Cellular Actions of Etretinate in Psoriasis: Enhanced Epidermal Differentiation and Reduced Cell-mediated Inflammation Are Unexpected Outcomes

Retinoids are potent cell growth and differentiation modulators, but cellular effects of therapeutic retinoids in psoriasis are unknown. We studied the effects of etretinate on pathological activation of keratinocytes and lymphocytes in patients treated systemically with this agent for 8 weeks. Ten patients with extensive psoriasis vulgaris were treated with etretinate at 0.75 mg/kg for 8 weeks. Skin biopsies obtained before and at 8 weeks of treatment were studied using immunohistochemical markers for keratinocyte proliferation or differentiation and for the presence of T-lymphocyte subsets or associated inflammatory proteins. During 8 weeks of treatment, the clinical severity decreased by a mean of 64% (p < 0.001). Compared to a similar group of patients treated with bath PUVA, psoriatic plaque erythema resolved more slowly and less completely (p < 0.05), but improvements in plaque thickness and scale were not significantly different between etretinate and PUVA treatments. Etretinate produced a 44% decrease in epidermal thickness (p < 0.001) and a 62% reduction in keratinocyte proliferation (p < 0.001) after 8 weeks of treatment. Unexpectedly, keratinocyte differentiation was enhanced following etretinate treatment as indicated by increased filaggrin production, increased number and size of keratohyaline granules, greater abundance of keratin filaments, and increased secretion of intercellular lipids from Odland bodies. The stratum corneum in resolving psoriatic lesions was unusually thin, probably caused by retinoid-induced shedding of corneocytes. "Regenerative" epidermal growth was maintained during etretinate treatment, as marked by continued expression of keratin 16 and alpha 3-integrin by suprabasal keratinocytes. Surprisingly the inflammation-associated proteins HLA-DR and ICAM-1 were no longer produced by epidermal keratinocytes following etretinate treatment, and CD3+, CD8+, and CD25+ T-lymphocyte subsets were reduced by 50-65% in lesional tissue (p < 0.01). Etretinate shows unexpected anti-inflammatory and pro-differentiation actions in psoriasis. Etretinate appears to function as a disease suppressive agent which improves hyperplasia, keratinocyte differentiation and tissue inflammation mediated by cellular immune elements.