A single-center model for implementation of SLEDAI documentation adherence in childhood-onset systemic lupus erythematosus (cSLE).

BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease with variable disease expression but noted association with significant disease-related damage, morbidity, and mortality. The European Alliance of Associations for Rheumatology (EULAR) recommends routine monitoring of SLE through validated disease activity and chronicity indices, including the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Despite this, physician adherence with SLEDAI documentation remains elusive at various academic institutions. The aim of our study was to determine baseline SLEDAI documentation rates at our center and assess the change in adherence in SLEDAI documentation rate with electronic clinical decision support (CDS) reminders facilitated through the electronic medical record (EMR) over a 2-year period. METHODS: All SLE encounters over a 24-month period at a pediatric academic center were reviewed in order to obtain baseline SLEDAI documentation percentages. Physicians subsequently received monthly email reminders, initiated at month 4 of project initiation, with subsequent CDS reminder 13 months after project initiation prompted by anti-dsDNA lab result. Chart review was repeated continuously for each provider, and SLEDAI documentation rates were emailed to each provider monthly. Physicians completed a post-intervention survey regarding barriers to SLEDAI documentation at the end of the study. RESULTS: A total of 1980 SLE encounters were reviewed for this study. Baseline SLEDAI documentation rates were 10%. Following the introduction of monthly emails reminding physicians to document SLEDAI, rates increased to 55%. After the initiation of electronic in-basket reminders prompted by lab results, rates increased to 60%. Noted barriers to documentation were cited to be forgetfulness (67%) and lack of time (33%). CONCLUSION: Our study demonstrates that monthly email reminders as well as EMR-mediated electronic in-basket reminders increased SLEDAI documentation rates at an academic center. Noted barriers to documentation were reported to be forgetfulness (67%) and lack of time (33%).

Impact of follow-up adherence on disease activity in childhood-onset systemic lupus erythematosus (cSLE).

BACKGROUND/PURPOSE: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, with a potential for significant disease damage, morbidity, and mortality. In comparison to the adult population, childhood-onset SLE (cSLE) tends to be more aggressive given the higher preponderance of renal and neuropsychiatric disease and increased disease activity. There is a paucity of literature examining relationship between disease activity, rheumatology follow-up visits, and health care utilization. The objective of this study is to determine whether adherence with outpatient clinic visits would affect disease activity in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS: 41 children <18 years of age at time of diagnosis with SLE who met Systemic Lupus International Collaborative Clinics (SLICC) criteria and not evaluated in clinic within the previous 120-day period were identified as eligible for inclusion. Patients were continuously searched between December 2021 and July 2022 for eligibility evaluation. Through retrospective chart review, we assessed disease activity (SLE Disease Activity Index) at the last clinic visit. The patients were stratified into two cohorts of lower and higher disease activity, with SLE disease activity index (SLEDAI) ≤ 3 and SLEDAI ≥ 4, respectively. Descriptive statistics and Willcox Rank Sum (numerical variables) and Fisher's test (categorical variables) were used to compare these two groups. RESULTS: Clinical, epidemiological, and serological data were compared between the two groups, with observed statistically significant differences to include current use of high dose prednisone associated with higher SLEDAI scores (p = 0.019). In nonparametric analysis, time to follow-up (p < 0.001), hospitalizations (p = 0.017), and Emergency Department visits (ED) (p < 0.001) were found to be associated with higher SLEDAI scores. CONCLUSION: Our findings suggest that cSLE patients with higher disease activity are at risk for increased health care utilization with respect to ED visits as well as hospitalizations in the setting of follow-up nonadherence. While further studies are required to enhance our understanding of this association, this links the importance of disease-related outcome and routine outpatient visits in this particularly vulnerable patient population.

Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-ß (adenovirus transforming growth factor-ß) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-ß-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-ß, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.

PTPα promotes fibroproliferative responses after acute lung injury.

The acute respiratory distress syndrome (ARDS) is a major healthcare problem, accounting for significant mortality and long-term disability. Approximately 25% of patients with ARDS will develop an overexuberant fibrotic response, termed fibroproliferative ARDS (FP-ARDS) that portends a poor prognosis and increased mortality. The cellular pathological processes that drive FP-ARDS remain incompletely understood. We have previously shown that the transmembrane receptor-type tyrosine phosphatase protein tyrosine phosphatase-α (PTPα) promotes pulmonary fibrosis in preclinical murine models through regulation of transforming growth factor-ß (TGF-ß) signaling. In this study, we examine the role of PTPα in the pathogenesis of FP-ARDS in a preclinical murine model of acid (HCl)-induced acute lung injury. We demonstrate that although mice genetically deficient in PTPα (Ptpra-/-) are susceptible to early HCl-induced lung injury, they exhibit markedly attenuated fibroproliferative responses. In addition, early profibrotic gene expression is reduced in lung tissue after acute lung injury in Ptpra-/- mice, and stimulation of naïve lung fibroblasts with the BAL fluid from these mice results in attenuated fibrotic outcomes compared with wild-type littermate controls. Transcriptomic analyses demonstrate reduced extracellular matrix (ECM) deposition and remodeling in mice genetically deficient in PTPα. Importantly, human lung fibroblasts modified with a CRISPR-targeted deletion of PTPRA exhibit reduced expression of profibrotic genes in response to TGF-ß stimulation, demonstrating the importance of PTPα in human lung fibroblasts. Together, these findings demonstrate that PTPα is a key regulator of fibroproliferative processes following acute lung injury and could serve as a therapeutic target for patients at risk for poor long-term outcomes in ARDS.

Quality of life measures and physical activity in childhood systemic lupus erythematosus.

Childhood systemic lupus erythematosus (cSLE) is a life-long disease with significant morbidity and mortality, and with associated significant impact on health-related quality of life (HRQOL). Previous literature supports that physical activity has positive impact on HRQOL in patients with chronic diseases, including cSLE. We sought to describe the physical activity of our patients with cSLE and determine the relationship between physical activity, SLE activity, treatment modalities and HRQOL in cSLE. Children ≤18 years of age with cSLE and their parents were enrolled and completed corresponding child and parent Simple Measure of Impact of Lupus Erythematosus in Youngsters© reports (cSMILEY© and pSMILEY©, respectively), and the Physical Activity Questionnaire for Children (PAQ-C) or Adolescents (PAQ-A). Through retrospective chart review, we assessed the SLE Disease Activity Index (SLEDAI) using the SLEDAI-2K assessment tool. Descriptive statistics as well as Pearson's correlation coefficients were performed with the data obtained. Forty-four children and their parents were enrolled; clinical data, SMILEY© and PAQ-C or PAQ-A scores of cSLE subjects were evaluated. The most frequently reported physical activity modality was walking (61.3%), with mean frequency of 3.7 ± 1.8 days a week, and a median of 3.5 days a week. Although there was no correlation noted between treatment modalities and PAQ-C/PAQ-A, there was weak correlation between SLEDAI and PAQ-C/PAQ-A (Pearson correlation= 0.2, ρ = 0.1, p = 0.9, n = 44). There was a weak correlation between SMILEY total score and PAQ [cSMILEY© and PAQ-C/PAQ-A combined cohorts (Pearson correlation = 0.2, ρ = 0.3, p = 0.07, n = 44), and modest correlation between pSMILEY© scores and PAQ-C/PAQ-A combined cohorts (Pearson correlation = 0.3, ρ = 0.3, p = 0.05, n = 44)]. Our study emphasizes the need for larger samples to understand the prognostic value of activity levels and the extent to which increasing physical activity might be linked to improvements in HRQOL in this vulnerable population.

Protein tyrosine phosphatase-α amplifies transforming growth factor-ß-dependent profibrotic signaling in lung fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal, fibrosing lung disease for which treatment remains suboptimal. Fibrogenic cytokines, including transforming growth factor-ß (TGF-ß), are central to its pathogenesis. Protein tyrosine phosphatase-α (PTPα) has emerged as a key regulator of fibrogenic signaling in fibroblasts. We have reported that mice globally deficient in PTPα (Ptpra-/-) were protected from experimental pulmonary fibrosis, in part via alterations in TGF-ß signaling. The goal of this study was to determine the lung cell types and mechanisms by which PTPα controls fibrogenic pathways and whether these pathways are relevant to human disease. Immunohistochemical analysis of lungs from patients with IPF revealed that PTPα was highly expressed by mesenchymal cells in fibroblastic foci and by airway and alveolar epithelial cells. To determine whether PTPα promotes profibrotic signaling pathways in lung fibroblasts and/or epithelial cells, we generated mice with conditional (floxed) Ptpra alleles (Ptpraf/f). These mice were crossed with Dermo1-Cre or with Sftpc-CreERT2 mice to delete Ptpra in mesenchymal cells and alveolar type II cells, respectively. Dermo1-Cre/Ptpraf/f mice were protected from bleomycin-induced pulmonary fibrosis, whereas Sftpc-CreERT2/Ptpraf/f mice developed pulmonary fibrosis equivalent to controls. Both canonical and noncanonical TGF-ß signaling and downstream TGF-ß-induced fibrogenic responses were attenuated in isolated Ptpra-/- compared with wild-type fibroblasts. Furthermore, TGF-ß-induced tyrosine phosphorylation of TGF-ß type II receptor and of PTPα were attenuated in Ptpra-/- compared with wild-type fibroblasts. The phenotype of cells genetically deficient in PTPα was recapitulated with the use of a Src inhibitor. These findings suggest that PTPα amplifies profibrotic TGF-ß-dependent pathway signaling in lung fibroblasts.

Effect of collagen and elastin content on the burst pressure of human blood vessel seals formed with a bipolar tissue sealing system.

BACKGROUND: Bipolar devices are routinely used to seal blood vessels instead of sutures and clips. Recent work examining the impact of vascular proteins on bipolar seal performance found that collagen and elastin (CE) content within porcine arteries was a significant predictor of a vessel's burst pressure (VBPr). This study examined seal performance across a range of human blood vessels to investigate whether a similar relationship existed. In addition, we compared VBPr and CE content between porcine and human blood vessels. Our primary hypothesis is that higher collagen-to-elastin ratio will predict higher VBPr in human vasculature. METHODS: In six cadavers, 185 blood vessels from nine anatomic locations were sealed using a bipolar electrosurgical system. A linear mixed model framework was used to evaluate the impact of vessel diameter and CE content on VBPr. RESULTS: The effect of CE ratio on VBPr is modified by vessel size, with CE ratio having larger influence on VBPr in smaller diameter vessels. Seal burst pressure of vessels 2-5 mm in diameter was significantly associated with their CE content. Comparison of average VBPr between species revealed porcine carotid and iliac arteries (440-670 mmHg) to be the best vessel types for predicting the seal strength of most human blood vessels (420-570 mmHg) examined. CONCLUSIONS: CE content significantly modified the seal strength of small to medium sized blood vessels but had limited impact on vessels >5 mm.

Muscle activation levels of the gluteus maximus and medius during standing hip-joint strengthening exercises using elastic-tubing resistance.

CONTEXT: No published studies have compared muscle activation levels simultaneously for the gluteus maximus and medius muscles of stance and moving limbs during standing hip-joint strengthening while using elastic-tubing resistance. OBJECTIVE: To quantify activation levels bilaterally of the gluteus maximus and medius during resisted lower-extremity standing exercises using elastic tubing for the cross-over, reverse cross-over, front-pull, and back-pull exercise conditions. DESIGN: Repeated measures. SETTING: Laboratory. PARTICIPANTS: 26 active and healthy people, 13 men (25 ± 3 y) and 13 women (24 ± 1 y). INTERVENTION: Subjects completed 3 consecutive repetitions of lower-extremity exercises in random order. MAIN OUTCOME MEASURES: Surface electromyographic (EMG) signals were normalized to peak activity in the maximum voluntary isometric contraction (MVIC) trial and expressed as a percentage. Magnitudes of EMG recruitment were analyzed with a 2 × 4 repeated-measures ANOVA for each muscle (α = .05). RESULTS: For the gluteus maximus an interaction between exercise and limb factor was significant (F3,75 = 21.5; P < .001). The moving-limb gluteus maximus was activated more than the stance limb's during the back-pull exercise (P < .001), and moving-limb gluteus maximus muscle recruitment was greater for the back-pull exercise than for the cross-over, reverse cross-over, and front-pull exercises (P < .001). For the gluteus medius an interaction between exercise and limb factor was significant (F3,75 = 3.7; P < .03). Gluteus medius muscle recruitment (% MVIC) was greater in the stance limb than moving limb when performing the front-pull exercise (P < .001). Moving-limb gluteus medius muscle recruitment was greater for the reverse cross-over exercise than for the cross-over, front-pull, and back-pull exercises (P < .001). CONCLUSIONS: From a clinical standpoint there is no therapeutic benefit to selectively activate the gluteus maximus and gluteus medius muscles on the stance limb by resisting sagittal- and frontal-plane hip movements on the moving limb using resistance supplied by elastic tubing.

Secukinumab Therapy in Refractory Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA), the most common chronic rheumatologic condition in childhood, remains a cause of significant morbidity, particularly in those with spondyloarthropathy, including psoriatic arthritis (PsA) and enthesitis-related arthritis (ERA). While secukinumab was recently approved for the treatment of children and adolescents with ERA and PsA, there is limited published data on its use in JIA, particularly in refractory cases, despite its efficacy in the treatment of adult arthritis. We aim to examine the use of this therapy in JIA in a single pediatric rheumatology center. A retrospective chart review was performed and 10 JIA patients who received treatment with secukinumab were identified. Data extracted included disease activity, patient demographics, comorbidities, medications, and laboratory data. Seven ERA, 2 PsA, and 1 poly JIA patient were treated with secukinumab at our center between April 2011 and July 2021. These patients had notably resistant disease, with a mean disease-modifying antirheumatic drug (DMARD) failure rate of 3.8. One hundred percent of patients who underwent magnetic resonance imaging (MRI) after being on at least 3 months of secukinumab therapy demonstrated improvement in their MRI findings. One patient developed a flare of uveitis while on secukinumab therapy, with no other adverse events recorded in our patients. Secukinumab therapy was recently approved for children and adolescents with ERA and PsA, and may offer an efficacious option given its demonstrated improvement in imaging and joint examination, as well as qualitative reports of pain, even in those who have failed other therapies. However, caution may be warranted in those with a history of uveitis and warrants further study.

COVID-19 after rituximab therapy in cSLE patients.

Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease associated with significant morbidity and mortality. Rituximab is a B-cell depleting therapy utilized in the treatment of SLE. In adults, rituximab has been associated with increased risk of adverse outcomes in patients who develop coronavirus disease 2019 (COVID-19). We aimed to assess the impact of prior rituximab treatment on clinical outcomes from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in children with SLE. To describe the impact of rituximab on outcomes from SARS-CoV-2 infection, we conducted a retrospective study of pediatric SLE patients in our center diagnosed with COVID-19 who had previously received rituximab between February 2019 and October 2022. Patients' clinical characteristics, disease activity, and outcomes were assessed. Of the eight subjects assessed, five required hospitalizations for COVID-19, four required ICU admission, and two were seen in the emergency department for their symptoms. One patient ultimately expired from her illness. The median time between rituximab administration and COVID-19 diagnosis was 3 months. We assessed the clinical outcomes, including the need of ICU admission and fatal outcome, of COVID-19 in our cSLE patient population after rituximab administration. Approximately 60% of our patients required hospitalization for their illness, and seven out of eight patients required healthcare utilization to include hospitalization and/or emergency department visits.

Presentation of SLE after COVID vaccination in a pediatric patient.

BACKGROUND: The outbreak of severe acute respiratory syndrome coronavirus 2 has had an enormous impact on global health. Vaccination remains one of the most effective interventions for disease prevention. Clinically significant vaccine side effects are uncommon, though autoimmune-mediated disease occurs in a small percentage of vaccine recipients. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with significant morbidity and mortality. Childhood-onset SLE tends to have more severe disease manifestations than adult-onset SLE. In adults, there are a few reported cases of SLE developing soon after coronavirus disease 2019 (COVID-19) mRNA vaccination. CASE PRESENTATION: A 14-year-old previously healthy male developed laboratory and clinical evidence of SLE, including maculopapular malar rash, arthritis, pleuritic chest pain, and class V (membranous) lupus nephritis, 2 days after his third dose of the Pfizer-BioNTech COVID-19 vaccine. The patient's symptoms improved after initiation of prednisone and mycophenolate mofetil. We also summarize eleven prior case reports describing SLE after COVID-19 vaccine in adults. CONCLUSION: To our knowledge, this is the first reported pediatric patient with new onset SLE following COVID-19 mRNA vaccination. While potential mechanistic links exist between COVID-19 vaccination and SLE development, additional studies are necessary to elucidate the exact nature of this relationship.

Clinical Determinants of Childhood Onset Systemic Lupus Erythematosus among Early and Peri-Adolescent Age Groups.

Introduction: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with significant morbidity and mortality. SLE disproportionately affects women and minorities. Childhood-onset SLE (cSLE) in particular tends to be more aggressive than adult-onset SLE. Despite substantial improvements in the treatment of cSLE, there is significant variability in treatment responses and long-term outcomes. Furthermore, there is a paucity of studies involving cSLE, and in particular, cSLE among different age groups. The aim of this study was to test the hypothesis that an early-onset cSLE cohort would demonstrate unique characteristics with distinctive clinical and laboratory features at disease onset. We specifically investigated whether clinical, epidemiological, or serological factors are differentially associated with early- and late-onset cSLE. This could have direct impact on clinical management with the goal of improving outcomes and quality of life for children with SLE. Methods: Our study was conducted at a large tertiary center. We included 213 subjects seen at our pediatric rheumatology clinic aged 4−17 years. Epidemiologic, clinical phenotype, disease severity, serology, treatment, and outcome data were compared between subjects with cSLE onset prior to 10 years of age (early-onset disease, n = 43) and those with cSLE onset greater than 10 years of age (peri-adolescent disease, n = 170). We compared clinical features between early- and peri-adolescent onset cSLE in order to investigate the association between age at disease onset of cSLE and clinical disease expression and outcomes. Results: Of the 213 subjects with cSLE in our study, 43 subjects had early-onset disease (age 2 to ≤9 years) and 170 patients had peri-adolescent onset disease. We found that early-onset cSLE was associated with a higher prevalence of positive anti-dsDNA antibody at cSLE diagnosis, higher anti-dsDNA antibody titer at cSLE diagnosis, rash, and azathioprine use (p < 0.001, p = 0.004, p = 0.011, and p = 0.008, respectively). In contrast, we found that peri-adolescent onset cSLE (≥10 years of age) was associated with worse disease activity (SLEDAI range 0−24) (p < 0.001), higher SLICC at diagnosis (p < 0.001), as well as a higher rate of mycophenolate mofetil and hydroxychloroquine use (p = 0.003 and p < 0.001, respectively). There were no significant differences in the prevalence of neuropsychiatric symptoms or the development of Class IV/Class V lupus nephritis between the early-onset and peri-adolescent groups.

Giant Coronary Aneurysms in Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 Infection.

Multisystem inflammatory syndrome in children (MIS-C) can cause a myriad of cardiac manifestations, including coronary dilation and aneurysms; giant aneurysms are infrequent. We describe 3patients with giant coronary aneurysms associated with MIS-C, including the youngest case reported to date, treated with intravenous immunoglobulin, corticosteroids, and biologic agents. (Level of Difficulty: Intermediate.).