Topical tocoretinate improved hypertrophic scar, skin sclerosis in systemic sclerosis and morphea.

Four patients with systemic scleroderma (SSc), 4 patients with morphea, and 4 patients with hypertrophic scar were treated with topical tocoretinate for 6 months to 3 years and studied clinically and histopathologically. Clinically, all of the lesions responded to this therapy. The stiffness of the skin lesions, glossy appearance of the lesions, and telangiectasia improved. Histopathologically, the proliferated collagen fibers decreased in thickness, and the inter-fiber spaces increased. Immunoreactive tenascin-C expressed in the proliferated deep dermal fibers of the SSc and hypertrophic scar lesions was markedly decreased compared with the level before the topical tocoretinate therapy. Topical tocoretinate has been used for the treatment of ulcers; it is also a potent treatment for sclerotic skin diseases.

Allopurinol hypersensitivity syndrome: hypersensitivity to oxypurinol but not allopurinol.

Allopurinol is a xanthine oxidase inhibitor widely used to control plasma uric acid levels. Episodes of hypersensitivity to the drug are not rare. A severe form of this with a generalized exanthem, fever and liver involvement has been termed the allopurinol hypersensitivity syndrome (AHS). Patch testing and lymphocyte stimulation testing (LST) are not helpful in confirming this sensitivity. Allopurinol works as a substrate of xanthine oxidase, and is rapidly oxidized into oxypurinol in vivo. Therefore, the biological half-life of oxypurinol is markedly longer than that of allopurinol. In addition, conspicuous pre-existing renal impairment has been noted in many AHS patients. Thus, it is possible that AHS is a manifestation of hypersensitivity to oxy-, not allopurinol. Here, we now report three cases of AHS in which there were significant lymphoproliferative reactions to oxypurinol but not allopurinol.

Increased endothelial and epidermal thrombomodulin expression and plasma thrombomodulin level in progressive systemic sclerosis.

To clarify the relation between systemic and cutaneous vascular endothelial injury in progressive systemic sclerosis (PSS), we examined thrombomodulin (TM) expression in PSS skin lesions immuno-histopathologically and compared it with plasma soluble TM levels measured by specific enzyme-linked immunosorbent assay. The plasma soluble TM level in PSS patients was significantly higher than that of normal controls and was as high as the levels of SLE patients. In relation to disease activities, the plasma TM levels of sclerotic phase PSS patients were significantly higher than that of atrophic phase PSS patients. The plasma samples with anti-Scl-70 antibody showed a high TM level than samples with anti-centromere antibody or anti-RNP antibody. Barnett's types or systemic corticosteroid treatment did not affect the TM level. Histopathologically, the dermal endothelial TM expression significantly increased in the sclerotic skin and moderately increased in the non-sclerotic skin of PSS compared with that of normal control skin. In addition, immunoreactive TM expression in the epidermis also increased in PSS. Disease activity-dependent elevation of plasma TM levels and immuno-histopathological expression of TM suggested generalized endothelial and epidermal cell involvement in PSS, and compensation in part by overproduction of TM by endothelial cells.

Tissue factor and thrombomodulin expression on keratinocytes as coagulation/anti-coagulation cofactor and differentiation marker.

Immunohistochemistry was used to investigate the expression of tissue factor (TF) as a coagulation factor and thrombomodulin (TM) as an anticoagulation cofactor in the epidermis. TM was expressed on Malpighian layer keratinocytes while TF was located on the supra-Malpighian layer. Epidermal shave extracts were biologically active for both factors. Keratinocytes cultured in high calcium, but not low calcium media, expressed both TF and TM. In pemphigus vulgaris pemphigus foliaceus and bullous pemphigoid, TF expression was increased on keratinocytes shielding the blister compared to the down-regulated TM expression by keratinocytes around the blister.

Functional and immunoreactive thrombomodulin expressed by keratinocytes.

In an immunohistopathologic study using two monoclonal antibodies that recognize independent epitopes on human thrombomodulin, we detected expression of thrombomodulin on Malpighian-layer keratinocytes, but not on the basal or upper granular-layer keratinocytes. Western blotting and thrombomodulin-specific enzyme-linked immunosorbent assay performed on both shaved skin and cultured SV40-transformed keratinocytes showed the expression of full-length thrombomodulin, indistinguishable from endothelial thrombomodulin. Thrombomodulin was expressed by keratinocytes in 1 mM calcium but not in reduced calcium. A functional assay for thrombomodulin revealed that epidermal-derived thrombomodulin possessed cofactor activity for thrombin-catalyzed protein C activation. The limited pattern of expression of thrombomodulin in epidermis implies that this molecule may be a differentiation marker of keratinocytes in addition to being a potent anticoagulant in the skin.