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Protein kinases and phophodiesterases in psoriasis: time to refocus on biochemistry

In this issue of the BJD, Snape et al. report a clinical study of topical phosphodiesterase 4 (PDE4) inhibitors for the treatment of plaque psoriasis. The study is a phase I trial, designed, analysed and funded by industry. It is randomized, placebo-controlled and single-blinded to the clinical investigator. The study reported efficacy with two PDE4 inhibitors as measured by changes in thickness of inflammatory infiltrates in psoriatic lesions. Study numbers were small, but the authors reported lesion improvements that were unidirectional, consistent, dose dependent and statistically significant. Given the preliminary nature of the study, it is easy to point out significant limitations to the methodology and results of the report. However, the findings do fulfil several Bradford Hill criteria for causation with respect to the efficacy of PDE4 inhibitors on inflammatory components of psoriasis. Beyond methodological analysis, a critical element of the criteria is biological plausibility. Accordingly, consideration of potential putative mechanisms by which PDE4 alleviate psoriasis is of great interest and importance. Cyclic nucleotide phosphodiesterases catalyse hydrolysis of cAMP and cGMP, thus regulating intracellular concentration and function of second messengers in signal transduction through their respective cellular effectors, PKA and PKG. There are 11 structurally related but functionally distinct gene families (PDE1 to PDE11) that comprise the PDE superfamily, with the PDEs exhibiting divergent amino-terminal regulatory regions and a conserved carboxy-terminal catalytic core. Some PDEs specifically hydrolyse cAMP (PDE4, PDE7 and PDE8) while others specifically hydrolyse cGMP (PDE5, PDE6 and PDE9). Alternatively, other PDEs hydrolyse both (PDE1, PDE2, PDE3, PDE10 and PDE11). The N-terminal regulatory regions of PDEs contain structural determinants that target individual PDEs to different subcellular sites and signalosomes and allow individual PDEs to respond specifically to different post-translational modifications, regulatory molecules and signals. PDE4 inhibitors exhibit potent cAMP-mediated anti-inflammatory activity in various cellular and animal models, and have been useful in inflammation-related pulmonary and skin diseases, in particular atopic dermatitis and psoriasis. The PDE4 inhibitors act mainly on inflammatory cells like T lymphocytes and macrophages to block tumour necrosis factor-a secretion and interleukin (IL)-17 and IL-23 cytokines. As such, the PDE4 inhibitors in psoriasis may be mainly antiinflammatory and may not specifically target changes that are specific to psoriatic hyperproliferation (elongation of rete ridges, parakeratosis, suprapapillary thinning, increased proliferating cell nuclear antigen expression as assessed by the Ki-67 immunohistochemical marker). Therefore, more studies are needed to see whether PDE4 inhibitors also affect pathophysiological components specific to psoriasis. Normalization of these psoriatic changes have been observed to be necessary for resolution of psoriasis and for achieving prolonged remission after withdrawal from treatment. One disconcerting effect of PDE4 inhibitors is the finding of tachyphylaxis with roflumilast after repeated dosing in patients with chronic obstructive pulmonary disease. This is due to upregulation of PDE4B, which counteracts the suppression of inflammation by the PDE4 inhibitors. The mechanism involves the synergistic interaction between the PDE4 inhibitor (roflumilast) and bacteria (Haemophilus influenzae) to upregulate PDE4B2 expression in the airways. Reports of high prevalence of Staphylococcus aureus with superantigen production in psoriasis increases the likelihood that tachyphylaxis may occur with the use of PDE4 inhibitors in this disease.