Abstract

Background: Childhood-onset Systemic Lupus Erythematosus (cSLE) is a chronic, severe autoimmune disorder with a risk of early organ damage[1]. Identifying paediatric-specific predictors is vital for preventing such damage. Objectives: To ascertain how clinical, demographic, and treatment variables correlate with damage accrual in cSLE. Furthermore, by stratifying patients according to average disease activity levels over the course of their disease, to identify independent predictors of damage even in patients who have low levels of disease activity. Methods: Analysis included UK JSLE Cohort Study participants diagnosed at ≤18 years and meeting ≥4 ACR 1997 classification criteria. New damage was defined as an increase in ≥1 unit in the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC SDI) score. Univariable, followed by multivariable Prentice-Williams-Peterson (PWP) gap-time models investigated how age, gender, ethnicity, time-adjusted mean prednisolone dosage, methylprednisolone exposure, time-adjusted mean Physicians Global Assessment (PGA) score, baseline organ damage, baseline renal involvement, and average disease activity influenced the hazards of new damage. Analyses were performed across the entire cohort and two subgroups based on disease activity: one with low activity, marked by a time-adjusted average SLEDAI-2K score of ≤4 (AMS ≤4) throughout the observed follow-up period, and the other with moderate-to-high activity, with an AMS >4. Results: A total of 430 patients and 4738 visits were analysed with a median follow-up period of 46 months (IQR 18-63), including a median of 10 visits per patient (IQR 5-15). Overall, 99 patients (23%) experienced organ damage during follow-up. 15 patients (3.5%) had only one recorded visit so were not included in the AMS subgroup analyses. Within the entire cohort, factors associated with damage accrual within the multivariable analyses (Table 1) were: methylprednisolone exposure (HR 2.20, [CI 1.33-3.62]; p=0.002); time-adjusted mean PGA score (HR 2.87, [CI 1.48-5.56]; p=0.002] and AMS score (HR 1.13, [CI 1.03-1.24], p=0.013). Within the low disease activity subgroup (Table 2), 40/195 (20.5%) patients accrued new damage, and multivariable analysis demonstrated the following factors to be associated with damage accrual: methylprednisolone exposure (HR 2.61, [CI 1.04-6.53]; p=0.040) and time-adjusted mean PGA score (HR 3.41, [CI 1.52-7.76]; p=0.003). Within the moderate/high disease activity subgroup (Table 2), 59/210 patients (28.1%) experienced damage with methylprednisolone exposure (HR 2.29, [CI 1.31-4.00]; p=0.004); time-adjusted mean PGA score (HR 2.66, [CI 1.20-5.87]; p=0.016) and AMS score (HR 1.15, [CI 1.03-1.29]; p=0.014) being significant predictors of damage. Conclusion: The study underscores methylprednisolone exposure as a significant and potentially modifiable risk factor for damage in cSLE, necessitating a review of paediatric dosage limits, which typically exceed adult recommendations[2]. Additionally, a direct link was found between disease activity and damage, with every one unit increase in SLEDAI score raising the risk of damage by 13-15% in those with moderate-to-severe activity. This was not observed in patients with AMS ≤4, suggesting that low disease activity, maintained via treat-to-target strategies, could substantially reduce damage risk. This highlights the need for updated treatment protocols that limit corticosteroid use whilst managing disease activity effectively. REFERENCES: [1] Lythgoe, H., et al., Prospective epidemiological study of juvenile-onset Systemic Lupus Erythematosus in the United Kingdom and Republic of Ireland. Rheumatology (Oxford), 2022. [2] Gordon, C., et al., The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology, 2018. 57(1): p. e1-e45. Acknowledgements: The authors would like to acknowledge all patients and their families for participating in the UK JSLE Cohort Study. Specifically, we are grateful to all the support given by all principal investigators and the entire multi-disciplinary team within each of the paediatric centres who are part of the UK JSLE Study Group (https://www.liverpool.ac.uk/translational-medicine/research/ukjsle/jsle/). This study was supported by the UK's 'Experimental Arthritis Treatment Centre for Children' (supported by Versus Arthritis, the University of Liverpool and Alder Hey Children's NHS Foundation Trust), the Medical Research Foundation and the Royal College of Physicians Wolfson Award. Disclosure of Interests: None declared.