Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10-8) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.

Towards development of treat to target (T2T) in childhood-onset systemic lupus erythematosus: PReS-endorsed overarching principles and points-to-consider from an international task force.

OBJECTIVES: Application of 'treat-to-target' (T2T) in childhood-onset systemic lupus erythematosus (cSLE) may improve care and health outcomes. This initiative aimed to harmonise existing evidence and expert opinion regarding T2T for cSLE. METHODS: An international T2T Task Force was formed of specialists in paediatric rheumatology, paediatric nephrology, adult rheumatology, patient and parent representatives. A steering committee formulated a set of draft overarching principles and points-to-consider, based on evidence from systematic literature review. Two on-line preconsensus meeting Delphi surveys explored healthcare professionals' views on these provisional overarching principles and points-to-consider. A virtual consensus meeting employed a modified nominal group technique to discuss, modify and vote on each overarching principle/point-to-consider. Agreement of >80% of Task Force members was considered consensus. RESULTS: The Task Force agreed on four overarching principles and fourteen points-to-consider. It was agreed that both treatment targets and therapeutic strategies should be subject to shared decision making with the patient/caregivers, with full remission the preferred target, and low disease activity acceptable where remission cannot be achieved. Important elements of the points-to-consider included: aiming for prevention of flare and organ damage; glucocorticoid sparing; proactively addressing factors that impact health-related quality of life (fatigue, pain, mental health, educational challenges, medication side effects); and aiming for maintenance of the target over the long-term. An extensive research agenda was also formulated. CONCLUSIONS: These international, consensus agreed overarching principles and points-to-consider for T2T in cSLE lay the foundation for future T2T approaches in cSLE, endorsed by the Paediatric Rheumatology European Society.

Principles of pediatric lupus nephritis in a prospective contemporary multi-center cohort.

Lupus nephritis (LN) is a life-threatening manifestation of systemic lupus erythematosus (SLE) and is more common in children than adults. The epidemiology and management of childhood-onset SLE (cSLE) have changed over time, prompting the need to reassess expected outcomes. The purpose of this study is to use the Childhood Arthritis and Rheumatology Research Alliance (CARRA) prospective registry to validate historical principles of LN in a contemporary, real-world cohort. After an extensive literature review, six principles of LN in cSLE were identified. The CARRA registry was queried to evaluate these principles in determining the rate of LN in cSLE, median time from cSLE diagnosis to LN, short-term renal outcomes, and frequency of rituximab as an induction therapy. Of the 677 cSLE patients in the CARRA registry, 32% had documented LN. Decline in kidney function was more common in Black cSLE patients than non-Black patients (p = 0.04). Black race was associated with worse short-term renal outcomes. In short-term follow up, most children with LN had unchanged or improved kidney function, and end stage kidney disease (ESKD) was rare. Ongoing follow-up of cSLE patients in the CARRA registry will be necessary to evaluate long-term outcomes to inform risk, management, and prognosis of LN in cSLE.

Tackling global challenges in pediatric rheumatology.

PURPOSE OF THE REVIEW: To highlight the current challenges in diagnosis and clinical care of pediatric rheumatic disease and barriers to research and education of pediatric rheumatologists worldwide. RECENT FINDINGS: Recent studies and reports demonstrate a paucity of studies on epidemiology, outcomes, and management guidelines from many regions of the world. There have been noteworthy efforts to bridge the gap in under resourced areas. An analysis of the global burden of rheumatic disease has demonstrated that while understudied, musculoskeletal diseases are prevalent and increasingly contribute to loss of years of healthy life. In juvenile idiopathic arthritis, two milestone publications in global pediatric rheumatology have recently been published. An international study evaluated the epidemiology, treatment, and outcomes of juvenile idiopathic arthritis and demonstrated global diversity in both clinical manifestations and outcomes. Notably, the first guidelines for managing pediatric rheumatic disease in a less resourced setting have been published for juvenile idiopathic arthritis. This document offers the first publication targeted to address challenges faced by pediatric rheumatology caregivers in low-resourced settings. These documents serve as exemplars for international collaboration in pediatric rheumatology and can be used as models for other pediatric rheumatic disease research. Other efforts are making progress in various arenas towards increasing access to care, education, and training in pediatric rheumatology. SUMMARY: The global burden of rheumatic disease in the pediatric population is poorly understood but unrecognized disease greatly impacts the overall morbidity and mortality in this population. More studies in lesser resourced regions are needed to prioritize access to pediatric rheumatology care and prioritize a further increase in research capacity and education moving forward.

Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016.

OBJECTIVE: To determine trends in survival among adult and paediatric patients with systemic lupus erythematosus (SLE) from 1950 to the present. METHODS: We performed a systematic literature review to identify all published cohort studies on survival in patients with SLE. We used Bayesian methods to derive pooled survival estimates separately for adult and paediatric patients, as well as for studies from high-income countries and low/middle-income countries. We pooled contemporaneous studies to obtain trends in survival over time. We also examined trends in major causes of death. RESULTS: We identified 125 studies of adult patients and 51 studies of paediatric patients. Among adults, survival improved gradually from the 1950s to the mid-1990s in both high-income and low/middle-income countries, after which survival plateaued. In 2008-2016, the 5-year, 10-year and 15-year pooled survival estimates in adults from high-income countries were 0.95, 0.89 and 0.82, and in low/middle-income countries were 0.92, 0.85 and 0.79, respectively. Among children, in 2008-2016, the 5-year and 10-year pooled survival estimates from high-income countries were 0.99 and 0.97, while in low/middle-income countries were 0.85 and 0.79, respectively. The proportion of deaths due to SLE decreased over time in studies of adults and among children from high-income countries. CONCLUSIONS: After a period of major improvement, survival in SLE has plateaued since the mid-1990s. In high-income countries, 5-year survival exceeds 0.95 in both adults and children. In low/middle-income countries, 5-year and 10-year survival was lower among children than adults.

Update on cardiovascular disease in lupus.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE) and cannot be fully explained by traditional cardiovascular risk factors. Recent immunologic discoveries have outlined putative pathways in SLE that may also accelerate the development of atherosclerosis. RECENT FINDINGS: Aberrant innate and adaptive immune responses implicated in lupus pathogenesis may also contribute to the development of accelerated atherosclerosis in these patients. Defective apoptosis, abnormal lipoprotein function, autoantibodies, aberrant neutrophil responses, and a dysregulated type I interferon pathway likely contribute to endothelial dysfunction. SLE macrophages have an inflammatory phenotype that may drive progression of plaque. SUMMARY: Recent discoveries have placed increased emphasis on the immunology of atherosclerotic cardiovascular disease. Understanding the factors that drive the increased risk for cardiovascular disease in SLE patients may provide selective therapeutic targets for reducing inflammation and improving outcomes in atherosclerosis.

Barriers and facilitators to medical care retention for pediatric systemic lupus erythematosus in South Africa: a qualitative study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a life-threatening, chronic, autoimmune disease requiring long term subspecialty care due to its complex and chronic nature. Childhood-onset SLE (cSLE) is more severe than adult-onset, and the cSLE population in South Africa has been reported to have an even higher risk than patients elsewhere. Therefore, it is critical to promptly diagnose, treat, and manage cSLE. In this paper, we aim to describe and evaluate barriers and enablers of appropriate long-term care of cSLE South Africa from the perspective of caregivers (parents or family members). METHODS: Caregivers (n = 22) were recruited through pediatric and adult rheumatology clinics. Individuals were eligible if they cared for youth (≤ 19 years) who were diagnosed with cSLE and satisfied at least four of the eleven ACR SLE classification criteria. Individual in-depth, semi-structured interviews were conducted between January 2014 and December 2014, and explored barriers to and facilitators of ongoing chronic care for cSLE. Data were analyzed using applied thematic analysis. RESULTS: Four barriers to chronic care engagement and retention were identified: knowledge gap, financial burdens, social stigma of SLE, and complexity of the South African medical system. Additionally, we found three facilitators: patient and caregiver education, robust support system for the caregiver, and financial support for the caregiver and patient. CONCLUSION: These findings highlight multiple, intersecting barriers to routine longitudinal care for cSLE in South Africa and suggest there might be a group of diagnosed children who don't receive follow-up care and are subject to loss to follow-up. cSLE requires ongoing treatment and care; thus, the different barriers may interact and compound over time with each follow-up visit. South African cSLE patients are at high risk for poor outcomes. South African care teams should work to overcome these barriers and place attention on the facilitators to improve care retention for these patients and create a model for other less resourced settings.

Barriers and facilitators to medical care retention for pediatric systemic lupus erythematosus in South Africa: a qualitative study.

Background: Systemic lupus erythematosus (SLE) is a life-threatening, chronic, autoimmune disease requiring long term subspecialty care due to its complex and chronic nature. Childhood-onset SLE (cSLE) is more severe than adult-onset, and the cSLE population in South Africa has been reported to have an even higher risk than patients elsewhere. Therefore, it is critical to promptly diagnose, treat, and manage cSLE. In this paper, we aim to describe and evaluate barriers and enablers of appropriate long-term care of cSLE South Africa from the perspective of caregivers (parents or family members). Methods: Caregivers (n=22) were recruited through pediatric and adult rheumatology clinics. Individuals were eligible if they cared for youth (≤19 years) who were diagnosed with cSLE and satisfied at least four of the eleven ACR SLE classification criteria.Individual in-depth, semi-structured interviews were conducted between January 2014 and December 2014, and explored barriers to and facilitators of ongoing chronic care for cSLE. Data were analyzed using applied thematic analysis. Results: Four barriers to chronic care engagement and retention were identified: knowledge gap, financial burdens, social stigma of SLE, and complexity of the South African medical system. Additionally, we found three facilitators: patient and caregiver education, robust support system for the caregiver, and financial support for the caregiver and patient. Conclusion: These findings highlight multiple, intersecting barriers to routine longitudinal care for cSLE in South Africa and suggest there might be a group of diagnosed children who don't receive follow-up care and are subject to attrition. cSLE requires ongoing treatment and care; thus, the different barriers may interact and compound over time with each follow-up visit. South African cSLE patients are at high risk for poor outcomes. South African care teams should work to overcome these barriers and place attention on the facilitators to improve care retention for these patients and create a model for other less resourced settings.

The inequity of global healthcare in pediatric rheumatology.

In pediatric rheumatology, global health inequity relates to the uneven distribution of healthcare resources, accessibility, and health outcomes among children with rheumatic conditions across various countries, regions, and socioeconomic groups. This inequity can manifest in various ways. This review article provides an overview of common rheumatic diseases, such as juvenile idiopathic arthritis and systemic lupus erythematosus, which significantly contribute to and are affected by disparities in global healthcare. Subsequently, we delve into the inequalities in accessing patient care, encompassing issues related to diagnosis and treatment. Additionally, we address challenges in educational advancement and identify research gaps within the field of pediatric rheumatology. We also reveal successful global collaborations, such as a Global Task Force for Pediatric Musculoskeletal Health and special working groups among international organizations, aimed at bridging the disparities gap. Through these efforts, we try to enhance understanding, cooperation, and resource allocation to ensure equal access to quality care worldwide for children with rheumatic conditions. Futhermore, we present a case study from Thailand, highlighting their successful initiatives in developing pediatric rheumatology within their healthcare system.

Renal Response Outcomes of the EuroLupus and National Institutes of Health Cyclophosphamide Dosing Regimens in Childhood-Onset Proliferative Lupus Nephritis.

OBJECTIVE: We compared clinical characteristics and renal response in patients with childhood-onset proliferative lupus nephritis (LN) treated with the EuroLupus versus National Institutes of Health (NIH) cyclophosphamide (CYC) regimen. METHODS: A retrospective cohort study was conducted at 11 pediatric centers in North America that reported using both CYC regimens. Data were extracted from the electronic medical record at baseline and 3, 6, and 12 months after treatment initiation with CYC. To evaluate the adjusted association between CYC regimen (EuroLupus vs NIH) and renal response over time, generalized estimating equations with a logit link were used. An interaction between time and CYC regimen was included, and a contrast between CYC regimens at 12 months was used to evaluate the primary outcome. RESULTS: One hundred forty-five patients (58 EuroLupus, 87 NIH) were included. EuroLupus patients were on average older at the start of current CYC therapy, had longer disease duration, and more commonly had relapsed or refractory LN compared with the NIH group. After multivariable adjustment, there was no significant association between CYC regimen and achieving complete renal response at 12 months (odds ratio [OR] of response for the EuroLupus regimen, reference NIH regimen: 0.76; 95% confidence interval [CI] 0.29-1.98). There was also no significant association between CYC regimen and achieving at least a partial renal response at 12 months (OR 1.35, 95% CI 0.57-3.19). CONCLUSION: Our study failed to demonstrate a benefit of the NIH regimen over the EuroLupus CYC regimen in childhood-onset proliferative LN. However, future prospective outcome studies are needed.

Lack of association between folate receptor autoantibodies and conotruncal congenital heart defects.

Conotruncal cardiac defects are partially prevented by maternal folic acid supplementation. However, the biochemical mechanism is unknown. Maternal autoantibodies to folate receptors, previously associated with increased risk for neural tube defects, also may account for this effect. This study aimed to examine the titers of folate receptor-blocking autoantibodies in mothers of children with conotruncal congenital heart defects and to compare them with those in the general population. Serum samples were obtained from 22 women whose pregnancies were complicated by conotruncal congenital heart malformations. Groups of samples were analyzed for autoantibodies against [(3)H] folic acid-labeled folate receptors, quantitative amounts of immunoglobulin G (IgG) and IgM autoantibodies to the folate receptor, and for ability to block-bind folic acid to receptors. No elevated levels of antibodies binding to [(3)H] folic acid-labeled folate receptors were found. No difference was found in antifolate receptor alpha-IgG or IgM median levels between cases (261 vs. 240 µg/mL) and control subjects (773 vs. 924 µg/mL). There was no increased blocking of folic acid binding between cases [0.69 ng/mL; 95 % confidence interval (CI), 0.006-0.01] and control subjects (0.69 ng/mL; 95 % CI, 0.003-0.013). Although epidemiologic evidence suggests that periconceptual folic acid may prevent many conotruncal congenital heart defects, the current study suggests that this effect is unlikely to be explained by the presence of maternal autoantibodies to folate receptor. These data suggest that a strategy of screening women for such autoantibodies will not identify a high-risk group of women to target for supplemental folic acid to prevent congenital heart defects.

Health Equity Implications of Missing Data Among Youths With Childhood-Onset Systemic Lupus Erythematosus: A Proof-of-Concept Study in the Childhood Arthritis and Rheumatology Research Alliance Registry.

OBJECTIVE: Health disparities in childhood-onset systemic lupus erythematosus (SLE) disproportionately impact marginalized populations. Socioeconomically patterned missing data can magnify existing health inequities by supporting inferences that may misrepresent populations of interest. Our objective was to assess missing data and subsequent health equity implications among participants with childhood-onset SLE enrolled in a large pediatric rheumatology registry. METHODS: We evaluated co-missingness of 12 variables representing demographics, socioeconomic position, and clinical factors (e.g., disease-related indices) using Childhood Arthritis and Rheumatology Research Alliance Registry childhood-onset SLE enrollment data (2015-2022; n = 766). We performed logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for missing disease-related indices at enrollment (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and/or Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) associated with data missingness. We used linear regression to assess the association between socioeconomic factors and SLEDAI-2K at enrollment using 3 analytic methods for missing data: complete case analysis, multiple imputation, and nonprobabilistic bias analyses, with missing values imputed to represent extreme low or high disadvantage. RESULTS: On average, participants were missing 6.2% of data, with over 50% of participants missing at least 1 variable. Missing data correlated most closely with variables within data categories (i.e., demographic). Government-assisted health insurance was associated with missing SLEDAI-2K and/or SDI scores compared to private health insurance (OR 2.04 [95% CI 1.22, 3.41]). The different analytic approaches resulted in varying analytic sample sizes and fundamentally conflicting estimated associations. CONCLUSION: Our results support intentional evaluation of missing data to inform effect estimate interpretation and critical assessment of causal statements that might otherwise misrepresent health inequities.

Childhood-Onset Lupus Nephritis in the Childhood Arthritis and Rheumatology Research Alliance Registry: Short-Term Kidney Status and Variation in Care.

OBJECTIVE: The goal was to characterize short-term kidney status and describe variation in early care utilization in a multicenter cohort of patients with childhood-onset systemic lupus erythematosus (cSLE) and nephritis. METHODS: We analyzed previously collected prospective data from North American patients with cSLE with kidney biopsy-proven nephritis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry from March 2017 through December 2019. We determined the proportion of patients with abnormal kidney status at the most recent registry visit and applied generalized linear mixed models to identify associated factors. We also calculated frequency of medication use, both during induction and ever recorded. RESULTS: We identified 222 patients with kidney biopsy-proven nephritis, with 64% class III/IV nephritis on initial biopsy. At the most recent registry visit at median (interquartile range) of 17 (8-29) months from initial kidney biopsy, 58 of 106 patients (55%) with available data had abnormal kidney status. This finding was associated with male sex (odds ratio [OR] 3.88, 95% confidence interval [95% CI] 1.21-12.46) and age at cSLE diagnosis (OR 1.23, 95% CI 1.01-1.49). Patients with class IV nephritis were more likely than class III to receive cyclophosphamide and rituximab during induction. There was substantial variation in mycophenolate, cyclophosphamide, and rituximab ever use patterns across rheumatology centers. CONCLUSION: In this cohort with predominately class III/IV nephritis, male sex and older age at cSLE diagnosis were associated with abnormal short-term kidney status. We also observed substantial variation in contemporary medication use for pediatric lupus nephritis between pediatric rheumatology centers. Additional studies are needed to better understand the impact of this variation on long-term kidney outcomes.

Pediatric Rheumatic Disease in Lower to Middle-Income Countries: Impact of Global Disparities, Ancestral Diversity, and the Path Forward.

Pediatric rheumatology subspecialists treat chronic autoimmune diseases with onset in childhood. Prompt diagnosis and ongoing management of these conditions are imperative to prevent damage from ongoing inflammation. Here, we aim to describe the current landscape of pediatric rheumatic disease in lower to middle-income countries (LMICs) and explore current barriers to understanding global disease burden. We then examine innovative strategies to promote a more equitable future for children and young people living with rheumatic diseases worldwide.

Use of EuroLupus Cyclophosphamide Dosing for the Treatment of Lupus Nephritis in Childhood-onset Systemic Lupus Erythematosus in North America.

OBJECTIVE: Childhood-onset systemic lupus erythematosus (cSLE) has higher rates of lupus nephritis (LN) than adult-onset SLE, often requiring intensive immunosuppression. This study examined North American practices and preferences for the low-dose EuroLupus cyclophosphamide (CYC) protocol, as compared to the high-dose National Institutes of Health (NIH) CYC protocol, to treat LN in cSLE. METHODS: A 35-item Web-based survey was distributed to Childhood Arthritis and Rheumatology Research Alliance (CARRA) and Pediatric Nephrology Research Consortium (PNRC) providers. The survey assessed participant demographics, CYC prescribing practices, perceptions of EuroLupus protocol, and LN vignette treatment decisions; 1 vignette was taken from a 2009 CARRA survey and responses were compared. Multivariable logistic regression analyzed provider factors associated with use of low- vs high-dose CYC. RESULTS: Responses were provided by 185/421 (44%) pediatric rheumatologists (CARRA) and 40/354 (11%) pediatric nephrologists (PNRC). Among respondents who prescribed CYC for pediatric LN over the past year (n = 135), half reported using EuroLupus. When presented with the same vignette about an adolescent with class IV LN, 32% of pediatric rheumatologists chose EuroLupus dosing in 2020, vs 6% in 2009. Provider factors associated with choosing the low-dose regimen were familiarity with the protocol (OR 4.2, P = 0.006) and greater perceived benefit (OR 1.6, P < 0.0001). Pediatric nephrologists had similar responses to the pediatric rheumatology providers. Overall, 78% of respondents perceived EuroLupus protocol efficacy to be equivalent to the high-dose protocol in cSLE LN. CONCLUSION: Pediatric specialists are currently more likely to use low-dose CYC to treat cSLE LN than they were a decade ago. Nevertheless, familiarity with EuroLupus dosing remains low.

Rheumatology capacity building: implementing a rheumatology curriculum for Liberian health-care providers in 2016.

INTRODUCTION: Liberia has no rheumatology providers for the nation's 4.7 million people. We proposed a short course format rheumatology curriculum to educate Liberian providers as an initial step in providing graduate medical education in musculoskeletal health. METHOD: A 1-week training curriculum in rheumatology encompassing introduction to musculoskeletal exam and approach to rheumatology diagnosis and management was designed. The curriculum used multiple education methods including interactive lectures, bedside training, and hands-on learning. RESULTS: A 1-week rheumatology training curriculum for 24 local physicians was feasible. The execution of the designed rheumatology curriculum in Liberia relied upon a mixed method format that was both didactic and case-based. A survey of the Liberian trainees revealed that the curriculum was salient to care of patients and barriers to optimal learning such as time and space limitations were identified. CONCLUSIONS: A 1-week rheumatology training education program is possible and relevant to local providers, but training length and setting may need to be optimized. Future training will aim to minimize barriers to education and expand the cohort of providers with rheumatologic knowledge in Liberia.Key Points• Liberia, like many nations in sub-Saharan Africa, has no trained rheumatologists to serve the nation's population.• Education and capacity building for rheumatologic care in short course format are relevant and feasible to local health-care providers.• Further efforts are needed to develop and evaluate continuing rheumatology education in Liberia.

Signal recognition particle RNA localization within the nucleolus differs from the classical sites of ribosome synthesis.

The nucleolus is the site of ribosome biosynthesis, but is now known to have other functions as well. In the present study we have investigated how the distribution of signal recognition particle (SRP) RNA within the nucleolus relates to the known sites of ribosomal RNA synthesis, processing, and nascent ribosome assembly (i.e., the fibrillar centers, the dense fibrillar component (DFC), and the granular component). Very little SRP RNA was detected in fibrillar centers or the DFC of the nucleolus, as defined by the RNA polymerase I-specific upstream binding factor and the protein fibrillarin, respectively. Some SRP RNA was present in the granular component, as marked by the protein B23, indicating a possible interaction with ribosomal subunits at a later stage of maturation. However, a substantial portion of SRP RNA was also detected in regions of the nucleolus where neither B23, UBF, or fibrillarin were concentrated. Dual probe in situ hybridization experiments confirmed that a significant fraction of nucleolar SRP RNA was not spatially coincident with 28S ribosomal RNA. These results demonstrate that SRP RNA concentrates in an intranucleolar location other than the classical stations of ribosome biosynthesis, suggesting that there may be nucleolar regions that are specialized for other functions.

Pediatric systemic lupus erythematosus patients in South Africa have high prevalence and severity of cardiac and vascular manifestations.

BACKGROUND: Pediatric onset of systemic lupus erythematosus (SLE) is associated with major organ involvement, and African patients tend to develop more aggressive disease than patients of European descent. Although cardiovascular involvement is common in pediatric SLE, there are few published reports on the subject. This study describes the frequency and characteristics of cardiac and vascular manifestations of pediatric SLE in a multi-ethnic South African cohort. METHODS: Demographic, clinical, and echocardiographic data were collected from pediatric SLE patients at two centers in Cape Town, South Africa. At the time of investigation, this cohort consisted of 93 participants diagnosed with SLE according to international classification criteria prior to the age of 19. Individuals with cardiac and/or vascular involvement were identified by retrospective chart review. Cardiac manifestations were defined as presence of pericardial effusion, myocarditis, cardiomyopathy, cardiac failure, Libman-Sacks endocarditis, myocardial infarction, and arrhythmia. Vascular manifestations included deep vein thrombosis, pulmonary embolism, sinus thrombosis, stroke, critical limb ischemia, cerebral vasculitis and systemic vasculitis. Statistical analysis was performed using R (v3.4.1). RESULTS: Cardiac and vascular involvement was present in 47% of the cohort. Previous studies have reported prevalence of 5%-50%. Demographic features of those with cardiac/vascular involvement did not differ from the overall cohort. Echocardiographic data were available for 23 participants. The most common cardiac manifestations were pericardial effusion (n = 24) and cardiac failure (n = 8), while the most common vascular manifestations were cerebral vasculitis (n = 9), stroke (n = 7), and pulmonary embolism (n = 7). Cardiovascular manifestations were frequently severe; one third of pericardial effusion cases required intervention, including three cases of cardiac tamponade. Cardiac and vascular involvement conferred an increased risk of mortality (31.1% versus 10.4%). CONCLUSIONS: Cardiac and vascular involvement were highly prevalent in this South African cohort. The mortality rate was high, and severe manifestations were frequent. Prospective research is needed to improve knowledge of pediatric SLE in Africa and to improve outcomes for this high-risk population.

Missed opportunities for timely diagnosis of pediatric lupus in South Africa: a qualitative study.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a serious multisystem autoimmune disease, which is more aggressive in children and people of African descent. In South Africa, pediatric SLE (pSLE) patients are at high risk for severe disease. Similar to pSLE worldwide, South African children and adolescents with SLE require subspecialized medical care. The aim of this study is to describe the care-seeking experiences of families and examine factors that contribute to delays in the diagnosis of pSLE. Specifically, we sought to identify factors to inform interventions that support the timely referral and diagnosis of pediatric SLE patients in South Africa. METHODS: In-depth, semi-structured interviews were conducted with 22 caregivers of pSLE patients recruited from two government hospitals in Cape Town, South Africa in 2014. Interviews were audio-recorded, transcribed, and analyzed for themes related to barriers to diagnosis. RESULTS: Six themes were identified and classified as either caregiver or health system barriers to diagnosis. Caregiver barriers included lack of knowledge regarding SLE, financial difficulties, and the social stigma of SLE. Health system barriers were lack of trained staff, a complex medical system, and misdiagnosis. CONCLUSION: Caregivers reported missed opportunities for diagnosing pSLE in their children. Raising public awareness may improve caregiver awareness and reduce stigma of pSLE. Improving family education at diagnosis holds potential to increase patient-physician trust and mitigate fear. Education modules for primary care providers at initial point of contact with the health care system may improve recognition of early pSLE and facilitate expedited referral to a specialist.