Concomitant sickle cell disease and systemic lupus erythematosus: A single-center case series.

Sickle cell disease (SCD) and systemic lupus erythematosus (SLE) are two uncommon disorders each characterized by multisystemic manifestations. Individuals with SCD exhibit abnormalities in the complement pathway, which may predispose patients to develop autoimmune disorders such as SLE. As many manifestations of SLE mimic those of SCD, diagnosis and therapeutic management of SLE in a patient with known SCD may be delayed. In this study, we describe our institutional experience of diagnosing and managing concomitant SCD and SLE. We offer insights into the complex interplay between these conditions to enhance early recognition and effective management of concurrent SCD and SLE.

Pediatric Rheumatology Care and Outcomes Improvement Network's Quality Measure Set to Improve Care of Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To describe the selection, development, and implementation of quality measures (QMs) for juvenile idiopathic arthritis (JIA) by the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN), a multihospital learning health network using quality improvement methods and leveraging QMs to drive improved outcomes across a JIA population since 2011. METHODS: An American College of Rheumatology-endorsed multistakeholder process previously selected initial process QMs. Clinicians in PR-COIN and parents of children with JIA collaboratively selected outcome QMs. A committee of rheumatologists and data analysts developed operational definitions. QMs were programmed and validated using patient data. Measures are populated by registry data, and performance is displayed on automated statistical process control charts. PR-COIN centers use rapid-cycle quality improvement approaches to improve performance metrics. The QMs are revised for usefulness, to reflect best practices, and to support network initiatives. RESULTS: The initial QM set included 13 process measures concerning standardized measurement of disease activity, collection of patient-reported outcome assessments, and clinical performance measures. Initial outcome measures were clinical inactive disease, low pain score, and optimal physical functioning. The revised QM set has 20 measures and includes additional measures of disease activity, data quality, and a balancing measure. CONCLUSION: PR-COIN has developed and tested JIA QMs to assess clinical performance and patient outcomes. The implementation of robust QMs is important to improve quality of care. PR-COIN's set of JIA QMs is the first comprehensive set of QMs used at the point-of-care for a large cohort of JIA patients in a variety of pediatric rheumatology practice settings.

Preventing Teen Pregnancies on Teratogenic Drugs by Quality Improvement and Behavioral Economics.

BACKGROUND: Adolescents with chronic disease engage in sexual activity similar to their healthy peers, with generally low utilization of contraception. Adolescents with rheumatic diseases prescribed teratogenic medications may be at risk for unplanned pregnancy. METHODS: Using structured quality improvement (QI) methods with behavior economic (BE) principles, a multidisciplinary team aimed to implement pregnancy prevention processes for females on high-risk medications. We leveraged BE-inspired interventions including improved accessibility of consents, utilizing distinctly colored consent forms, real-time reminders, peer comparison, and audit and feedback. Our primary aim was to increase the number of days between pregnancies for postmenarcheal females followed in rheumatology clinics who were taking teratogenic medications. Phase 1 focused on annual consenting of female adolescents prescribed teratogenic drugs. Phase 2 emphasized sexual history screening and pregnancy prevention planning at every clinic visit for females ≥12 years on teratogenic medications. RESULTS: We increased the days between pregnancies for female adolescents prescribed teratogenic medications from 52 days to >900 days by using QI methodology with BE strategies. In phase 1, annual consents for postmenarcheal patients on teratogenic medications improved from 0% in 2017 to 95% in 2021. In phase 2, sexual history screening and pregnancy prevention planning at every clinic visit improved from 2% in 2019 to over 78% in 2021. CONCLUSIONS: A multiphase, multidisciplinary QI project with integration of behavior economic strategies can improve patient and caregiver counseling to prevent unplanned pregnancies for adolescents on teratogenic medications.

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Kawasaki Disease.

OBJECTIVE: To provide evidence-based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists. METHODS: Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel. RESULTS: We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment-refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high-risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted. CONCLUSION: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Kawasaki Disease.

OBJECTIVE: To provide evidence-based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists. METHODS: Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel. RESULTS: We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment-refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high-risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted. CONCLUSION: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.

Translating research into practice-implementation recommendations for pediatric rheumatology; Proceedings of the childhood arthritis and rheumatology research alliance 2020 implementation science retreat.

The translation of research findings into clinical practice is challenging, especially fields like in pediatric rheumatology, where the evidence base is limited, there are few clinical trials, and the conditions are rare and heterogeneous. Implementation science methodologies have been shown to reduce the research- to- practice gap in other clinical settings may have similar utility in pediatric rheumatology. This paper describes the key discussion points from the inaugural Childhood Arthritis and Rheumatology Research Alliance Implementation Science retreat held in February 2020. The aim of this report is to synthesize those findings into an Implementation Science Roadmap for pediatric rheumatology research. This roadmap is based on three foundational principles: fostering curiosity and ensuring discovery, integration of research and quality improvement, and patient-centeredness. We include six key steps anchored in the principles of implementation science. Applying this roadmap will enable researchers to evaluate the full range of research activities, from the initial clinical design and evidence acquisition to the application of those findings in pediatric rheumatology clinics and direct patient care.

Implementation Science in Pediatric Rheumatology: A Path to Health Equity.

Implementation science is the study of processes that promote reliable uptake of evidence-based practices into clinical care. The integration of implementation science and health disparities research approaches has been proposed as a method to reduce health inequity through detection, understanding, and implementation of health equity-focused interventions. In this review, we provide an argument for the study of implementation science in pediatric rheumatology in light of previously observed health disparities, present a framework for the study of health equity and implementation science in pediatric rheumatology, and propose next steps to accelerate action.

Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series.

BACKGROUND: Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. CASE PRESENTATION: We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). CONCLUSIONS: In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

Exploring Pediatric Tele-Rheumatology Practices During COVID-19: A Survey of the PRCOIN Network.

Healthcare providers were rapidly forced to modify the way they practiced medicine during the coronavirus disease 2019 (COVID-19) pandemic. Many providers transitioned from seeing their patients in person to virtually using telemedicine platforms with limited training and experience using this medium. In pediatric rheumatology, this was further complicated as musculoskeletal exams typically require hands-on assessment of patients. The objective of this study was to examine the adoption of telemedicine into pediatric rheumatology practices, to assess its benefits and challenges, and to gather opinions on its continued use. A survey was sent to the lead representatives of each Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) site to collect data about their center's experience with telemedicine during the COVID-19 pandemic. Quantitative data were analyzed using descriptive statistics, and qualitative data were thematically analyzed. Responses were received from the majority [19/21 (90%)] of PR-COIN sites. All respondents reported transitioning from in-person to primarily virtual patient visits during the COVID-19 pandemic. All centers reported seeing both new consultations and follow-up patients over telemedicine. Most centers reported using both audio and video conferencing systems to conduct their telemedicine visits. The majority of respondents [13/19 (68%)] indicated that at least 50% of their site's providers consistently used pediatric Gait Arms Legs and Spine (pGALS) to perform active joint count assessments over telemedicine. Over half of the centers [11/19 (58%)] reported collecting patient-reported outcomes (PROs), but the rate of reliably documenting clinical components varied. A few sites [7/19 (37%)] reported performing research-related activity during telemedicine visits. All centers thought that telemedicine visits were able to meet providers' needs and support their continued use when the pandemic ends. Benefits reported with telemedicine visits included convenience and continuity of care for families. Conversely, challenges included limited ability to perform physical exams and varying access to technology. Pediatric rheumatology providers were able to transition to conducting virtual visits during the COVID-19 pandemic. Healthcare providers recognize how telemedicine can enhance their practice, but challenges need to be overcome in order to ensure equitable, sustainable delivery of quality and patient-centered care.

Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): a framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group.

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. There is considerable heterogeneity in management strategies and a lack of evidence-based treatment guidelines. Consensus treatment plans (CTPs) are standardized treatment regimens that are derived based upon best available evidence and current treatment practices that are a way to enable comparative effectiveness studies to identify optimal therapy and are less costly to execute than randomized, double blind placebo controlled trials. The purpose of this project was to develop CTPs and response criteria for PFAPA. METHODS: The CARRA PFAPA Working Group is composed of pediatric rheumatologists, infectious disease specialists, allergists/immunologists and otolaryngologists. An extensive literature review was conducted followed by a survey to assess physician practice patterns. This was followed by virtual and in-person meetings between 2014 and 2018. Nominal group technique (NGT) was employed to develop CTPs, as well as inclusion criteria for entry into future treatment studies, and response criteria. Consensus required 80% agreement. RESULTS: The PFAPA working group developed CTPs resulting in 4 different treatment arms: 1. Antipyretic, 2. Abortive (corticosteroids), 3. Prophylaxis (colchicine or cimetidine) and 4. Surgical (tonsillectomy). Consensus was obtained among CARRA members for those defining patient characteristics who qualify for participation in the CTP PFAPA study. CONCLUSION: The goal is for the CTPs developed by our group to lead to future comparative effectiveness studies that will generate evidence-driven therapeutic guidelines for this periodic inflammatory disease.

Previsit Planning Improves Pneumococcal Vaccination Rates in Childhood-Onset SLE.

BACKGROUND: Childhood-onset systemic lupus erythematosus (c-SLE) is a complex autoimmune disease that requires systemic immunosuppressive therapy. Infections are the second leading cause of death in these patients, with invasive pneumococcal infections being a major preventable cause of morbidity and mortality. Pneumococcal vaccination is recommended in this population; however, vaccination rates remain low. METHODS: The plan-do-study-act method of quality improvement was applied. We calculated baseline vaccination rates for pneumococcal conjugate and pneumococcal polysaccharide vaccines in patients with c-SLE in the rheumatology clinic from January 2015 to August 2016. We developed an age-based algorithm to simplify the vaccination guidelines. The clinical pharmacist and nurses performed weekly previsit planning to update vaccine records, make targeted recommendations, and ensure vaccine availability. The primary outcome measure was the percentage patients with of c-SLE seen per month who had received age-appropriate pneumococcal vaccination. RESULTS: The percentage of children receiving at least 1 pneumococcal vaccine increased from 24.9% to 92.7% by 12 months. By 18 months, the compliance rate with both pneumococcal vaccines increased from 2.5% to 87.3%, with sustained results. No serious adverse events or disease flares were reported. CONCLUSIONS: By identifying the major barriers to pneumococcal vaccination in our population with c-SLE, we significantly improved vaccination rates while decreasing time burden on providers. We attribute our success to a team-based quality improvement approach and plan to implement alerts in the electronic health record to streamline the process.

Using the Electronic Medical Record to Correlate Kawasaki Disease Phenotypes With Clinical Outcomes.

BACKGROUND: We sought to systematically standardize the documentation of clinical and laboratory features in Kawasaki disease (KD) on the day of initial treatment and correlate the presentation with clinical outcomes. METHODS: Kawasaki disease features and classification were documented by the attending physician using a standardized documentation tool on the day of treatment for KD, including confidence in the KD diagnosis on a 4-point scale. Incomplete KD was further classified using American Heart Association (AHA) criteria (sufficient or insufficient) and baseline echocardiogram data. We prospectively recorded intravenous immunoglobulin (IVIG) resistance, coronary artery abnormalities (CAAs), periungual peeling, and retrospectively identified subsequent diagnoses of autoimmune/inflammatory disease. RESULTS: From November 2012 to October, 2015, 162 patients were treated for KD: 105 with complete KD (Group 1), 7 with incomplete KD based on CAAs on day of KD diagnosis (Group 2), 23 with incomplete KD meeting AHA criteria (Group 3), and 27 with incomplete KD and insufficient AHA criteria (Group 4). Group 4 patients had lower baseline median C-reactive protein levels (Group 4 median 4.65 mg/dL [interquartile range {IQR}, 2.3-13.6] vs Group 1 median 8.0 mg/dL [IQR, 4.5-17], Group 2 median 13.9 mg/dL [IQR, 1.4-18.2], Group 3 median 13.3 mg/dL [IQR, 4.9-20.2]), and no coronary abnormalities developed, although 11% had IVIG resistance. Group 4 had higher rates of subsequent autoimmune/inflammatory conditions diagnosed (11.1% in Group 4 vs <5% for all others, P = .02). CONCLUSIONS: Standardized documentation and classification of KD features may be useful to correlate with clinical outcomes, including subsequent diagnosis of autoimmune/autoinflammatory disease. Among patients with incomplete KD who did not meet AHA criteria and had a normal baseline echocardiogram, the IVIG resistance rate may have been related to a lower likelihood of an accurate diagnosis of KD.

Approach to Membranous Lupus Nephritis: A Survey of Pediatric Nephrologists and Pediatric Rheumatologists.

OBJECTIVE: To describe treatment practices for childhood pure membranous lupus nephritis (MLN). METHODS: Survey study of Childhood Arthritis and Rheumatology Research Alliance and American Society of Pediatric Nephrology members. RESULTS: There were 117 respondents who completed the survey (60 pediatric nephrologists, 57 pediatric rheumatologists). Steroids and nonsteroid immunosuppression (NSI) were routinely used by the majority for MLN. Mycophenolate mofetil was the favored initial NSI. Nephrologists used steroids (60% vs 93%) and NSI (53% vs 87%) less often than did rheumatologists for MLN without nephrotic syndrome (NS). CONCLUSION: Pediatric rheumatologists and nephrologists both recommend steroids and NSI for children with MLN, with or without NS.

Major infections in a cohort of 120 patients with juvenile-onset systemic lupus erythematosus.

In order to describe the incidence and characteristics of major infections in juvenile-onset systemic lupus erythematosus (jSLE), we studied a cohort of 120 patients (51% Hispanic and 28% African American, 49% with renal involvement and 12% with neuropsychiatric manifestations). There were 101 major infections affecting 44 patients (37%) for an incidence of 169/1000 patient-years of follow-up. Active disease at jSLE diagnosis, renal involvement, neuropsychiatric manifestations, higher cumulative dose of prednisone, and treatment with cyclophosphamide or mycophenolate mofetil were all associated with major infection (p<0.05). By logistic regression, the combined effect of treatment with cyclophosphamide and cumulative dose of prednisone was associated with major infection (p=0.04). Two patients died, one due to cytomegalovirus infection. Major infection was associated with damage (p=0.004). In conclusion, in a large cohort of jSLE patients, major infections were common, were associated with active disease and its treatment, and resulted in noteworthy morbidity.

Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus.

OBJECTIVE: To formulate consensus treatment plans (CTPs) for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (SLE). METHODS: A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance after considering the existing medical evidence and current treatment approaches. RESULTS: After an initial Delphi survey (response rate = 70%), a 2-day consensus conference, and 2 followup Delphi surveys (response rates = 63-79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypical patients defined by eligibility characteristics, and included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized dosages for 6 months. Additionally, the CTPs describe 3 options for standardized use of glucocorticoids, including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be candidates for the treatment with the CTPs. CONCLUSION: CTPs for induction therapy of proliferative LN in juvenile SLE based on the available scientific evidence and pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies for proliferative LN in juvenile SLE.

Current and novel therapeutics in the treatment of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant clinical heterogeneity. Recent advances in our understanding of the genetic, molecular, and cellular bases of autoimmune diseases and especially SLE have led to the application of novel and targeted treatments. Although many treatment modalities are effective in lupus-prone mice, the situation is more complex in human subjects. This article reviews the general approach to the therapy of SLE, focusing on current approved therapies and novel approaches that might be used in the future.

Variants of ST8SIA1 are associated with risk of developing multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios (affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS.

A novel frameshift mutation of FOXC2 gene in a family with hereditary lymphedema-distichiasis syndrome associated with renal disease and diabetes mellitus.

Lymphedema-distichiasis (LD) syndrome is a clinically variable autosomal dominant disorder. The disorder is caused by mutations in the forkhead transcription factor FOXC2 gene on chromosome band 16q24.3. Here, we report the sequence of the FOXC2 gene in a German-Irish family with LD in six affected relatives over three generations and identify a single adenine base pair insertion at nt 1006--1007. This insertion creates a frameshift mutation that predicts a premature stop at codon 462. In addition to LD, four of the affected family members have renal disease and three have diabetes mellitus (DM), not usually seen in the LD syndrome. Polymorphisms of FOXC2 in diabetics have been studied in different populations. Our sequence analysis of the 5' untranslated region (UTR) C-512T shows the homozygous T allele in all family members tested. The sequencing data in this family suggests the possibility of a novel phenotype-haplotype. This novel phenotype, LD/renal disease/type 2 diabetes, might be the result of a combination of the nt 1006--1007 insA and the upstream UTR homozygous T polymorphism.