A randomized, double-blind, placebo-controlled phase 1 study of multiple ascending doses of subcutaneous M1095, an anti-interleukin 17A/F nanobody, in moderate-to-severe psoriasis.

BACKGROUND: Interleukin 17 is involved in the pathogenesis of psoriasis, a chronic debilitating disease. OBJECTIVES: To evaluate the safety/tolerability, immunogenicity, pharmacokinetics/pharmacodynamics, and efficacy of M1095, an anti-interleukin 17A/F nanobody, in moderate-to-severe plaque psoriasis. METHODS: This multicenter, double-blind, placebo-controlled dose escalation phase 1 study randomized 44 patients 4:1 to treatment with subcutaneous M1095 (30, 60, 120, or 240 mg) or placebo biweekly for 6 weeks, in 4 ascending dose cohorts. RESULTS: The most frequent treatment-emergent adverse events with M1095 were pruritus (n = 4) and headache (n = 3); 2 patients withdrew owing to adverse events (injection site reaction and elevated liver enzyme levels). The terminal half-life of M1095 was 11 to 12 days. The area under the curve/maximum concentration was dose proportional. Of 10 M1095-treated patients positive for antidrug antibodies, 5 showed treatment-emergent antidrug antibody responses. There was no effect on M1095 exposure. Marked decreases in psoriasis inflammatory markers were observed with M1095. By day 85, 100% and 56% of patients receiving M1095, 240 mg, achieved psoriasis area and severity index 90 and 100, respectively. Improvements in static Physician's Global Assessment and affected body surface area were also seen. LIMITATIONS: Interpretation of efficacy data is limited by the small sample size. CONCLUSION: Multiple subcutaneous doses of M1095 showed a favorable safety profile with dose-dependent improvements in psoriasis.

IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects.

BACKGROUND: Intravenous immunoglobulin (IVIG) is a biological agent composed of polyclonal antibodies prepared from a large cohort of human plasma pools. IVIG is increasingly used for the treatment of various antibody-mediated diseases, including pemphigus vulgaris (PV). OBJECTIVE: The aim of the study was to evaluate the benefit and safety profiles of high dose IVIG therapy in PV patients determined by clinical remission, corticosteroid-sparing and immunomodulatory effects, and adverse events at 12 months' follow up. METHODS: Ten PV patients underwent 3-8 monthly cycles of IVIG therapy at a dose of 2 g/kg per cycle. The pemphigus disease area index (PDAI) score, direct immunofluorescence (DIF), indirect immunofluorescence (IIF), and corticosteroid dosage were evaluated before IVIG therapy, after each cycle, and at 6 and 12 months' follow up. RESULTS: The baseline PDAI score was 75.70 ± 21.0 and baseline prednisone dosage was 201.60 ± 71.7 mg/day. The PDAI score reduction of 98% was achieved at 12 months' follow up and a corticosteroid dose reduction of 90% corresponded to clinical improvement. The decrease in both values was statistically significant (P = 0.002, respectively). At 12 months' follow up, seven patients were shown to be negative on IIF, of whom three proved to be negative on DIF. Adverse events were mild and transient and did not require the cessation of IVIG therapy. CONCLUSION: IVIG induced long-term clinical remission, while displaying a corticocorticosteroid-sparing effect and evoking a long-standing immunomodulatory effect in PV patients. The safety profile of IVIG therapy was assessed as good.

Pemphigus vulgaris: a clinical study of 44 cases over a 20-year period.

BACKGROUND: Pemphigus vulgaris (PV) is a rare, life-threatening, autoimmune bullous disease with unpredictable progression and prognosis. OBJECTIVES: This study aimed to analyze long-term outcomes in patients with PV, focusing on factors that may influence the prognosis of the disease, including the phenotype of PV, age at onset, multiplicity of mucosal involvement, relapse and remission rates, and survival functions. METHODS: A retrospective analysis was conducted in 44 patients who were diagnosed and monitored from 1993 to 2012. Statistical analyses were conducted using the Mann-Whitney test and Kruskal-Wallis test. Survival data were analyzed using Kaplan-Meier and log rank tests. Fisher's exact test was used to assess statistical significance at P < 0.05. RESULTS: A total of 79.5% of patients were identified as having mucocutaneous PV. The female : male gender ratio was 1.58; in severe PV, this increased to 2.8. The difference between the genders in age at onset was statistically significant (P = 0.05). Furthermore, multiple mucosal involvements in the oral cavity and at other sites were associated with severe mucocutaneous PV. Multiple relapses occurred more frequently in patients with severe PV than in those with mild PV (P = 0.001). The remission survival of females was longer than that of males (P = 0.003). CONCLUSIONS: Poor prognosis factors include the severe mucocutaneous type of PV, especially in female patients, and multiple mucosal involvements in the oral cavity and other mucosal sites. Female patients were younger than male patients and were more often observed to have severe mucocutaneous PV and to have a higher median period of remission survival than male patients.

HLA DRB1* and DQB1* alleles are associated with disease severity in patients with pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is a rare autoimmune disease that involves the skin and mucosa. The etiology of PV is multifactorial and includes genetic, environmental, hormonal, and immunological factors. OBJECTIVES: The purpose of this study was to examine the relationships between human leukocyte antigen (HLA) class II alleles associated with PV and variations in the disease phenotype. METHODS: Forty-four PV patients were diagnosed and analyzed at the Bullous Disorders Unit in cooperation with the Institute of Immunology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. HLA class II alleles previously found to be associated with PV (DRB1*04:02, DRB1*04:04, DRB1*14:54, DRB1*14:04, DRB1*14:05, DQB1*03:02 and DQB1*05:03) were analyzed according to disease severity, PV type, and gender distribution. RESULTS: Correlations emerged between PV severity scores and HLA alleles. The DRB1*04:02 and DQB1*03:02 alleles were associated with severe PV (P = 0.001); DRB1*04:02 was associated with the mucocutaneous type (P = 0.024), and DQB1*03:02 was found more frequently in female than in male patients (P = 0.016). Analyses of the other alleles did not reveal significant associations with the clinical parameters evaluated. CONCLUSIONS: The HLA DRB1* and DQB1* alleles influence susceptibility to PV and may contribute to PV severity and type. These results suggest that genetic background may contribute to disease outcome by affecting the disease course and efficacy of treatment because some of the alleles were found significantly more frequently in patients with severe disease.

Giant seborrheic keratoses on penis.

INTRODUCTION: Seborrheic keratoses are very common benign epidermal tumors. Despite the high frequency, the pathogenesis is still unknown. They are extremely rare in the genital area. The participation of human papilloma viruses (HPVs) in pathogenesis of seborrheic keratoses is being discussed. AIMS: The aims of this case report are to inform about extremely rare lesion in genital area in a young man and evaluate the association of HPVs in the development of seborrheic keratoses. METHODS: We used histopathological examination to establish the correct diagnosis, which revealed signs of seborrheic keratosis. The real-time polymerase chain reaction method confirmed low-risk HPV 6 from the lesions. MAIN OUTCOME MEASURES: HPVs may play a role in pathogenesis of seborrheic keratoses. RESULTS: The patient was successfully treated with shave excision under spinal anesthesia. Six-month follow-up was without any recurrence. We suggest that HPVs can be considered as etiologic factor in creation of seborrheic keratosis. CONCLUSIONS: Seborrheic keratoses are very common on sun-exposed skin, but they are rare in the genital area, such as on the shaft of penis. This localization may lead to misdiagnosis. Seborrheic keratoses in genital area might negatively influence the sexual life of the patient. Containing HPV 6 low-risk virus, they never lead to malignant transformation.

Footwear contact dermatitis from dimethyl fumarate.

BACKGROUND: Dimethyl fumarate (DMF) is an effective inhibitor of mold growth. In very low concentrations, DMF is a potent sensitizer that can cause severe allergic contact dermatitis (ACD). It has been identified as the agent responsible for furniture contact dermatitis in Europe. The aim of this study was to evaluate patients in Slovakia with footwear ACD associated with DMF, with regard to clinical manifestations, patch test results, and results of chemical analysis of their footwear. METHODS: Nine patients with suspected footwear contact dermatitis underwent patch testing with the following allergens: samples of their own footwear, commercial DMF, the European baseline, shoe screening, textile and leather dye screening, and industrial biocides series. The results were recorded according to international guidelines. The content of DMF in footwear and anti-mold sachets was analyzed using gas chromatography and mass spectrometry. RESULTS: Acute ACD was observed in nine Caucasian female patients. All patients developed delayed sensitization, as demonstrated by positive patch testing using textile footwear lining. Seven patients were patch tested with 0.1% DMF, and all seven were positive. Chemical analysis of available footwear showed that DMF was present in very high concentrations (25-80 mg/Kg). CONCLUSIONS: Dimethyl fumarate is a new footwear allergen and was responsible for severe ACD in our patients. To avoid an increase in the number of cases, the already approved European preventive measures should be accepted and commonly employed.

Effect of Mahonia aquifolium active compounds on interleukin-8 production in the human monocytic cell line THP-1.

The effect of the crude extract and of two alkaloid fractions prepared from Mahonia aquifolium on interleukin-8 (IL-8) production in the lipopolysaccharide (LPS)-stimulated human monocytic cell line THP-1 was studied. The production of IL-8 by cells stimulated with 20 ng/ml LPS after 48 h treatment with 20 microg/ml crude extract was inhibited by about 30 %. LPS-stimulated cells treated with 0.1 microg/ml bisbenzylisoquinoline alkaloid fraction exhibited a 40% inhibition of IL-8 production in comparison with control cells. The fraction of protoberberine alkaloids had no significant inhibitory activity. Weak or no inhibition of IL-8 production was found after treatment with 0.5 microg/ml of protoberberine alkaloids berberine and jatrorrhizine and with berbamine from the group of BBI alkaloids. In contrast, the production was inhibited after treatment with BBI alkaloids baluchistine (about 20%) and aromoline (up to 30%).