A. Dobozy

A Short-Term Trial of Tacrolimus Ointment for Atopic Dermatitis

BACKGROUND Tacrolimus (FK 506) is an effective immunosuppressant drug for the prevention of rejection after organ transplantation, and preliminary studies suggest that topical application of tacrolimus is effective in the treatment of atopic dermatitis. METHODS We conducted a randomized, doubleblind, multicenter study that compared 0.03 percent, 0.1 percent, and 0.3 percent tacrolimus ointment with vehicle alone in patients with moderate to severe atopic dermatitis. The ointment was applied twice daily to a defined, symptomatic area of 200 to 1000 cm2 of skin for three weeks. The primary end point was the change in the summary score for erythema, edema, and pruritus between the first and last days of treatment. RESULTS After three weeks of treatment, the median percentage decrease in the summary score for dermatitis on the trunk and extremities was 66.7 percent for the 54 patients receiving 0.03 percent tacrolimus, 83.3 percent for the 54 patients receiving 0.1 percent tacrolimus, 75.0 percent for the 51 patients receiving 0.3 percent tacrolimus, and 22.5 percent for the 54 patients receiving vehicle alone (P<0.001). The results for the face and neck were similar. The differences among the three tacrolimus groups were not statistically significant. A sensation of burning at the site of application was the only adverse event that was significantly more frequent with tacrolimus than with vehicle alone (P<0.001). Throughout the study, most patients in all three tacrolimus groups had blood concentrations of tacrolimus below 0.25 ng per milliliter. The highest concentration was 4.9 ng per milliliter, which was reported in the group receiving 0.3 percent tacrolimus. CONCLUSIONS The short-term application of tacrolimus ointment is effective in the treatment of atopic dermatitis, with the sensation of burning being the main side effect.

Identification and Characterization of a Novel, Psoriasis Susceptibility-related Noncoding RNA gene, PRINS

To identify genetic factors contributing to psoriasis susceptibility, gene expression profiles of uninvolved epidermis from psoriatic patients and epidermis from healthy individuals were compared. Besides already characterized genes, we identified a cDNA with yet unknown functions, which we further characterized and named PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress). In silico structural and homology studies suggested that PRINS may function as a noncoding RNA. PRINS harbors two Alu elements, it is transcribed by RNA polymerase II, and it is expressed at different levels in various human tissues. Real time reverse transcription-PCR analysis showed that PRINS was expressed higher in the uninvolved epidermis of psoriatic patients compared with both psoriatic lesional and healthy epidermis, suggesting a role for PRINS in psoriasis susceptibility. PRINS is regulated by the proliferation and differentiation state of keratinocytes. Treatment with T-lymphokines, known to precipitate psoriatic symptoms, decreased PRINS expression in the uninvolved psoriatic but not in healthy epidermis. Real time reverse transcription-PCR analysis showed that stress signals such as ultraviolet-B irradiation, viral infection (herpes simplex virus), and translational inhibition increased the RNA level of PRINS. Gene-specific silencing of PRINS by RNA interference revealed that down-regulation of PRINS impairs cell viability after serum starvation but not under normal serum conditions. Our findings suggest that PRINS functions as a noncoding regulatory RNA, playing a protective role in cells exposed to stress. Furthermore, elevated PRINS expression in the epidermis may contribute to psoriasis susceptibility.

Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes

Neuropeptides released from the cutaneous sensory nerve endings have neurotransmitter and immunoregulatory roles; they exert mitogenic actions and can influence the functions of different cell types in the skin. The aims of this study were a systematic investigation of the effects of the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and galanin (GAL) on the inflammatory cytokine production (IL-1alpha, IL-8 and TNF-alpha) of the keratinocytes, and a study of their role in the production and secretion of nerve growth factor (NGF) and its precursor molecule (proNGF). Cultures of normal human keratinocytes were treated with 10(-8)M SP, CGRP, VIP or GAL for 30 min. After different time intervals, cells were harvested for total RNA isolation; in addition, cell lysates and supernatants were collected. The effects of the neuropeptides on the mRNA expressions of the different cytokines and NGF were investigated by Q-RT-PCR and the protein levels were studied by means of ELISA assays and Western blotting. Each of the four neuropeptides induced increases in the expressions of IL-1alpha, IL-8 and TNF-alpha mRNA. Increases appeared in the amount of the IL-1alpha protein in the supernatants of neuropeptide-treated cells, and the IL-8 secretion was mildly elevated, while secretion of TNF-alpha remained undetectable. The four neuropeptides increased the NGF mRNA expression to different extents. In the cell lysates of the keratinocytes, only proNGF could be detected, its concentration in the neuropeptide-treated cells being approximately twice that in the time-matched controls. Both control cultures and neuropeptide-treated cultures were found to secrete proNGF and mature NGF, but neuropeptide-treated cell cultures produced markedly higher (3-7-fold) amounts of NGF-like immunoreactive materials. The results demonstrated that neuropeptides released from cutaneous nerves after an injurious stimulus are able to induce an upregulation of IL-1alpha and IL-8 production; they are additionally able to influence the expressions of proNGF/NGF and their secretion from the keratinocytes. These findings may contribute toward an understanding of the neural influence on skin health and disease.

0.03% Tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial

Background  Topical corticosteroids are the usual treatment for atopic dermatitis (AD) in children but can have side‐effects.

The role of innate immunity in the pathogenesis of acne

Acne is a multifactorial disease of the pilosebaceous follicle. The most significant pathogenetic factors of acne are: abnormal ductal keratinization, increased sebum secretion, abnormalities of the microbial flora and inflammation. The pilosebaceous unit is an immunocompetent organ. Keratinocytes and sebocytes may act as immune cells capable of pathogen recognition and abnormal lipid presentation, and they might have an important role in initiating and perpetuating the activation of both innate and adaptive immune responses. The elements of the skin immune system are involved in the development of both noninflammatory and inflammatory acne lesions.

Repigmentation of localized vitiligo with the xenon chloride laser

Sir, Topical 5-aminolaevulinic acid (5-ALA) photodynamic therapy (PDT) has become an effective treatment option in dermatology. We report a 70-year-old man who presented with extensive erythematous patches on his abdomen and infiltrated plaques on his arms and neck. These were preceded by extensive figurate and annular erythema on his trunk and limbs for 10 years. He had a history of congestive cardiac failure, atrial fibrillation and chronic obstructive airway disease. Mycosis fungoides (MF) was confirmed histopathologically and he cleared with a course of oral 8-methoxypsoralen (8-MOP) plus ultraviolet A (PUVA). During the next year his MF progressed in extent and he also developed a solitary tumour (1 ́5 1 ́5 cm) on his left posterior thigh. The extensive patch and plaque MF cleared with a further course of oral 8-MOP PUVA, but the nodule remained and became ulcerated and painful over the next 3 months. Biopsy of this tumour showed an ulcerated epidermis with replacement of the subcutaneous tissue by a dense infiltrate of malignant CD31 T cells (Fig. 1a). There was no lymphadenopathy or organomegaly. Blood investigations were normal. Computed tomographic scans of the thorax and abdomen were negative. The tumour was treated with 5-ALA PDT: 5-ALA 20% in a cream base (Aladerm, Crawford Pharmaceuticals, Milton Keynes, U.K.) was applied, under polythene occlusion, to the tumour. Four hours later, excess 5-ALA was wiped off and fluorescence was graded as satisfactory using Woods light. He received 20 J cm at 20 mW cm using a Waldmann PDT lamp (MSR 1200; 580±740 nm). Irradiance was measured using a calibrated handheld meter (International Light 1400A and Selo33/F/W/QND52 detector with spectral shaping and neutral density filters calibrated by D.Taylor, Gloucester, U.K.). He graded pain during treatment as 8/10 but experienced no other adverse effects. The lesion cleared after five consecutive treatments over 12 weeks. Repeat biopsy showed a lymphohistocytic infiltrate but complete clearing of the original infiltrate of malignant T cells (Fig. 1b). During his course of PDT his generalized patch and plaque MF relapsed. The tumour site has remained clear on clinical examination 1 years later. He has required two courses of PUVA therapy for generalized patch and plaque MF during this period. Topical 5-ALA PDT has been proven to be effective for superficial cutaneous cancers, but there are few reports of its use in treating MF. Shanler et al. treated patch/ plaque-stage cutaneous T-cell lymphoma and showed that protoporphyrin IX accumulated within lymphocytic infiltrates; early therapeutic results were promising. Boehncke et al. using an argon laser at 630 nm showed inhibition of proliferation of malignant transformed T cells in vitro and in vivo. Wolf et al. have demonstrated the efficacy of PDT (20% 5-ALA) using a broad-spectrum source (40 J cm at 44 mW cm) in two patients with MF who cleared after four and five PDT treatments, respectively. However, Amman and Hunziker reported a poor response for an infiltrated plaque of MF to just one PDT treatment using an identical regimen. This suggests that multiple treatments are required to obtain a complete histological response. We have demonstrated the benefits of low light dose, low dose rate topical 5-ALA PDT for nodular MF, but a formal study is needed to confirm our findings.

HHV8 DNA IN ANGIOLYMPHOID HYPERPLASIA OF THE SKIN

1986-89 recorded an incidence of 0-7% of failed treatment in patients initially sputum positive-ie, still sputum positive after 6 months of chemotherapy. The default rate was 17-8% over one year. Many patients had previous treatment in other camps, but they rarely admitted it. There was no HIV infection in Somalia at the time. Recreational drug consumption in Somalia was limited to harmless Xat. In the

The anti-apoptotic protein G1P3 is overexpressed in psoriasis and regulated by the non-coding RNA, PRINS

Please cite this paper as: The anti‐apoptotic protein G1P3 is overexpressed in psoriasis and regulated by the non‐coding RNA, PRINS. Experimental Dermatology 2010; 19: 269–278.

Pyodermatitis-pyostomatitis vegetans

A 43‐year‐old woman developed annular and pustular cutaneous lesions preceded by tiny yellow pustules coating the surface of the oral mucosa. The clinical, histological and immunopathological evidence clearly showed that the patient had pyodermatitis–pyostomatitis vegetans. It is suggested that this disease is a distinct entity which should be differentiated from pemphigus vegetans.

CD3+CD56+ NK T cells are significantly decreased in the peripheral blood of patients with psoriasis

Psoriasis is a chronic, inflammatory, hyperproliferative skin disease, in which autoimmunity plays a great role. Natural killer T cells (NK T cells), are suggested to be involved in the pathogenesis of different autoimmune diseases. To examine the involvement of CD3+CD56+ NK T cells in the pathogenesis of psoriasis, we investigated the lymphocyte subpopulations obtained from blood samples of psoriatic patients before and after treatment, and of healthy controls, using two‐colour flow cytometry. We found no significant differences between total T cells, total B cells, T helper cells, T cytotoxic cells and NK cells in patients with psoriasis before and after treatment and in controls. Increased percentage of memory T cells and decreased percentage of naive T cells was detected in psoriatic patients compared to controls, but these changes were not statistically significant. The CD3+CD56+ cells of psoriatic patients were significantly decreased relative to controls. The percentage of CD3+CD56+ cells increased after different antipsoriatic therapies, but remained significantly lower than those found in controls. CD3+CD56+ cells of healthy controls were capable of rapid activation, while in psoriatic patients activated NK T cells were almost absent. The decrease in the number of CD3+CD56+ cells may represent an intrinsic characteristic feature of patients with psoriasis, which is supported by the fact that after treatment NK T cells do not reach the values found in controls. In conclusion our results suggest that CD3+CD56+ NK T cells could be actively involved in the development of Th1 mediated autoimmune diseases.