Vitiligo: current medical and scientific understanding.

Vitiligo is a relatively common acquired skin depigmentary disease with a complex presentation, therapy, and etiology. Both the prognosis and therapeutic response for patients with vitiligo is unpredictable. Multiple current therapies exist however the efficacy of these are not optimal. The cause of vitiligo appears to be a combination of genetic effects in both the immune system and the melanocyte itself with a precipitating factor instigating their interaction and resulting in the melanocyte destruction. Headway is being made in understanding the etiology of vitiligo that should culminate in new and improved therapies.

The safety of hydroquinone.

Hydroquinone is one of the most effective molecules for the treatment of hyperpigmentary disorders, with over 40 years of efficacy and safety data. Concerns over its safety have been raised because of the fact that it is a derivative of benzene and because of the long-term side-effects observed with cosmetic products containing high concentrations of hydroquinone. However, despite 40-50 years use of hydroquinone for medical conditions, there has not been a single documented case of either a cutaneous or internal malignancy associated with this drug. This article reviews the evidence for the safety of hydroquinone in the treatment of hyperpigmentation conditions.

Terminal differentiation and senescence in the human melanocyte: repression of tyrosine-phosphorylation of the extracellular signal-regulated kinase 2 selectively defines the two phenotypes.

Melanocytes are pigmented cells distributed in humans in several organs like the epidermis, the leptomeninges, the eye, and the inner ear. Epidermal melanocytes, whether derived from adult or neonatal skin, proliferate well in a medium supplemented with phorbol esters and other mitogens before they undergo senescence. Potent cAMP inducers like cholera toxin are also growth promoters for neonatal melanocytes but only transient growth stimulators for cells derived from adults. We used this cellular system to delineate biochemical pathways involved in proliferation and in terminal differentiation. Here we show that after a period of 4-8 wk of sustained proliferation in the presence of cholera toxin, the adult melanocytes became round, flat, and enlarged. These changes were associated with terminal growth and preceded by a five- to sixfold increase in cAMP levels and an 8- to 10-fold increase in melanin content. The simultaneous addition of phorbol esters and cholera toxin did not prevent cells from reaching terminal differentiation. Identified targets for phorbol esters are protein kinase C (PKC) and the mitogen-activated kinases (MAPKs), also called extracellular signal-regulated kinases (ERKs). PKC was found to be similarly regulated in proliferating and in terminally differentiated melanocytes. Proliferating melanocytes in early or late passage showed identical activation of the kinase ERK2. This kinase was rapidly phosphorylated upon phorbol 12-myristate 13-acetate (PMA) addition and specifically accumulated in the nucleus of the cells, whereas in unstimulated cells it had a perinuclear distribution. In contrast, senescent and terminally differentiated cells were unable to phosphorylate tyrosine residues of the ERK2 gene product in spite of presenting normal amounts of ERK2 protein. In addition, ERK2 did not show the nuclear accumulation observed in proliferating melanocytes after PMA activation and remained localized in the perinuclear area. These results demonstrate that senescent and terminally differentiated melanocytes share a common block in a critical pathway thought to integrate multiple intracellular signals transmitted by various second messengers and specifically prevent the continuation of the signal transduction cascade initiated by PMA activation of PKC.

Management of vitiligo.

Vitiligo is a disease of unknown origin that causes destruction of melanocytes in the skin, mucous membranes, the eyes, and occasionally in hairbulbs and in the ears. The loss of melanocytes alters both structure and function of these organs. The goals of therapy are multifold. The primary goal is to restore melanocytes to the skin so that the epidermis has a normal morphology. Such repigmented skin regains its normal immune/inflammatory functions.

Modulation of the population density of identifiable epidermal Langerhans cells associated with enhancement or suppression of cutaneous immune reactivity.

The epidermis on the backs or ears of DBA/2 mice treated for 7 days with a 20% concentration of monobenzyl ether of hydroquinone (MBEH) had a significantly greater population density of ATPase- and Ia-positive cells compared with control mice treated with diluent. There was no decrease or increase in ATPase- or Ia-positive cells at sites distal from the treated tissue. This increase in population density of Langerhans cells was associated with a significant increase in functional afferent immune reactivity measured by allergic contact hypersensitivity. We also found evidence for enhanced efferent immune reactivity. Animals treated on the ears for 7 days with MBEH were sensitized to DNFB on untreated back. MBEH treated ears with more Ia-positive Langerhans cells demonstrated a threefold greater increase in swelling after the DNFB challenge than the control mice. Results of other studies suggest that the afferent and efferent enhanced immune reactivity produced by MBEH are local effects. We postulated that MBEH produced its effects by activating the oxidation of arachidonic acid (AA) to prostaglandins. To test this, we applied AA to mouse skin. AA has a biphasic effect on epidermal Langerhans cells: in low doses it increases their number; in high amounts it decreases the number of identifiable cells with either the Ia or the ATPase technique. An increased population density of identifiable epidermal Langerhans cells induced with AA was correlated with an increase in afferent and efferent immune reactivity. In contrast, reduction of Langerhans cells with larger amounts of AA suppress the afferent and efferent limb of the immune response. DNFB applied to skin with decreased Langerhans cell density from AA induced a state that mimics immune tolerance. The findings are significant because we report the only method to either increase or decrease the population density of Langerhans cells: and to modulate up or down the afferent or efferent limbs of the cutaneous immune response. Our results also suggest that the Langerhans cell may be involved in the efferent limb of the immune efferent response. These effects may be modulated in part by products of AA metabolism.

New observations on vitiligo and ocular disease.

We examined 223 consecutive patients with vitiligo for ocular disease and 154 consecutive patients with uveitis for vitiligo to better determine the nature of the relationship between vitiligo and ocular disease. Of the 129 patients whose uveitis had an unknown cause, seven (5.4%) had cutaneous depigmentation, poliosis, or early graying of hair. The incidence is 0.5% in the general population (P less than .02). None of the 25 patients whose uveitis had a known cause had vitiligo. Eleven (4.8%) of 223 patients with vitiligo had uveitis at the time of the study or had had it within the previous two years. Of 27 patients in whom vitiligo was associated with cutaneous melanoma, five (18.5%) had had uveitis within the previous two years. In three of these five, the uveitis began within one month of the appearance of cutaneous changes. Evidence of old chorioretinal scars were present in 69 of 223 patients with vitiligo (30.9%) but in only two of 148 control patients (P less than .001). Sixty of 223 patients with vitiligo (26.9%) had evidence of hypopigmentation or atrophy of the retinal pigment epithelium, or both, not related to old chorioretinitis or macular degeneration but only six of 148 controls did (P less than .001).

The proliferative and toxic effects of ultraviolet light and inflammation on epidermal pigment cells.

The ear of the mouse is useful for studying the effects of ultraviolet light on epidermal pigment cells. The quantity of light penetrating into the skin causing an inflammatory response can be assessed easily by measuring with an engineering calipers the swelling of the ear. The inflammatory response of the ear exhibits a linear relationship to the dose of light delivered. We observed that doses of shortwave ultraviolet light which are noninflammatory when repeated at daily intervals induce moderate to severe inflammation. Small doses of psoralen and prolonged exposure to UVA (PUVA) were more inflammatory than larger amounts of psoralen and short exposure to light. Doses of shortwave ultraviolet light and PUVA which produce only a minimal inflammation of the skin stimulate the proliferation of epidermal melanocytes. In contrast, PUVA in doses sufficiently large to cause a marked inflammatory reaction in the skin seems injurious to pigment cells and kills them or causes only a minimal proliferative response. The inflammatory reaction itself does not seem to stimulate or inhibit the proliferation of melanocytes. Prostaglandins A, E, and F2 alpha have no effect on the proliferation of epidermal pigment cells. In contrast, dimethyl sulfoxide (DMSO) and allergic contact dermatitis increase the numerical density of pigment cells. Steroids may block the function of the enzyme tyrosinase. Our experiments indicate that pigment cells, like many other varieties of cells, are susceptible to injury and can be killed at least by large doses of PUVA.