Oral retinoic acid metabolism blocking agent Rambazole for plaque psoriasis: an immunohistochemical study.
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 retinoic acid (RA). Well-known effects of RA are normalization of aberrant epithelial growth and differentiation. Hence, rambazole might be beneficial in the treatment of plaque psoriasis.


OBJECTIVE
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 clinical 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 < 0.05). Improvements were also detected for epidermal proliferation (-63%; P < 0.01) and K10 expression (+29%; P < 0.01), compared with baseline. No induction of retinoid-specific keratinization (K13, K19) was observed. A nonsignificant reduction of all pathogenic T-cell subsets and cells expressing NK-receptors was observed at week 8 of treatment (P > 0.05).


CONCLUSIONS
Clinical efficacy of rambazole is primarily the result of restoring proliferation (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.
Bovenschen
H J
HJ
Department of Dermatology, Radboud University Nijmegen Medical Center, NL- 6500 HB Nijmegen, The Netherlands. j.bovenschen@derma.umcn.nl
Otero
M E
ME
Langewouters
A M G
AM
van Vlijmen-Willems
I M J J
IM
van Rens
D W A
DW
Seyger
M M B
MM
van de Kerkhof
P C M
PC
D000284:Administration, Oral; D000328:Adult; D052160:Benzothiazoles / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D003879:Dermatologic Agents / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007641:Keratolytic Agents / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy*; D014212:Tretinoin / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000008:administration & dosage*
D052160:Benzothiazoles; D003879:Dermatologic Agents; D007641:Keratolytic Agents; D014230:Triazoles; D014212:Tretinoin; C406527:R 115866