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Abstract
Objective Cognitive dysfunction is a characteristic yet heterogeneous feature of systemic lupus erythematosus (SLE) that can impact quality of life. In a phase 2 trial (NCT03656562) comprising two separate, placebo-controlled cohorts evaluating ianalumab and iscalimab in patients with SLE of moderate-to-severe activity, we employed Cambridge Automated Neuropsychological Test Battery (CANTAB) assessments to characterize patients’ baseline cognitive function and explore associations with clinical parameters and biomarkers associated with disease severity. Here we report baseline results, with further exploration of potential treatment effects in the ianalumab cohort.
Methods CANTAB was administered at baseline, 12 and 28 weeks. Scores indexed episodic memory, working memory, executive function and attention, normalized by age and gender relative to individuals without known cognitive dysfunction. A global composite comprised the mean of four domain scores for each assessment.
Results Baseline CANTAB scores (n=104 patients) indicated cognitive dysfunction in this sample for executive function, working memory, and global cognition (t-test for group mean <0; figure 1). Correlations between cognitive assessment scores and standard clinical (e.g., FACIT-Fatigue) and biomarker parameters of disease activity were generally low, with the highest correlation observed between global cognition and anti-Smith antibody status (r= -0.4, FDR <0.05; figure 2). Although the primary lupus disease outcome objective was met for the ianalumab treatment cohort (n=64; reported separately), we did not observe a treatment effect on CANTAB scores. In consideration of heterogenous cognitive dysfunction in SLE, we explored treatment effect heterogeneity using biomarkers and clinical parameters putatively associated with cognitive dysfunction in SLE. Here, a SomaScan® aptamer to complement component C1q showed a significant treatment interaction for working memory and executive function.
Conclusions These results are consistent with a heterogenous profile of cognitive dysfunction in SLE. However, limited association between CANTAB scores and clinical and laboratory disease markers makes clinical interpretation challenging. We did not detect an ianalumab treatment effect after 28 weeks but cannot exclude the possibility of benefit over longer treatment intervals, or detection by more frequent CANTAB assessments. SLE trials testing treatment effects on cognitive function may benefit from stronger biomarkers to identify individuals experiencing disease-related cognitive dysfunction most likely to benefit from an efficacious therapy.
Baseline CANTAB scores across assessed cognitive domains
Baseline CANTAB scores grouped by anti-Smith antibodies status
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