Treatment of pyoderma gangrenosum with cyclosporine.

Background And Design: Pyoderma gangrenosum is a chronic inflammatory ulcerative skin disease of unknown origin, often associated with various diseases including inflammatory bowel disease, inflammatory arthritis, monoclonal gammopathies, hepatitis, and myeloproliferative disorders. Treatment of associated systemic disorders may improve the ulcers, but lesions may be recalcitrant and persist for months to years. Therapy for pyoderma gangrenosum includes high-dose systemic corticosteroids, sulfa drugs such as sulfasalazine, clofazimine, and immunosuppressive agents such as mercaptopurine and azathioprine; these drugs are sometimes ineffective.

Substance P induces the expression of an endothelial-leukocyte adhesion molecule by microvascular endothelium.

Leukocyte trafficking in normal and diseased skin appears to be initially governed by endothelial surface glycoproteins that promote adhesive interactions with circulating leukocytes. In a separate study, we have demonstrated that one of these glycoproteins, endothelial-leukocyte adhesion molecule-1 (ELAM-1), is rapidly induced on postcapillary dermal venules as a direct consequence of experimentally-elicited degranulation of adjacent mast cells (Proc Natl Acad Sci USA 86:8972-8976, 1989). A principle endogenous mediator of mast cell degranulation is the neuropeptide substance P.

Degranulation of human mast cells induces an endothelial antigen central to leukocyte adhesion.

To understand better the role of mast cell secretory products in the genesis of inflammation, a system was developed for in vitro degranulation of human mast cells in skin organ cultures. Within 2 hr after morphine sulfate-induced degranulation, endothelial cells lining microvessels adjacent to affected mast cells expressed an activation antigen important for endothelial-leukocyte adhesion. Identical results were obtained when other mast cell secretagogues (anti-IgE, compound 48/80, and calcium ionophore A23187) were used.