Phosphodiesterase-4 Inhibition in Psoriasis

Abstract

Psoriasis is a chronic immune-mediated inflammatory disorder. Phosphodiesterase-4 (PDE-4) is an enzyme that mediates inflammatory responses and plays a role in psoriasis pathogenesis. PDE-4 degrades its substrate cyclic adenosine monophosphate (cAMP) to adenosine monophosphate (AMP), which subsequently leads to the production of pro-inflammatory mediators. Inhibitors of PDE-4 work by blocking the degradation of cAMP, which leads to a reduction in inflammation. Apremilast is the only approved oral PDE-4 inhibitor for the treatment of psoriasis. While it is effective for some patients, it may be limited by adverse effects in others. A topical PDE-4 inhibitor, roflumilast, is being investigated in psoriasis and showing promising results. Crisaborole, a topical PDE-4 inhibitor approved for use in atopic dermatitis, has also been investigated in psoriasis. This is an updated comprehensive review to summarize the currently available evidence for the PDE-4 inhibitors apremilast, roflumilast and crisaborole in the treatment of psoriasis, with a focus on data from randomized clinical trials.

Keywords: PDE-4; phosphodiesterase inhibitors; psoriasis; topical therapies.

Figure 1

Overview of the PDE4/PKA cascade pathway. Panel (A). In a proinflammatory state, PDE-4 promotes production of inflammatory cytokines through activation of NFκB and reduces production of anti-inflammatory cytokines such as IL-10 by degrading cAMP which is responsible for maintaining immune homeostasis. Panel (B). Inhibition of PDE4 leads to elevation of cAMP which triggers the PKA pathway. PKA suppresses the production of proinflammatory mediators and promotes the production of anti-inflammatory mediators, such as IL-10, through gene transcription driven by CREB and ATF-1.

Figure 2

Summary of phase 3 apremilast clinical trials; PASI 75 results at week 16.

Figure 3

(A) Summary of Roflumilast Clinical Trials – Mean Percentage Change from Baseline in TPSSxTPA at week 4. (B) Summary of Roflumilast Clinical Trials – Mean Percentage Change from Baseline PASI at week 6.