Introduction

Childhood-onset systemic lupus erythematosus (cSLE) is a systemic autoimmune disease with no known cure. Approximately one in every five patients has disease onset in childhood years. The patients with onset in childhood years have more severe disease and worse outcomes [1]. Individuals with cSLE acquire more organ damage than adult counterparts, despite having fewer comorbidities [2]. Although this patient group is at high risk for early mort

ality and morbidity, [3] there is a paucity of research on this population. Here, we summarize recent global advances in cSLE, summarized according to geographic region. Additionally, we acknowledge that many health disparities align across higher incomes countries (HIC) in the Global North (defined as North America, Europe, Israel, Japan, South Korea, New Zealand and Australia,) and lower to middle income countries (LMIC) in the Global South (broadly comprised of Africa, Asia excluding Japan and South Korea, and the South Pacific excluding Australia and New Zealand) [4]. We describe challenges to cSLE research in different settings, and outline a path forward towards addressing gaps in cSLE care and research globally.

Recent Advances in cSLE by Region 

Asia–Pacific

The Asia–Pacific region is home to approximately 4.3 billion people, (about 60% of the world’s population) and about 25% are children under 15 years of age [5]. Despite a lack of robust epidemiologic studies defining the incidence or prevalence of cSLE in Asia, more than 100,000 children are estimated to have lupus in the Asia–Pacific region [6]. Asian children are more likely to have oral ulcers and neuropsychiatric disease, [7] and have higher disease activity at presentation, possibly due to delay in diagnosis [8]. Damage accrual is comparable to that found in patients with cSLE in the United Kingdom [9]. In Southeast Asia, age of cSLE onset is similar to reports from high income countries (HIC) (with some regional differences), [10] but patients exhibit severe disease, with high disease activity scores, high rates of proliferative lupus nephritis (LN), and other organ involvement. An Australian retrospective longitudinal cohort study of patients with cSLE reported higher rates of SLE in the Indigenous population, high prevalence of LN (64%) and high rates of organ damage [11].

Management of cSLE in Asia–Pacific regions remains a challenge. Recent data from Thailand showed that only 47% of children achieved low lupus disease activity state (LLDAS) after 12 months of treatment, [9] while in India it was achieved by 57.7% of children enrolled in an inception cohort, [12] indicating a huge gap remains in achieving treat-to-target in all patients. Infections, including bacterial, viral and mycobacterial infections, are a major issue in managing patients as they are significant contributors to morbidity and mortality [13]. Mortality in the region is higher than in HIC, but some regions have shown improvement in recent years. However, infections remain the leading cause of mortality in this population. For patients with severe LN who progress to end-stage kidney disease (ESKD), the high cost of renal replacement therapy in low to middle income countries (LMIC) makes this therapy inaccessible to many patients. Lack of access to therapy further increases the mortality due to nephritis in these areas [14].

Recently, important advances in translational research have come from the Asia–Pacific region. In a recent analysis of more than 35,000 SLE patients GWAS data from European and Han Chinese ancestry it was revealed that many loci confer SLE susceptibility across ancestry, but some are specifically seen in Asian patients. A novel SLC23A9 intronic variant was disease associated in Han Chinese SLE patients [15]. This variant impairs lysosomal function and may lead to increased TLR signaling, which has been recognized in many recent studies as pivotal to cSLE pathogenesis [16]. The Asia–Pacific region is ancestrally diverse, therefore dedicated genomic and translational studies which focus on the various populations in this region are needed.

Africa

The African continent is home to almost 1.5 billion diverse individuals. Despite evidence worldwide that lupus is more common and more severe in people of African ancestry, there are fewer cases reported of childhood or adult-onset lupus from Africa compared to Europe and North America [17]. This lack of reporting reflects the lack of access to appropriate care for diagnosis and testing rather than a true lack of disease, and those of us working on the continent know that the burden of lupus in Africa is large and severely underestimated [18]. Diagnostic challenges are widespread across the continent [19]. A systematic review of LN diagnosis revealed less than 20% of studies used the recommended LN classification criteria, with better reporting and survival noted in the North African countries [19].

Data on SLE in Africa primarily comes from adult populations. The largest study to date, a meta-analysis of 896 in-hospital adult-onset SLE (aSLE) cases from 15 studies in sub-Saharan Africa, estimates an in-hospital prevalence of 1.7% for lupus [20]. The mean age of SLE onset in this analysis was 28 years, younger than in the Northern hemisphere. Infection still poses a major survival threat to lupus patients in sub-Saharan Africa: in a recent study reported a 43% mortality rate among lupus patients admitted, almost all deaths were due to infections and renal disease [21]. Other risk factors associated with death included fever, disease flare, musculoskeletal involvement, and depression [21]. A recent review and meta-analysis on the global tuberculosis (TB) incidence and prevalence in individuals with SLE noted an increased prevalence in regions. with a high TB burden, like Africa [22]. Extra pulmonary TB (EPTB) patients were significantly younger, developed TB sooner after SLE diagnosis, and had more active disease compared to pulmonary TB (PTB) patients [22].

There are even fewer studies of childhood-onset lupus than adult-onset in Africa, largely limited to small case series and case reports [23, 24]. The pediatric SLE (PULSE) cohort in South Africa, one of the largest established cohorts of individuals with cSLE in Africa to date, reports patients have a similar mean age of diagnosis and female predominance compared to those reported from North America. Notably, individuals with cSLE in this cohort had high disease activity, multi-organ involvement at diagnosis and significant disease damage at enrollment [25,26,27], suggesting delays in diagnosis. Qualitative studies in South Africa and Ghana reported caregivers of lupus patients face challenges including lack of exposure or awareness of the disease, financial hardships, and the social stigma of SLE. Health system barriers to an cSLE diagnosis were identified as lack of rheumatology informed healthcare workforce, a complexity of the medical system, and misdiagnosis [26, 28, 29]. Similar issues were reported in Kenya, revealing gaps in pediatric rheumatology knowledge amongst healthcare workers that contribute to delayed diagnosis and suboptimal management [30].

The formation of The Pediatric Society of the African League Against Rheumatism(PAFLAR) represents an important advance for cSLE research in Africa [31]. PAFLAR offers opportunities among African health workers treating children with rheumatic and musculoskeletal diseases to collaborate and disseminate information and improve the outcomes for patients. PAFLAR facilitates learning and collaboration through monthly educational webinars with a hybrid, synchronous and asynchronous learning platform, an annual hybrid congress uniting experts, healthcare professionals, and stakeholders in the field from over 73 countries across 5 continents, and the PAFLAR registry, which creates the opportunity to collect multi-center standardized data across the African continent. While in the early stages, this registry lays the foundation for future clinical and translational cSLE projects. PAFLAR has patient-centered care as a focus, highlighted in a pioneer project of Therapeutic Patient Education (TPE) for children with rheumatic disease across different regions in Africa. The PAFLAR efforts highlight the advances that can be made through collaborative efforts by leaders in Africa.

While there are few clinical studies which focus on cSLE in Africa, there are even fewer translational research studies from this region. A collaborative, multinational study on the genetics of cSLE included patients from South Africa, and identified many novel, rare SLE risk variants, supporting evidence from HIC that cSLE patients are enriched in rare variants [32].

South America

South America, with 447 million people ( almost half of whom live in Brazil), consists of 13 countries, with important differences in economics and healthcare access between regions [33]. There are no comprehensive studies on cSLE prevalence and incidence across South America. Some countries including Brazil and Argentina have pediatric rheumatologists, but other countries still lack any pediatric rheumatology providers [34].

The Brazilian Multicenter Group of Children and Adolescents with Pediatric Systemic Lupus Erythematosus (Brazilian Childhood-onset SLE Registry Group) is an observational cohort, with 1528 patients with cSLE from 27 university centers in Brazil [35]. They reported higher disease activity associated with earlier age of onset of lupus (< 6 years) in this cohort. Patients with cSLE in this cohort had higher rates of LN and neuropsychiatric SLE, and higher mortality rates than in HIC [36]. The main causes of death in this cohort were infections (sepsis and opportunistic infections) and alveolar hemorrhage. Patients with ESKD and central nervous system (CNS) SLE had a higher mortality risk, likely due to the severe disease and intense immunosuppression increasing infection susceptibility. Patients with cSLE with positive dsDNA, low C3, and proteinuria were at risk for early-onset LN, increased morbidity, and higher mortality [37]. In those with LN, 5.4% developed chronic kidney disease (CKD); those with proliferative LN on biopsy and CKD had lower survival rates [36]. Axonal dysfunction in patients with cSLE in Brazil correlated with levels of interferon (IFN)-γ and symptoms of depression. Measuring axonal dysfunction may be a way to predict NP-SLE [38]. Although the Brazilian Childhood-onset SLE Registry Group is a large multicenter cohort, they represent a single country and cannot be assumed to represent all of South America or other areas of the world. Individuals with cSLE in this region are more likely to have 1st and 2nd degree relatives with SLE than aSLE patients, supporting enrichment of genetic drivers of disease in this population [39]. More dedicated genomic and translational studies in South America are needed to explore the biologic drivers of cSLE in this population.

Europe

Europe, though smaller in geographical area and population than Asia, Africa, or South America, has many HIC with access to pediatric rheumatology care and research. A significant recent advance in cSLE clinical studies of cSLE is the development of Treat-to-target (T2T) strategies for cSLE. Interest in adopting T2T approaches is growing on a global scale for both cSLE [40,41,42,43,44,45] and aSLE [46]. Extensive validation of T2T endpoints in aSLE has demonstrated improved outcomes, including reduced organ damage [47,48,49,50,51,52], fewer flares [53], glucocorticoid sparing [50, 53], improved quality of life [54], and lower healthcare costs [55], though no randomized trials have assessed the efficacy of this approach. The UK’s TARGET LUPUS© research program has been established to develop T2T strategies for cSLE [40, 41]. An International cSLE T2T Task Force, including cSLE experts from the principle professional networks (PReS, CARRA, UK JSLE) across six continents. Together the Task Force has developed ‘principles and points to consider for cSLE T2T’, endorsed by the Paediatric Rheumatology European Society (PReS) [56]. They have also created consensus based, age-appropriate target definitions, including Childhood Lupus Low Disease Activity State (cLLDAS), cSLE clinical remission on steroids (cCR), and cSLE clinical remission off steroids (cCR-0) [57]. These definitions sufficiently align with the aSLE definitions, while incorporating changes to improve applicability to cSLE [57]. Future efforts are needed to validate cSLE T2T endpoints.

The Treatment Response Measure for SLE (TRM-SLE) Taskforce is developing a new clinical outcome assessment (COA) for SLE clinical trials to capture treatment effects that hold clinical significance for both patients and practitioners, aiming to serve as a trial endpoint conducive to regulatory endorsement of new SLE treatments. This COA addresses the historical challenges of gauging meaningful treatment responses in SLE, as legacy disease activity metrics did not originate within a clinical trial setting and did not integrate substantial patient input in their design, as contemporary COA guidelines recommend [58, 59].

Emphasizing a life-course approach, the TRM-SLE Task Force has incorporated pediatric rheumatologists in its steering committee and workgroups to ensure the inclusion of pediatric perspectives in defining measurement goals, selecting assessments, and establishing consensus on domain scoring and treatment response criteria. This strategy aims to help to expedite the available treatments for younger patients, who often experience more severe disease trajectories and outcomes, thereby addressing a critical gap in therapeutic development [60]. By designing the TRM-SLE with inherent suitability for both cSLE and aSLE populations, the initiative is poised to enhance methodological robustness in aSLE and cSLE trials, increasing the likelihood of their success, and ensuring that trial endpoints are relevant and applicable across the patient lifespan [58, 59].

There have been numerous advances in cSLE translational research, specifically genomics, in Europe in recent years [61,62,63,64,65]. Gene variants regulating Type I IFNs have are important in the pathogenesis of cSLE; including those associated with primary and secondary interferonopathies [61]. Elevated Type I IFN levels induce autoantibody production and switch the production of non-neutralizing to neutralizing antibodies [62]. One study identified pathogenic genetic variants in 3.5% of a UK cSLE cohort, with 75% of those genes modifying Type I IFN production [63]. Dedicator of cytokinesis 11 (DOCK11) variants, causing deficiency of DOCK11 and disturbance of platelet morphology, have been reported in eight French patients with cSLE [64]. Variants in Protein kinase C delta (PRKCD) have been implicated in cSLE development, [66] with a recent study demonstrating that these variants upregulate the PI3K/mTOR pathway [65].

A Netherlands-based study has used targeted multiomics to stratify patients with cSLE into different biological phenotypes. This pilot study of 17 patients with cSLE employed unsupervised hierarchical clustering and high-dimensional flow cytometry to identify three unique clusters characterized by different sets of genes, cytokines, and disease activity states [67]. It is crucial that patients from ethnically and ancestrally diverse backgrounds are included in future translational cSLE studies to fully advance understanding of cSLE, with validation of results in ethnically distinct patient cohorts. CSLE studies have the disadvantage of being relatively small compared to adult studies. Collaborative efforts, such as the British-French studies investigating the genetics of cSLE cohorts, [68] are encouraging, but further work is required in larger, more diverse patient populations.

North America

Similar to Europe, a small share of the world’s pediatric population resides in North America, but this region is well-resourced with better access to clinical care and research than regions in LMIC. Despite these resources, children with SLE in North America continue to be a high-risk population. The most severe disease manifestations such as LN and neuropsychiatric lupus (NP SLE) are ongoing research priorities in cSLE [69]. Individuals with cSLE are at risk for lupus nephritis. In the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry, 32% of children with lupus had renal disease [70]. Black patients were more likely to have progression of renal disease over the 2 year follow up period, but the role of systemic inequity could not be analyzed properly in this retrospective report. Another study reported male patients or those with older age at disease onset were more likely to have abnormal kidney function in short-term follow up, although a large variation was observed [71]. Patients with LN who require hospitalization are at high risk for readmission, with nearly 20% readmitted after discharge [72]. NP SLE is more common in cSLE, with more prevalent depression, anxiety and cognitive dysfunction in cSLE than unaffected peers of the same age, [73] which can affect medication adherence and quality of life [74, 75]. Cardiovascular disease is an important driver of SLE mortality. Abnormal blood pressure has been identified as an important predictor of renal damage and cardiac disease. Loss of the physiologic dipping of nocturnal blood pressure is prevalent in cSLE and is associated with atherosclerotic changes [76]. Patients with cSLE are at higher risk for heart failure, with hypertension and cardiac involvement likely important contributors to this risk [77].

Health disparities have been reported in individuals with cSLE, and mirror those of aSLE, where Black and Hispanic patients have higher morbidity and mortality than White counterparts [78]. Systemic racism affects health outcomes across all diseases, and SLE is no different. Inequitable inclusion in registries and clinical trials and lack of data can exacerbate existing disparities [79]. The adolescent period is a vulnerable time, as patients who are undergoing developmental stages of adolescence which include rebellion and concrete thinking often struggle with adhering to medications. The transition time, where patients must change from pediatric to adult care, has been identified as high-risk period for delays or lapses in care, culminating in disease flare [80,81,82].

Childhood-onset SLE patients, with early age of onset and more severe disease, may be a population enriched in genetic risk variants. Common variant studies have demonstrated that individuals with cSLE have similar or increased number of common SLE risk variants when compared to adult-onset patients, with some variation in ancestry [83]. Other studies have found differing associations with age of onset and association with common variants inside and outside the HLA region [84]. Many studies have reported an enrichment of rare, damaging SLE risk variants in cSLE cohorts, [32] with rates of 10–13% of cohorts when investigating with next generation sequencing [85]. Additional studies are needed to identify both known and novel risk genes in cSLE cohorts.

Optimizing treatment remains challenging in cSLE, due to highly heterogenous disease presentations with a lack of reliable predictors of prognosis or flares. Few clinical trials have focused on cSLE, and children/adolescent patients are infrequently included in adult clinical trials. Therefore, treatment protocols are often extrapolated from adult trials, and refined with case series or observational data. Cyclophosphamide (CYC) remains an important therapy for the severe manifestations such as NPSLE and LN. Recently, it was reported that pediatric rheumatologists were familiar with EuroLupus dosing regimens of CYC, and are using this more frequently than a decade ago [86]. A multicenter retrospective study did not find significant differences between EuroLupus or NIH protocol in children and adolescents with SLE [87]. Prospective trials with proper randomization are needed to compare these regimens. A retrospective study of 21 patients with cSLE from a single center revealed that individuals who received belimumab were able to reduce glucocorticoid dose [88]. Few patients in the study had lupus nephritis, but this trend may change over time. In the past few years, anti- CD-19 chimeric antigen receptor (CAR) T therapy has emerged as an exciting new therapy for refractory SLE patients [89]. These cells target eliminate CD-19 positive B cells, including pathogenic autoreactive B cells, and have demonstrated sustained remission in refractory patients [90]. While it has not yet been studied in patients who are below the age of 18, many of these refractory patients in the initial case series had age of onset before 18, again demonstrating the high severity of cSLE. These studies may provoke researchers to consider this therapy for very severe patients who are not yet adult age. Long term data about the risks and benefits will help to guide this decision.

Shared Challenges in Caring for Individuals with cSLE

Access to Care

There is no region of the world that has sufficient access to pediatric rheumatology for cSLE care [91,92,93]. Many areas of the world with the greatest number of pediatric individuals have few or no pediatric rheumatology providers [94]. In LMIC, musculoskeletal diseases are not a priority among the non-communicable leading to a lack of government funding [95]. Furthermore, access to proper cSLE diagnosis and therapy usually occurs in tertiary care hospitals in major urban centers, which translates to long travel distance for specialist care [29, 96, 97]. (Fig. 1A) This increases the cost of care as well as the indirect cost of travel and loss of wages. Even in tertiary care centers, limits of access to diagnostics and high out of pocket cost of medications and diagnostics limit access to equitable care for cSLE [98]. Large travel distances, lack of access to trained rheumatologists, affordable diagnostics and medicines all create barriers to SLE diagnosis and follow-up care, which can translate to permanent damage for individuals with cSLE (Fig. 1A) [99, 100].

Fig. 1
figure 1

A Barriers to equitable access to care and research fir childhoof onset SLE patients worldwide. B Faciliatators of equitable access to care and research for childhood-onset SLE patients worldwide. Figure created with BioRender.com

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Even when there is a trained pediatric rheumatologist in a region, sustained training to ensure access to care can be difficult. Sole providers are often overwhelmed with clinical demands, making it difficult to establish a formal training program as there is little time or funding for these efforts. Most pediatric rheumatology trainees are found in countries with large rheumatology workforces, reflecting the need for a critical mass of providers to sustain clinical training. limited exposure to pediatric rheumatology during medical school and pediatric training hinders development of a sustainable pediatric rheumatology workforce [101]. The absence of a local training program, the cost and burden of extended travel for fellowship training impede the development of the pediatric rheumatology workforce (Fig. 1A).

Limited data from patients with cSLE globally hinders understanding of the true burden and impact of cSLE. Key obstacles include: patients with cSLE are a smaller patient population than aSLE, and few multicenter prospective studies or clinical trial have been executed in this population. The lack of research training and infrastructure in LMIC remains a barrier to advancing cSLE research [102]. Inconsistent data collection methods, at the regional, national and international level, impede comparative studies. Lack of sustained research funding in LMICs further restricts advancing research, even if there are trained physician scientists in the region. There is enormous phenotypic and genetic diversity in Africa, the Asia–Pacific, and South America, and the lack of inclusion of diverse patients in lupus research decreases the global odds of meaningful translational research discovery. Inclusive research encompassing diverse geographic and ancestral diversity of patients with cSLE is crucial for efficient and economical use of research funding to investigate lupus.

Solutions

Training

Training of medical graduates and pediatric postgraduates in early recognition of cSLE is important. These efforts would include, but not be limited to, training of medical students, family physicians, and pediatricians in the primary health care network in cSLE, with focus on early recognition and diagnosis, and referral to specialized centers for appropriate treatment. This training can be implemented by medical schools, courses or training given by pediatric rheumatologists, or promoted by local or regional rheumatology associations/leagues such as APLAR, PAFLAR, PANLAR, EULAR, and CARRA (Fig. 1B) [103, 104]. These courses should be periodic until they reach all first-line health care workers who may care for individuals with childhood-onset systemic lupus erythematosus. Interval courses for general pediatricians and general practitioners can be supported with online education such as the open access virtual training website Pediatric Musculoskeletal Matters [96] which provides training resources in many languages for healthcare providers caring for patients with rheumatic disease. Additionally, dedicated programs and funding for training pediatric rheumatologists in underserved regions are needed.

Access to Care

Access to care can be improved at many levels. We should create region-specific guidelines for diagnosis, management, and referral, as well as educational programs related to symptom identification, therapeutic strategies, and effective communication skills [105]. Diagnostic and therapeutic guidelines and algorithms are developed and tested in HIC (including USA and Europe), based on patient phenotypes and access to care that may differ greatly from many LMIC. We need to report cSLE cases worldwide so that we may include children from LMIC in global data and develop and test diagnostic and treatment protocols tailored to these patients and their context. Recently, guidelines for juvenile arthritis in less resourced settings were published, and a similar effort in cSLE is recommended by this group [106]. Training, as described above, is a critical piece of sustainable access to care [25, 26]. Healthcare systems should be bolstered to improve affordable healthcare and access to well-developed multi-disciplinary care [105].

A strategy practiced in LMIC sites (namely India) that deserves further study is using expensive tests sparingly (at time of flare or suspected infection) to reduce cost. Other low-cost studies (urine studies, blood pressure monitoring) could be made available in or near home followed by teleconsultation. Telehealth can improve access to care and should be used in combination with occasional in-person visits, tailored for disease activity, travel burden, and patient preference (Fig. 1B) [107]. The authors recognize the need for study of pragmatic approaches to care which is the currently reality for many settings. These protocols should consider availability of medications in the setting, and region-specific risks. Some examples of such management may include studying the use of low-cost therapies, and using minimal steroids to reduce infection rates as infection load is higher in certain areas, such as those with endemic tuberculosis [108]. We continue to advocate for equitable cSLE care, and advocate for policies and programs that will enable equity. Equitable care does not mean universal guidelines, but rather location-specific guidelines that provide optimal care for the setting.

In addition, we need to establish robust referral pathways for better utilization of resources.

Raising awareness in the general public may improve awareness of patients and caregivers and mitigate some stigma of cSLE [25, 26]. Improving education about SLE at diagnosis holds potential to increase caregiver-physician trust and lower fear [25, 26]. Proposed patient interventions to be considered include social support in addition to education [105]. Community interventions that can be implemented include outreach awareness campaigns, mobilizing monetary support for patients’ care, and mobilizing patients to access diagnostic and therapeutic interventions [105].

Access to Research

One of the biggest challenges for lupus in less resourced settings is to recognize and report cases to advocate for the allocation of resources for care and research. Improving awareness and training among healthcare professionals at all levels would improve diagnosis, reporting, and create data to inform governments when allotting healthcare budgets [102]. National registries such as CARRA, PAFLAR, JIR, and UKSLE have made progress at the regional level. Recently, a team of cSLE experts convened to create infrastructure to harmonize registries across the world [109]. We call on the international lupus research community to support the inclusion of children from LMIC in global grant applications and lupus research. Funding such large registries will allow practitioners to understand cSLE natural history and factors that lead to poor outcomes in historically understudied areas. Further, we call upon policy makers and funders to create a strong and varied mechanism for funding global SLE research. We advocate for ensuring research priorities in LMIC are determined by researchers from these locations, with robust and sustained funding support which recognizes local expertise [110]. Understanding the longitudinal outcome of systemic lupus erythematosus across different countries through research and data can elucidate the role of genetics, environmental exposures, and other factors in the progression of the disease [21].

Conclusions

cSLE is a chronic, organ and life-threatening disease which begins before adulthood and confers a high risk of early mortality. The literature review of cSLE by region highlights the disparity in clinical and translational research from high-, middle-, and low-income settings. We call upon the global pediatric rheumatology community to create funding and infrastructure to begin to provide access to care and research for all children with SLE, regardless of location.