FC05 Circulating monocytes in psoriasis patients treated with apremilast reveal potential cardioprotective effects
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a systemic inflammatory condition characterized by inflamed plaques on the skin that is associated with an increased risk of cardiovascular disease (CVD) including myocardial infarction, hypercholesterolaemia, and hypertension. It is hypothesized that the systemic inflammation associated with psoriasis contributes to the development of CVD; however, the precise mechanism(s) and the impact of systemic therapy remain unknown. We previously demonstrated that circulating monocytes from individuals with psoriasis exhibit a hyperactivated adhesive transcriptional gene expression endotype. Additionally, patients with elevated monocyte doublets at baseline had normalization of these levels following treatment with apremilast. This suggests that aberrant adhesive monocytes contribute to CVD in psoriasis and that apremilast may not only be effective at treating cutaneous disease but may also have cardioprotective effects via monocyte modulation. Our goals were to (i) identify the top differentially expressed genes (DEGs) and associated pathways in psoriasis patients circulating CD14+ monocytes following treatment with apremilast through a prospective cohort study, and (ii) determine if psoriasis patients treated with apremilast have a lower relative risk of CVD vs. those treated with topical corticosteroid (TCS) alone through a retrospective cohort analysis. First, we conducted a prospective cohort study of 14 individuals with psoriasis where CD14+ monocytes were negatively selected from whole blood for transcriptome analysis at baseline and 16 weeks post-treatment. Next, a retrospective cohort study using TriNetX was utilized to determine if apremilast treatment in psoriasis is associated with a lower relative risk (RR) for developing CVD within 5 years compared with those receiving TCS. The top DEGs post-treatment included KCNS1, WNT4, and CASS4 (increased) and ID1, ENKUR, and PIM1 (decreased). Key pathways identified were macrophage differentiation, NADPH oxidase complex activation, and lipoprotein clearance. In the retrospective analysis, 9269 individuals in each group (apremilast vs. TCS) were matched for age, sex, body mass index, race, Type 2 diabetes mellitus, nicotine dependence, alcohol-related disorders, chronic kidney disease, aspirin, antilipemic agents and anticoagulation. Comparisons between individuals treated with apremilast vs. TCS revealed that apremilast treatment was associated with a lower RR of new-onset myocardial infarction (0.754; 0.606–0.939), cerebral infarction (0.667; 0.542–0.820), deep vein thrombosis (0.812; 0.662–0.997), and hypertension (0.702; 0.633–0.778). Concordant with the finding that apremilast modified monocytes lipoprotein clearance, apremilast treatment resulted in reduced risk of hypercholesterolaemia (0.671; 0.610–0.738) and elevated low-density lipoprotein (0.628; 0.532–0.742) relative to those receiving TCS alone. In conclusion, apremilast therapy reduces the risk of new-onset CVD, hypertension, and thrombotic events in individuals with psoriasis, which may be mediated by alteration of circulating monocyte reactive oxygen species and lipoprotein clearance.