Systemic Lupus Erythematosus (SLE) is a complex autoimmune/inflammatory disease. Juvenile-onset (j)SLE affects 15-20% of lupus patients and is characterized by increased organ involvement and damage, and higher need for immune suppressive treatment. Clinical heterogeneity between ethnicities, age groups and individual patients suggest variable pathophysiology. This study aimed at the definition of patient sub-cohorts with “genetic” vs. “classical” SLE to allow individualized care.
Applying target enrichment and new generation sequencing, jSLE patients (N=348) from the UK JSLE Cohort Study were screened for disease-causing mutations. Findings were integrated with demographic information and clinical datasets, including SLEDAI, pBILAG organ domain and SLICC damage scores.
Approximately 5.5% of jSLE patients carried disease-causing mutations, primarily affecting nucleic acid sensing and metabolism (68%), immune complex clearance (11%), their combination (11%), immune cell signalling (5%) and NFκB signalling (5%). Patients with “genetic SLE” were younger, and exhibited less organ involvement and damage at diagnosis (neuropsychiatric, haematological, gastrointestinal), while neuropsychiatric involvement developed over time. When compared to the remaining cohort, “genetic SLE” associated with anti-dsDNA antibody positivity at diagnosis, and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit which may explain reduced renal and haematological involvement.
Genetic disease accounts for ≥5.5% of jSLE cases. It associates with peri-pubertal onset, and distinct immunological and clinical pictures. As less commonly present after treatment induction, in “genetic SLE”, autoantibodies may be the result of tissue damage. Routine sequencing will allow for patient stratification, risk assessment, and target-directed treatment with reduced toxicity and increased efficacy.