Treat-To-Target: Emergence of Second-Generation CD40L Inhibitors for Treatment of SLE-Identifying Beneficial Patient Candidates for CD40L Inhibitors in a Cross-Sectional SLE Cohort.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterised by heterogeneous clinical manifestations and varying degrees of organ involvement. The CD40-CD40 Ligand (CD40L) pathway is implicated in autoimmune responses, with elevated levels of soluble CD40L (sCD40L) observed in SLE patients. This study investigates sCD40L as a biomarker for disease activity and its utility in stratifying patients for CD40L-targeted therapies. Plasma levels of sCD40L were quantified in SLE patients (n = 169) and healthy controls (n = 100). Correlations between sCD40L levels and disease activity measures were analysed using Spearman's correlation and logistic regression. K-means clustering grouped patients based on sCD40L concentrations, and principal component analysis (PCA) was performed to assess relationships among disease activity variables. SLE patients exhibited significantly higher sCD40L levels (median 2.2 ng/mL) than healthy controls (median 0.81 ng/mL; p = 0.0079). Elevated sCD40L levels correlated weakly with higher SLE Disease Activity Index (SLEDAI) scores (p = 0.0418), positive Anti-Nuclear Antibody status (p = 0.0133), increased IgG levels (p = 0.0148) and decreased lymphocyte counts (p = 0.0327). Clustering analysis and PCA revealed that patients with higher sCD40L levels tended to have increased disease activity, elevated anti-dsDNA antibody concentrations, and higher C-reactive protein (CRP) levels. Elevated sCD40L levels in SLE patients correlate with disease activity markers, suggesting its potential as a biomarker for monitoring disease progression and severity. Additionally, sCD40L may aid in stratifying patients who could benefit from CD40L-targeted therapies within a treat-to-target framework. Further longitudinal studies with larger cohorts are warranted to validate and explore the role of sCD40L in personalised SLE treatment strategies.