CLINICAL AND LABORATORY INVESTIGATIONS DOI 10.1111/j.1365-2133.2006.07660.x Oral retinoic acid metabolism blocking agent Rambazole TM for plaque psoriasis: an immunohistochemical study H.J. Bovenschen, M.E. Otero, A.M.G. Langewouters, I.M.J.J. van Vlijmen-Willems, D.W.A. van Rens, M.M.B. Seyger and P.C.M. van de Kerkhof Department of Dermatology, Radboud University Nijmegen Medical Center, PO Box 9101, NL- 6500 HB Nijmegen, The Netherlands Correspondence H.J. Bovenschen. E-mail: j.bovenschen@derma.umcn.nl Accepted for publication 23 June 2006 Key words epidermal proliferation and differentiation, natural killer T cells, psoriasis, Rambazole, retinoic acid metabolism blocking agent, T-cell subsets Conflicts of interest This study was financially supported by Barrier Therapeutics, Geel, Belgium. There are no conflicts of interest. Summary Background The novel systemic all-trans retinoic acid metabolism blocking agent (RAMBA) R115866 (Rambazole TM ; Barrier Therapeutics, Geel, Belgium; further referred to as rambazole) increases intracellular levels of endogenous all-trans reti- noic acid (RA). Well-known effects of RA are normalization of aberrant epithelial growth and differentiation. Hence, rambazole might be beneficial in the treat- ment of plaque psoriasis. Objectives The dynamics of epidermal proliferation, keratinization, lesional T-cell subsets and cells expressing natural killer (NK)-receptors in plaque psoriasis were assessed during treatment with rambazole, as part of a phase IIa open-label clin- ical trial. Methods Six patients were treated with rambazole, 1 mg, once daily, for 8 weeks. At weeks 0, 2 and 8, psoriatic plaque severity scores (SUM) and biopsies from a target lesion were assessed. Epidermal proliferation (Ki67), keratinization markers (K10, K13, K19), T-cell subsets (CD3, CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+, GITR+) and cells expressing NK-receptors (CD94, CD161) were immunohistochemically stained and quantified with image analysis. Results At week 2 the mean SUM-score was virtually equal to baseline, which was accompanied immunohistochemically by equal epidermal hyperproliferation, a nonsignificant decrease in K10 positive epidermis and, overall, a nonsignificant increase in immunocyte subsets. At week 8, in contrast, plaque severity was reduced by 34% from baseline (P <0Æ05). Improvements were also detected for epidermal proliferation ()63%; P <0Æ01) and K10 expression (+29%; P <0Æ01), compared with baseline. No induction of retinoid-specific keratini- zation (K13, K19) was observed. A nonsignificant reduction of all pathogenic T-cell subsets and cells expressing NK-receptors was observed at week 8 of treat- ment (P >0Æ05). Conclusions Clinical efficacy of rambazole is primarily the result of restoring prolif- eration (Ki67) and differentiation (K10) of epidermal keratinocytes. Secondly, relevant T-cell subsets and cells expressing NK-receptors showed nonsignificant reductions after 8 weeks of treatment with rambazole. The triazole derivative R115866 (Rambazole TM ; Barrier Thera- peutics, Geel, Belgium; further referred to as rambazole) is a second-generation all-trans retinoic acid metabolism blocking agent (RAMBA), which has cytochrome P-450 inhibiting properties. Inhibition of these enzymes results in a selective block of hydroxylases involved in the metabolic inactivation pathways of all-trans retinoic acid (RA), increasing the levels of endogenous RA in both plasma and skin. 1 It is well established that the effects of retinoids on growth and differentiation of the epidermis are beneficial in the treatment of psoriasis. 2–7 The present study was part of a multicentre phase IIa open- label, proof-of-principle trial with 17 subjects (Verfaille C et al., unpublished data). Previous clinical phase I studies showed that rambazole 0Æ5 mg twice daily is a clinically safe dose and leads to sufficient plasma levels of rambazole. Fur- ther knowledge of the class of RAMBA molecules has been derived from the trials with the first-generation RAMBA, liarozole, which has been shown to be effective for the treatment of psoriasis and has also been shown to exert antitumour activity. 4–10 There is evidence that rambazole is a Ó 2006 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp263–270 263