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Received 3 December 2006; returned 26 February 2007; revised 20 March 2007; accepted 18 April 2007Objectives: Aminopenicillin-induced exanthema poses a problem in the management of infectious dis-eases. Due to theoretically possible immunological cross-reactivity, all b-lactam drugs, i.e. penicillins,penicillin derivatives and cephalosporins, are usually avoided. The available alternative antibiotics(macrolides, quinolones and glycopeptides) may be less effective, have more side effects, and theiruse increases medical costs. Moreover, their use contributes to the increasing bacterial resistance toantibiotics. The aim of the study is to demonstrate that patients with aminopenicillin-inducedexanthema may receive specific b-lactams for future antibiotic therapy.Methods: Skin testing followed by oral challenges to identify b-lactams that are tolerated by patientsdespite confirmed delayed-type non-immunoglobulin E (IgE)-mediated allergic hypersensitivity to ami-nopenicillins.Results: Sixty-nine out of 71 patients (97.2%) with non-IgE-mediated allergic hypersensitivity to amino-penicillins tolerate cephalosporins without an aminobenzyl side chain such as cefpodoxime or cefix-ime and 51 patients (71.8%) also tolerate phenoxymethyl penicillin.Conclusions: The majority of patients with non-IgE-mediated allergic hypersensitivity to aminopenicil-lins do not cross-react to certain cephalosporins or phenoxymethyl penicillin. Skin and drug challengetests can be helpful to determine individual cross-reactivity.Keywords: drug challenge, drug provocation, non-IgE-mediated allergic hypersensitivity, skin tests

Treatment of autoimmune blistering diseases consists of systemic glucocorticosteroids usually in combination with additional immunosuppressants such as azathioprine and mycophenolate mofetil or immunomodulators such as dapsone, antibiotics, intravenous immunoglobulins, and immunoadsorption. In some patients, these treatment regimens are not sufficient to control disease activity and/or lead to intolerable adverse events. Rituximab, originally developed for the treatment of non-Hodgkin's lymphoma, is an anti-CD20 humanized monoclonal antibody leading to transitory B-cell depletion. For this indication, rituximab is widely employed, and severe side-effects rarely observed. Subsequently, the B-cell-depleting effect of rituximab has been exploited successfully in various autoimmune disorders, including autoimmune blistering diseases. Here, we review the effect of rituximab in such diseases. To date, application of rituximab has been reported in 26 treatment-resistant patients with the vulgaris, foliaceus, and paraneoplastic variants of pemphigus as well as in bullous pemphigoid and epidermolysis bullosa acquisita. All but a single patient showed clinical improvement with reduction of lesion formation. In about a third, a clinical remission requiring further immunsuppressive medication was achieved, and in about a quarter, complete remission was induced. In addition, the mode of action and adverse events of rituximab as well as adjuvant immunosuppressive treatments, and the effect on levels of circulating autoantibodies in these patients are discussed.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with circulating autoantibodies to the hemidesmosomal antigens BP180 and BP230. We report two cases of therapy-refractory BP adjuvantly treated by tryptophan immunoadsorption. In both patients, this treatment was associated with rapid clinical improvement and reduction in the required corticosteroid dosage. In addition, levels of circulating anti-BP180 autoantibodies decreased markedly. Antibodies that were eluted from the tryptophan matrix bound to BP180 and induced dermal-epidermal separation in cryosections of human skin. Our observations suggest that immunoadsorption may be a helpful adjuvant treatment in severe BP.

Dendritic cells (DCs) are major antigen-presenting cells of the immune system, which need to be activated in order to initiate an immune response. Here, we describe the immunostimulatory effects on human monocyte-derived DCs observed upon infection with Listeria monocytogenes or after treatment with listerial lipoteichoic acid (LTA) and lipopolysaccharide (LPS), respectively. All stimuli caused upregulation of costimulatory molecules, induced T-cell proliferative responses and secretion of cytokines in vitro. Infection of DCs with L. monocytogenes induced release of interleukin (IL)-12 and IL-18. In contrast treatment with purified listerial LTA yielded high levels of IL-18 release, but only minimal IL-12 production. Treatment of DCs with LPS conversely induced significant amounts of IL-12 production, but no IL-18. The release of both stimulating cytokines IL-12 and IL-18 upon infection with entire bacteria suggests that attenuated strains of L. monocytogenes may be a valuable tool for subunit vaccine delivery.

Most patients with epidermolysis bullosa acquisita develop an autoimmune response to the non-collagenous (NC) 1 domain of type VII collagen. We report a 4-year-old girl of white European descent presenting with widespread blistering disease involving the face, hands, genital area and oral mucosa. Histopathology revealed subepidermal blisters, and linear deposits of IgG and C3 were seen along the dermal-epidermal junction on direct immunofluorescence (IF) microscopy of a perilesional skin biopsy. On indirect IF microscopy, circulating autoantibodies exclusively stained the dermal side of 1 mol L-1 NaCl-split skin. The patient's IgG autoantibodies labelled a 290-kDa protein on Western blotting of dermal extracts, and reacted with the NC1, NC2 and triple helical domains of type VII collagen on immunoblotting of recombinant and cell-derived fragments obtained by pepsin and collagenase digestion of the full-length protein. Oral methylprednisolone and dapsone led to clearance of lesions, which healed with mild scarring and milia formation. Treatment was discontinued after 1 year and the patient has now been in remission for more than 3 years.

Cicatricial pemphigoid is a heterogeneous group of autoimmune subepidermal blistering diseases associated most commonly with autoantibodies to bullous pemphigoid (BP)180 and less frequently with those to laminin 5 or type VII collagen. In addition, a few cases have been described with autoantibodies to the beta4 subunit of alpha6beta4 integrin. We describe a patient with extensive disease of ocular, oral, pharyngeal, laryngeal and genital mucous membranes that healed with scarring of conjunctivae. IgG autoantibodies bound to the dermal-epidermal junction on direct immunofluorescence (IF) microscopy and to the epidermal side of 1 mol L(-1) NaCl-split skin on indirect IF microscopy. Our patient's circulating IgG recognized a 205-kDa protein in extracts of 293T cells transfected with the beta4 subunit of alpha6beta4 integrin and in the cell extract of DJM-1 cells. Our patient's IgG and IgA autoantibodies also reacted with full-length BP180 derived from epidermal extracts and the ectodomain of BP180 (LAD-1) derived from culture supernatant of keratinocytes. In addition, a weak IgG reaction with BP230 was noted. The disease rapidly responded to dexamethasone-cyclophosphamide pulse therapy, and immunoblot reactivity to both beta4 integrin and BP180 decreased according to disease activity.

Despite a major effort in clinical research scrutinizing various treatment regimens for patients suffering from metastatic melanoma the prognosis for these patients still remains poor. The treatment options tested have ranged from monochemotherapy, polychemotherapeutic approaches including highly toxic regimens requiring autologous bone marrow rescue, immuno-modulatory therapies, e.g. defined cytokines such as interferon-alpha and interleukin-2 as well as vaccination therapy with dendritic cells or genetically modified tumour cells, and bio-chemotherapy. Although immuno-modulatory approaches are currently regarded as the most promising, to date no improved overall survival has been achieved by any of these measures especially if tested in large multicentre trials. The focus of this review will be on classical chemotherapy with emphasis on both cutaneous and uveal melanoma.

Linear psoriasis is a very unusual clinical variation of psoriasis. Typical clinical features include early onset of erythematosquamous lesions along Blaschko's lines, ability to elicit psoriatic features, absence of pruritus and positive family history for psoriasis. Recently, the term 'superimposed linear psoriasis' was coined for cases with development of nonlinear psoriatic lesions at predilection sites in later life. We report a 19-year-old woman meeting all criteria for the diagnosis of superimposed linear psoriasis including typical histological features. Remarkably, treatment with topical steroids and dithranol cleared the psoriatic lesions on predilection sites whereas the linear lesions were resistant to topical therapy. Linear psoriatic lesions are believed to be caused by genetic alterations in early embryogenesis leading to loss of heterozygosity at a gene locus involved in the pathogenesis of psoriasis. Comparison of mosaic keratinocytes derived from linear lesions with wild-type keratinocytes from the same person may therefore allow identification of key regulatory genes.

As a neutrophilic vascular reaction of small vessels in the subcutaneous tissue and a neutrophilic inflammatory infiltrate are common histopathological features found in initial erythema nodosum (EN) lesions, we asked the question whether activated polymorphonuclear neutrophils (PMN) might play a role in the pathogenesis of EN. We analysed the production of reactive oxygen intermediates (ROI) as a marker for activated neutrophils in the peripheral blood of patients suffering from EN (n = 10) and healthy volunteers (n = 10). FACS analysis of dihydrorhodamine 123-stained PMN was used to detect ROI production due to respiratory burst activity. Patients suffering from EN had a fourfold higher percentage of preactivated ('primed') ROI-producing PMN compared with healthy volunteers. Activation of PMN with formylated methionyl-leucyl-phenylalanine and phorbol 12-myristate 13-acetate led to an increase of ROI production per cell but had no influence on the percentage of activated cells. The percentage of ROI-producing cells in patients with EN correlated with the clinical severity. From these data, we conclude that ROI might play a role in the pathogenesis of EN. ROI might exert their effects by oxidative tissue damage and by promoting tissue inflammation.

Porokeratoses are disorders of epidermal keratinization, the aetiology of which remains to be elucidated. We present the uncommon case of a 70-year-old man with genitoanocrural porokeratotic lesions successfully treated by CO2 laser vaporization. The patient's occupational history and the late onset, site and multiplicity of the lesions suggest their induction by benzene, a known carcinogen.

We report three cases of acute generalized exanthematous pustulosis (AGEP) following oral administration of nystatin. All cases showed similar clinical features and histopathological findings, and a delayed-type hypersensitivity to nystatin could be demonstrated in patch and prick testing. Drug eruptions to nystatin are extremely rare, and, to our knowledge. AGEP has not been reported previously.

Temporal arteritis, a variant of giant cell arteritis, is a systemic granulomatous vasculitis of large and medium-sized arteries. Usually the clinical features are dominated by ophthalmological and neurological complications. In rare instances, ischaemic necrosis, especially of the scalp, may lead patients to the dermatologist. We report a 76-j , ear-old woman presenting with a unilateral scalp necrosis, accompanied by a dramatic ipsilateral impairment of vision. Immediately after duplex-sonography of the extracranial vessels and after initiation of corticosteroid therapy, the diagnosis of temporal arteritis was confirmed by temporal arteria biopsy. One month later, because of insufficient secondary healing of the ulcer, the defect was covered by a mesh graft. The taking of the graft was delayed due to immunosuppressive therapy, but was complete. The patient unfortunately died as a result of complications related to surgical removal of an aspergilloma in the sphenoid cavity secondary to immunosuppressive therapy We discuss the technique of artery biopsy and the possibility of surgical management of scalp necrosis in temporal arteritis. Giant cell arteritis is a systemic segmental granulomatous vasculitis of large and medium-sized arteries. Common histopathological features are found in temporal arteritis (TA), polymyalgia rheumatica and Takayasu's arteritis. Clinically, TA and polymyalgia rheumatica may overlap, whereas Takayasu's arteritis is considered to be a separate entitle. 1 While polymyalgia rheumatica and Takayasu's arteritis do not involve the skin, TA may become a dermatologic problem. TA is a disease of the elderly, occurring most commonly in the seventh and eighth decades of life with a higher prevalence in females and in populations of northern latitudes.2 TA may take a course of three stages.3 In a prodromal stage, lasting from weeks to several years, nonspecific signs and symptoms such as malaise, weight loss, low-grade fever and depression may occur. The acute stage is characterized by severe, mostly bilateral, diffuse or localized headaches. The superficial temporal arteries are frequently focally thickened, with their pulses weak or even absent. Jaw claudication is considered to be a pathognomonic sign of TA. 4 The retinal artery or other arteries supplying the eye are involved in approximately 50% of cases with sudden or gradual, mostly permanent impairment of vision, ischaemic optic neuritis, amblyopia and diplopia. 4 Involvement of other cerebral arteries may lead to nausea, disturbances of speech, psychoses or even lethal ischaemic stroke. 5,6 The disease activity may then tend to decrease over weeks or months, leading to a chronic stage with gradual reduction and disappearance of many symptoms. However, uni- or bilateral amaurosis is irreversible in most cases. In the case of scalp necrosis, the dermatologist may be confronted with TA. We describe such a patient with progressive ulceration of the scalp.

We report a 24-year-old woman, her 6-year-old son and her 17-month-old daughter, who all suffer from a rare congenital genodermatosis first delineated by Huriez et al. in the 1960s. The clinical features of this autosomal dominant condition include scleroatrophy of the hands and feet, nail hypoplasia, mild palmoplantar keratoderma and hypohidrosis. Histological changes are non-specific, but immunohistological and ultrastructural examination in our index patient revealed an almost complete absence of epidermal Langerhans cells in the affected skin. This new finding may be linked to the cancer proneness of the scleroatrophic skin. In this family, the grandmother had died at the age of 37 years from metastatic squamous cell carcinoma which had arisen on the thenar eminence.