Juvenile-onset systemic lupus erythematosus (JSLE)
JSLE (commonly referred to as Childhood Lupus) is a chronic autoimmune disease in children that can affect any part of the body including skin, joints and other major organs. Between 15-20% of lupus patients develop the disease in childhood.
Despite advances in our understanding of JSLE, the exact underlying causes remain unknown. Based on the facts that disease activity is higher, organ complications are more common and severe, and gender distribution is distinctly different in children when compared to adults. It is striking that diagnosis and treatment are based on observations in adult SLE patients.
The EATC4Children’s Lupus workstream seeks to understand the genetics and disease mechanisms underpinning lupus, develop novel biomarkers for early diagnosis of the disease, and improve our care and understanding of this complex condition. Together, these studies lay the foundation for stratified medicine and approaches and individualisation of care in paediatric lupus, leveraging both clinical patterns and molecular signatures to optimise outcomes through more personalised care.
Alder Hey in Liverpool was the UK’s first LUPUS UK Centre of Excellence for Children and Young People. It provides the highest level of specialist care to children and adolescents across the region. Their department is leading in paediatric research with links to all major centres across the UK and around the world.
The UK JSLE Study Group
The EATC4Children supports and coordinates the whole of the UK JSLE Study Group. Started in 2006, it is a multi-disciplinary team of over 140 clinicians, nurses, health professionals, translational scientists, Masters and PhD students and clinical trainees, all focussed on improving the care and our understanding of lupus in children and young people.
UK JSLE Cohort Study and Repository
The EATC4Children is the national coordinating centre for the UK JSLE Cohort Study and Repository (CI: Professor Beresford), exploring the clinical and immunopathological characteristics of this disease and fostering a robust translational programme of research directed towards clinical trials in lupus. It recruits children and young people from over 20 centres across the UK, collecting detailed clinical and outcome data from clinics enabling identification of characteristics of lupus in children and young people and drivers of disease progression.
Improved knowledge of disease mechanism will help to identify potential targets for possible new drugs and the identification of new biomarkers of disease activity.
Through the UK JSLE Cohort Study and Repository, we have undertaken detailed clinical phenotyping to identify drivers of disease progression. For example, our recent multicentre study identified corticosteroid exposure and persistent disease activity as key contributors to long-term organ damage in children with lupus, highlighting the importance of longitudinal clinical data in risk stratification.
Genetic, Epigenetic and Transcriptomic Profiling in Childhood Lupus
Our Laboratory programme integrates clinical and molecular phenotyping to build tools for patient stratification, identification of biomarkers and guide individualised care. It is led by Professor Hedrich and builds on the strength of the UK JSLE Cohort and Repository.
Large-scale genetic sequencing, epigenomic profiling and their integration with clinical datasets help us to derive genetic risk scores (rare and common variants) and epigenetic signatures that predict clinical phenotypes, treatment responses and outcomes. This has helped us to discover previously unappreciated disease mechanisms mediated by both rare and common variants in SLE-associated genes. Several recent key outcomes include:
- We demonstrated that type I interferon–associated epistasis may underlie early disease-onset and high disease activity in jSLE
- We showed that HLA risk haplotypes and associated complement C4 deficiency, as well as ‘common’ variants in TLR7 differentially contribute to disease expression and phenotypes across ancestral groups, supporting ancestry-informed patient stratification and care
- For the first time, we have established that genetic variation around SLE-associated genes inversely corelated with age at onset, disease severity, and organ involvement in jSLE in an ancestry-specific manner.
Treat-to-Target and identification of related biomarkers (Treat-to-Target)
Dr Eve Smith and Professor Beresford lead our TARGET LUPUS programme, which integrates data science, biomarker discovery, and international collaboration to improve outcomes for children and young people with Lupus. We lead the International Treat-to-Target Task Force, a global collaboration of leaders in childhood lupus, developing international consensus on the principles and framework for Treat-to-Target in children and young people with Lupus.
Our Treat-to-Target programme is determining the parameters for Treat-to-Target in children of disease activity status to reduce subsequent disease flare or organ damage, and developing an approach to dual target identification, along with our patient partners. Aligned with this are studies of advance our molecular phenotyping strategy to define biological subtypes of childhood lupus that predict disease activity state and treatment responses. This work is a major step toward biomarker-supported T2T strategies in childhood lupus.
NEPHROTARGET is an important study assessing the steps needed to implement Treat-to-Target in clinical practice. It is also testing novel disease‐monitoring tools including urine biomarkers and nailfold capillaroscopy. It is jointly led by Liverpool and Manchester. It aims to refine monitoring and guide treatment escalation in renal lupus, in accordance with Treat-to-Target principles.