Disease flares with baricitinib dose reductions and development of flare criteria in patients with CANDLE/PRAAS.

OBJECTIVES: Patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) respond to the janus kinase inhibitor 1/2 inhibition with baricitinib at exposures higher than in rheumatoid arthritis. Baricitinib dose reductions to minimise exposure triggered disease flares which we used to develop 'flare criteria'. METHODS: Of 10 patients with CANDLE/PRAAS treated with baricitinib in an open-label expanded-access programme, baricitinib doses were reduced 14 times in 9 patients between April 2014 and December 2019. Retrospective data analysis of daily diary scores and laboratory markers collected before and after the dose reductions were used to develop 'clinical' and 'subclinical' flare criteria. Disease flare rates were compared among patients with <25% and >25% dose reductions and during study visits when patients received recommended 'optimized' baricitinib doses (high-dose visits) versus lower than recommended baricitinib doses (low-dose visits) using two-sided χ2 tests. RESULTS: In the 9/10 patients with CANDLE with dose reduction, 7/14 (50%) times the dose was reduced resulted in a disease flare. All four dose reductions of >25% triggered a disease flare (p <0.05). Assessment of clinical and laboratory changes during disease flares allowed the development of disease flare criteria that were assessed during visits when patients received high or low doses of baricitinib. Disease flare criteria were reached during 43.14% of low-dose visits compared with 12.75% of high-dose visits (p <0.0001). Addition of an interferon score as an additional flare criterion increased the sensitivity to detect disease flares. CONCLUSION: We observed disease flares and rebound inflammation with baricitinib dose reductions and proposed flare criteria that can assist in monitoring disease activity and in designing clinical studies in CANDLE/PRAAS.

Risk factors for haemodynamic compromise in multisystem inflammatory syndrome in children: a multicentre retrospective study.

OBJECTIVES: To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support. METHODS: This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease. RESULTS: Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease. CONCLUSION: Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.

Multisystem inflammatory syndrome in children associated with COVID-19 presenting as cervical inflammation.

AIM: The major clinical manifestations multisystem inflammatory syndrome in children (MIS-C) are fever, gastrointestinal and cardiac. The aim of this study was to describe MIS-C in a series of patients who presented primarily with cervical manifestations. METHODS: We retrospectively reviewed medical records of all patients who met the Centers for Disease Control and Prevention and World Health Organization MIS-C diagnostic criteria treated at Hadassah-Hebrew University Medical Center between April 2020 and September 2021. RESULTS: Of 37 children diagnosed with MIS-C (median age: 10.2 years, range 1.5-18 years, 20 male) five, 13.5% (median age: 14.4 years, range 9.2-17.5 years) presented with cervical symptoms mimicking neck infections. One was hospitalised with a working diagnosis of retropharyngeal abscess, and four with acute cervical lymphadenitis that did not respond to early antibiotic treatment. All developed full MIS-C phenotype. CONCLUSION: MIS-C may present as cervical inflammation. An ill-appearing child with symptoms and/or signs of cervical inflammation should be evaluated for clinical and laboratory features of MIS-C, thereby facilitating prompt treatment of this potentially fatal disorder.

Platelet count and risk of severe illness in hospitalised children with Influenza-Like illness.

AIM: To examine the clinical significance of thrombocytosis (platelets > 500 × 109 /L) in admitted children with an influenza-like illness. METHODS: We performed a database analysis consisting of patients evaluated at our medical centers with an influenza-like illness between 2009 and 2013. We included paediatric patients and examined the association between platelet count, respiratory viral infections, and admission outcomes (hospital length of stay and admission to the paediatric intensive care unit) using regression models adjusting for multiple variables. RESULTS: A total of 5171 children were included in the study cohort (median age 0.8 years; interquartile range, 0.2-1.8; 58% male). Younger age, and not the type of viral infection, was associated with a high platelet count (p < 0.001). Elevated platelet count independently predicted admission outcomes (p ≤ 0.05). The presence of thrombocytosis was associated with an increased risk for a prolonged length of stay (odds ratio = 1.2; 95% Confidence interval = 1.1 to 1.4; p = 0.003) and admission to the paediatric intensive care unit (odds ratio = 1.5; 95% Confidence interval = 1.1 to 2.0; p = 0.002). CONCLUSION: In children admitted with an influenza-like illness, a high platelet count is an independent predictor of admission outcomes. Platelet count may be used to improve risk assessment and management decisions in these paediatric patients.

Outcomes of SARS-CoV-2 infection among children and young people with pre-existing rheumatic and musculoskeletal diseases.

OBJECTIVES: Some adults with rheumatic and musculoskeletal diseases (RMDs) are at increased risk of COVID-19-related death. Excluding post-COVID-19 multisystem inflammatory syndrome of children, children and young people (CYP) are overall less prone to severe COVID-19 and most experience a mild or asymptomatic course. However, it is unknown if CYP with RMDs are more likely to have more severe COVID-19. This analysis aims to describe outcomes among CYP with underlying RMDs with COVID-19. METHODS: Using the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database, we obtained data on CYP with RMDs who reported SARS-CoV-2 infection (presumptive or confirmed). Patient characteristics and illness severity were described, and factors associated with COVID-19 hospitalisation were investigated. RESULTS: 607 CYP with RMDs <19 years old from 25 different countries with SARS-CoV-2 infection were included, the majority with juvenile idiopathic arthritis (JIA; n=378; 62%). Forty-three (7%) patients were hospitalised; three of these patients died. Compared with JIA, diagnosis of systemic lupus erythematosus, mixed connective tissue disease, vasculitis, or other RMD (OR 4.3; 95% CI 1.7 to 11) or autoinflammatory syndrome (OR 3.0; 95% CI 1.1 to 8.6) was associated with hospitalisation, as was obesity (OR 4.0; 95% CI 1.3 to 12). CONCLUSIONS: This is the most significant investigation to date of COVID-19 in CYP with RMDs. It is important to note that the majority of CYP were not hospitalised, although those with severe systemic RMDs and obesity were more likely to be hospitalised.

Neurological and neurodevelopmental symptoms in children with familial Mediterranean fever and their siblings.

Familial Mediterranean fever is a common autoinflammatory disease characterized by periodic attacks of fever and serositis. There are few reports describing neurological symptoms in patients with FMF. The aim of this study was to systematically assess the neurologic and developmental involvement in pediatric patients with FMF. Between the years 2016 and 2019, parents of children with FMF were asked to complete a questionnaire regarding the presence of neurological and developmental symptoms in their children with and without FMF. Demographic data, clinical characteristics, and disease course of FMF patients were collected from the medical charts. Neurodevelopmental manifestations were compared between the children with FMF and their siblings. A total of 205 children were enrolled (11.6 ± 4.7 years of age): 111 children with FMF and 94 healthy siblings in the control group. Neurological morbidity was frequently reported in children with FMF: 44 (40%) had recurrent headaches, 31 (28%) ADHD symptoms, 27 (24%) learning disabilities, and 10 (9%) febrile convulsions. Headaches and febrile convulsions were significantly more prevalent in children with FMF as compared to their siblings (ps < 0.05). ADHD and learning disabilities were associated with poor adherence to colchicine treatment.Conslusions: The present study found an increased prevalence of ADHD, learning disabilities, headaches, and febrile seizures in children with FMF. The findings underscore the importance of addressing the neurodevelopmental domain in children with FMF. In addition, detection and treatment of ADHD and learning disabilities could improve adherence with therapy and control of the underlying disease. What is Known: • Familial Mediterranean fever (FMF) is the most common inherited auto-inflammatory disease, characterized by recurrent attacks of fever, serositis, and arthritis. • Some previous case reports also described rare neurological manifestations in children with FMF. What is New: • The study found an increased prevalence of headaches, febrile seizures, ADHD, and learning disabilities, in children with FMF. • The findings underscore the importance of addressing the neurological domain in this population, which could potentially improve adherence with therapy and control of the underlying disease.

Increased prevalence of attention-deficit hyperactivity disorder symptomatology in patients with familial Mediterranean fever.

OBJECTIVES: Previous studies suggest that exposure to inflammation in infancy may increase the risk for attention-deficit and hyperactivity disorder (ADHD). We studied the ADHD manifestations among 124 familial Mediterranean fever (FMF) patients and examined the relationship between FMF patient characteristics and ADHD. METHODS: Clinical, demographic, and genetic data were abstracted from patients' medical records and supplemented by information obtained during clinic visits. ADHD manifestations were assessed using the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) questionnaire. RESULTS: ADHD was diagnosed in 42 (32.8%) FMF patients, a rate significantly higher than in unselected populations (∼8%). A majority (n = 27, 64.3%) had combined inattentive, hyperactive-impulsive manifestations. Eight (19%) had predominantly hyperactive-impulsive, and seven (16.6%) had predominantly inattentive symptoms. FMF patients with severe manifestations reported more ADHD symptoms. FMF patients with ADHD symptoms were less adherent to their treatment regimen, with only 61.9% of the patients with ADHD symptoms adhering to colchicine therapy compared to 92.7% of the patients without ADHD symptoms. CONCLUSION: The high prevalence of ADHD characteristics in children with FMF may support the neuroimmune hypothesis that chronic inflammation increases the risk for ADHD. Children with FMF should be screened for ADHD as its presence may adversely affect adherence to treatment.

Pyogenic sacroiliitis in children: don't forget the very young.

Pyogenic sacroiliitis (PS) is rare with less than 100 pediatric cases reported in the medical literature. To better characterize PS in the pediatric population, we investigated a series of children presenting with PS. Retrospective data analysis was done at an academic tertiary center between the years of 2000 and 2017. All hospitalized children ≤ 16 years of age with PS were evaluated. Of the 894 children hospitalized with osteoarticular infections, 18 were diagnosed with PS (2%) and are included in the review. Two clinically distinct groups were identified. PS in infants (n = 13, 72.2%, mean age 1.1 years) had an indolent course and a faster recovery without any bacterial source identified. In contrast, the group of older children (n = 5, 27.8%, mean age 11.6 years) had a more complicated course and a higher rate of identified bacterial infections.Conclusion: We describe an under-recognized entity of PS in infants with a mild clinical course and fast recovery that differ from the "classical" septic sacroiliitis. Infants with PS did not suffer from invasive complications, and pathogen characteristics of older children were not identified. Infants with fever, irritability, decreased range of motion in the pelvic area, and pain during diapering should alert the clinician to this diagnosis. What is Known: • Pediatric pyogenic sacroiliitis is an extremely rare condition usually caused by Staphylococcus aureus with highest incidence in adolescents. • The diagnosis of PS is challenging due to its rarity and difficulty in assessing the sacroiliac joint. What is New: • We describe an under-recognized entity of PS in infants with a mild clinical course, without invasive complications and with fast recovery that differ from "classical" septic sacroiliitis. • Infants with fever, irritability, decreased range of motion in the pelvic area and pain during diapering should raise clinical suspicion of this diagnosis.

Japanese scoring systems to predict resistance to intravenous immunoglobulin in Kawasaki disease were unreliable for Caucasian Israeli children.

AIM: This study assessed the validity of using established Japanese risk scoring methods to predict intravenous immunoglobulin (IVIG) resistance to Kawasaki disease in Israeli children. METHODS: We reviewed the medical records of 282 patients (70% male) with Kawasaki disease from six Israeli medical centres between 2004 and 2013. Their mean age was 2.5 years. The risk scores were calculated using the Kobayashi, Sano and Egami scoring methods and analysed to determine whether a higher risk score predicted IVIG resistance in this population. Factors that predicted a lack of response to the initial IVIG dose were identified. RESULTS: We found that 18% did not respond to the first IVIG dose. The three scoring methods were unable to reliably predict IVIG resistance, with sensitivities of 23%-32% and specificities of 67%-87%. Calculating a predictive score that was specific for this population was also unsuccessful. The factors that predicted a lacked of response to the first IVIG dose included low albumin, elevated total bilirubin and ethnicity. CONCLUSION: The established risk scoring methods created for Japanese populations with Kawasaki disease were not suitable for predicting IVIG resistance in Caucasian Israeli children, and we were unable to create a specific scoring method that was able to do this.

Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Therapy with eculizumab for patients with CD59 p.Cys89Tyr mutation.

OBJECTIVE: The objective of this work was to report on the outcome of eculizumab treatment in pediatric patients with recurrent acute predominantly motor, demyelinating neuropathy with conduction block, and chronic hemolysis attributed to p.Cys89Tyr mutation in the CD59 gene. METHODS: Four patients were recruited from our new registry of patients with homozygosity for the p.Cys89Tyr mutation on CD59. Participants received repeated intravenous eculizumab. In this 24-month open-label phase IIa study, we aimed to determine whether eculizumab reduces chronic hemolysis, and cumulative doses of steroids and intravenous immunoglobulin (IVIG), and ameliorates neurological deficits, compared to pretreatment status. Treatment response was evaluated every 2 to 4 weeks over 104 weeks and included examination with gross motor scoring by American Spinal Injury Association Impairment Scale and Inflammatory Neuropathy Cause and Treatment disability score, laboratory examination, well-being [12-item Short Form Health Survey; SF-12]). Neurological relapses and cumulative dose of IVIGs and/or corticosteroids before and after treatment were documented. Red blood cells (RBCs) and neutrophils were stained to evaluate C5b-9 deposition. ClinicalTrials.gov: NCT01579838. RESULTS: Dramatic and significant neurological amelioration in the upper limbs and trunk with more-modest amelioration in the lower limbs was observed in all patients. Corticosteroid and IVIG treatment was completely stopped. No patient relapsed during treatment despite infections, and there were no hospital admissions. Decreased C3bi and C5b-9 deposition on RBCs and neutrophils was documented (p < 0.0001). The SF-12 health questionnaires indicated significant improvement (p < 0.003). INTERPRETATION: Eculizumab was safely administered to these patients. Marked clinical improvement suggests that eculizumab may be a life-saving treatment for patients with acute predominantly motor, demyelinating neuropathy with conduction block, and secondary axonal damage attributed to primary p.Cys89Tyr mutation in the CD59 gene. Ann Neurol 2016;80:708-717.

High-dose aspirin for Kawasaki disease: outdated myth or effective aid?

OBJECTIVES: To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes. METHODS: This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage. RESULTS: The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups. CONCLUSIONS: We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered.

Familial Mediterranean fever.

PURPOSE OF REVIEW: Familial Mediterranean fever (FMF) is the oldest and most common of the hereditary autoinflammatory diseases (AIDs). A large body of information has been accumulated over recent years on the pathophysiology, diagnosis and treatment of these diseases. The purpose of this review is to bring an up-to-date summary of the clinic manifestations, diagnostic criteria and treatment of FMF. RECENT FINDINGS: An overview of the pathophysiologic basis of FMF as part of the AID is discussed. Over the last year, attempts to establish new criteria for childhood FMF, new guidelines for treatment and follow-up of disease and novel treatment for FMF were made. A comparison of the different disease severity scores for research purposes suggests that a new score is needed. New evidence for antiinterleukin-1 blockade as a new treatment modality is described. SUMMARY: New diagnostic criteria, disease severity score, treatment and follow-up guidelines have been proposed, and need validation in the next several years.

Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency.

Adenosine deaminase 2 deficiency is an autoinflammatory disease, characterized by various forms of vasculitis. We describe 5 patients with adenosine deaminase 2 deficiency with various hematologic manifestations, including pure red cell aplasia, with no evidence for vasculitis.

Sudden onset unexplained encephalopathy in infants: think of cannabis intoxication.

UNLABELLED: The use of cannabis as both a therapeutic agent and recreational drug is common, and its availability is increasing as a result of legalization in many countries. Among older children, the manifestations of cannabis intoxication are numerous and include both neurological and systemic manifestations that are frequently non-specific. There have been only a few reports detailing cannabis intoxication in infants and toddlers. We describe three infants who presented to the emergency department with encephalopathic signs without prominent systemic manifestations. During the initial interview of caregivers, no history of exposure to neurotoxic agents was obtained. All three patients were subsequently diagnosed with cannabis intoxication based on urine toxic screens for delta-9-tetrahydrocannabinol (THC). The infants recovered with supportive care that included fluids and monitoring. The non-specific symptomatology of cannabis intoxication in infants together with the wide differential for unexplained acute onset encephalopathy may delay diagnosis and lead to inappropriate procedures and interventions such as antimicrobial treatments and imaging studies. CONCLUSION: Healthcare personnel of emergency rooms, urgent care centers, and general clinics should be aware of the potential risk of cannabis ingestion in young infants. A thorough medical history and toxic screen are warranted in all infants with unexplained decreased sensorium.

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1ß monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).