Christina Antoniou

Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans.

Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD2. Que and cromolyn also inhibit histamine, leukotrienes and PGD2 from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.

Safety and efficacy of low-dose bexarotene and PUVA in the treatment of patients with mycosis fungoides.

AbstractBackground:The new rexinoid bexarotene is a retinoid X receptor antagonist and immune response modifier. Although combinations of oral bexarotene and psoralen plus UVA (PUVA) have been tried in patients with all stages of mycosis fungoides (MF), the dosage of bexarotene used in these combination regimens has been variable. Objective: To assess the efficacy and safety of low-dose oral bexarotene and PUVA in patients with relapsed or treatment-refractory MF following monotherapy with multiple agents including PUVA, narrow-band UVB, interferon-?, oral bexarotene, and topical corticosteroids. Method: Combination therapy with PUVA three times weekly and low-dose oral bexarotene (150 or 300 mg/day, depending on physicians’ preference) was administered to 14 patients, seven men and seven women (median age 49.5 years, range 30-75 years), with relapsed or refractory MF stages I-III. All responders received maintenance treatment at the same bexarotene dose that induced remission until progression or unacceptable toxicity. Results: Low-dose oral bexarotene combined with PUVA was associated with an overall response rate (complete response or partial response) in 67% of the nine patients with refractory MF who completed the treatment course. Of these nine patients, four had a complete response, two had a partial response, one had stable disease, and two had progressive disease. Five patients withdrew because of hyperlipidemia. Oral bexarotene was continued as maintenance therapy in three of the four complete responders (one refused); two of these patients relapsed 2-10 months after PUVA discontinuation. Patients with partial response or stable disease received the combination for 3-5 months and were switched to another treatment regimen because of lack of further response. Therapy was fairly well tolerated. Conclusion: In a select population of patients who had not responded to at least one monotherapy for early-stage MF, a combination of low-dose oral bexarotene and PUVA was successful in achieving a satisfactory overall response rate in 67% of patients who completed the treatment course and was fairly well tolerated. Limitations of the study include the small number of patients evaluated, its retrospective nature, and the fact that patients were commenced on different bexarotene starting doses (150 or 300 mg/day), depending on physicians’ preference.

Increased serum CRH levels with decreased skin CRHR-1 gene expression in psoriasis and atopic dermatitis

There is increased serum CRH with decreased lesional skin CRHR-1 gene expression in psoriasis and atopic dermatitis, suggesting possible involvement in stress-induced worsening of symptoms.

Serum neurotensin (NT) is increased in psoriasis and NT induces vascular endothelial growth factor release from human mast cells

Summary Background  Psoriasis involves skin inflammation that often worsens with stress, but the mechanism of this effect remains obscure. We have shown that corticotropin‐releasing hormone (CRH) is increased in the serum of patients with psoriasis. A peptide, neurotensin (NT), can trigger skin histamine release and augment the ability of CRH to increase skin vascular permeability.

TINEA VERSICOLOR TREATED WITH FLUCONAZOLE SHAMPOO

Thirty-two patients having tinea versicolor were entered into a comparative study of fluconazole 2% shampoo versus the vehicle shampoo. All patients who met the criteria for inclusion were required to sign an informed consent form before entering the study and were randomized into treatment groups (16 patients each group) for a 5-day trial. Medication was given to each patient in a numbered box, following a sequential order. The characteristics of the patients of these two groups are summarized in Tables 1 and 2. The patients did not have any other treatment for at least 2 weeks prior to the use of the shampoo and for the duration of the study. The diagnosis in each case was based on the clinical picture and was confirmed by direct microscopy. For microscopy, a thin layer of epidermal scales and fungi was obtained by scratching and examined with light microscopy, after processing with KOH solution. Laboratory examination was performed, before entering the study and at days 6 and 15. The patients were told to shampoo their body with fluconazole shampoo 2%* or the placebo shampoo, which came in identical packages. They had to leave the shampoo on for 5 minutes before rinsing. They repeated this procedure for 5 days. A statistical analysis between the two groups, concerning the results, was performed by using t-test for age, sex, and duration of the disease; two-tailed Fishers exact test for the effectiveness of the shampoo was used.

Stimulated human melanocytes express and release interleukin-8, which is inhibited by luteolin: relevance to early vitiligo.

Vitiligo is a disorder of depigmentation, for which the pathogenesis is as yet unclear. Interleukin (IL)‐8 (CXCL8) is a key inflammatory chemokine. We investigated the regulation of IL‐8 production in human melanocytes, and the IL‐8 serum levels and skin gene expression in patients with vitiligo and in controls. Cultured melanocytes were stimulated for 24 h with tumour necrosis factor (TNF) 100 ng/mL and IL‐1β 10 ng/mL, with or without pretreatment with luteolin 50 μmol/L for 30 min, and IL‐8 release was measured by ELISA. Serum cytokines were measured by a microbead array. Skin biopsies were taken from healthy subjects (n = 14) as well as from marginal lesional and nonlesional skin from patients with vitiligo (n = 15). IL‐8 gene expression was evaluated by quantitative real time PCR. Both TNF and IL‐1β stimulated significant IL‐8 release (P < 0.01) from melanocytes, whereas pretreatment with luteolin significantly inhibited this effect (P < 0.01). IL‐8 gene expression was significantly increased in vitiligo compared with control skin (P < 0.05). IL‐8 may be involved in vitiligo inflammation. Inhibition by luteolin of IL‐8 release could be useful for vitiligo therapy.

Association of thyroid autoimmunity with acne in adult women

Background  During the last decades an increase has been observed regarding acne in adults and especially women.

A comprehensive immunohistochemical approach of AKT/mTOR pathway and p-STAT3 in mycosis fungoides

BACKGROUND Although the expression pattern of phosphorylated (p)-mTOR pathway components has attracted scientific interest in several neoplasms, to our knowledge, there is no published information regarding its significance in mycosis fungoides (MF). OBJECTIVE We sought to perform a comprehensive simultaneous assessment of key members of AKT/mTOR pathway along with p-extracellular signal-regulated kinase (ERK), NOTCH1, and p-STAT3 in patients with MF. METHODS In all, 54 skin biopsy specimens (21 tumors, 30 plaques, and 3 folliculotropic MF) from 50 patients with MF were analyzed immunohistochemically for p-mTOR, its upstream p-AKT, its downstream effectors p-p70S6K and p-4E-BP1, and for p-ERK1/2, NOTCH1, and p-STAT3. RESULTS p-mTOR was coexpressed with p-p70S6K in 67.3% of lesions, but coexpression with other molecules was less common. p-p70S6K and marginally NOTCH1 displayed higher H-scores in tumors than in plaques. Significant correlations were recorded between p-ERK and p-4E-BP1, as well as between NOTCH1 and p-p70S6K or p-4E-BP1. NOTCH1, p-4E-BP1, and p-p70S6K expression were associated with advanced stage. In survival analysis simultaneous overexpression of p-AKT and p-p70S6K, along with p-4E-BP1 positivity, adversely affected cancer-specific, disease-free, and progression-free survival in advanced-stage cases. LIMITATIONS A limitation may be the small number of cases included in our investigation, precluding multivariate survival analysis. CONCLUSIONS Activation of AKT/mTOR pathway in MF appears to be correlated with NOTCH1, p-ERK, and p-STAT3 and is implicated in the acquisition of a more aggressive phenotype. The combination of p-AKT, p-p70S6K, and p-4E-BP1 emerges as a significant potential prognostic marker in patients with advanced stage.

Mycosis fungoides in the era of antitumour necrosis factor-α treatments

DEAR EDITOR, Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma (CTCL), but its aetiology remains largely unknown. Typically, it presents as erythematous patches or plaques located mainly on sun-protected areas, progressing to indurated plaques, tumours or erythroderma. During its early stages diagnosis may be difficult, given the considerable overlap with common inflammatory dermatoses, such as eczema and psoriasis. Monoclonal antibodies targeting T-helper 1 (TH1) responses, and particularly tumor necrosis factor alpha (TNF-a), have been widely used against various chronic inflammatory diseases, including psoriasis, and have proven highly effective and well tolerated. However, it is clear that blocking TNF-a is immunosuppressive, giving concerns regarding its potential to induce malignancies, such as non-Hodgkin lymphoma (NHL). Likewise, data on the related risk of CTCL are sparse. The purpose of our study was to review all cases of MF followed at the ‘A. Sygros’ Lymphoma Clinic from January 2009 to December 2013, and treated with anti-TNF-a agents prior to lymphoma diagnosis. In order to minimize the possibility of psoriasis misdiagnosis, only patients with a histological confirmation of psoriasis and/or definite prior positive response to ciclosporin or anti-TNF-a treatment were included. Histological and immunohistochemical findings from all skin biopsies were assessed by two experienced haematopathologists. Clinical data extracted from medical files included sex, age and disease stage at the time of diagnosis; history of psoriasis; previous immunomodulatory treatments and level of therapy response. We identified 11 patients with MF previously treated with an anti-TNF-a agent. Strong clinical evidence to support a correlation between anti-TNF-a treatment and lymphoma development was established for eight patients (Table 1). The remaining three patients were excluded due to a high probability of psoriasis misdiagnosis. Of the eight patients finally included in our analysis, six shared a psoriasis history (histologically confirmed in five), one was diagnosed with ankylosing spondylitis and one with rheumatoid arthritis. Three patients had been treated with infliximab, two with adalimumab and one with etanercept, while two of them had subsequently received two anti-TNF-a agents. Ciclosporin was administered in five patients for a period of 2–25 months prior to anti-TNF-a treatment. Three patients had stage IA disease at MF diagnosis, four patients stage IB and one patient stage IIB, according to the TNM classification. According to our cohort data, it appears that MF was already present at the time of anti-TNF-a initiation in the majority of the cases, and it became fully apparent during that treatment. Blockade of TNF-a is immunosuppressive, therefore associated lymphoma risk has been of potential concern. The biological activity of TNF-a is pleiotropic and not fully understood. Initially, TNF-a was described as an apoptotic and cell death cytokine. That feature is of major interest, for both normal growth and tumour death, as it forces neoplastic cells into selective apoptosis. Moreover, TNF-a blockade strongly inhibits cell-mediated immunity, in part by blocking Th1 cytokine production. The latter represents abnormal immunosurveillance for malignancy. We know that immunological surveillance is crucial in MF, especially at its early stages. Data indicate that in the early stages of MF Th1 cytokines predominate, whereas in the later stages a change in cytokine expression profile occurs, with a shift to Th2 immune responses. We believe that in our series the suppression of immune responses is induced by TNF-a inhibition, probably demasking the coexisting MF and accelerating the disease evolution. Several studies have assessed the risk of lymphoma development in patients treated with TNF-a blockers. There are reports of an increased risk of lymphoma compared with the general population. However, data provided by national registries, where patients exposed to anti-TNF-a agents were compared with nonexposed patients, failed to confirm such a risk. The overall relative risk, as estimated by a meta-analysis of published prospective registries, was 1 11 [95% confidence interval (CI) 0 70–1 51]. Although several case reports on MF development after anti-TNF treatment have been published, data on CTCL are still sparse. Recently, Deepak et al. carried out a review study of all cases of T-cell NHL that were diagnosed after anti-TNF-a treatment and were reported to the US Food and Drug Administration. They showed that exposure to TNF-a inhibitors was associated with a greater proportion of cases of MF and S ezary syndrome and a higher hepatosplenic T-cell lymphoma rate, compared with the Surveillance Epidemiology and End Results-17 registry. The analysis of Mariette et al. reported two risk factors for lymphoma development in patients treated with TNF-a inhibitors: treatment duration < 2 years and treatment with monoclonal antibodies (infliximab and adalimumab) vs. the soluble receptor (etanercept). Our study also revealed that lymphoma

Psoriasis in patients with Mycosis Fungoides: Α clinicopathological study of 25 patients

It has been reported that patients with psoriasis are at increased risk for developing lymphoma including cutaneous T‐cell lymphomas (CTCL). However, the comorbidity and the histopathologic correlation of psoriasis and mycosis fungoides (MF) have been less studied.