Time-of-day-dependent immune dynamics are associated with disease severity and therapeutic response in psoriasis.

Abstract

Psoriasis is a chronic inflammatory skin disease associated with substantial patient burden. Symptoms often worsen later in the day, suggesting time-of-day (ToD)-dependent variation, although the underlying systemic immune correlates remain poorly understood. To investigate ToD-dependent variation in immune parameters and inflammatory mediators in psoriasis and their associations with disease severity and treatment response. Peripheral blood samples were collected in the morning and evening before and after anti-IL-23 therapy. Immune cell subsets, serum cytokines, and chemokines were quantified. Public skin transcriptomic datasets were analysed using the ZeitZeiger algorithm to infer sampling time and assess ToD-dependent inflammatory signatures. Patients with psoriasis exhibited attenuated time-of-day variation in circulating lymphocytes, largely driven by reduced evening lymphocyte counts. In parallel, patients showed an evening-biased inflammatory profile characterized by increased cytokines and chemokines involved in inflammation and leukocyte migration. Anti-IL-23 therapy reduced inflammatory mediator levels and partially restored disrupted diurnal immune dynamics, particularly at the evening time point. The extent of diurnal variation was associated with disease severity: ToD-dependent variation in IL-31 positively correlated with PASI, whereas variation in Th17 cells and the CD4+/CD8+ ratio showed negative correlations. Non-responders exhibited higher pre-treatment evening IL-31 levels and a more pro-inflammatory immune profile. Consistently, transcriptomic analyses revealed enhanced late-ToD inflammatory activity and immune cell infiltration in lesional psoriatic skin, both of which were attenuated after treatment. Psoriasis is characterized by altered time-of-day-dependent immune dynamics, including reduced ToD variation in circulating lymphocytes and a late-ToD pro-inflammatory profile. These findings suggest that temporal immune dysregulation is associated with disease activity and treatment response, and that anti-IL-23 therapy may partially restore disrupted time-of-day immune variation. Consideration of temporal immune context may improve biomarker interpretation and help inform future therapeutic strategies.