Heat shock protein 90: a pathophysiological factor and novel treatment target in autoimmune bullous skin diseases.

The chaperone heat shock protein 90 (Hsp90), a cell stress-inducible molecule that regulates activity of many client proteins responsible for cellular growth, differentiation and apoptosis, has been proposed as an important therapeutic target in patients with malignancies. More recently, its active participation in (auto)immune processes has been recognized as evidenced by amelioration of inflammatory disease pathways through pharmacological inhibition of Hsp90 in rodent models of autoimmune encephalomyelitis, rheumatoid arthritis and systemic lupus erythematosus. Based on own current research results, this viewpoint essay provides important insights that Hsp90 is also involved as a notable pathophysiological factor in autoimmune blistering dermatoses including epidermolysis bullosa acquisita, bullous pemphigoid and possibly dermatitis herpetiformis. The observed in vitro, ex vivo and in vivo efficacy of anti-Hsp90 treatment in experimental models of autoimmune bullous diseases and its underlying multimodal anti-inflammatory mechanisms of interference with key contributors to autoimmune-mediated blister formation supports the introduction of selective non-toxic Hsp90 inhibitors into the clinical setting for the treatment of patients with these disorders.

[Sneddon-Wilkinson disease: efficacy of intermittent adalimumab therapy after lost response to infliximab and etanercept]. / Maladie de Sneddon-Wilkinson échappant à l'infliximab et à l'étanercept: efficacité de l'adalimumab.

BACKGROUND: Sneddon-Wilkinson disease (SWD) is a rare chronic neutrophilic dermatosis. The first-line treatment is dapsone but resistance to treatment may sometimes pose a challenge. CASE REPORT: We report a multidrug-resistant patient who responded dramatically before gradually losing response to infliximab and then etanercept. Complete remission was again obtained with adalimumab. DISCUSSION: Our case confirms the previously reported dramatic efficacy of anti-TNF biological agents in recalcitrant SWD but highlights the possibility of subsequent loss of response. Furthermore, it illustrates the efficacy of adalimumab in this indication.

Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) with absence of desmoglein 1 and 3 antibodies: case report and literature review.

Subcorneal pustular dermatosis (SPD) [Sneddon-Wilkinson disease] is a benign and uncommon disorder characterized by a chronic, relapsing vesiculopustular eruption of unknown etiology. We present a case of SPD in a young Black woman in whom ELISA was performed to test for desmoglein 1 and 3 antigens (the first reported case of evaluation for these antigens in a patient with SPD). The test revealed the absence of both antibodies. The patient was successfully treated with topical corticosteroids and narrow-band UVB phototherapy. In this report, we review both the pathophysiology of SPD, which has yet to be clarified, and its treatment. Data obtained from our case report add further support to the hypothesis that a non-antibody-mediated mechanism is operative in SPD. The treatment of choice for SPD is dapsone. However, the combination of corticosteroids and UVB phototherapy should be considered a valid therapeutic option in patients who are not appropriate candidates for dapsone therapy.

Amicrobial pustulosis associated with autoimmune diseases: healing with zinc supplementation.

Amicrobial pustulosis associated with autoimmune diseases is an eruption involving the cutaneous flexures and scalp. We report two young women with this disease, in whom pustulosis healed with zinc supplementation. We suggest that it may be relevant to measure plasma zinc level in patients with such a disease.

Drug-induced linear IgA disease with antibodies to collagen VII.

Linear IgA disease (LAD) is characterized by circulating and tissue-bound IgA antibodies against heterogeneous antigens in the cutaneous basement membrane zone. In most cases the cause is unknown, but a minority of cases has been drug induced. We report a 76-year-old man who developed an acute blistering eruption following high-dose penicillin treatment for pneumococcal septicaemia. Indirect immunofluorescence demonstrated dermal binding IgA antibodies, and Western blotting of serum showed reactivity with a 250 kDa dermal antigen corresponding to collagen VII of anchoring fibrils. Indirect immunoelectron microscopy showed antibody labelling in the lamina densa and sublamina densa zone. This is one of the few cases of drug-induced LAD in which the target antigen profile has been characterized, and the first in which the antigen has been shown to correspond to collagen VII.

A case of generalized pustular psoriasis followed by bullous disease: an atypical case of bullous pemphigoid or a novel bullous disease?

We describe a 31-year-old Japanese woman with generalized pustular psoriasis treated with PUVA who subsequently developed a bullous disease. Throughout the disease course, there was no phase of psoriasis vulgaris. Although several reports describe coexistence of psoriasis vulgaris and bullous disease such as bullous periphigoid, coexistence of generalized pustular psoriasis without any phase of psoriasis vulgaris and bullous disease is rare. As for the bullous disease, direct immunofluorescence study showed IgG and C3 deposition along the basement membrane zone. Indirect immunofluorescence disclosed IgG antibasement membrane zone antibodies. Indirect immunofluorescence on 1 mol/l sodium chloride-split skin demonstrated linear IgG staining almost exclusively on the dermal side of the split. Western immunoblot analysis revealed that the antibody was directed to neither epidermolysis bullosa acquisita antigen nor bullous pemphigoid antigens. Considering the unusual clinical course, we suspect the possibility of a novel autoimmune blistering disease.

Treatment of autoimmune blistering diseases.

This review highlights some of the recent advances and controversies in the treatment of autoimmune blistering diseases, with an emphasis on the practical management of these patients for the clinician. The indications, dosages, and side effects of drugs commonly used to treat these conditions are reviewed. Corticosteroids, administered either topically or systemically, are commonly used in the management of these disorders. Agents that may act as anti-inflammatory agents may offer some benefit, including gold, dapsone, antibiotics, and niacinamide. Immunosuppressants, particularly azathioprine or cyclophosphamide, are used as adjuvants in patients whose condition is not controlled on high-dosage corticosteroids or who cannot tolerate the side effects of steroids.

An analysis of 24 patients with IgA deposition at the BMZ.

A study of 24 patients with IgA deposition at the BMZ of the skin showed that five conditions could be recognized: 1) linear IgA bullous dermatosis in adults (LAD, 7 cases); 2) linear IgA and IgG bullous dermatosis in adults (LAGD, 10 cases); 3) chronic bullous disease of childhood (CBDC, 3 cases); 4) dermatitis herpetiformis (DH, 1 case), and 5) systemic lupus erythematosus (SLE, 3 cases). Histopathologically, 5 of 7 patients with LAD were similar to the DH group, but 7 of 10 patients with LAGD were similar to the BP group. Half the patients with LAD and LAGD had oral lesions, and most of them had excellent responses to dapsone and Tripterygium Wilfordii, but the patients with CBDC did not respond to these treatments. In the patients with LAD and LAGD, the positivity rates of IgA anti-BMZ antibodies examined by indirect immunofluorescence (IIF) on intact skin and NaCl split skin were 41% and 64%, respectively. The heterogeneity of the histopathologic pictures of LAD and LAGD, the incidence of DH, and the value of using NaCl split skin for IIF are discussed.

Clinical perspectives on seabather's eruption, also known as 'sea lice'.

Seabather's eruption is usually a benign clinical syndrome that resolves spontaneously, although severe symptoms and long-term sequelae have been identified. Recent research has implicated the larvae of a jellyfish, Linuche unguiculata, as the cause of this syndrome; confirmation by serological and experimental studies is pending. Clinical signs and symptoms are consistent with this etiology. Outbreaks occur when jellyfish larvae are transported to shore by ocean currents. Treatment is symptomatic and involves use of antihistamines and steroids.

UVB phototherapy of the pruritic papular eruption of the acquired immunodeficiency syndrome.

BACKGROUND: Pruritic papular eruption (PPE) is a chronic dermatosis frequently seen in human immunodeficiency virus (HIV)-positive patients. UVB phototherapy has been successfully used to treat a similar inflammatory condition (Ofuji disease) as well as pruritus of systemic origin. OBJECTIVE: We describe the successful treatment with UVB of seven of eight patients with PPE. METHODS: Eight HIV-positive patients with PPE were treated. The number of papules in a specified area of skin and the intensity of pruritus were monitored before, during, and after UVB phototherapy given three times a week. Biopsy specimens were taken before and after therapy and systemic immune function was evaluated. RESULTS: Both the number of papules as well as pruritus decreased after UVB treatment in all but one patient. Immunoperoxidase staining showed a relative decrease in CD4+, CD8+, and CD2+ cells in all samples studied except for the patient noted to be unresponsive to the therapy. CONCLUSION: UVB phototherapy is effective in the treatment of patients with PPE. This is associated with a significant decrease in inflammation and number of T cells from various subsets within the dermis, thereby implicating these cells in the pathogenesis of this disorder.

Pustulosis vegetans.

Sterile pustules and crusted vegetative plaques on the trunk and limbs developed in a 24-year-old man. They left cribriform scars after healing. Histologically, the lesions showed epidermal proliferation and pustulosis resembling that found in "pyoderma vegetans" and pemphigus vegetans. The lesions were effectively suppressed in two months by the topical application of methoxsalen followed by UV-A irradiation. Studies revealed that the chemotactic activity of polymorphonuclear leukocytes (PMNs) in the patient's peripheral blood was enhanced and that an extract of lesional crusty scales showed the presence of a PMN chemotactic factor. This factor had a molecular weight near 12,500 daltons similar to that reported in psoriasis scales. We speculate that tissue destruction due to complement activation, possibly induced by immune complex-mediated reactions in the dermis, provoked a process of transepithelial elimination of the inflammatory products.

The effect of retinoic acid on the expression of pemphigus and pemphigoid antigens in cultured human keratinocytes.

Vitamin A and its derivatives (retinoids) have both profound effects on epidermal differentiation and beneficial therapeutic effects in various dermatologic diseases. In order to understand these effects, much work has been done with cultured keratinocytes, which show specific morphologic, cellular, and biochemical changes modulated by retinoids. In an attempt to further define specific molecular effects of retinoids in cultured human keratinocytes, we studied the expression of pemphigus (P) and pemphigoid (BP) antigens by human keratinocytes cultured with retinoic acid (RA) in concentrations which modulated differentiation. Cultures of human keratinocytes in medium with 10% delipidized fetal bovine serum (vitamin A-depleted medium) demonstrated areas of extensive differentiation with flattened stratifying cells, keratohyaline granules, and an anucleate stratum corneum-like superficial layer. These cells also synthesized a 67 kd keratin, characteristic of well-differentiated epidermis. In contrast, cultures of human keratinocytes in the same medium supplemented with (10(-7) M, 3 X 10(-7) M, or 10(-6) M) RA demonstrated less differentiated small cuboidal cells that were stratified but did not form an anucleate layer or keratohyaline granules, and did not synthesize the 67 kd keratin. In order to detect P and BP antigens in these cultures, we used indirect immunofluorescence. In vitamin A-depleted cultures, P antigen either was not detected or was seen focally on the cell surface of basal cells. BP antigen was seen on the basal pole of the basal cells, approximating its in vivo location. In RA-treated cells, P antigen was seen on the cell surface of most of the cells, and BP antigen was seen throughout the cytoplasm of the basal cells. In order to study the expression of newly synthesized antigens, we radiolabeled cultures with 14C-amino acids and quantitatively immunoprecipitated the antigens, which were then identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis. We detected a major decrease in newly synthesized P antigen precipitated from extracts of vitamin A-depleted cells compared to RA-supplemented cells, whereas amounts of newly synthesized BP antigen were about the same. Taken together these data demonstrate that RA, at concentrations that decrease differentiation of cultured human keratinocytes, increases the expression of P antigen and changes the subcellular location of BP antigen.

Subcorneal pustular dermatosis with vesiculo-bullous eruption. Demonstration of subcorneal IgA deposits and a leukocyte chemotactic factor.

We report an unusual case of subcorneal pustular dermatosis with widespread vesiculobullous lesions. Reduction of the oral prednisone dosage provoked a severe exacerbation, with erythroderma associated with massive pustule formation. This was effectively controlled by topical PUVA. Subsequent recurrence of skin lesions responded well to oral etretinate. Investigation revealed intercellular IgA deposits at the upper epidermis of the paralesional skin, but no circulating antibodies were detected. Characterization of the chemotactic activity of the soluble components of the scales revealed the presence of a 12,000 molecular weight leukotactic factor resembling that found in psoriasis. Furthermore, the vesicle fluid showed only this chemotactic factor, indicating that it may be a major factor in the pathogenesis of subcorneal pustules.