Publications by authors named "Ronald Laxer"

160 Publications

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Nat Genet 2021 Apr 29;53(4):500-510. Epub 2021 Mar 29.

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
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http://dx.doi.org/10.1038/s41588-021-00803-4DOI Listing
April 2021

Extracutaneous Involvement Is Common and Associated with Prolonged Disease Activity and Greater Impact in Juvenile Localized Scleroderma.

Rheumatology (Oxford) 2021 Mar 12. Epub 2021 Mar 12.

Department of Pediatrics, University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis,IN.

Objective: To evaluate factors associated with extracutaneous involvement (ECI) in juvenile localized scleroderma (jLS).

Methods: A prospective, multi-center, 6-month observational study was performed. Collected data included disease features, global assessments, and subject symptoms. Bivariate and linear multilevel regression analyses were performed.

Results: Eighty-six jLS subjects (80% female, 80% Caucasian), median age of disease onset 7.7 years, were evaluated. Most had linear scleroderma or mixed morphea. Fourty-nine subjects (57%) had 125 extracutaneous problems (median 2 (IQR 1, 3) per subject) from 9 organ systems. Most of these subjects had multiple musculoskeletal problems. ECI was associated with more extensive cutaneous involvement, higher number of symptoms, family history of autoimmunity, and ANA and rheumatoid factor positivity. Subjects with ECI had higher scores for physician global assessment of damage (PGA-D), and parental global assessment of disease impact, but not baseline physician global assessment of disease activity (PGA-A). Although subjects with ECI received more methotrexate and glucocorticoid treatment, they had a slower reduction in PGA-A scores and symptoms over time, suggesting a poorer response to treatment. In logistic regression modeling, female sex had the largest effect on parental impact scores.

Conclusions: ECI occurred in the majority of subjects with jLS, and was associated with more medication use, longer treatment duration, higher PGA-D scores, and higher parental assessment of disease impact. Our findings suggest that jLS subjects with ECI have greater overall disease burden, both cutaneous and extracutaneous, and poorer response to treatment. More study of the treatment needs of this population is warranted.
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http://dx.doi.org/10.1093/rheumatology/keab238DOI Listing
March 2021

NETosis in Rheumatic Diseases.

Curr Rheumatol Rep 2021 Jan 28;23(2). Epub 2021 Jan 28.

Departments of Pediatrics and Medicine, Division of Rheumatology, The Hospital for Sick Children, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Purpose Of Review: Neutrophils are the most numerous and the first responder cells of the innate immune system. Evidence suggests that neutrophils may play an essential role in the pathogenesis of multiple systemic diseases. A novel mechanism of neutrophil extracellular traps (NETs) leading to breaking of self-tolerance and generation of autoimmune responses in predisposed individuals has been described in various autoimmune conditions. The purpose of the review is to identify these important mechanisms of NETs leading to autoimmunity in various rheumatic diseases.

Recent Findings: NETs contain histone and chromatin, which contain important autoantigens. Many autoimmune conditions are associated with increased NET-generating capacity, unique low-density granulocyte population, and impaired NET degradation leading to persistent inflammation and tissue damage. NETs can also activate other immune cells, and their components may amplify the inflammatory response by activation of complement pathways and inflammasomes. NETs can also contribute to autoantibody formation in disorders such as rheumatoid arthritis, ANCA-associated vasculitis, and systemic lupus erythematosus by providing a constant source of autoantigens. NETs can also serve as biomarkers providing insights into disease diagnosis and therapeutics. NETs seem to play a primary role in inflammatory disease pathogenesis. Identification of different NET pathogenic pathways in various rheumatic conditions could provide new insights into disease pathogenesis and therapeutic targets could be developed towards the future treatment of inflammatory autoimmune diseases.
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http://dx.doi.org/10.1007/s11926-020-00977-6DOI Listing
January 2021

Multicentric carpotarsal osteolysis syndrome (MCTO) with generalized high bone turnover and high serum RANKL: Response to denosumab.

Bone Rep 2021 Jun 8;14:100747. Epub 2021 Jan 8.

Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada.

MCTO is a rare disorder, caused by mutations in the gene, a negative regulator of receptor activator of nuclear factor-кB ligand (RANKL). Manifestations include carpal and tarsal osteolysis and renal failure. Pathophysiology is poorly understood, and no effective treatment is available. In this case report we describe a patient with MCTO (, mutation c.206C>T, p.Ser69Leu), diagnosed at the age of 5 years. At 7 years, skeletal survey showed diffuse osteopenia. BMD was mildly reduced, and bone turnover markers increased. He was treated with denosumab, a human monoclonal RANKL inhibitor for two years. Each injection was followed by a marked reduction in C-telopeptide (CTX). Following denosumab his BMD and bone symptoms improved and the osteolysis stabilized. At the age of 13 years, osteoporosis was diagnosed using high resolution peripheral quantitative computed tomography (HRpQCT) and serum RANKL was found to be markedly increased. This initial experience suggests that the associated osteoporosis may be ameliorated by denosumab, although further study will be needed to understand the appropriate dose, frequency, and the extent of efficacy. Monitoring of CTX and bone specific alkaline phosphatase will be especially useful in this regard. Further study in other MCTO patients is also needed to determine whether high bone turnover is specific to this mutation or more common than previously appreciated. We propose a model in which osteolysis in this condition is strongly associated with the systemic osteoporosis.
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http://dx.doi.org/10.1016/j.bonr.2021.100747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815641PMC
June 2021

A 10-year-old girl with cervical lymphadenopathy, fever, and cytopenia.

Paediatr Child Health 2020 Oct 29;25(6):342-344. Epub 2019 Aug 29.

Department of Paediatrics, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario.

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http://dx.doi.org/10.1093/pch/pxz114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492631PMC
October 2020

Feasibility of Using Elastography Ultrasound in Pediatric Localized Scleroderma (Morphea).

Ultrasound Med Biol 2020 Dec 18;46(12):3218-3227. Epub 2020 Sep 18.

Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada; Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

Assessment and monitoring of inflammation and tissue damage is crucial in localized scleroderma (LS), but validated diagnostic tools are lacking. We aimed to determine the feasibility of using acoustic radiation force imaging ultrasound elastography in the assessment of pediatric-onset LS lesions. Conventional ultrasound and shear-wave elastography (SWE) imaging were used to characterize changes in pre-assigned LS lesions in 13 prospectively recruited participants. Contralateral sites were used as controls. Mean SWE values were compared. LS lesions were significantly stiffer than control sites in the dermis and the hypodermis using both parametric and non-parametric tests, before and after skin-thickness normalization. We show that SWE imaging is a feasible way to discriminate between normal skin and LS lesions in the pediatric population.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.08.007DOI Listing
December 2020

Whole-Body MRI Quantification for Assessment of Bone Lesions in Chronic Nonbacterial Osteomyelitis Patients Treated With Pamidronate: A Prevalence, Reproducibility, and Responsiveness Study.

J Rheumatol 2020 Sep 15. Epub 2020 Sep 15.

J. Panwar, MD, FRCR, Department of Radiodiagnosis, Christian Medical College and Hospital, Vellore, India and Department of Diagnostic Imaging, The Hospital for Sick Children, Department of Medical Imaging, University of Toronto, Toronto, Ontario; M. Tolend, BSc, A.S. Doria, MD, PhD, MSc, MBA, J. Stimec, MD, FRCPC, Department of Diagnostic Imaging, The Hospital for Sick Children, Department of Medical Imaging, University of Toronto, Toronto, Ontario; L. Lim, MD, FRCPC, Division of Pediatric Rheumatology, Department of Pediatrics, University of Alberta, Edmonton, Alberta; S.M. Tse, MD, FRCPC, R.M. Laxer, MDCM, FRCPC, Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. The authors declare no conflicts of interest. Address correspondence to Dr. J. Panwar, Department of Radiodiagnosis, Christian Medical College and Hospital, Vellore 632004, India, and Department of Diagnostic Imaging, The Hospital for Sick Children, Department of Medical Imaging, University of Toronto, Toronto, ON M5G 1X8, Canada. Email: Accepted for publication September 5, 2020.

Objective: The purpose of this study was (1) to assess the interreader reliability in detecting and scoring the inflammatory bone lesions in pediatric patients with chronic nonbacterial osteomyelitis (CNO) by using whole-body magnetic resonance imaging (WB-MRI), and (2) to evaluate the responsiveness of the MRI-detected CNO lesions to pamidronate therapy.

Methods: Eighty-eight WB-MRI examinations were independently reviewed and scored by 2 radiologists blinded to clinical details in 32 retrospectively enrolled pediatric patients with CNO. Inflammatory bone lesions, soft tissue abnormality, and bony structural changes were scored before and after pamidronate therapy. Lesion responsiveness was calculated by using standardized response mean and interreader reliability was assessed by k statistics.

Results: There was good to excellent interreader agreement for the detection and quantification of bone lesions. After the first cycle of pamidronate in all 32 patients, 96 of the 279 lesions (34%; after excluding 108 lesions of hand and feet) resolved, whereas in a subset of 11 patients with 2 or more cycles, 76% of lesions resolved after the second cycle. Twenty-one (7.5%) lesions worsened and 46 (16.4%) new lesions developed after 1 cycle in all 32 patients. In these 11 patients, the number of worsened lesions reduced to 2 (2%) and new lesions to 14 (14.9%) after the second cycle as detected on MRI. Vertebral lesions had the highest response to treatment.

Conclusion: WB-MRI is a reliable tool for objective quantification and assessment of response to treatment of pediatric CNO bone lesions and could be used to monitor disease activity for clinical and research purposes.
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http://dx.doi.org/10.3899/jrheum.200329DOI Listing
September 2020

Follow the complex bread crumbs: A review of autoinflammation for the general paediatrician.

Paediatr Child Health 2020 Aug 18;25(5):279-285. Epub 2019 Jul 18.

Pediatric Rheumatology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario.

Autoinflammatory diseases have emerged as a group of disorders that have significant morbidity, and even mortality. Since their onset predominately occurs during childhood, it is important that paediatricians are aware of what these diseases are, how they present, when to include them in differential diagnoses, and when to refer to a specialist. This review will focus on the clinical indicators suggestive of autoinflammatory disease, how the presence of an autoinflammatory disease may influence routine care, indications for immediate referral, and both their acute and chronic complications.
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http://dx.doi.org/10.1093/pch/pxz072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395328PMC
August 2020

Monogenic autoinflammatory diseases in children: single center experience with clinical, genetic, and imaging review.

Insights Imaging 2020 Jul 31;11(1):87. Epub 2020 Jul 31.

Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

Purpose: 1. To review the contemporary literature and present a list of the imaging findings for patients with autoinflammatory diseases from our hospital. All these patients are found to have a genetic mutation that is responsible for their disease. 2. To present follow-up imaging findings, when available, and correlate those with symptoms and type of treatment administered in approximately 40 patients with autoinflammatory diseases of a single tertiary pediatric health care center including familial Mediterranean fever, Cryopyrin-associated autoinflammatory syndrome, PAPA (pyogenic arthritis, pyoderma gangrenousum, and acne) syndrome, and more. These findings are related to disease progression, treatment response, or treatment-induced changes.

Conclusion: Autoinflammatory diseases are relatively rare entities that can affect any system of the body. Given the many nonspecific imaging features, awareness of these diseases and good communication with clinicians aid in reaching an accurate diagnosis.
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http://dx.doi.org/10.1186/s13244-020-00889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394994PMC
July 2020

American College of Rheumatology Guidance for the Management of Pediatric Rheumatic Disease During the COVID-19 Pandemic: Version 1.

Arthritis Rheumatol 2020 11 28;72(11):1809-1819. Epub 2020 Sep 28.

Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Objective: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic.

Methods: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus.

Results: The task force drafted 33 guidance statements, which were voted upon during the second and third rounds of voting. Of these 33 statements, all received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n = 6) or high consensus (n = 27). Statements with similar recommendations were combined, resulting in 27 final guidance statements.

Conclusion: These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated.
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http://dx.doi.org/10.1002/art.41455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404941PMC
November 2020

Secondary Hypertrophic Osteoarthropathy in Pediatric Hodgkin lymphoma.

Arthritis Rheumatol 2020 11 10;72(11):1891. Epub 2020 Sep 10.

The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/art.41445DOI Listing
November 2020

The iCanCope pain self-management application for adolescents with juvenile idiopathic arthritis: a pilot randomized controlled trial.

Rheumatology (Oxford) 2021 01;60(1):196-206

Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario.

Objectives: To evaluate the feasibility and preliminary effectiveness of iCanCope with Pain (iCanCope), a smartphone-based pain self-management program, in adolescents with JIA. iCanCope featured symptom tracking, goal-setting, pain coping skills and social support.

Methods: A two-arm pilot randomized controlled trial was used to evaluate the iCanCope app compared with a version with symptom tracking only. Primary (feasibility) outcomes were: participant accrual/attrition rates, success of app deployment, acceptability and adherence. Secondary (preliminary effectiveness) outcomes were: pain intensity, pain-related activity limitations and health-related quality of life. Outcomes were assessed at baseline and 8 weeks. Adherence was defined as the proportion of completed symptom reports: 'low' (≤24%); 'low-moderate' (25-49%); 'high-moderate' (50-75%); or 'high' (76-100%). Linear mixed models were applied for preliminary effectiveness analyses as per intention-to-treat.

Results: Adolescents (N = 60) were recruited from three paediatric rheumatology centres. Rates of accrual and attrition were 82 and 13%, respectively. Both apps were deployed with high success (over 85%) and were rated as highly acceptable. Adherence was similar for both groups, with most participants demonstrating moderate-to-high adherence. Both groups exhibited a clinically meaningful reduction in pain intensity (≥1 point) that did not statistically differ between groups. There were no significant changes in activity limitations or health-related quality of life.

Conclusion: The iCanCope pilot randomized controlled trial was feasible to implement in a paediatric rheumatology setting. Both apps were deployed successfully, with high acceptability, and were associated with moderate-to-high adherence. Preliminary reductions in pain intensity warrant a future trial to evaluate effectiveness of iCanCope in improving health outcomes in adolescents with JIA.

Trial Registration: ClinicalTrials.gov identifier: NCT02764346.
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http://dx.doi.org/10.1093/rheumatology/keaa178DOI Listing
January 2021

A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.

Nat Commun 2020 06 19;11(1):3150. Epub 2020 Jun 19.

The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl, that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).
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http://dx.doi.org/10.1038/s41467-020-16819-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305203PMC
June 2020

Image guided sacroiliac joint corticosteroid injections in children: an 18-year single-center retrospective study.

Pediatr Rheumatol Online J 2020 Jun 17;18(1):52. Epub 2020 Jun 17.

Division of Image Guided Therapy, Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.

Background: Sacroiliitis is commonly seen in enthesitis-related arthritis (ERA), a subtype of juvenile idiopathic arthritis (JIA). Sacroiliitis is characterized by the inflammation of the sacroiliac (SI) joints (+/- adjacent tissues). The treatment options include systemic therapy with or without corticosteroid SI joint injections. Image guided SI joint injections are frequently requested in pediatric patients with sacroiliitis. The purpose of this study was to evaluate the feasibility and efficacy of SI joint injections in children with sacroiliitis.

Methods: A retrospective study of patients referred to Interventional Radiology (IR) for SI joint corticosteroid injections (2000-2018). Clinical information was collected from Electronic Patient Charts and procedural details from PACS. Efficacy was determined clinically, by MRI, or both when available.

Results: 50 patients (13.8 years; M:F = 35:15) underwent image-guided SI joint corticosteroid injections. Most common indications were JIA (84%) and inflammatory bowel disease (14%). 80% had bilateral injections. 80% were performed under general anesthesia and 20% under sedation. The corticosteroid of choice was triamcinolone hexacetonide in 98% of patients. Needle guidance and confirmation was performed using CT and fluoroscopy (54%), Cone Beam CT (CBCT, 46%), with initial ultrasound assistance in 34%. All procedures were technically successful without any complications. 32/50 patients had long-term follow-up (2 years); 21/32 (66%) had clinical improvement within 3-months. Of 15 patients who had both pre- and post-procedure MRIs, 93% showed short-term improvement. At 2 years, 6% of patients were in remission, 44% continued the same treatment and 47% escalated treatment.

Conclusion: Image-guided SI joint injections are safe and technically feasible in children. Imaging modalities for guidance have evolved, with CBCT being the current first choice. Most patients showed short-term clinical and imaging improvement, requiring long-term maintenance or escalation of medical treatment.
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http://dx.doi.org/10.1186/s12969-020-00435-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301971PMC
June 2020

Associations of clinical and inflammatory biomarker clusters with juvenile idiopathic arthritis categories.

Rheumatology (Oxford) 2020 05;59(5):1066-1075

Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada.

Objective: To identify discrete clusters comprising clinical features and inflammatory biomarkers in children with JIA and to determine cluster alignment with JIA categories.

Methods: A Canadian prospective inception cohort comprising 150 children with JIA was evaluated at baseline (visit 1) and after six months (visit 2). Data included clinical manifestations and inflammation-related biomarkers. Probabilistic principal component analysis identified sets of composite variables, or principal components, from 191 original variables. To discern new clinical-biomarker clusters (clusters), Gaussian mixture models were fit to the data. Newly-defined clusters and JIA categories were compared. Agreement between the two was assessed using Kruskal-Wallis analyses and contingency plots.

Results: Three principal components recovered 35% (three clusters) and 40% (five clusters) of the variance in patient profiles in visits 1 and 2, respectively. None of the clusters aligned precisely with any of the seven JIA categories but rather spanned multiple categories. Results demonstrated that the newly defined clinical-biomarker lustres are more homogeneous than JIA categories.

Conclusion: Applying unsupervised data mining to clinical and inflammatory biomarker data discerns discrete clusters that intersect multiple JIA categories. Results suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Applying data mining analyses to complex datasets can generate insights into JIA pathogenesis and could contribute to biologically based refinements in JIA classification.
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http://dx.doi.org/10.1093/rheumatology/kez382DOI Listing
May 2020

Gut microbiota in chronic inflammatory disorders: A focus on pediatric inflammatory bowel diseases and juvenile idiopathic arthritis.

Clin Immunol 2020 06 9;215:108415. Epub 2020 Apr 9.

Department of Paediatrics, Faculty of Medicine, University of Toronto, Canada; Division of Rheumatology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Electronic address:

The gut microbiota is integral to human health, including maintaining the delicate balance between tolerance and protection against potentially harmful pathogens. A growing body of evidence implicates the intestinal microbiome in immune-mediated inflammatory disorders; these data span the spectrum from genetic and environmental disease risk factors, to animal studies (particularly germ-free and gnotobiotic models) and human studies, including evidence of dysbiosis in diseased individuals compared to healthy populations. In this review, we summarize both animal and human data supporting a link between the gut microbiota and inflammatory bowel diseases (IBD) and systemic inflammatory arthritis, as models for chronic inflammatory disorders, while offering a pediatric focus (pediatric IBD and juvenile idiopathic arthritis). We discuss relevant mechanisms related to the crosstalk between the gut microbiota and the innate and adaptive immune system. We close with a brief discussion of emerging microbe-altering interventions, including fecal microbial transplantation and its immunologic effects.
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http://dx.doi.org/10.1016/j.clim.2020.108415DOI Listing
June 2020

The Challenges and Opportunities of Classifying Childhood Arthritis.

Curr Rheumatol Rep 2020 01 11;22(1). Epub 2020 Jan 11.

Departments of Paediatrics and Medicine, Division of Rheumatology, University of Toronto and The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.

Purpose Of Review: Childhood arthritis is in need of a new system of classification, owing to deficiencies in the International League of Associations for Rheumatology (ILAR) criteria. We briefly review the history of classification of childhood arthritis, discuss the major criticisms of the current system, and highlight current initiatives to address those concerns.

Recent Findings: Recent studies in both pediatric and adult rheumatology into the biologic basis of disease as well as the clinical patterns of presentation have informed the efforts toward developing a new classification system. Several efforts are currently underway to improve the classification of childhood arthritis, most notably the project of the Pediatric Rheumatology International Trials Organization (PRINTO). This international alliance of pediatric rheumatologists has begun a 4-step process to create new classification criteria for childhood arthritis. They are currently on step 3 of the process.
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http://dx.doi.org/10.1007/s11926-020-0880-3DOI Listing
January 2020

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.

J Clin Invest 2020 04;130(4):1669-1682

Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USA.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
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http://dx.doi.org/10.1172/JCI129301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108905PMC
April 2020

Childhood GPA, EGPA, and MPA.

Clin Immunol 2020 02 11;211:108325. Epub 2019 Dec 11.

Departments of Pediatrics and Medicine, University of Toronto, Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address:

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a term used to describe rare primary systemic vasculitides affecting small and medium-sized blood vessels. AAV diseases which include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), Microscopic Polyangiitis (MPA) and renal limited ANCA vasculitis. These multisystemic disorders involve upper and lower respiratory tract and kidneys associated with organ damage and long term sequelae. Newer understanding of pathogenesis in AAV have paved the way for clinical research with different biologic therapies. In spite of the paucity of clinical trials in pediatric AAV, the long-term survival of patients with AAV has improved dramatically. International collaborations will help to conduct clinical trials in pediatric AAV and help in better understanding of remission rates, relapse rates, and other outcomes. This article aims to provide a comprehensive review of pediatric AAV with a focus on epidemiology, disease pathogenesis, treatment trials, and prognosis.
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http://dx.doi.org/10.1016/j.clim.2019.108325DOI Listing
February 2020

A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1.

Nature 2020 01 11;577(7788):109-114. Epub 2019 Dec 11.

The MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
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http://dx.doi.org/10.1038/s41586-019-1830-yDOI Listing
January 2020

Initial Results from a Pilot Comparative Effectiveness Study of 3 Methotrexate-based Consensus Treatment Plans for Juvenile Localized Scleroderma.

J Rheumatol 2020 08 15;47(8):1242-1252. Epub 2019 Oct 15.

From the Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack Meridian School of Medicine at Seton Hall University, Nutley, New Jersey; UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Duke University School of Medicine, Durham, North Carolina; Boston Children's Hospital, Boston, Massachusetts; Children's Mercy Hospital, Kansas City, Missouri; University of Iowa Carver College of Medicine; University of Iowa Stead Family Children's Hospital, Iowa City, Iowa; Children's Medical Center of Dallas and UT Southwestern, Dallas, Texas; The Ohio State University, Columbus, Ohio; Mayo Clinic, Rochester, Minnesota; University of Colorado-Denver and Children's Hospital Colorado, Denver, Colorado; Rutgers University, School of Public Health, Newark, New Jersey, USA; University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada.

Objective: To perform a comparative effectiveness feasibility study in juvenile localized scleroderma (LS), using standardized treatment regimens (consensus treatment plans; CTP).

Methods: A prospective, multicenter 1-year pilot observational cohort study was performed by Childhood Arthritis and Rheumatology Research Alliance (CARRA) LS workgroup members. Patients with active, moderate to severe juvenile LS were treated with one of 3 CTP: methotrexate alone, or in combination with intravenous (30 mg/kg/dose for 3 mos) or oral corticosteroids (2 mg/kg/day tapered by 48 weeks).

Results: Fifty patients, with demographics typical for juvenile LS, were enrolled, and 44 (88%) completed the study. Most had extracutaneous involvement. Patients improved in all 3 CTP, with > 75% having a major or moderate level of improvement compared to baseline. Damage accrued in some patients. Major deviations from prescribed regimen resulted from medication intolerance (n = 6; 14%) or treatment failure (n = 11; 25%); failures occurred in all 3 CTP. Significant responses to treatment were demonstrated by LS skin scoring measures and overall physician assessments, with differences in response level identified in some patient subsets. Response differences were associated with baseline disease activity level, LS subtype, skin disease extent, and extracutaneous involvement.

Conclusion: This study demonstrates the feasibility of conducting juvenile LS comparative effectiveness studies. The CTP were found to be safe, effective, and tolerable. Our assessments performed well. Because damage is common and may progress despite effective control of activity, we recommend initial treatment efficacy be evaluated primarily by activity measures. Potential confounders for response were identified that warrant further study.
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http://dx.doi.org/10.3899/jrheum.190311DOI Listing
August 2020

Towards therapeutic drug monitoring of TNF inhibitors for children with juvenile idiopathic arthritis: a scoping review.

Rheumatology (Oxford) 2020 02;59(2):386-397

Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

Objectives: Before a clinician decides whether treatment with TNF inhibition in children with JIA has failed, one should ensure adequate systemic exposure has been achieved. Therapeutic drug monitoring might allow for improved treatment outcome with lower treatment-associated costs. However, this requires understanding of the pharmacokinetic (PK) characteristics, and the pharmacokinetic/pharmacodynamic (PK/PD) relationship for children with JIA. We performed a scoping review to summarize the available literature and identify areas for future research.

Methods: A systematic search was conducted of the Medline, EMBASE, Web of Science and Cochrane databases as well as the clinicaltrials.gov registry. In total, 3959 records were screened and 130 publications were selected for full text assessment.

Results: Twenty publications were included and divided into three categories: PK (n = 9), PK/PD (n = 3) and anti-drug antibodies (n = 13). Industry involvement was significant in 14 publications. Although data are limited, systemic exposure to TNF inhibitors is generally lower in younger children but meta-analysis is not possible. The PK/PD relationship has had limited study but there is partial evidence for infliximab. Anti-drug antibodies are common, and are related to impaired clinical outcome with adalimumab and infliximab therapy.

Conclusion: The current knowledge about the PK and PK/PD of TNF inhibitors in the treatment of children with JIA is limited, which prevents the introduction of TDM. Re-analysis of available data from previous trials, incorporation of pharmacologic assessments into existing biorepository studies as well as new prospective PK and PK/PD trials are required to obtain this knowledge.
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http://dx.doi.org/10.1093/rheumatology/kez285DOI Listing
February 2020

Developing comparative effectiveness studies for a rare, understudied pediatric disease: lessons learned from the CARRA juvenile localized scleroderma consensus treatment plan pilot study.

Pediatr Rheumatol Online J 2019 Jul 15;17(1):43. Epub 2019 Jul 15.

The Ohio State University and Nationwide Children's Hospital, Columbus, OH, USA.

Background: We designed and initiated a pilot comparative effectiveness study for juvenile localized scleroderma (jLS), for which there is limited evidence on best therapy. We evaluated the process we used, in relation to the specific protocol and to the general task of identifying strategies for implementing studies in rare pediatric diseases.

Methods: This was a prospective, multi-center, observational cohort study of 50 jLS patients initiating treatment, designed and conducted by the jLS group of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) from 2012 to 2015. A series of virtual and physical meetings were held to design the study, standardize clinical assessments, generate and refine disease activity and damage measures, and monitor the study. Patients were initiated on one of three standardized methotrexate-based treatment regimens (consensus treatment plans, CTPs) and monitored for 1 year. An optional bio-banking sub-study was included.

Results: The target enrollment of 50 patients was achieved over 26 months at 10 sites, with patients enrolled into all CTPs. Enrolled patients were typical for jLS. Study eligibility criteria were found to perform well, capturing patients thought appropriate for treatment studies. Minor modifications to the eligibility criteria, primarily to facilitate recruitment for future studies, were discussed with consensus agreement reached on them by the jLS group. There were marked differences in site preferences for specific CTPs, with half the sites treating all their patients with the same CTP. Most patients (88%) completed the study, and 68% participated in the bio-banking substudy.

Conclusions: We demonstrate the feasibility of our approach for conducting comparative effectiveness research in a rare pediatric disease. Multi-center collaboration by dedicated investigators who met regularly was a key factor in the success of this project. Other factors that facilitate these studies include having a sufficient number of investigators to enroll in each regimen, and streamlining study approval and management.
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http://dx.doi.org/10.1186/s12969-019-0350-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632199PMC
July 2019

Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?

Orphanet J Rare Dis 2019 06 27;14(1):156. Epub 2019 Jun 27.

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, M5G 1X8, Canada.

Background: Familial digital arthropathy-brachydactyly (FDAB) and Thiemann disease are non-inflammatory digital arthropathies with many phenotypic similarities. Thirty-three cases of Thiemann disease have been described so far (Mangat et al, Ann Rheum Dis 64:11-2, 2005; Ha et al, Thiemann's disease: a case Report, 2017) but no gene variants have been identified as causative to date. FDAB is reported in only a few patients and has been associated with three heterozygous missense variants in the Transient receptor potential vanilloid 4 (TRPV4) gene. We report a TRPV4 variant in a father and son referred with a diagnosis of Thiemann disease and compare the clinical and radiological features of Thiemann disease with Familial digital arthropathy-brachydactyly (FDAB). We hypothesize that these two entities may be one and the same.

Methods: We describe a father and son referred with a diagnosis of Thiemann disease who were subsequently identified with a heterozygous variant (c.809G > T) in TRPV4. The identical genetic variant was previously reported to cause FDAB. A PUBMED® database search was conducted to retrieve articles related to Thiemann disease and FDAB. We were able to review the clinical and radiological findings of nineteen individuals affected by Thiemann disease and compare them with three families affected by FDAB.

Results: Thiemann disease initially affects the proximal interphalangeal joints and primarily the middle phalangeal bases. In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes. Radial deviation has only been described in FDAB. Our analysis determined that 5 of 20 individuals affected by Thiemann disease have clinical and radiological findings that also fit well with FDAB.

Conclusion: FDAB and Thiemann disease are non-inflammatory digital arthropathies with phenotypic overlap. Although more extensive joint involvement, a distal hand joint preponderance and brachydactyly are expected in FDAB, there are striking clinical and radiological similarities between the two entities. Our analysis suggests that these two phenotypes may represent phenotypic variability of the same entity. Despite many attempts to identify other reported patients affected by Thiemann disease, we were not able to procure DNA from any of the cases to verify our findings. Genetic testing of an affected individual will be crucial in order to provide accurate reproductive genetic counselling about the autosomal dominant nature of this condition.
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http://dx.doi.org/10.1186/s13023-019-1138-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598251PMC
June 2019

Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist.

Pediatr Rheumatol Online J 2019 Jun 26;17(1):31. Epub 2019 Jun 26.

Department of Pediatrics, Division of Rheumatology, Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a complex group of systemic vasculitides that are characterized by primary small-to-medium sized blood vessel inflammation with the presence of autoantibodies known as ANCA. AAV diseases include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA). AAVs are challenging conditions associated with high cumulative disease and treatment related morbidity and mortality. Given its rarity and the resulting paucity of pediatric-specific clinical trial evidence, pediatric rheumatologists have had to often extrapolate from adult literature for management and therapeutic decisions. The aim of this review is to provide a comprehensive overview of the important findings and overall conclusions of critical landmark clinical trials in the induction and maintenance treatments in adult AAV for the pediatric rheumatologist. This review also highlights the outcomes of recent pediatric AAV observational studies and discusses the future research priorities in pediatric AAV management.
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http://dx.doi.org/10.1186/s12969-019-0343-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595671PMC
June 2019

Rapid and Sustained Long-Term Efficacy and Safety of Canakinumab in Patients With Cryopyrin-Associated Periodic Syndrome Ages Five Years and Younger.

Arthritis Rheumatol 2019 11 9;71(11):1955-1963. Epub 2019 Sep 9.

University of Toronto and the Hospital for Sick Children, Toronto, Ontario, Canada.

Objective: To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS).

Methods: CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization.

Results: Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy.

Conclusion: Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age.
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http://dx.doi.org/10.1002/art.41004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899890PMC
November 2019

Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans.

Proc Natl Acad Sci U S A 2019 06 28;116(24):11872-11877. Epub 2019 May 28.

Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of , a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of were introduced in mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of abolished the inflammatory phenotype in mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of Fgr are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in , including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.
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http://dx.doi.org/10.1073/pnas.1819825116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6575637PMC
June 2019

Classification criteria for autoinflammatory recurrent fevers.

Ann Rheum Dis 2019 08 24;78(8):1025-1032. Epub 2019 Apr 24.

Clinica Pediatrica e Reumatologia, PRINTO, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Background: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.

Methods: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.

Results: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).

Conclusion: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
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http://dx.doi.org/10.1136/annrheumdis-2019-215048DOI Listing
August 2019

PANDAS/PANS in childhood: Controversies and evidence.

Paediatr Child Health 2019 May 9;24(2):85-91. Epub 2018 Dec 9.

Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Since first defined in 1998, paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and its later, broader iteration, paediatric acute-onset neuropsychiatric syndrome (PANS), have garnered significant attention and controversy. The role of streptococcal infection in children with explosive onset obsessive-compulsive disorder and new onset tics, the natural history of this entity, and the role of symptomatic and disease-modifying therapies, including antibiotics, immunotherapy, and psychoactive drugs, are all issues that have yet to be definitively addressed. While definitive proof of the autoimmune hypothesis of PANDAS is lacking, given the heightened attention to this entity and apparent rise in use of this diagnostic category, addressing questions around diagnosis, treatment, and etiology is imperative. In this paper, we review current working definitions of PANDAS/PANS, discuss published evidence for interventions related to this entity, and propose a clinical approach to children presenting with acute symptoms satisfying criteria for PANDAS/PANS.
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http://dx.doi.org/10.1093/pch/pxy145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462125PMC
May 2019