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. RESULTS: We present a series of 11 patients with pyoderma gangrenosum, with a wide range of underlying diseases, whose ulcers were refractory to usual therapy and who were treated with low-dose cyclosporine. Ten of the 11 patients cleared rapidly and completely with cyclosporine therapy. CONCLUSIONS: Cyclosporine should be seriously considered as a primary form of treatment for pyoderma gangrenosum.

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. In this study, we exposed organ cultures of neonatal human foreskins for 45 min to substance P or to a substance P analogue (D-pro4, D-trp7,9)SP(4-11) that binds to the identical mast cell surface receptor but which does not provoke histamine release. Dermal mast cells were uniformly degranulated only in explants exposed to substance P, as judged by ultrastructural analysis. After subsequent culture in medium alone for 6 h, superficial venules of explants exposed to substance P showed evidence of ELAM-1 induction, as documented histochemically using H4/18 monoclonal antibody. ELAM-1 was not induced by substance P analogue. Furthermore, preincubation of explants with analogue or with the mast cell inhibitor, cromolyn sodium, abrogated the ability of substance P to induce ELAM-1. From these results we suggest that substance P endogenously released by dermal nerve fibers upon physiologic or electrical stimulation may be important in the regulation of endothelial-leukocyte interactions in vivo. This concept provides further evidence for a neurogenic and psychogenic modulation of the immune response, and may be relevant to the course of naturally occurring dermatoses (e.g., psoriasis) that are commonly exacerbated by emotional stress.

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. Induction of this antigen was abrogated by preincubation with cromolyn sodium, an inhibitor of mast cell secretion, and by antiserum to tumor necrosis factor alpha. These findings indicate that degranulation of mast cells activates dermal endothelium through tumor necrosis factor-dependent mechanisms. This event may be critical to the elicitation phase of cutaneous inflammation.

Dermatologic findings associated with human immunodeficiency virus infection.

Both human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are associated with an increased prevalence of several dermatologic diseases. We studied healthy homosexual men with negative reactivity to HIV antibody, homosexual men without AIDS but with positive reactivity to HIV antibody, and homosexual men with AIDS to compare the prevalence of dermatologic disease in these groups. We found that five cutaneous disorders were increased in persons with HIV infection. Oral hairy leukoplakia was increased both in seropositive subjects without AIDS and in subjects with AIDS. Condylomata acuminata and seborrheic dermatitis were slightly increased in seropositive non-AIDS subjects and significantly increased in the AIDS group. Molluscum contagiosum and oral candidiasis were increased only in the AIDS group.

Uncombable-hair syndrome.

Four children had short, unmanageable, pale blond hair. They had no associated abnormalities and no family histories of abnormal hair. Light microscopy of the hair was normal in three patients, with pili torti present in the fourth. Electron microscopy of hairs from all four children revealed longitudinal grooves in the hair shaft, diagnostic of uncombable-hair syndrome.

Calcium enhances the sensitivity of immunofluorescence for pemphigus antibodies.

Indirect immunofluorescence (IF) to detect pemphigus and pemphigoid autoantibodies is commonly performed with monkey esophagus (ME) as substrate and phosphate-buffered saline (PBS) as a diluent. The purpose of this study was to evaluate comparative IF titers using human skin (HS) as substrate with variations in the buffers employed. Substrates (ME or HS) were incubated in PBS, Tris-acetate-buffered saline (TAS), TAS with 5 mM CaCl+2 (TAS-Ca+2), and PBS or TAS with 1 mM EDTA, prior to incubation with pemphigus or pemphigoid sera for indirect IF. We examined sera from 11 patients with pemphigus vulgaris (PV), 10 patients with Brazilian pemphigus foliaceus (BPF), and 4 patients with bullous pemphigoid. In 20 of 21 pemphigus sera, endpoint indirect IF titers were highest on normal skin with TAS-Ca+2. Six sera (2 PV and 4 BPF) had endpoints that were 5 double dilutions higher than the endpoints obtained with ME and PBS. Six sera (3 PV and 3 BPF) were 4 double dilutions higher, 7 sera (3 PV and 4 BPF) were 2-3 double dilutions higher, and 2 PV sera were equivalent with both substrate/buffers. Preincubation of either tissue with EDTA prior to indirect IF abolished PV and BPF antibody binding completely. Exposure to EDTA after the tissue was incubated with PV or BPF sera did not affect indirect IF titers. In the presence of Ca+2, the antigen was resistant to trypsin in concentrations of 0.001%; however, in the absence of added Ca+2 it was destroyed by 0.0001% trypsin. These differences were not observed with bullous pemphigoid sera; all 4 sera had similar endpoint indirect IF titers. This study shows a significant increase in the sensitivity of indirect IF assays for pemphigus autoantibodies by the use of Ca+2-supplemented buffers on human skin. This finding may also have implications for procedures designed to purify and/or detect pemphigus antigens.