Evolution of Cardiovascular Findings in Multisystem Inflammatory Syndrome in Children (MIS-C) Across COVID-19 Variants: Common Trends and Unusual Presentations.

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following COVID-19 infection. Cardiac involvement is common and includes left ventricular systolic dysfunction, cardiac marker elevation, electrocardiogram (ECG) changes, and coronary artery dilation. This single-center retrospective cohort study compares cardiovascular disease between three major SARS-CoV-2 variants and describes the evolution of findings in medium-term follow-up. Of 69 total children (mean age 9.2 years, 58% male), 60 (87%) had cardiovascular involvement with the most common features being troponin elevation in 33 (47%) and left ventricular dysfunction in 22 (32%). Based on presumed infection timing, 61 patients were sorted into variant cohorts of Alpha, Delta, and Omicron. Hospitalization was longer for the Delta group (7.7 days) vs Alpha (5.1 days, p = 0.0065) and Omicron (4.9 days, p = 0.012). Troponin elevation was more common in Delta compared to Alpha (13/20 vs 7/25, p = 0.18), and cumulative evidence of cardiac injury (echocardiographic abnormality and/or troponin elevation) was more common in Delta (17/20) compared with Alpha (12/25, p = 0.013) or Omicron (8/16, p = 0.034). Forty-nine (77%) of the original cohort (n = 69) had no cardiac symptoms or findings beyond 3 months post-hospitalization. Cardiac MRI was performed in 28 patients (between 3 and 6 months post-hospitalization) and was normal in 25 patients (89%). The differences in the variant cohorts may be due to alteration of the immune landscape with higher severity of COVID-19 infection. Despite overall reassuring cardiac outcomes, it is important to note the variability of presentation and remain vigilant with future variants.

Resin infiltration for white spot lesions: An in vitro experimental trial.

OBJECTIVE: To evaluate the aesthetic outcome by varying the duration allowed for infiltrant penetration when treating white spot lesions with resin infiltration. DESIGN: An in vitro, experimental randomised study. METHODS: Artificially created white spot lesions (WSLs) were induced on 100 extracted anterior teeth (T1). Teeth were divided into enamel and dentine groups depending on the extent of the lesion and then randomly assigned into different treatment protocol groups: penetration times of 3, 6 and 9 min. Resin infiltration treatment was applied according to the treatment protocol assigned (T2). Samples were thermocycled for 10,000 cycles (1 clinical year) (T3). The samples from the 3-min enamel and dentine groups were then randomly assigned into either a repeat treatment or no additional treatment group (T4). Samples were then thermocycled for an additional 10,000 cycles (T5). Spectrophotometric analysis was measured colour change (ΔE) for all groups. RESULTS: Mean ΔE values equal to or greater than the critical value (3.7) indicate a detectable clinical difference in colour of the treated WSL when compared to before WSL formation. Mean ΔE values, for the enamel groups, were slightly above or significantly below the critical value, and for the dentine groups, were significantly above the critical value. Mean ΔE values within the enamel and dentine groups both demonstrated a downward trend with increasing time allowed for resin infiltrant penetration (P < 0.05). No significant mean ΔE difference (P = 0.53) was found between groups that received a single or repeat treatment. After the first thermocycling event, no significant difference in colour change was observed in all groups except for the deep dentine lesion treated for 3 min. There was a significant difference in colour change for all groups except the enamel group that received a single treatment following thermocycling after a single or repeat treatment. CONCLUSION: Increasing the resin infiltrant penetration time to at least 9 min is advised as the most optimised treatment protocol. Resin infiltration treatment should be done only once to treat a particular white spot lesion as subsequent treatment for the same lesion results in marginal colour improvement. The colour improvement of WSLs resulting from the resin infiltration treatment can be expected to last for at least 1 year. Resin infiltration treatment of shallow lesions with a single and optimised infiltration technique can be expected to last an additional year.

Alagille Syndrome and Chronic Arthritis: An International Case Series.

We describe 10 children with Alagille syndrome and inflammatory arthritis. In our centers, the prevalence of chronic arthritis in patients with Alagille syndrome is approximately 50 times higher compared with the general population. Arthritis was refractory to most treatment. Patients with Alagille syndrome should routinely be screened for musculoskeletal symptoms.

Current management of juvenile idiopathic arthritis affecting the craniovertebral junction.

PURPOSE: Craniovertebral instability is a rare and serious problem. While previously treated surgically, better understanding of disease processes has permitted the field to move towards conservative management. Juvenile idiopathic arthritis (JIA) is one cause of pediatric craniovertebral instability. Early recognition and institution of appropriate medical therapy and bracing in a multidisciplinary fashion is critical to avoid long-term instability, joint abnormalities, or morbid surgical procedures. We seek to highlight cases of this rare problem and provide a principled approach to management decisions. METHODS: We review 6 cases that have presented over the last 6 years and highlight 3 cases in particular regarding craniovertebral instability as a presentation of JIA. We reviewed the clinical records and radiographic features with particular emphasis of the stability of the craniovertebral junction. RESULTS: Age range of the subjects was from 5 to 12. All patients presented with neck pain and abnormal head rotation. Four of the patients responded to medical management and/or cervical bracing with no long-term sequelae or instability. Two patients had refractory rotary subluxation, one that responded to manual reduction under pharmacological paralysis and bracing; the other had an incompetent transverse ligament requiring surgical reduction and fixation. CONCLUSIONS: Neck pain and abnormal head rotation in an older child is rare finding but should prompt suspicion as a manifestation of JIA to the general pediatrician or initial provider. Appropriate serologic studies and MRI studies with contrast at the craniovertebral junction is necessary for evaluation. Early institution of medical management and cervical bracing under a multidisciplinary team of pediatric rheumatology and neurosurgery is key to avoiding surgical intervention and long-term abnormalities at the craniovertebral junction.

Limited Wegener's Granulomatosis Presenting with an Isolated Abduction Deficit.

Wegener's granulomatosis often affects the orbit, typically presenting with painful proptosis. The authors describe a 14 year-old girl, with limited Wegener's granulomatosis, who initially presented with an isolated painless abduction deficit that spontaneously resolved over several weeks. She subsequently developed painful proptosis and diplopia, followed by facial and oral nodules. This case demonstrates that limited Wegener's granulomatosis can rarely present with an isolated painless abduction deficit.

Capturing the Range of Disease Involvement in Localized Scleroderma: The Localized Scleroderma Total Severity Scale.

OBJECTIVE: Juvenile localized scleroderma (jLS) is a chronic autoimmune disease commonly associated with poor outcomes, including contractures, hemiatrophy, uveitis, and seizures. Despite improvements in treatment, >25% of patients with jLS have functional impairment. To improve patient evaluation, our workgroup developed the Localized scleroderma Total Severity Scale (LoTSS), an overall disease severity measure. METHODS: LoTSS was developed as a weighted measure by a consensus process involving literature review, surveys, case vignettes, and multicriteria decision analysis. Feasibility was assessed in larger Childhood Arthritis and Rheumatology Research Alliance groups. Construct validity with physician assessment and inter-rater reliability was assessed using case vignettes. Additional evaluation was performed in a prospective patient cohort initiating treatment. RESULTS: LoTSS severity items were organized into modules that reflect jLS disease patterns, with modules for skin, extracutaneous, and craniofacial manifestations. Construct validity of LoTSS was supported by a strong positive correlation with the Physician Global Assessment (PGA) of severity and damage and weak positive correlation with PGA-Activity, as expected. LoTSS was responsive, with a small effect size identified. Moderate-to-excellent inter-rater reliability was demonstrated. LoTSS was able to discriminate between patient subsets, with higher scores identified in those with greater disease burden and functional limitation. CONCLUSION: We developed a new LS measure for assessing cutaneous and extracutaneous severity and have shown it to be reliable, valid, and responsive. LoTSS is the first measure that assesses and scores all the major extracutaneous manifestations in LS. Our findings suggest LoTSS could aid assessment and management of patients and facilitate outcome evaluation in treatment studies.

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series.

OBJECTIVE: To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS: Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS: Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION: Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.

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

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.

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

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.

Childhood Arthritis and Rheumatology Research Alliance Consensus Clinical Treatment Plans for Juvenile Dermatomyositis with Persistent Skin Rash.

OBJECTIVE: Juvenile dermatomyositis (JDM) is the most common form of idiopathic inflammatory myopathy in children. While outcomes are generally thought to be good, persistence of skin rash is a common problem. The goal of this study was to describe the development of clinical treatment plans (CTP) for children with JDM characterized by persistent skin rash despite complete resolution of muscle involvement. METHODS: The Childhood Arthritis and Rheumatology Research Alliance, a North American consortium of pediatric rheumatologists and other healthcare providers, used a combination of Delphi surveys and nominal group consensus meetings to develop CTP that reflected consensus on typical treatments for patients with JDM with persistent skin rash. RESULTS: Consensus was reached on patient characteristics and outcome assessment. Patients should have previously received corticosteroids and methotrexate (MTX). Three consensus treatment plans were developed. Plan A added intravenous immunoglobulin (IVIG) if it was not already being used. Plan B added mycophenolate mofetil, while Plan C added cyclosporine. Continuation of previous treatments, including corticosteroids, MTX, and IVIG, was permitted in plans B and C. CONCLUSION: Three consensus CTP were developed for use in children with JDM and persistent skin rash despite complete resolution of muscle disease. These CTP reflect typical treatment approaches and are not to be considered treatment recommendations or standard of care. Using prospective data collection and statistical methods to account for nonrandom treatment assignment, it is expected that these CTP will be used to allow treatment comparisons, and ultimately determine the best treatment for these patients.

Immunosuppressive Treatment for Retinal Degeneration in Juvenile Neuronal Ceroid Lipofuscinosis (Juvenile Batten Disease).

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) presents with progressive vision loss at 4-7 years of age. Blindness results within 2 years, followed by inexorable neurologic decline and death. There is no treatment or cure. Neuroinflammation is postulated to play a role in the neurodegeneration. The JNCL mouse model demonstrated decreased neuroinflammation and improved motor skills with immunosuppression. Based on this work, a short-term human clinical trial of mycophenolate mofetil has begun, however longer term effects, and whether immunosuppression modulates vision loss, have not been studied. We report a JNCL patient treated with immunosuppressive therapy in whom visual function was comprehensively characterized over 2 years.

Development of consensus treatment plans for juvenile localized scleroderma: a roadmap toward comparative effectiveness studies in juvenile localized scleroderma.

OBJECTIVE: Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS. METHODS: A core group of pediatric rheumatologists, dermatologists, and a lay advisor was engaged by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) to develop standardized treatment plans and assessment parameters for juvenile LS using consensus methods/nominal group techniques. Recommendations were validated in 2 face-to-face conferences with a larger group of practitioners with expertise in juvenile LS and with the full membership of CARRA, which encompasses the majority of pediatric rheumatologists in the US and Canada. RESULTS: Consensus was achieved on standardized treatment plans that reflect the prevailing treatment practices of CARRA members. Standardized clinical assessment methods and provisional treatment response criteria were also developed. Greater than 90% of pediatric rheumatologists responding to a survey (66% of CARRA membership) affirmed the final recommendations and agreed to utilize these consensus plans to treat patients with juvenile LS. CONCLUSION: Using consensus methodology, we have developed standardized treatment plans and assessment methods for juvenile LS. The high level of support among pediatric rheumatologists will support future comparative effectiveness studies and enable the development of evidence-based guidelines for the treatment of juvenile LS.

Juvenile xanthogranulomatosis with bilateral and multifocal ocular lesions of the iris, cornealscleral limbus, and choroid.

A 14-month-old boy with juvenile xanthogranuloma skin lesions presented with increased intraocular pressure, hyphema, anterior uveitis, iris mass, and a subconjunctival limbal mass of the right eye. He subsequently developed a subretinal mass in the left eye. The anterior uveitis resolved after 2 periocular injections of triamcinolone in addition to the administration of topical prednisolone and oral prednisone and methotrexate. The subretinal mass in the left eye also resolved during the course of 1 year. He developed a cataract in the right eye and underwent lensectomy with anterior vitrectomy. This is the first published case in which methotrexate was used as an adjunctive treatment of juvenile xanthogranuloma in a child.

B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients.

OBJECTIVE: To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). METHODS: Blood samples collected from patients with pediatric SLE (n = 56) and patients with JIA (n = 54) at the beginning and end of a 6-month interval were analyzed for plasma BLyS protein levels by enzyme-linked immunosorbent assay and for blood leukocyte full-length BLyS and DeltaBLyS messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n = 34) of these patients served as controls. RESULTS: In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months. CONCLUSION: Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder.