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Objectives Cenerimod is an investigational highly selective S1PR1 receptor modulator with potential therapeutic benefits in autoimmune disease. The Phase 2b CARE study ( NCT03742037) evaluated the efficacy and safety of cenerimod at doses 0.5, 1, 2, and 4 mg in moderate to severe systemic lupus erythematosus (SLE) patients. Fatigue, reported by 67% to 90% of SLE patients, is often the most bothersome symptom, impairing health-related quality of life. This outcome was measured in the CARE study, and the results of these analyses, focusing on patients treated with 4 mg (both the whole group and the IFN-1-high subgroup), are presented in this abstract.Methods The fatigue scores were collected using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale score, and the fatigue component of the Lupus Quality of Life (QoL) questionnaire. Observed changes from baseline to month 6 were analyzed descriptively using the full analysis set.Results In the overall study population (n=427), an increase in FACIT-Fatigue score, indicating improved fatigue, was observed in all treatment groups at month 6, with no dose-dependent trends. The median (IQR) change from baseline was 3.0 (0.8.0) in the cenerimod 4 mg arm and 2.0 (-1.79, 9.0) in the placebo arm. In the subgroup analysis of patients with high IFN-1 gene expression, the median (IQR) change from baseline was much better in the 4 mg arm, 5.00 (1.0, 9.50), than in the placebo arm, 1.00 (-5.33, 6.00) (T.The results from the Lupus QoL fatigue scores (higher scores also indicate improved fatigue) showed similar trends. The median (IQR) change from baseline was 12.50 (0, 18.75) in the 4 mg arm and 3.125 (-6.25, 18.75) in the placebo arm in overall population. The 4 mg group exhibited a greater median (IQR) change of 15.63 (3.13, 25.0) compared to placebo 0.00 (-9.38, 12.50) in the high IFN-1 gene expression subgroup (table 1).Conclusions Improvements in mSLEDAI-2K scores in SLE patients treated with cenerimod 4 mg for 6 months were paralleled by relevant improvements in fatigue scores compared to placebo in the subgroup of patients with high IFN-1 gene expression.