Inhibition of p38 kinase suppresses the development of psoriasis-like lesions in a human skin transplant model of psoriasis

Funding sources: the study was supported by Schering‐Plough and Palau Pharma, SA. Conflicts of interest: none declared. A.M.B. and R.L.N. contributed equally to this work. Madam, Diverse environmental stressors and cytokines activate p38 kinases that mediate the production of proinflammatory cytokines such as interleukin (IL)‐1, IL‐6 and tumour necrosis factor (TNF)‐α, which have been associated with the development of autoimmunity (e.g. psoriasis and rheumatoid arthritis).1 A clinical study showed increased activity of p38 kinase in lesional psoriatic skin.2 As activation of p38 kinase is also reported to occur in keratinocytes by stress stimuli, such as cytokines and ultraviolet irradiation,3, 4 the increased activity of p38 kinase may be a key element in the development of psoriasis. Interestingly, a recent study postulated that inhibition of activity of p38 kinase, as a consequence of TNF‐α neutralization in epidermal keratinocytes, reduces expression of a variety of p38 kinase‐regulated genes encoding proinflammatory cytokines, thereby serving as the main driver for the clinical efficacy seen with adalimumab (anti‐TNF‐α) therapy in patients with psoriasis.5 Clinical efficacy of the p38 kinase inhibitor BIRB‐796 was explored previously in a 4‐week trial of plaque‐type psoriasis but a satisfactory outcome was not reported.6 As the dose‐limiting liver toxicity is a clear issue for BIRB‐796,7 the lack of clinical efficacy may be attributed to insufficient levels of target inhibition with BIRB‐796. To date, solid evidence for efficacy of p38 kinase inhibitors in psoriasis is lacking.