Safety and efficacy of mesenchymal stromal cell therapy for multi-drug-resistant acute and late-acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.

Graft versus host disease (GvHD) remains a significant risk for mortality and morbidity following allogeneic hematopoietic stem cell transplantation (HSCT). A growing literature supports successful applications of mesenchymal stromal cells (MSCs) for the treatment of steroid-refractory acute GvHD (aGvHD). However, there is limited knowledge about the effects of MSC treatment on late-acute GvHD (late aGvHD). In this article, we present our multicenter study on the safety and efficacy of MSC therapy for patients with steroid-refractory late aGvHD in comparison to those with aGvHD. The outcome measures include non-relapse mortality (NRM) and survival probability over a 2-year follow-up. The study includes a total of 76 patients with grades III-IV aGvHD (n = 46) or late aGvHD (n = 30), who had been treated with at least two lines of steroid-containing immunosuppressive therapy. Patients received weekly adipose or umbilical cord-derived MSC infusions at a dose of median 1.55 (ranging from 0.84 to 2.56) × 106/kg in the aGvHD group, and 1.64 (ranging from 0.85 to 2.58) × 106/kg in the late aGvHD group. This was an add-on treatment to ongoing conventional pharmaceutical management. In the aGvHD group, 23 patients received one or two infusions, 20 patients had 3-4, and three had ≥ 5. Likewise, in the late aGvHD group, 20 patients received one or two infusions, nine patients had 3-4, and one had ≥ 5. MSC was safe without acute or late adverse effects in 76 patients receiving over 190 infusions. In aGvHD group, 10.9% of the patients had a complete response (CR), 23.9% had a partial response (PR), and 65.2% had no response (NR). On the other hand, in the late aGvHD group, 23.3% of the patients had CR, 36.7% had PR, and the remaining 40% had NR. These findings were statistically significant (p = 0.031). Also, at the 2-year follow-up, the cumulative incidence of NRM was significantly lower in patients with late aGvHD than in patients with aGvHD at 40% (95% CI, 25-62%) versus 71% (95% CI, 59-86%), respectively (p = 0.032). In addition, the probability of survival at 2 years was significantly higher in patients with late aGvHD than in the aGvHD group at 59% (95% CI, 37-74%) versus 28% (95% CI, 13-40%), respectively (p = 0.002). To our knowledge, our study is the first to compare the safety and efficacy of MSC infusion(s) for the treatment of steroid-resistant late aGVHD and aGVHD. There were no infusion-related adverse effects in either group. The response rate to MSC therapy was significantly higher in the late aGvHD group than in the aGvHD group. In addition, at the 2-year follow-up, the survival and NRM rates were more favorable in patients with late aGVHD than in those with aGVHD. Thus, the results are encouraging and warrant further studies to optimize MSC-based treatment for late aGVHD.

Assessment of a novel continuous cleaning device using metatranscriptomics in diverse hospital environments.

Introduction: Despite routine implementation of cleaning and disinfection practices in clinical healthcare settings, high-touch environmental surfaces and contaminated equipment often serve as reservoirs for the transmission of pathogens associated with healthcare-associated infections (HAIs). Methods: The current study involved the analysis of high-touch surface swabs using a metatranscriptomic sequencing workflow (CSI-Dx™) to assess the efficacy of cleanSURFACES® technology in decreasing microbial burden by limiting re-contamination. This is a non-human single center study conducted in the Emergency Department (ED) and on an inpatient Oncology Ward of Walter Reed National Military Medical Center that have followed hygienic practices during the COVID-19 pandemic environment. Results: Although there was no difference in observed microbial richness (two-tailed Wilcoxon test with Holm correction, P > 0.05), beta diversity findings identified shifts in microbial community structure between surfaces from baseline and post-intervention timepoints (Day 1, Day 7, Day 14, and Day 28). Biomarker and regression analyses identified significant reductions in annotated transcripts for various clinically relevant microorganisms' post-intervention, coagulase-negative staphylococci and Malassezia restricta, at ED and Oncology ward, respectively. Additionally, post-intervention samples predominantly consisted of Proteobacteria and to a lesser extent skin commensals and endogenous environmental microorganisms in both departments. Discussion: Findings support the value of cleanSURFACES®, when coupled with routine disinfection practices, to effectively impact on the composition of active microbial communities found on high-touch surfaces in two different patient care areas of the hospital (one outpatient and one inpatient) with unique demands and patient-centered practices.

Improvement in Disease Activity in Refractory Juvenile Dermatomyositis Following Abatacept Therapy.

OBJECTIVE: This open-label, 24-week study was conducted to evaluate the safety and efficacy of abatacept in patients with refractory juvenile dermatomyositis (DM). METHODS: Ten patients ≥7 years of age with moderate disease activity were enrolled in a 24-week study to examine the safety of subcutaneous abatacept and patient responses to the treatment. The primary endpoint was the International Myositis Assessment and Clinical Studies (IMACS) group Definition Of Improvement (DOI). Secondary endpoints included safety, changes in the core set activity measures (CSMs) of the IMACS group and the Pediatric Rheumatology International Trials Organization, and improvements in disease activity based on the American College of Rheumatology (ACR)/EULAR response criteria for juvenile DM. Radiologists blinded with regard to participant data assessed magnetic resonance images (MRIs) of patient thigh muscles. Interferon (IFN)-regulated gene score was performed on whole-blood RNA samples using a NanoString assay, and cytokines were assessed using a Luminex assay. RESULTS: Five patients achieved DOI at week 12, and 9 patients achieved DOI at week 24, including 2 patients with minimal, 4 patients with moderate, and 3 patients with major improvement by the 2016 ACR/EULAR response criteria for juvenile DM when patients were assessed using the CSMs of the IMACS Group. Improvements from baseline were seen in all CSMs at weeks 12 and 24, except in muscle enzymes. Daily glucocorticoid doses decreased from a mean of 16.7 mg at baseline to 10.2 mg at week 24 (P = 0.002). Average MRI muscle edema scores decreased from a mean baseline score of 5.3 to 2.3 at week 24 (P = 0.01). Six patients had down-trending IFN-regulated gene scores and galectin-9 expression at week 24. Decreases in IFN-regulated gene scores and in levels of interferon-γ-inducible protein 10kDa, galectin-9, and interleukin-2 correlated with improvements in disease activity and in muscle edema shown on MRI. Eleven grade 2 or 3 treatment-emergent adverse events were observed. CONCLUSION: This open-label study demonstrated that abatacept may be beneficial for patients with treatment-refractory juvenile DM.

A pilot study for treatment of severe COVID-19 pneumonia by aerosolized formulation of convalescent human immune plasma exosomes (ChipEXO™).

This is a single-center prospective, open-label, single arm interventional study to test the safety and efficacy of recently described ChipEXO™ for severe COVID-19 pneumonia. The ChipEXO™ is a natural product derived from convalescent human immune plasma of patients recovered from moderate COVID-19 infection. In September 2021, 13 patients with pending respiratory failure were treated with ChipEXO™ adapted for aerosolized formulation delivered via jet nebulizer. Patients received 1-5x1010 nano vesicle/5 mL in distilled water twice daily for five days as an add-on to ongoing conventional COVID-19 treatment. The primary endpoint was patient safety and survival over a 28-day follow-up. The secondary endpoint was longitudinal assessment of clinical parameters following ChipEXO™ to evaluate treatment response and gain insights into the pharmacodynamics. ChipEXO™ was tolerated well without any allergic reaction or acute toxicity. The survival rate was 84.6% and 11 out of 13 recovered without any sequel to lungs or other organs. ChipEXO™ treatment was effective immediately as shown in arterial blood gas analyses before and two hours after exosome inhalation. During the 5 days of treatment, there was a sustainable and gradual improvement on oxygenation parameters: i.e. respiratory rate (RR) [20.8% (P < 0.05)], oxygen saturation (SpO2) [6,7% (P < 0.05)] and partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2) [127.9% (P < 0.05)] that correlated with steep decrease in the disease activity scores and inflammatory markers, i.e. the sequential organ failure assessment (SOFA) score (75%, p < 0.05), C-reactive protein (46% p < 0.05), ferritin (58% p = 0.53), D-dimer (28% p=0.46). In conclusion, aerosolized ChipEXO™ showed promising safety and efficacy for life-threatening COVID-19 pneumonia. Further studies on larger patient populations are required to confirm our findings and understand the pathophysiology of improvement toward a new therapeutic agent for the treatment of severe COVID-19 pneumonia.

The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist.

BACKGROUND: The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. OBJECTIVE: To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. METHODS: A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. RESULTS: The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. CONCLUSION: The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.

The 2021 EULAR/American College of Rheumatology Points to Consider for Diagnosis, Management and Monitoring of the Interleukin-1 Mediated Autoinflammatory Diseases: Cryopyrin-Associated Periodic Syndromes, Tumour Necrosis Factor Receptor-Associated Periodic Syndrome, Mevalonate Kinase Deficiency, and Deficiency of the Interleukin-1 Receptor Antagonist.

BACKGROUND: The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin- associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. OBJECTIVE: To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. METHODS: A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. RESULTS: The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. CONCLUSION: The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.

Cell Based Treatment of Autoimmune Diseases in Children.

Mesenchymal stem cells have recently been recoined as medicinal signaling cells (MSC) for their ability to promote tissue homeostasis through immune modulation, angiogenesis and tropism. During the last 20 years, there has been a plethora of publications using MSC in adults and to lesser extent neonates on a variety of illnesses. In parts of the world, autologous and allogeneic MSCs have been purified and used to treat a range of autoimmune conditions, including graft versus host disease, Crohn's disease, multiple sclerosis, refractory systemic lupus erythematosus and systemic sclerosis. Generally, these reports are not part of stringent clinical trials but are of note for good outcomes with minimal side effects. This review is to summarize the current state of the art in MSC therapy, with a brief discussion of cell preparation and safety, insights into mechanisms of action, and a review of published reports of MSC treatment of autoimmune diseases, toward the potential application of MSC in treatment of children with severe autoimmune diseases using multicenter clinical trials and treatment algorithms.

Post-COVID-19 Multisystem Inflammatory Syndrome in Children and Adults: What Happens After Discharge?

Introduction Classification criteria and practice guidelines for inpatient management of multisystem inflammatory syndrome (MIS) exist, but reports on outpatient management and clinical outcomes are lacking. Here we describe the management and clinical outcomes of four children and four adults with MIS seen at Walter Reed National Military Medical Center (WRNMMC) from diagnosis to six months follow-up. Methods This retrospective, case-series describes the initial presentation and management of MIS in four children and four adults seen at WRNMMC from March 2020 to September 2021. Data on each patient was collected from the time of exposure to the SARS-CoV-2 virus to six months post-diagnosis with MIS. Extracted data includes: demographics, comorbidities, initial MIS presentation, inpatient treatment, outpatient treatment, and clinical outcomes. Results A total of 62.5% of patients presented in shock. All pediatric patients received IVIG, methylprednisolone, and anakinra; no adult received this combination. Steroids and immunomodulatory medications were discontinued in 1-2 months outpatient. Three children and two adults had full symptomatic resolution. One child and two adults had persistent deconditioning at six months follow-up. One adult had persistent dyspnea. Conclusions MIS appears to be monophasic with no recurrences at six months follow-up in our patients who only required 1-2 months of glucocorticoid or immunomodulatory medications. The better outcomes in children raise the question of how much of this difference can be attributed to early combination therapy versus physiologic differences in children and adults.

Preclinical Studies on Convalescent Human Immune Plasma-Derived Exosome: Omics and Antiviral Properties to SARS-CoV-2.

The scale of the COVID-19 pandemic forced urgent measures for the development of new therapeutics. One of these strategies is the use of convalescent plasma (CP) as a conventional source for passive immunity. Recently, there has been interest in CP-derived exosomes. In this report, we present a structural, biochemical, and biological characterization of our proprietary product, convalescent human immune plasma-derived exosome (ChipEXO), following the guidelines set forth by the Turkish Ministry of Health and the Turkish Red Crescent, the Good Manufacturing Practice, the International Society for Extracellular Vesicles, and the Gene Ontology Consortium. The data support the safety and efficacy of this product against SARS-CoV-2 infections in preclinical models.

Is Long COVID a State of Systemic Pericyte Disarray?

The most challenging aspect of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) or Long COVID remains for the discordance between the viral damage from acute infection in the recent past and susceptibility of Long COVID without clear evidence of post infectious inflammation or autoimmune reactions. In this communication we propose that disarray of pericytes plays a central role in emerge of Long COVID. We assume pericytes are agents with "Triple-A" qualities, i.e., analyze-adapt and advance, necessary for sustainability of host homeostasis. Based on this view, we further suggest Long COVID may provide a model system to integrate system theory and complex adaptive systems to explore a new class of maladies those are currently not well defined and with no remedies.

Uncharted waters: mesenchymal stem cell treatment for pediatric refractory rheumatic diseases; a single center case series.

BACKGROUND: With the advent of innovative therapies including biologics and Janus kinase inhibitors, children with rheumatic diseases are more likely to have improved outcomes. Despite these advances, some children do not respond, or they, or their parents fear adverse events and seek other alternatives. Increasingly, private companies are offering mesenchymal stem cells (MSC) as an alternative, which are described as natural therapies for rheumatic diseases, often insinuating them as a cure. MSC have immunomodulatory properties, and transplantation of these stem cells have been used to successfully treat immunologic conditions like graft-versus-host disease. Lately, MSC research in adult lupus has been encouraging, but the clinical trials are still underway and in most, MSC therapy is not a standalone treatment. This retrospective case series will highlight three cases of pediatric refractory autoimmune disease whose parents sought out and received MSC therapy as a self-decision without first seeking medical advice from our specialty. The three families felt that their children were improved and in two believed that their child was cured. MSC have the potential of beneficial immunomodulation and may be a powerful tool in the therapy of rheumatic disease, but well controlled clinical trials are necessary and should be designed and monitored by experts in childhood rheumatic disease. CASE PRESENTATION: Three children with three different rheumatic diseases; systemic lupus erythematosus, mixed connective tissue disease and juvenile idiopathic arthritis were under the care of pediatric rheumatology at a large, tertiary-care, teaching institution. Multiple non-biologic and biologic disease-modifying anti-rheumatic drugs failed to significantly decrease disease activity, and as a result, the families chose to undergo MSC therapy. After transplantation, all children improved per patient and parent report and tapered off conventional immunosuppressive drugs. No serious adverse events occurred in these three patients. CONCLUSION: The three cases presented in this report reflect comparable beneficial outcomes and minimal risks published in adult studies. These were not controlled studies, however, and benefit was reported rather than documented. These cases suggest that MSC transplantation may prove a promising adjunctive treatment option; however, further research, development of standardized infusion therapy protocols, and well-designed monitored clinical trials are essential.

Sixteen Weeks Later: Expanding the Risk Period for Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) has been observed in temporal association with coronavirus disease 2019 (COVID-19), typically within 2 to 6 weeks of illness or exposure. We present a case of MIS-C occurring 16 weeks after initial COVID-19 illness to highlight the prolonged period of risk for developing MIS-C.

Multisystem Inflammatory Syndrome in Children during the COVID-19 Pandemic: A Case Report on Managing the Hyperinflammation.

The novel human coronavirus of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly swept throughout the entire world. As the ongoing pandemic has spread, recent studies have described children presenting with a multisystem inflammatory disorder sharing the features of Kawasaki disease (KD) and toxic shock syndrome, now named Multisystem Inflammatory Syndrome in Children (MIS-C). These cases report a similar phenotype of prolonged fever, multisystem involvement, and biomarkers demonstrating marked hyperinflammation that occurs temporally in association with local community spread of SARS-CoV-2. Herein, we describe the presentation, clinical characteristics, and management of an 11-year-old boy with prolonged fever, strikingly elevated inflammatory markers, and profound, early coronary artery aneurysm consistent with a hyperinflammatory, multisystem disease temporally associated with coronavirus disease 2019. We highlight our multidisciplinary team's management with intravenous immunoglobulin, methylprednisolone, and an interleukin-1 receptor antagonist, anakinra, as a strategy to manage this multisystem, hyperinflammatory disease process.

Intrarenal injection of mesenchymal stem cell for treatment of lupus nephritis in mice - a pilot study.

The current project is to explore feasibility of direct intra-renal injection of human bone marrow derived mesenchymal stem cells (hMSC) for treatment of lupus nephritis in mice. The treatment protocol involved aged male BXSB (20 weeks) injected with 1 × 106 hMSC unilaterally under the renal capsule. Mice were harvested after 10 weeks follow-up for postmortem exam. Controls included untreated age matched male BXSB and healthy C57Bl/6. At the end of follow-up period, the survival of treated BXSB was 10 folds higher at 62.5% compared to survival of untreated control at 6.3%. The survival of C57Bl/6 remained at 100% with or without similar treatment. The renal pathology review was most significant for decreased tissue inflammation in treated BXSB compared to untreated controls. Renal tissue expression of IL-1b, IL17 were decreased and CTLA-4 was increased by RT PCR among treated compared to untreated BXSB. Thus, direct delivery of hMSC by intrarenal injection is a promising route for treatment of lupus nephritis as shown in this xenogeneic model. Further studies -using expanded numbers of mice to include other lupus strains- are warranted to investigate the mechanisms involved and to optimize treatment protocol for safety and efficacy.

Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate.

OBJECTIVES: Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment. METHODS: Children aged 4-17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, ≤3.8) and inactive disease (ID, ≤1). RESULTS: Of 171 patients enrolled, 62 (36%) completed the long-term extension. Twelve serious infections in 11 patients were reported through 592.8 patient-years of exposure. No cases of congestive heart failure-related AEs, demyelinating disease, lupus-like syndrome, malignancies, tuberculosis or deaths were reported. JIA ACR 30/50/70/90 responses and JADAS27 LDA were achieved in 66% to 96% of patients at week 104, and 63 (37%) patients achieved clinical remission (JADAS27 ID sustained for ≥6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis). CONCLUSIONS: Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate.

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis-A Critical Review of Its Pathogenesis and Treatment.

MIS-C is a newly defined post-viral myocarditis and inflammatory vasculopathy of children following COVID-19 infection. This review summarizes the literature on diagnosis, parameters of disease severity, and current treatment regimens. The clinical perspective was analyzed in light of potential immunopathogenesis and compared to other post-infectious and inflammatory illnesses of children affecting the heart. In this paradigm, the evidence supports the importance of endothelial injury and activation of the IL-1 pathway as a common determinant among MIS-C, Kawasaki disease, and Acute Rheumatic fever.

Long-term outcomes in Juvenile Myositis patients.

OBJECTIVE: Juvenile idiopathic inflammatory myopathies (JIIM) are rare, chronic autoimmune muscle diseases of childhood, with the potential for significant morbidity. Data on long-term outcomes is limited. In this study we investigate correlations between clinical and demographic features with long-term outcomes in a referral population of adult patients with JIIM. METHODS: Forty-nine adults with JIIM were assessed at two referral centers between 1994 and 2016. Features of active disease and damage at a cross-sectional assessment were obtained. Regression modeling was used to examine factors associated with long-term outcomes, defined by the presence of calcinosis or a higher adjusted Myositis Damage Index (MDI) score. A multivariable model of MDI was constructed using factors that were statistically significant in bivariate models. RESULTS: At a median of 11.5 [IQR 4.5-18.9] years following diagnosis, median American College of Rheumatology (ACR) functional class was 2 [1.5-3.0], Health Assessment Questionnaire (HAQ) score was 0.4 out of 3.0 [0.0-1.0], and manual muscle testing (MMT) score was 229 out of 260 [212.6-256.8]. Median MDI score was 6.0 [3.5-8.9], with the most commonly damaged organ systems being cutaneous and musculoskeletal. Factors associated with an elevated MDI score were the presence of erythroderma and other cutaneous manifestations, disease duration, and ACR functional class. Calcinosis was present in 55% of patients. The strongest predictors of calcinosis were disease duration, periungual capillary changes, and younger age at diagnosis. CONCLUSION: In a tertiary referral population, long-term functional outcomes of JIIM are generally favorable, with HAQ scores indicative of mild disability. Although most patients had mild disease activity and virtually all had significant disease damage, severe or systemic damage was rare. Certain clinical features are associated with long-term damage and calcinosis.

Fashionably Late: A Case of Delayed Cutaneous Manifestations in Juvenile Dermatomyositis.

Juvenile dermatomyositis (JDM) is a rare, but well recognized multi-systemic inflammatory myopathy in children defined by proximal muscle weakness and distinctive skin lesions, that if recognized and treated early result in decreased morbidity and mortality. The 1975 criteria established by Bohan and Peter center around the propensity for early development of heliotrope and Gottron's lesions in combination with specific laboratory abnormalities, and are still the leading diagnostic tool. The following case demonstrates a toddler with an atypical presentation of JDM in which delayed dermatologic manifestations hindered initial diagnosis. A previously healthy 2 years and 11 months old female presented to the emergency department with a 7-month history of bilateral knee pain and progressive muscular weakness. Initial evaluation yielded a diagnosis of idiopathic rhabdomyolysis but progressive deterioration prompted additional workup. During her course of care, the patient required admission at numerous facilities for specialty procedures including swallow studies, electromyography, Nissen fundoplication with G-tube insertion, and eventual muscle biopsy, resulting in pathology clinching the diagnosis. Post-diagnosis the development of a heliotrope and malar rash ensued, 11 months after commencement of original presentation. As the Bohan and Peter criteria of 1975 can help to aid in diagnosis of JDM for textbook presentations, atypical cases such as ours suggest that revision to current diagnostic criteria needs to be established. Also, with many pediatric rheumatologists opting for less invasive methods than muscle biopsy to aid in diagnosis, in combination with the heterogeneous nature of currently tracked serous markers, the risk for delayed or missed diagnosis is amplified. As prior research has demonstrated, early diagnosis leads to better outcomes for children battling JDM. Therefore, it is vital that criteria be revised and additional research be conducted for more sensitive and specific markers to help aid in early diagnosis of JDM.

Environmental factors associated with disease flare in juvenile and adult dermatomyositis.

Objective: The aim was to assess environmental factors associated with disease flare in juvenile and adult dermatomyositis (DM). Methods: An online survey of DM patients from the USA and Canada examined smoking, sun exposure, infections, medications, vaccines, stressful life events and physical activity during the 6 months before flares, or in the past 6 months in patients without flares. Differences were evaluated by χ 2 and Fisher's exact tests, and significant univariable results were examined in multivariable logistic regression. Residential locations before flare were correlated with the National Weather Service UV index. Results: Of 210 participants (164 juvenile and 46 adult DM), 134 (63.8%) experienced a disease flare within 2 years of the survey. Subjects more often reported disease flare after sun exposure [odds ratio (OR) = 2.0, P = 0.03], although use of photoprotective measures did not differ between those with and without flare. Urinary tract infections (OR = 16.4, P = 0.005) and gastroenteritis (OR = 3.2, P = 0.04) were more frequent in the preceding 6 months in those who flared. Subjects who flared recently used NSAIDS (OR = 3.0, P = 0.0003), blood pressure medicines (OR = 3.5, P = 0.049) or medication for depression or mood changes (OR = 12.9, P = 0.015). Moving to a new house (OR = 10.3, P = 0.053) was more common in those who flared. Only sun exposure (OR = 2.2) and NSAIDs (OR = 1.9) were significant factors in multivariable analysis. Conclusion: Certain classes of environmental agents that have been associated with the initiation of DM, including sun exposure and medications, may also play a role in disease flares.