Follow-up and management of serologically active clinically quiescent cases in pediatric systemic lupus erythematosus.

OBJECTIVES: Our aim is to identify the presence of serologically active clinically quiescent (SACQ) episodes in pediatric systemic lupus erythematosus (SLE) patients. We aim to identify serologic biomarkers associated with SACQ episodes and discuss risks and benefits of escalating treatments. MATERIAL AND METHODS: We evaluated 25 pediatric SLE patients, 13 of whom experienced SACQ episodes. Serologically active clinically quiescent was defined as two consecutive clinic visits without any clinical symptoms or clinical examination findings of a lupus flare with a clinical Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of zero, but either elevated anti-ds-DNA antibodies or low complement (C3 and/or C4) levels. RESULTS: Among the 13 patients who experienced a SACQ episode, there were a total of 24 episodes, with each patient experiencing 1-4 SACQ episodes. Erythrocyte sedimentation rate (ESR) was the most commonly elevated laboratory marker in a SACQ episode, followed by low hemoglobin levels, and then elevated anti-dsDNA antibodies. Of the 17 episodes treated during a SACQ episode, 15 (88%) did not progress to a clinical flare within six months, while two did. Furthermore, of the 7 patients who were not treated during their SACQ episode, 2 (29%) continued to be SACQ without flare, whereas 5 led to a clinical flare within six months. CONCLUSIONS: Serologically active clinically quiescent episodes were identified in pediatric SLE patients, suggesting that the presence of SACQ is not limited to adults with SLE. Serologic markers such as increased ESR, hemoglobin, and elevated anti-dsDNA antibodies are preliminarily associated with pediatric SACQ episodes. Treating these SACQ episodes in pediatric SLE patients was less likely to lead to a clinical flare within six months when compared to not treating (p < 0.05). More research with a larger sample size is needed to define SACQ episodes, determine the prevalence in pediatric SLE patients, and establish SACQ treatment guidelines.

COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; revisiting the Western New York approach as the pandemic evolves.

Multisystem inflammatory syndrome of children (MIS-C) continues to be a highly concerning diagnosis in those recently infected with SARS-CoV-2. The diagnosis of MIS-C cases will likely become even more challenging as vaccine uptake and natural immunity in previously infected persons leads to lower circulating rates of SARS-CoV-2 infection and will make cases sporadic. Febrile children presenting with cardiac dysfunction, symptoms overlapping Kawasaki disease or significant gastrointestinal complaints warrant a thorough screen in emergency departments, urgent care centers, and outpatient pediatric or family medicine practices. An increased index of suspicion and discussion regarding higher level of care (transferring to pediatric tertiary care centers or to intensive care) continues to be recommended. Herein we outline a broad approach with a multidisciplinary team for those meeting the case definition and believe such an approach is crucial for successful outcomes.

Response to treatment with intra-articular triamcinolone hexacetonide and triamcinolone acetonide in oligo articular juvenile idiopathic arthritis.

BACKGROUND: Oligo-articular juvenile idiopathic arthritis (Oligo JIA) is the most common subtype of juvenile idiopathic arthritis. Intra-articular corticosteroid (IAC) injection is a mainstay treatment of oligo JIA providing pain relief, improving mobility and preventing further joint destruction in the majority of patients. In 2015, production of triamcinolone hexacetonide (TH) an intra-articular corticosteroid was discontinued in the United States leading to use of triamcinolone acetonide (TA) as an alternative. In this study, we compared response to treatment in children with oligo JIA who underwent therapy with intra-articular TA and TH injection. METHODS: Our study is a retrospective chart review of children with oligo JIA who were treated with IAC injections with TH between January 2012 and June 2015 and TA between J uly 2015 and December 2018. The two groups were followed at John R. Oishei Children's Hospital of Buffalo and were evaluated for response to treatment, side effects and predictors of response including duration of disease before treatment, erythrocyte sedimentation rate (ESR), and c-reactive protein (CRP). Response to treatment was defined as at least 6 months follow up without evidence of active arthritis in injected joints. Patients were considered to be non-responders if they continued to show active arthritis during their first follow up after joint injection. The primary objective was to evaluate whether there was a significant difference in rate of response between TH and TA. RESULTS: Forty-nine patients, 38 female and 11 male with oligo JIA were included in the study. The average age was 6.7 years. A total of 111 joints were injected includin g 78 knees, 13 ankles, 9 wrists, 4 hips, 4 elbows, 2 TMJ and one subtalar joint. In the TA group, 49% (29/59) did not show response to injection compared to 27% (14/52) in the TH group. After 6 months, response rates were better for individuals injected with TH compared to TA (73% vs. 51%). In general, response to intra-articular TH was superior to TA with P = .016 using chi-square test of independence. This difference in outcome was not influenced by other variables such as duration of illness before treatment (P value 0.784) or elevated ESR and CRP. No difference in side effects between the two groups were noted. CONCLUSION: Our results in conjunction with prior published data suggests that TH intra-articular joint injection in oligo JIA is superior to TA, although future controlled trials are necessary for confirmation. An effective, long lasting treatment can have a great impact on the outcome of these children.

CD4+ T cells from children with active juvenile idiopathic arthritis show altered chromatin features associated with transcriptional abnormalities.

Juvenile idiopathic arthritis (JIA) is one of the most common chronic diseases in children. While clinical outcomes for patients with juvenile JIA have improved, the underlying biology of the disease and mechanisms underlying therapeutic response/non-response are poorly understood. We have shown that active JIA is associated with distinct transcriptional abnormalities, and that the attainment of remission is associated with reorganization of transcriptional networks. In this study, we used a multi-omics approach to identify mechanisms driving the transcriptional abnormalities in peripheral blood CD4+ T cells of children with active JIA. We demonstrate that active JIA is associated with alterations in CD4+ T cell chromatin, as assessed by ATACseq studies. However, 3D chromatin architecture, assessed by HiChIP and simultaneous mapping of CTCF anchors of chromatin loops, reveals that normal 3D chromatin architecture is largely preserved. Overlapping CTCF binding, ATACseq, and RNAseq data with known JIA genetic risk loci demonstrated the presence of genetic influences on the observed transcriptional abnormalities and identified candidate target genes. These studies demonstrate the utility of multi-omics approaches for unraveling important questions regarding the pathobiology of autoimmune diseases.

Lyme Arthritis in Children on the Uptick in Western New York Area.

OBJECTIVE: This study explores a suspected increasing incidence of Lyme arthritis in the Western New York pediatric population. In addition, we aim to describe a clinical picture of Lyme arthritis and the clinical features that distinguish it from other forms of arthritis. METHODS: Patients diagnosed with Lyme arthritis between January 2014 and September 2018 were identified using International Classification of Diseases-10th Revision (ICD 10) codes for Lyme disease and Lyme arthritis. Patients were included in the study if they (1) exhibited arthritis, (2) tested positive for Lyme antibodies, and (3) exhibited a positive Western blot. RESULTS: A total of 22 patients were included in the study. There was a general trend toward an increasing number of cases of Lyme arthritis over the 45-month observation period. We identified 1 case in each 2014 and 2015, 4 cases in 2016, 7 in 2017, and 9 in the first 9 months of 2018. In total, 17 patients had arthritis as their only symptom at the time of diagnosis and 10 patients had a rash or a history that prompted suspicion of Lyme disease. The knee was the most frequent joint (86.4% of patients), and patients typically had 2 or fewer joints affected (86.4% of patients). CONCLUSIONS: A significant increase (P = .02) in Lyme arthritis cases was observed at Oishei Children's Hospital of Buffalo. Lyme arthritis may clinically present similarly to other forms of arthritis, such as oligoarticular juvenile idiopathic arthritis, so health care providers should be aware of distinguishing clinical features, which include rapid onset of swelling and patient age. Because the geographic area of endemic Lyme disease is expanding, all health care providers need to be aware of Lyme arthritis as a possible diagnosis.

The feasibility of developing biomarkers from peripheral blood mononuclear cell RNAseq data in children with juvenile idiopathic arthritis using machine learning approaches.

BACKGROUND: The response to treatment for juvenile idiopathic arthritis (JIA) can be staged using clinical features. However, objective laboratory biomarkers of remission are still lacking. In this study, we used machine learning to predict JIA activity from transcriptomes from peripheral blood mononuclear cells (PBMCs). We included samples from children with Native American ancestry to determine whether the model maintained validity in an ethnically heterogeneous population. METHODS: Our dataset consisted of 50 samples, 23 from children in remission and 27 from children with an active disease on therapy. Nine of these samples were from children with mixed European/Native American ancestry. We used 4 different machine learning methods to create predictive models in 2 populations: the whole dataset and then the samples from children with exclusively European ancestry. RESULTS: In both populations, models were able to predict JIA status well, with training accuracies > 74% and testing accuracies > 78%. Performance was better in the whole dataset model. We note a high degree of overlap between genes identified in both populations. Using ingenuity pathway analysis, genes from the whole dataset associated with cell-to-cell signaling and interactions, cell morphology, organismal injury and abnormalities, and protein synthesis. CONCLUSIONS: This study demonstrates it is feasible to use machine learning in conjunction with RNA sequencing of PBMCs to predict JIA stage. Thus, developing objective biomarkers from easy to obtain clinical samples remains an achievable goal.

Limits of Peripheral Blood Mononuclear Cells for Gene Expression-Based Biomarkers in Juvenile Idiopathic Arthritis.

Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic disease conditions affecting children in the USA. As with many rheumatic diseases, there is growing interest in using genomic technologies to develop biomarkers for either diagnosis or to guide treatment ("personalized medicine"). Here, we explore the use of gene expression patterns in peripheral blood mononuclear cells (PBMC) as a first step approach to developing such biomarkers. Although PBMC carry many theoretical advantages for translational research, we have found that sample heterogeneity makes RNASeq on PBMC unsuitable as a first-step method for screening biomarker candidates in JIA. RNASeq studies of homogeneous cell populations are more likely to be useful and informative.

C5a induces caspase-dependent apoptosis in brain vascular endothelial cells in experimental lupus.

Blood-brain barrier (BBB) dysfunction complicates central nervous system lupus, an important aspect of systemic lupus erythematosus. To gain insight into the underlying mechanism, vascular corrosion casts of brain were generated from the lupus mouse model, MRL/lpr mice and the MRL/MpJ congenic controls. Scanning electron microscopy of the casts showed loss of vascular endothelial cells in lupus mice compared with controls. Immunostaining revealed a significant increase in caspase 3 expression in the brain vascular endothelial cells, which suggests that apoptosis could be an important mechanism causing cell loss, and thereby loss of BBB integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become 'leaky'. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (HBMVECs), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a/C5aR1-dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and pro-apoptotic proteins death-associated protein kinase 1, Fas-associated protein (FADD), cell death-inducing DNA fragmentation factor 45 000 MW subunit A-like effector B (CIDEB) and BCL2-associated X protein were increased in HBMVECs treated with lupus serum or C5a, indicating that both the intrinsic and extrinsic apoptotic pathways could be critical mediators of brain endothelial cell apoptosis in this setting. Overall, our findings suggest that C5a/C5aR1 signalling induces apoptosis through activation of FADD, caspase 8/3 and CIDEB in brain endothelial cells in lupus. Further elucidation of the underlying apoptotic mechanisms mediating the reduced endothelial cell number is important in establishing the potential therapeutic effectiveness of C5aR1 inhibition that could prevent and/or reduce BBB alterations and preserve the physiological function of BBB in central nervous system lupus.

C5a alters blood-brain barrier integrity in a human in vitro model of systemic lupus erythematosus.

The blood-brain barrier (BBB) plays a crucial role in brain homeostasis, thereby maintaining the brain environment precise for optimal neuronal function. Its dysfunction is an intriguing complication of systemic lupus erythematosus (SLE). SLE is a systemic autoimmune disorder where neurological complications occur in 5-50% of cases and is associated with impaired BBB integrity. Complement activation occurs in SLE and is an important part of the clinical profile. Our earlier studies demonstrated that C5a generated by complement activation caused the loss of brain endothelial layer integrity in rodents. The goal of the current study was to determine the translational potential of these studies to a human system. To assess this, we used a two dimensional in vitro BBB model constructed using primary human brain microvascular endothelial cells and astroglial cells, which closely emulates the in vivo BBB allowing the assessment of BBB integrity. Increased permeability monitored by changes in transendothelial electrical resistance and cytoskeletal remodelling caused by actin fiber rearrangement were observed when the cells were exposed to lupus serum and C5a, similar to the observations in mice. In addition, our data show that C5a/C5aR1 signalling alters nuclear factor-κB translocation into nucleus and regulates the expression of the tight junction proteins, claudin-5 and zonula occludens 1 in this setting. Our results demonstrate for the first time that C5a regulates BBB integrity in a neuroinflammatory setting where it affects both endothelial and astroglial cells. In addition, we also demonstrate that our previous findings in a mouse model, were emulated in human cells in vitro, bringing the studies one step closer to understanding the translational potential of C5a/C5aR1 blockade as a promising therapeutic strategy in SLE and other neurodegenerative diseases.

Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

OBJECTIVE: To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. METHODS: International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course. RESULTS: A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide. CONCLUSION: The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors.

Multiple sclerosis (MS) is a demyelinating disease of the CNS involving T cell targeting of myelin antigens. During pregnancy, women with MS experience decreased relapses followed by a post partum disease flare. Using murine experimental autoimmune encephalomyelitis, we recapitulate pregnancy findings in both relapsing and progressive models. Pregnant mice produced less TNF-α, IL-17 and exhibited reduced CNS pathology relative to non-pregnant controls. Microparticles, called exosomes, shed into the blood during pregnancy were isolated and found to significantly suppress T cell activation relative to those from non-pregnant controls. These results demonstrate the immunosuppressive potential of pregnancy and serum-derived pregnancy exosomes.

The localized scleroderma skin severity index and physician global assessment of disease activity: a work in progress toward development of localized scleroderma outcome measures.

OBJECTIVE: To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments' clinimetric property and effect on quality of life (QOL). METHODS: A 3-phase study was conducted. The first phase involved 15 patients with LS and 14 examiners who assessed LoSSI [surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E)] twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children's Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined. RESULTS: Interrater reliability was excellent for ER [intraclass correlation coefficient (ICC) 0.71], ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners' experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman's rho = 0.71-0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy. CONCLUSION: mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.

Extended cycling of combined hormonal contraceptives in adolescents: physician views and prescribing practices.

PURPOSE: We sought to determine the practices of physicians who prescribe for adolescents extended cycles of combined hormonal contraception, in which hormones are taken for longer than 21 days and menstruation is delayed. METHODS: Five hundred physicians from the membership rosters of the Society for Adolescent Medicine and the North American Society for Pediatric and Adolescent Gynecology were asked to complete an online 39-question survey. RESULTS: The 222 respondents (44% of those contacted) were mostly pediatricians (55%) and gynecologists (34%). Ninety percent reported having ever prescribed extended cycles of hormonal contraception to adolescents, and 33% said extended cycles make up more than 10% of their total combined hormonal contraceptive prescriptions. Respondents most commonly prescribed extended cycles to accommodate patients' requests to induce amenorrhea for specific events (82%) or for fewer menses per year (72%), and to treat menorrhagia (68%), dysmenorrhea (65%), and endometriosis (62%). The most commonly prescribed extended regimen was 84 continuous hormone days followed by 7 hormone-free days (46%), most often with an oral contraceptive containing 30 mug of ethinyl estradiol. Gynecologists were more likely than other physicians to prescribe extended cycles frequently, to prescribe hormone-free intervals shorter than 7 days, and to prescribe continuous regimens that eliminate the hormone-free interval completely. CONCLUSIONS: Physicians prescribe extended cycles of combined hormonal contraceptives to adolescents to accommodate patient requests and to treat common gynecologic conditions. Currently, a variety of extended cycling regimens are prescribed, suggesting that further study is needed to determine the optimal regimen for this subset of patients and their individual needs.