Infliximab restores the balance between pro- and anti-apoptotic proteins in regressing psoriatic lesions.

BACKGROUND: Psoriasis and psoriatic arthritis are treated very efficaciously with infliximab, a chimaeric human-murine antitumour necrosis factor (TNF)-α antibody. As we reported earlier, infliximab, besides its anti-inflammatory properties, induces a caspase-independent programmed cell death of psoriatic keratinocytes. OBJECTIVES: To elucidate this finding further, we investigated the epidermal expression of proteins involved in the mitochondria-dependent (intrinsic) pathway of cell death. METHODS: Quantification of proteins with pro- (p53, AIF, Bax) and anti-apoptotic functions (Bcl-2, Bcl-XL) and of NF-κB was performed by means of immunohistochemistry and digital image analysis of the staining of nonlesional skin and lesional psoriatic skin from patients treated with infliximab at weeks 0, 2 and 6. RESULTS: Serial biopsies from psoriatic plaques of samples taken at days 0, 5, 14 and 21 of therapy demonstrated a significant downregulation of anti-apoptotic proteins Bcl-2, Bcl-XL and NF-κB during treatment and, in parallel, a significant upregulation of pro-apoptotic proteins p53, Bax and AIF. These differences in expression correlated with decreases in epidermal thickness and clinical outcome (Psoriasis Area and Severity Index). At day 21, expression levels of apoptosis-related proteins in lesional skin approximated those found in nonlesional skin. CONCLUSIONS: Our data therefore suggest that TNF-targeting agents may induce the regression of psoriasis at least in part by normalizing the expression of apoptosis-related proteins in lesional keratinocytes.

Topical photodynamic therapy significantly reduces epidermal Langerhans cells during clinical treatment of basal cell carcinoma.

BACKGROUND: Topical photodynamic therapy (PDT) is a widely applied treatment for basal cell carcinoma (BCC). PDT-induced immunosuppression leading to reduced antitumour immune responses may be a factor in treatment failure. OBJECTIVES: To examine the impact of topical PDT on leucocyte trafficking following clinical treatment of BCC. METHODS: Superficial BCCs in eight white caucasian patients were treated with methyl aminolaevulinate (MAL)-PDT. Biopsies for immunohistochemical assessment were taken from BCCs pre-PDT, 1 h and 24 h post-PDT and from untreated healthy skin. RESULTS: Treatment of BCC with MAL-PDT produced a rapid neutrophil infiltration, commencing by 1 h and significantly increased at 24 h post-PDT (P < 0·05 compared with baseline). An associated increase in the number of blood vessels expressing E-selectin was observed at 1 h and 24 h post-PDT (both P < 0·05 compared with baseline). In contrast, the number of epidermal Langerhans cells fell sharply by 1 h post-PDT, and remained significantly reduced at 24 h post-PDT (both P < 0·05 compared with baseline). CONCLUSIONS: Reduction of Langerhans cells during clinical treatment of BCC might potentially impact negatively on antitumour responses through reduced activation of tumour-specific effector cells. Investigation of modified PDT protocols with the aim to minimize immunosuppressive effects while maintaining antitumour efficacy is warranted.

In vivo detection of human papilloma virus-induced lesions of anogenital area after application of acetic acid: a novel and accurate approach to a trivial method.

Human papilloma virus infection is increasing at an alarming rate. The ability of the virus to establish a subclinical infection and its association with malignancy of the lower genital tract make the statistics even more worrisome. Topical application of acetic acid solution provokes temporal alterations of the light-scattering properties of human papilloma virus-induced lesions of anogenital area. For the in vivo study of the phenomenon, an imaging system has been employed, which performs time-lapse imaging and enables the calculation and display of the kinetics of the provoked alterations in any point within the examined area. Confirmation of diagnosis has been established with conventional histology and polymerase chain reaction. It has been shown that the method provides early detection and staging of skin alteration or transformation due to human papilloma virus infection and enables mapping of the infected area.

Assessment of nasal mucosa blood supply by quantitative endoscopic imaging of the back-scattered light.

In this article we present a method for the objective assessment and monitoring of tissue blood supply using a specially developed endoscopic imaging colorimeter that enables quantitative color modeling of the back-scattered light during endoscopic examination. Tissue blood volume changes in the nasal mucosa, induced by xylometazoline hydrochloride nasal spray, were evaluated with this method. It was found that quantitative imaging provides sensitive, reproducible, and reliable means for the monitoring and mapping of tissue blood supply and is easy to use routinely. The results showed that saturation decreases with time, being the most sensitive color parameter to the vasoconstriction procedure. It appears that objective indexes for optical tissue characterization and analysis may be promising in the understanding of the pathophysiology of tissue changes and in the objective evaluation of their response to different therapeutic schemes.

Programmed cell death of keratinocytes in infliximab-treated plaque-type psoriasis.

BACKGROUND: Tumour necrosis factor (TNF)-alpha blockade using infliximab, a chimeric anti-TNF-alpha antibody, is an effective treatment for plaque-type psoriasis, inducing remission in about 80% of patients. OBJECTIVES: To examine infliximab-induced programmed cell death (PCD) of keratinocytes in psoriatic plaques on serial skin biopsy samples. METHODS: Five patients with moderate to severe plaque-type psoriasis received infliximab infusions intravenously (5 mg kg(-1)) at weeks 0, 2 and 6. Biopsies of nonlesional and lesional skin (days 0, 5, 14 and 21) were obtained. Conventional microscopy was used to examine the morphology of the psoriatic keratinocytes. In situ detection of apoptosis was performed by electron microscopy and by immunohistochemical staining with anti-p53 and anti-caspase-3 antibodies. Results Infusion of infliximab induced a clinical response in all five patients with psoriasis, with a mean Psoriasis Area and Severity Index improvement of 24.8% already at day 5. This was accompanied by significant histopathological changes in the skin biopsy samples after infliximab treatment. Light and electron microscopic evaluation revealed apoptosis-like morphological changes in lesional keratinocytes, i.e. nuclear condensation, chromatin fragmentation and cytoplasmic vesiculation, visible already after the first infusion. These damaged keratinocytes stained positively for p53, but not for active caspase-3. CONCLUSIONS: The effects of infliximab in psoriasis extend beyond merely anti-inflammatory actions, and may include caspase-independent PCD of lesional keratinocytes. The PCD of keratinocytes may be an important mechanism that could explain at least in part the rapid and sustained therapeutic effect of infliximab in psoriasis.

Epidemiologic observations on the natural course of pemphigus vulgaris.

BACKGROUND: During the last 20 years, few prospective studies on the natural course of pemphigus vulgaris (PV) have been performed. METHODS: Various correlations of disease duration, clinical activity fluctuations, serology, and coexistence with other disease states were analyzed with regard to their impact upon the natural history of pemphigus. Thirty-seven consecutive PV patients were involved in this 1-year retrospective follow-up study. RESULTS: The disease activity decreases with time, but when exacerbated it is of unpredictable intensity; skin involvement is equally distributed between the sexes; relapses occur mostly during the first 2 years after disease onset, and can be marginally predicted by autoantibody titers. CONCLUSIONS: Notice should be taken of the relative frequencies of PV associated with neoplasia, ionizing radiation, and familial occurrence.

Environmental factors influencing the biologic behavior of patterns of pemphigus vulgaris: epidemiologic approach.

BACKGROUND: Pemphigus vulgaris is an autoimmune disorder, in which environmental factors seem to play a role, both in the pathogenesis and the activity of the disease. The purpose of the study was to correlate the biologic activity of pemphigus vulgaris with sun exposure and air temperature. METHODS: An epidemiologic study was carried out, analyzing results of serology, skin involvement, and proportional morbidity rates, related to sun exposure and air temperature. The study was based on retrospective and prospective series of patients. All data were evaluated in a yearly seasonal distribution. RESULTS: Strong correlations were shown between climatologic data and pemphigus activity in the populations studied. CONCLUSIONS: Environmental factors have a significant impact on the disease expression. This stresses the necessity of preventive measures against exposure to sun and high temperature.

Sunlight and air temperature affect autoantibody activity and skin involvement of bullous pemphigoid.

BACKGROUND AND DESIGN: Sunlight and air temperature are environmental parameters with considerable influence upon autoimmunity. Their impact on idiopathic bullous pemphigoid (BP) was studied 1) in a prospective series of 27 patients with regard to clinical activity and 2) in a retrospective series of 232 cases during a 7-year period with regard to immunoserology. RESULTS: Skin involvement and the onset of disease showed an immediate and cumulative pattern of response to sunlight and air temperature. Immunoserologic analysis showed a strong correlation of autoantibody expressivity with these two environmental measurements. CONCLUSIONS: This study verifies previous sporadic clinical and experimental data concerning the influence of environmental factors on BP. Accordingly, preventive measures against exposure to sunlight and high temperature are recommended.

Mycosis fungoides: evaluation of immunohistochemical criteria for the early diagnosis of the disease and differentiation between stages.

Lesional skin specimens from twenty-eight patients with mycosis fungoides were studied by evaluating immunohistochemical criteria, primarily with monoclonal antibodies. It was demonstrated that significant differences exist between the control and the premycotic-stage group in regard to the monoclonal antibodies BE1, BE2, and OKT9. The detection of specific antigenic determinants on the surface of cell populations early in the course of the disease seems to be of considerable value for the early diagnosis of the disease. Statistically significant differences were found between the premycotic stage and the plaque stage in regard to T lymphocytes, macrophages, OKT6+, OKT4+, OKT8+, and BE2+ cells in the dermal infiltrate. Significant differences were also shown between the plaque and tumorous groups, concerning macrophages, T cells, and OKT9+ cells in the dermis, as well as epidermal dendritic cells. Differences between stages may supplement histologic data for the follow-up of the disease with or without treatment.

Immunohistochemistry in histoid leprosy.

BACKGROUND: Histoid leprosy is a rare form of multibacillary leprosy as the result of secondary or even primary resistance to dapsone. The etiopathogenesis has not been clarified up to now. METHODS: An immunohistochemical study was carried out for the expression of various markers on epidermal and dermal cell populations using sections of frozen skin specimens from 5 patients with histoid leprosy as compared to specimens from 7 tuberculoid and 7 lepromatous patients. RESULTS: Dendritic epidermal cells, identified by monoclonal antibodies against CD1, HLA-DR, CD45, and CD36, were found reduced in histoid leprosy as compared to both tuberculoid and lepromatous groups. A gradual reduction of keratinocytic HLA-DR expression from tuberculoid to lepromatous to histoid leprosy was observed. The pattern of CD36, CD4, and CD8 expression of lymphomonocytic cells in the dermis of histoid lesions was similar to that of tuberculoid leprosy, but without the formation of an organized granuloma. CD45+ cells as well as activated lymphocytic cells, expressed by the activation immunophenotype (CD1, HLA-DR, CD25, CD71, EGF-R) were found frequently in all groups. CONCLUSIONS: The in situ immunohistochemical findings support a modified hypersensitivity reaction of the cellular type that results in an inhibition of the lesional expansion, but not in the destruction of the bacilli within the histoid lesion.

Recurrent condylomata acuminata: how routine immediate and delayed hypersensitivity parameters might provide a clue to their immunopathogenesis.

In 30 male patients suffering from recurrent condylomata acuminata, immediate hypersensitivity parameters (total IgE, PTT and prick tests) and delayed hypersensitivity against seven recall antigens (multi test) were studied. Thirty healthy male volunteers, matched in age, were the controls. Significantly higher immediate hypersensitivity activity was shown in the patient group. Qualitative evaluation of delayed type hypersensitivity showed that controls had a positive test 16 times more often than patients. A rather homogeneous suppression of delayed type hypersensitivity was found in the patient group mainly as regards the presumably most common antigens vs. the control group. This suppression was proved to be related to disease duration. The hypothesis of a CD4+ Th-2 lymphocyte predominance in recurrent condylomata, owed to longstanding or repetitive antigenic stimulation seems to adequately explain the findings of the present study.

A clinical and histological study of cutaneous leishmaniasis.

Sixty-five cases of proved cutaneous Leishmaniasis have been studied on clinical, histological and laboratory grounds. A new histological classification is proposed and emphasis is given to specific histological changes and their correspondence to distinct clinical signs.

In vivo fluorescence kinetics and photodynamic therapy in condylomata acuminata.

BACKGROUND: Topical application of 5-aminolaevulinic acid (ALA) to condylomata acuminata leads to accumulation of protoporphyrin IX (PpIX); therefore ALA-induced photodynamic therapy (ALA-PDT) appears to be a potential treatment. OBJECTIVES: To investigate in vivo the PpIX fluorescence time course after topical application of ALA in order to determine the optimal time for irradiation, and to assess the efficacy of subsequently performed ALA-PDT. METHODS: Fluorescence kinetics was studied in 12 male patients with condylomata acuminata. Confirmation of diagnosis was established with conventional histology and polymerase chain reaction. Lesions were treated with 20% ALA and irradiated at the optimal time with a dose of 70 J cm-2 or 100 J cm-2 light. An additional session with 100 J cm-2 was administered 1 week later to lesions that persisted. RESULTS: The in vivo study of fluorescence kinetics indicated that the optimal time for irradiation varied among patients from 6 to 11 h. The overall cure rate was 72.9%, 12 months after treatment. CONCLUSIONS: Topical ALA-PDT is a potentially effective treatment for condylomata acuminata.

Amicrobial pustulosis of the folds. A cutaneous manifestation associated with connective tissue disease.

Amicrobial pustulosis (AP) is a recently defined entity associated with connective tissue diseases. Few cases have appeared in the literature. We report a case of AP coexisting with a systemic lupus erythematosus-scleroderma overlap syndrome and marked photosensitivity. The patient presented prominent pustular skin lesions and a few discoid lupus ones. No significant differences in the inflammatory infiltrate were found between the two clinical variants. The infiltrate consisted mainly of CD4+ lymphocytes and many neutrophils. CD1a+ dendritic cells were few in both epidermis and dermis. AP introduces a potential source of diagnostic confusion, but increasing experience of this syndrome will improve the awareness and diagnostic potential among dermatologists.

Re-evaluation of the natural course of bullous pemphigoid. A prospective study.

BACKGROUND: Few studies of prospectively collected data regarding the natural course of bullous pemphigoid have been performed. METHODS: The following factors were combined both quantitatively and qualitatively to obtain results: gender, clinical activity based on the estimation of the body area involvement, disease duration, relapses, coexistence with other disease states, and serology Twenty-seven consecutive patients were followed up for 1 year. RESULTS: Most disease activity (85.2%) is exhibited in the first year after onset. There is a lack of parameters with clear predictive significance. The extent and severity of skin involvement are equally distributed between the sexes and not affected by the disease duration. The generalized form of the disease is predominant (86.5%). The average clinical activity in relapses within the year of follow-up is 48% of the initially observed attack. The probability for recurrence is higher in seropositive patients (overall 37%). Coexistence with other disease states seems to be a random chance event. CONCLUSIONS: The lack of parameters with predictive importance underlines the necessity of a thorough follow-up to prevent treatment-related complications in elderly patients.

Low molecular weight heparin; a novel alternative therapeutic approach for lichen planus.

Heparin analogues in low doses have antiproliferative and immunomodulatory properties. The aim of this study was to evaluate the effect of low-dose enoxaparin administered subcutaneously in lichen planus (LP). Eighteen patients with various types of LP were treated in an open study for 6-13 weeks. Efficacy and safety data were recorded. Complete remission was observed in 11 of 18 patients (61%) and marked improvement in two (11%). Widespread cutaneous involvement and reticulated oral LP had the best response, while in LP of the scalp the response was poor. Enoxaparin is a promising alternative therapy for various types of LP.

Photodynamic treatment of skin malignancies with aminolevulinic acid. Emphasis on anatomical observations and in vivo erythema visual assessment.

BACKGROUND: Photodynamic therapy with delta-aminolevulinic acid is a promising alternative treatment for superficial skin malignancies. OBJECTIVE: Further clinical experience, study of tissue alterations leading to recovery, and correlation/prediction of the therapeutic response through in vivo skin color changes as represented by erythema development. METHODS: The therapeutic procedure, sequential histology and histochemistry, and the development of a remote machine vision system to measure, map, and monitor the erythema development. RESULTS/CONCLUSIONS: A high cure response rate with adequate follow-up was shown. A significant correlation of the clinical-histologic response of tumors subjected to treatment with the erythema measurements implies that erythema inspection and quantitative analysis offer a reliable predictor of the therapeutic outcome and a clue for optimization of this treatment modality.

Cutaneous alternariosis in a patient with idiopathic pulmonary fibrosis.

A 78-year-old farmer presented with symptomless skin lesions for evaluation. Two years prior, he had developed idiopathic pulmonary fibrosis (IPF) and had been treated thereafter with oral prednisolone 20 mg/day and occasionally with colchicine 1 mg/day. On examination, erythematoviolaceous, slightly infiltrated plaques, measuring approximately 5 x 9 cm, rubbery in consistency, intermingled with pustules, sometimes eroded, with distinctive borders, were noted on the dorsum of both hands and on the extensor surface of both forearms. The lesions had developed over a 20-day period. The skin of these areas was atrophic or eroded with multiple ecchymoses (Fig. 1). The abnormal laboratory findings included an elevated white blood cell count of 17,100/mm3, with 79% neutrophils, 16% lymphocytes, and 5% monocytes, C-reactive protein of 33.15 mg/dL (normal, <0.8 mg/dL), and immunoglobulin G of 598 mg/dL (normal, 701-1545 mg/dL). Other blood and urine tests performed were within normal limits. The diagnosis of IPF was reconfirmed through radiology, high-resolution computed tomography, and spirometry, as well as bronchoscopy and bronchoalveolar lavage fluid analysis. Coexistence of presumptive pulmonary alternariosis was excluded. Hematoxylin and eosin stained sections of the excised cutaneous specimen showed focal ulceration of the epidermis adjacent to a mainly intradermal abscess cavity. Within the latter, remnants of a partly destroyed hair follicle were seen amongst degenerating polymorphonuclear leukocytes, as well as many histiocytes and a few Langhans-type multinucleated giant cells. Minute collections of polymorphonuclear leukocytes were seen in the adjacent epidermis. Periodic acid-Schiff (PAS) and Gomori's silver methenamine stains showed a multitude of broad branching fungal hyphae and large spores within the aforementioned cavity, both free and within the cytoplasm of giant cells (Fig. 2). Immunohistochemistry was performed by means of the alkaline phosphatase anti-alkaline phosphatase (APAAP) method. Sections showed that the infiltrate consisted of an almost equal number of B and T lymphocytes, whereas histiocytes and the few giant cells were labeled with anti-CD68 antibodies. Skin smears and biopsy specimens taken twice from all lesions were used for mycologic examination. Wet mounts revealed numerous, brownish, septate hyphae and ovoid Skin smears and biopsy specimens taken twice from all lesions were used for mycologic examination. Wet mounts revealed numerous, brownish, septate hyphae and ovoid structures. Biopsy material was plated on Sabourand's dextrose agar with cloramphenicol (0.05 mg/mL). After 7 days at 27 degrees C, dark, gray-white colonies with a dark brown underside appeared. Microscopic examination of the colonies revealed hyphae with typical conidia having transverse and longitudinal septa. Based on macroscopic and microscopic examination, the isolates were identified as Alternaria alternata (Fig. 3). Treatment with prednisolone was reduced to 10 mg/day and the patient received oral itraconazole (200 mg/day). This resulted in progressive improvement of alternariosis, and the lesions healed completely within 3 months, when treatment was interrupted. Two years later, there is no evidence of recurrence.

Early development of multiple epithelial neoplasms in Netherton syndrome.

We report a case of Netherton syndrome manifested as congenital ichthyosiform erythroderma, trichorrhexis invaginata and atopy, who in early adulthood developed multiple, aggressive epithelial neoplasms in sun-exposed areas of the skin, in areas with papillomatous skin hyperplasia and at the left parotid region. The occurrence of cutaneous neoplasia has been reported in syndromes with congenital ichthyosis and suggests that the underlying genetic defects may cause the development of cancer in prone patients.