Higher plasma catecholamine and metabolite levels in the early phase of nonsegmental vitiligo.

The etiology of vitiligo is still being debated, although neural factors seem to play a pivotal role in its pathogenesis. In our search for a link between vitiligo and the activity of monoaminergic systems, we used high-pressure liquid chromatography and electrochemical detector (HPLC-ED) methods to measure the plasma levels of the following substances in 35 healthy subjects and in 70 patients suffering from nonsegmental vitiligo at the different stages of the disease: catecholamines [norepinephrine (NE), epinephrine (E), and dopamine (DA)], their precursor 3,4-dihydroxyphenylalanine (DOPA), their metabolites [3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NMN), metanephrine (MN), and homovanillic acid (HVA)], and 5-hydroxyindolacetic acid (5-HIAA) as the major metabolite of serotonin. We found that the levels of NE, E, NMN, MN, HVA, and 5-HIAA were significantly higher in patients compared to controls. The patients at an active phase of the disease (n = 49/70) showed significantly higher levels of NE, NMN, MHPG, and HVA than ones at a stable phase. The patients with progressive vitiligo and at its more recent onset (< 1 year) showed significantly increased levels of E, NE, and MN in comparison with longer-term sufferers. No significant differences were observed when the patients were subdivided according to the type of vitiligo or their age at its onset. The higher catecholamine and metabolite levels in the early phase of the disease may reflect increased activity by monoaminergic systems, probably due to stressful events, including the onset of vitiligo itself.

Distribution of khellin in excised human skin following iontophoresis and passive dermal transport.

The aim of this work was to study in vitro khellin distribution into human skin after passive or iontophoretic transport. The experiments were performed on excised human skin, using vertical Franz-type diffusion cells. The effects of current application and reservoir pH were studied. At the end of the experiments the skin was sliced thinly and the drug was extracted and analyzed by HPLC. The results showed that khellin is able to penetrate through stratum corneum, to reach basal epidermis and upper dermis. The application time proved to be an important parameter. Current application (30 min; 0.5 mA/cm(2)), with a donor at pH 7.0, favored khellin accumulation even if the drug is not ionized. On the contrary, the use of a formulation at pH 3.2 inhibited drug accumulation. Leaving the drug reservoir in contact with the skin for 30 min after current application led to a dramatic increase of khellin concentration. A combination of dermal iontophoresis and passive diffusion is then a useful technique to govern khellin distribution in the skin.

Treatment of severe alopecia areata with squaric acid dibutylester in pediatric patients.

Topical squaric dibutylester (SADBE) is currently used in Europe to treat alopecia areata in adults. We attempted to determine this drug's effectiveness and convenience in treating children with severe alopecia areata who are psychologically disturbed and resistant to other therapies. Twenty-eight children under 13 years of age who had extensive and long-standing alopecia areata and were not responsive to conventional therapies were sensitized on the head with 2% SADBE in acetone and treated with weekly applications for 12 months. Nine patients (32.1%) achieved complete or cosmetically acceptable regrowth, and another six (21.4%) had significant regrowth. No correlation was found between response and sex, age of onset of illness, extent, duration, or clinical type of disease. In 14 patients followed for a period ranging from 18 months to 8 years SADBE remained efficacious for relapses as well. This study demonstrates that SADBE is a valid and suitable treatment for children, particularly those who are resistant to conventional therapies.

Normal-range plasma catecholamines in patients with generalized and acrofacial vitiligo: preliminary report.

BACKGROUND: There is a body of evidence that neutral factors may play a role in the pathogenesis of vitiligo. OBJECTIVE: We look for the existence of a relationship between vitiligo and monoaminergic systems. METHODS: We use high-pressure liquid chromatography to measure the plasma level of catecholamines, their precursor 3,4-dihydroxyphenylalanine and their metabolites 3-methoxy-4-hydroxy phenylglycol (MHPG), normetanephrine (NMN), metanephrine and homovanillic acid (HVA). Forty patients with the generalized (n = 31) and acrofacial (n = 9) types of vitiligo are studied. RESULTS: Significant differences are not found either between males and females or between the entire group of patients and the controls. HVA and NMN levels significantly correlate with age (r = 0.332, p < 0.05, and r = 0.331, p < 0.05, respectively). Significant correlations are also seen either between noradrenergic or between dopaminergic parameters (norepinephrine vs. MHPG, r = 0.326, p < 0.05; dopamine vs. HVA, r = 0.540, p < 0.01). When the patients are grouped on the basis of vitiligo type or age of disease onset, the plasma mean levels of the neural compounds are always nonsignificantly different from those of the controls. However, both catecholamines and metabolites show higher, although not significant, concentrations in patients with a shorter duration of disease. CONCLUSION: Monoaminergic systems seem unlikely to be related to vitiligo, at least to the generalized and acrofacial types. However, variations cannot be excluded in genetically predisposed individuals during the onset or the active phases of disease.

Expression, topography, and function of integrin receptors are severely altered in keratinocytes from involved and uninvolved psoriatic skin.

Psoriasis is a hyperproliferative cutaneous disease of unknown etiology and etiopathogenesis. Alteration of keratinocyte adhesiveness to basal lamina has been proposed as the initial disturbance leading to poorly controlled proliferation. Keratinocyte adhesion to basal lamina and lateral interactions among basal epidermal cells are mediated, besides other molecules, by integrin receptors that are segregated to discrete membrane domains. In this paper, the expression and function of integrins in psoriatic keratinocytes were examined, both in vivo and in vitro. We found that: (a) in psoriatic keratinocytes the integrin heterodimers alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 4 have lost their polarized distribution on the plasma membrane; (b) the role of these integrins in mediating keratinocyte adhesion in vitro is altered; (c) psoriatic keratinocytes form focal contacts containing both beta 1 and beta 4 integrins. In normal adult keratinocytes the alpha 5 beta 1 fibronectin receptor is poorly expressed and diffusely distributed on the basal keratinocyte plasma membrane and is not organized in defined adhesive structures. In contrast, psoriatic keratinocytes show a clear fibronectin receptor staining in vivo, and organize alpha 5 beta 1 in typical focal contacts in vitro without any obvious increase of its expression and synthesis. These multiple alterations of integrins are also present in uninvolved keratinocytes from psoriatic patients, suggesting a key role for altered integrin-mediated adhesion in the pathogenesis of this disease.

Photochemotherapy with topical khellin and sunlight in vitiligo.

In order to evaluate the efficacy of topical khellin the vitiligo macules of one side only were painted in 41 patients with a 2% solution of khellin in acetone and propylene glycol (90 and 10%, respectively) and exposed to sunlight for a period of 4 months with 3 weekly applications and with exposure times up to 90 min. The macules of the other side were treated in 36 of the 41 patients with acetone and propylene glycol only and sun-exposed with the same schedule, while in the remaining 5 patients they were neither treated with khellin or placebo nor sun-exposed. No significant difference was evidenced between the khellin and placebo-treated sides: no excellent result (repigmentation more than 75% of the affected area) was found, and good results (repigmentation more than 50%) were found in 24.9% of khellin- plus sunlight-treated macules and in 22.3% of placebo- plus sunlight-treated macules.

Polymorphisms of HLA class III genes in allergic contact dermatitis.

HLA class III polymorphisms (BF, C4A, C4B) were studied in 55 patients of different age and sex suffering from allergic contact dermatitis, with sensitization to different substances. In the overall group of patients no significant correlation between the disease and HLA markers was found. BF F allele was present in 34% and BS S in 64% of patients suffering from allergic contact dermatitis to nickel only versus 16.45% (relative risk, RR = 2.61) and 80.76% (RR = 0.42), respectively, of the control population. The BF FB subtype frequency was 23.91% versus 7.57% in the control samples (RR = 3.88). We thus hypothesize that this polymorphic serum protein might be involved in the pathogenesis of allergic contact dermatitis to nickel.

Autoimmunity in vitiligo: relationship with HLA, Gm and Km polymorphisms.

Eighty-six patients affected by vitiligo were investigated for Gm, and Km polymorphisms, HLA markers and the presence of organ and non organ-specific autoantibodies. Vitiligo patients had an increased frequency of autoantibodies (71%), in particular anti-parietal cells (26.6%), antithyroglobulin (24.4%) and antithyroid microsomal antibodies (43%). One patient was also affected by Hashimoto's thyroiditis, 4 by Graves' disease and two others by nontoxic, multinodular goiter. No correlation was found between chronologic age and sex and the presence of autoantibodies, while an increased frequency of organ-specific autoantibodies was found with longer duration of vitiligo. HLA-A3 and Gm (3; 23; 5, 10, 11, 13, 14) phenotype frequencies were significantly increased in patients without autoantibodies (P less than 0.05). Patients negative for these two phenotypes were significantly more prone to develop autoantibodies than those positive (P = 0.0032). C4AQO allele showed a significantly decreased frequency in the whole group of patients when compared to the controls (P less than 0.05).

Vitiligo is associated with a significant increase in HLA-A30, Cw6 and DQw3 and a decrease in C4AQ0 in northern Italian patients.

HLA polymorphisms of class I (HLA-A, B, C) of class II (HLA-DR, DQ) and of class III (C4A, C4B, BF) were investigated in 93 Northern Italian patients affected with vitiligo and in 388 controls. Vitiligo patients had significant increases in HLA-A30 (corrected p, pc = 0.0144), Cw6 (pc = 0.0189), DQw3 (pc less than 0.0003) and a significant decrease in C4AQ0 (pc = 0.003). Nonfamilial vitiligo is marked by increases in HLA-A30 and DQw3. Extensive vitiligo is marked by increases in HLA-A30 and Cw6. These findings suggest that immunogenetic mechanisms may be responsible for vitiligo and that unique HLA phenotypes may influence the expression of vitiligo in this population.

Age of onset in vitiligo: relationship with HLA supratypes.

HLA class I (A, B, C), class II (DR, DQ) histoglobulins and HLA class III (C4A, C4B and Bf) complement factors were analysed in 87 patients with vitiligo and in controls. Two HLA supratypes seem to mark different age of onset of vitiligo: HLA-BfS, C4A3, C4B1, DR5 (W11), DQW3 is characteristic of the pediatric form; while HLA-BfS, C4A3, C4B1, DR7, DQW2 marks the adult form of disease. The importance of defining HLA supratype, not single alleles, is discussed.

Prevalence of atopy in vitiligo. A preliminary report.

59 patients suffering from vitiligo were investigated anamnestically and clinically with intradermal (prick tests) and laboratory tests (RAST and total IgE count) for the presence of atopy. Clinical manifestations (allergic rhinitis, asthma) and intense positive prick tests and RAST with an increase in total IgE count were found in 13 patients (22%). This frequency was significantly higher than that found in the normal population in our area (11.9%; p = 0.0212). These patients had a significantly higher incidence of vitiligo in their families (76.9 vs. 29.7% of the non-atopic; p less than 0.025), an earlier onset (14.1 vs. 24 years of the nonatopic) and a rapid worsening of the disease.

Clonal structural chromosomal rearrangements in lymphocytes of four patients with Werner's syndrome.

Multiple numerical and structural chromosome abnormalities were found in cultured lymphocytes of four patients with Werner's syndrome. The proportion of metaphases with structural and/or numerical aberrations varied from 30 to 44% and several of them were clonal. These results confirm definitively that Werner's syndrome is a chromosome rearrangement syndrome and that these non-constitutional chromosome changes are not exclusive of cultured fibroblasts but present also in lymphocytes.

Alopecia areata: more on topical sensitizers.

Our experience on treating alopecia areata with topical sensitizers (diphencyprone, squaric acid dibutylester) is reported: staging, prognosis, side effects, follow-up, and psychological attitude of the patients towards this therapy and wigs are the focused aspects. The possible mechanisms of action of these allergens are discussed, reporting the case of a female patient with concomitant appearance of hair regrowth and psoriatic plaques in the same area after SADBE therapy.