis of PFAPA, especially as it pertains to the genetic susceptibility, tonsillar immunology, and the role of the microbiome.
Recent literature provides insights into the heritability, potential genetic modifiers, and the immunologic and microbiological profile of the tonsils in this syndrome.
Evidence is mounting that PFAPA is inherited as a complex genetic disease. Furthermore, tonsillectomy is curative in the majority of patients, including those who do not meet the complete clinical criteria for PFAPA. The tonsils in PFAPA patients may exhibit unique immunologic and microbiological features. The goal of this review is to outline these new developments.
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a ...systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4âº/CD25⺠T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4âº/HLA-DR⺠T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
The impact of the COVID-19 pandemic on new diagnoses of recurrent fevers and autoinflammatory diseases is largely unknown. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA/AID ...Working Group aimed to investigate the impact of the COVID-19 pandemic on the number of pediatric patients evaluated for recurrent fevers and autoinflammatory diseases in North America. The absolute number of new outpatient visits and the proportion of these visits attributed to recurrent fever diagnoses during the pre-pandemic period (1 March 2019-29 February 2020) and the first year of the COVID-19 pandemic (1 March 2020-28 February 2021) were examined. Data were collected from 27 sites in the United States and Canada. Our results showed an increase in the absolute number of new visits for recurrent fever evaluations in 21 of 27 sites during the COVID-19 pandemic compared to the pre-pandemic period. The increase was observed across different geographic regions in North America. Additionally, the proportion of new visits to these centers for recurrent fever in relation to all new patient evaluations was significantly higher during the first year of the pandemic, increasing from 7.8% before the pandemic to 10.9% during the pandemic year (
< 0.001). Our findings showed that the first year of the COVID-19 pandemic was associated with a higher number of evaluations by pediatric subspecialists for recurrent fevers. Further research is needed to understand the reasons behind these findings and to explore non-infectious triggers for recurrent fevers in children.
Objective
To provide evidence‐based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists.
Methods
...Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel.
Results
We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment‐refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high‐risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted.
Conclusion
These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.
Objective
To provide evidence‐based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists.
Methods
...Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel.
Results
We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment‐refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high‐risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted.
Conclusion
These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.
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