Immunopathogenesis of scleroderma--evolving concepts.

Scleroderma, or systemic sclerosis, is a connective tissue disease which may affect various organ systems including skin, lungs, gastrointestinal tract, cardiovascular system and kidneys. While the etiology is not clear, it is currently believed that scleroderma may represent an autoimmune response to an unknown antigen. In this regard, there is evidence that both humoral and cellular immunity may play roles. The pathophysiology is complex and consists of three major features: (1) vascular damage; (2) mononuclear cellular infiltrates; and (3) massive deposition of newly synthesized connective tissue, mainly collagen. The major pathologic features of scleroderma and the roles of humoral and cellular immunity in its pathogenesis are reviewed and summarized.

Current therapy of pemphigus vulgaris.

Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease of the skin and mucous membranes, characterized by flaccid bullae that rupture and leave erosions. Its treatment is challenging. Although the use of systemic corticosteroids remains the cornerstone of effective therapeutic regimens for PV, their prolonged administration may lead to serious side effects. It is therefore necessary, for many patients, to add immunosuppressive agents or use immunomodulatory procedures to achieve remission. This paper will summarize the treatments available for PV, while focusing on the most recently available therapeutic options.

Cutaneous granulomas masquerading as tuberculoid leprosy in a patient with congenital combined immunodeficiency.

Combined immunodeficiency disorders are characterized by abnormalities in cellular and humoral immunity. This classification includes common variable immunodeficiency (CVI), a primary immunodeficiency disorder characterized by hypogammaglobulinemia, recurrent bacterial infections, and significant T-cell abnormalities. Associated autoimmune diseases include rheumatoid arthritis, pernicious anemia, idiopathic thrombocytopenic purpura, and systemic lupus erythematous. Granulomatous lesions in lymphoid tissues, solid organs, and skin have been reported. We describe a patient with CVI who developed cutaneous granulomas with perineural invasion; to our knowledge, this is a previously undescribed feature.

Cutaneous polyarteritis nodosa after streptococcal necrotizing fasciitis.

Polyarteritis nodosa (PAN) is a necrotizing arteritis of small and medium-sized vessels. It may present with hypertension and/or renal insufficiency. Peripheral neuropathy, myopathy, joint pains, testicular pain, and ischemic myalgias may also be seen. Gastrointestinal involvement may lead to gangrene of the bowel, peritonitis, perforation, intra-abdominal hemorrhage, and pancreatitis. The cutaneous manifestations include tender subcutaneous nodules grouped along the course of superficial arteries of the lower extremities, with or without an overlying livedo reticularis. Although multisystem involvement is characteristic, sometimes only one organ or system may be involved. Associations with viral hepatitis (both B and C) and streptococcal infection have been established for PAN. Recurrent strep infections of the upper respiratory tract, streptococcal glomerulonephritis and rheumatic fever have previously been linked to PAN. This report extends the spectrum of associated streptococcal infections to include necrotizing fasciitis.

Zosteriform Darier's disease versus acantholytic dyskeratotic epidermal nevus.

Patients with keratotic lesions distributed in a unilateral, linear, zosteriform or localized pattern and revealing histologic features of dyskeratotic acantholysis have been reported. There is still some controversy regarding the appropriate nosologic placement of this entity. Some believe it represents a localized form of Darier s disease, while others argue it is a variant of epidermal nevus. We report a case of a 42-year-old physician who presented with a 15-year history of an asymptomatic eruption that had been diagnosed as "chronic zoster." Physical exam revealed hyperkeratotic papules and plaques in a dermatomal distribution. The controversy regarding the correct nosologic placement of such a patient is discussed.

Collagen loss in photoaged human skin is overestimated by histochemistry.

It is well known that photoaged skin is characterized by increases in dermal matrix components that include glycosaminoglycans, proteoglycans and masses of abnormal elastic fibers accompanied by substantial collagen loss. Histochemical staining of such tissue gives the impression of "massive" loss of collagen and its replacement by these other matrix components. Early biochemical studies have lent support to this notion with a reported decrease in total collagen of approximately 45% compared to protected skin. More recent studies report considerably less, but varying, amounts of collagen loss. Rarely have the two approaches, histochemistry and biochemical analysis, been used in the same study to examine the same tissue. In this study, collagen loss was quantified biochemically in paired biopsies from sun-protected and sun-exposed arm skin of moderately photoaged female subjects (age 51-77 years). The values obtained were compared with histochemical and immunochemical findings. Quantitatively, collagen loss on a per mg protein basis was small compared to the histochemical appearance.

Basement membrane alterations in psoriasis are accompanied by epidermal overexpression of MMP-2 and its inhibitor TIMP-2.

Psoriasis is most probably an inherited disease characterized by cell proliferation, angiogenesis, and an inflammatory process. The pathophysiology remains unknown, although an alteration in cell-cell and cell-matrix adhesion versus an autoimmune process has been proposed as the primary defect. Here, we show evidence of a new mechanism involving basement membrane alterations accompanied by keratinocyte overexpression of matrix metalloproteinase (MMP) 2 and tissue inhibitor of MMP-2 (TIMP-2) in both uninvolved and involved psoriatic skin. Immunocytochemistry with antibodies against collagen IV (alpha1, alpha2 chains) and laminins (alpha2, alpha5, beta1, gamma1 chains) revealed gaps, folding, and reduplication of the epidermo-dermal basement membrane. There was overexpression of MMP-2 in the cytoplasm of suprabasal keratinocytes. Gelatin zymography revealed pro-MMP-2 and its activated form, a-MMP-2, in both uninvolved and involved psoriatic skin, whereas pro-MMP-9 was only present in involved skin. TIMP-2 was expressed at the cell surface of psoriatic involved suprabasal keratinocytes whereas it was restricted to basal keratinocytes in uninvolved areas. Western blots showed a marked increase in a-MMP-2 and TIMP-2 in uninvolved and involved psoriatic skin although it was more pronounced in the latter. MT1-MP, known to activate pro-MMP-2, was increased in involved areas. In situ hybridization revealed strong signals of MMP-2 mRNA in both uninvolved and involved psoriatic epidermis. The overexpression of MMP-2 in uninvolved and involved psoriatic epidermis supports the concept that the primary alteration may reside in the keratinocyte. In addition, the presence of the activated form of MMP-2 could be responsible for cell-cell and cell-matrix changes noted in psoriatic epidermis.

All-trans-retinoic acid-induced scrotal ulcerations in a patient with acute promyelocytic leukemia.

Induction therapy with all-trans -retinoic acid has been shown to improve the outcome of patients with acute promyelocytic leukemia, although some side effects occur. Dry skin and lips are among the most common cutaneous side effects. We report a case of scrotal ulcerations induced by all-trans -retinoic acid in an American patient; to our knowledge this is the first such case reported.

Dermatofibrosarcoma protuberans in two patients with acquired immunodeficiency syndrome.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive cutaneous tumor of intermediate malignancy. Most commonly, it arises as an asymptomatic, indurated plaque on the trunk within which protuberant nodules develop over time. We describe its occurrence in two patients with human immunodeficiency virus, a previously unreported association. The first patient, a 41-year-old woman, complained of painful lesions around the left shoulder that developed within a scar from previous trauma to the area. The second patient, a 50-year-old man, developed a recurrent DFSP within the scar from a previous surgical procedure. Dermatofibrosarcoma protuberans was confirmed in both cases by the histopathologic and immunohistochemical findings.

Pseudoxanthoma elasticum: an update.

Pseudoxanthoma elasticum (PXE) is an inherited disorder of elastic tissue with many systemic manifestations. The disease varies widely in its degree of expression and inheritance patterns and is believed to be considerably underdiagnosed due to lack of familiarity with the condition among physicians. The purpose of this article was to provide an update on important topics in PXE. Common presentations of the disease as well as the histopathology are discussed. The genetics of PXE as well as the importance of early diagnosis and genetic counseling are addressed. Special areas of concern, such as PXE in childhood, are reviewed. Finally, the article concludes with management of the disease and current areas of research.

Souvenir from the Hamptons - a case of cutaneous larva migrans of six months' duration.

Cutaneous larva migrans is a distinctive serpiginous eruption caused by a reaction to burrowing hookworms. The infection is usually self-limited, normally lasting 2-8 weeks, but may persist for more than a year if misdiagnosed. Biopsies of the creeping eruption rarely reveal an organism. Thus, it is important for the infection to be recognized clinically, so that effective treatment may begin. We found topical thiabendazole to be fast and effective in treating this case of cutaneous larva migrans of six months' duration.

Paraneoplastic pemphigus with a pemphigus vegetans-like plaque as the only cutaneous manifestation.

Paraneoplastic pemphigus (PNP) is a recently recognized autoimmune mucocutaneous disease associated with a few unusual lymphoreticular neoplasms. Intractable stomatitis is the most constant clinical feature but the cutaneous presentations are characteristically variable. We describe a patient with PNP associated with chronic lymphocytic leukemia who presented with severe oral, laryngeal, and pharyngeal involvement. The only cutaneous finding was a pemphigus vegetans-like plaque, a previously undescribed manifestation. The plaque evolved from a flaccid blister that formed at a prior intravenous catheter site. The mucosal biopsy specimen demonstrated faint intercellular staining with IgG, whereas results for the cutaneous plaque were negative. Indirect immunofluorescence testing was positive on both monkey esophagus and rat bladder epithelium. Immunoprecipitation (IP) studies demonstrated a complex of 4 proteins with molecular weights of 250, 230, 210, and 190 kd, confirming the diagnosis of PNP.

Periumbilical pseudoxanthoma elasticum associated with chronic renal failure and angioid streaks--apparent regression with hemodialysis.

Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disease involving progressive fragmentation and dystrophic calcification of elastic fibers. Periumbilical disease as the exclusive site of cutaneous involvement is most commonly seen in the rare entity termed periumbilical perforating pseudoxanthoma elasticum (PPPXE). Patients with this disorder are generally obese, middle aged, multiparous black women with hypertension. The cutaneous lesions are well-demarcated, hyperpigmented, periumbilical plaques with keratotic papules on the periphery. Extracutaneous manifestations have rarely been described. We describe a patient with periumbilical PXE associated with chronic renal failure and bilateral angioid streaks. Histopathologic examination demonstrated typical calcification of elastic fibers with additional amorphous calcium deposits in the superficial dermis. Transepidermal elimination was not present. Normalization of the serum calcium-phosphate product resulted in regression of the lesions--both clinically and histopathologically. The relation between PPPXE and hereditary PXE is discussed. The role of chronic renal failure in precipitating PPPXE is considered.