Oral Roflumilast Suppresses Proinflammatory Cytokine Signaling and Reduces CD4+ T-Cell and Neutrophil Infiltration in Psoriasis

Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the treatment of chronic obstructive pulmonary disease. In a recent clinical trial, oral roflumilast demonstrated clinical efficacy and safety in psoriasis, but the underlying mechanisms in skin have not previously been studied. This substudy investigated the cellular and molecular effects of oral roflumilast treatment on psoriatic skin in vivo. In the PSORRO (Psoriasis Treatment with Oral Roflumilast) study, patients with moderate-to-severe plaque psoriasis were randomized 1:1 to monotherapy with 500 μg oral roflumilast once daily or placebo (ClinicalTrials.gov NCT04549870). Skin punch biopsies from 24 patients were obtained at baseline, week 4, and week 12 for RNA sequencing and quantitative immunohistochemistry. At week 12, genes encoding proinflammatory mediators (eg, CXCL1, CXCL8, IL1B, IL17A, IL23A, and IL36A) were significantly downregulated in patients treated with oral roflumilast compared with that in those treated with placebo. The gene signatures and histologic infiltration of several immune cell populations were also downregulated, most significantly for CD4+ T cells and neutrophils. The epidermal thickness of lesional skin decreased by 32% from baseline, compared with a 7% decrease in the placebo group. Our findings suggest that oral roflumilast downregulates numerous key proinflammatory gene and histologic biomarkers, supporting its potential as a systemic treatment for psoriasis.