Vitiligo: nonsurgical treatment options and the evidence behind their use
While the exact pathogenesis of the vitiligo is not known, several hypotheses are considered. The oldest and most prominent hypothesis is that the disease is due to an autoimmune reaction. A more recent hypothesis postulates that melanocyte destruction is due to abnormalities in the biochemical or metabolic pathways. A third hypothesis, the neural hypothesis, suggests that melanocyte destruction is caused by the dysfunction of sympathetic nerves, based on observations of the dermatomal, rather than Blaschkoid, distribution of segmental vitiligo.
Vitiligo carries a strong association with other autoimmune conditions, such as type 1 diabetes, pernicious anemia, Addison’s disease, systemic lupus erythematosus, rheumatoid arthritis, and polyglandular autoimmune disease. (2) Histological evidence further supports an autoimmune etiology. Vitiligo lesions have an infiltrate of inflammatory cells, particularly cytotoxic and helper T cells and macrophages. (3), (4) This infiltrate is most prominent in the perilesional skin just prior to the clinical appearance of vitiligo. (5) Additional studies have shown that patients with vitiligo often have elevated levels of antibodies against melanocyte antigens such as tyrosinase and tyrosinase-related proteins 1 and 2. (6), (7) Population case-control analyses have also shown associations between vitiligo and human leukocyte antigen (HLA) alleles. Significant examples include HLA-DR4, which is associated with antibody-mediated autoimmune diseases such as type I diabetes mellitus and cicatricial pemphigoid, and HLA-Cw6, which is also associated with psoriasis. (7)
By investigating families with vitiligo and other autoimmune diseases, researchers at the University of Colorado have found that certain chromosomal locations are associated with inheritance among these relatives. Of these, the locus 17pl3 was determined to contribute to vitiligo and systemic lupus erythematosus. Recently, they discovered that certain polymorphisms of a gene within this region, the NALP1 gene, are associated with an increased risk of generalized vitiligo and vitiligo-associated autoimmune disease. This was initially described in a study of 114 Caucasian families in the US and UK and was later confirmed in a population-based case control study of unrelated Romanian patients with generalized vitiligo. The product of this gene, NALP1, is an important part of the innate immune system and is highly expressed in T cells and Langerhans cells. (8), (9) As Langerhans cells are especially active in the epidermis, this may be evidence of an autoimmune reaction occurring specifically in the skin. The NALPl protein has pyrin domains and in its natural form detects bacterial motifs for innate immune defense. Pyrin gene mutations also play a role in Muckle-Wells syndrome (urticaria, deafness, and amyloidosis), familial Mediterranean fever, and the PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome.
Another recent genetic study identified a polymorphism in the melanocortin-1 receptor (MC1R) gene that is associated with protection against vitiligo. This gene encodes the melanocyte stimulating hormone receptor (MSHR) which, when bound by [alpha]-MSH, stimulates eumelanin production through a cAMP response. Single nucleotide polymorphisms (SNPs) of the MC1R gene have already been associated with red hair and/or fair skin and a susceptibility to skin cancer. In studying 108 vitiligo patients and 70 controls from a fair-skinned Hungarian population, Szell et al found that the C478T SNP in the MC1R gene was significantly higher in the control group. This SNP leads to an Arg l60Trp amino acid change in the second intracellular loop of the MSHR protein, a component of the protein kinase C target sequence. This location suggests that the SNP may confer protection against vitiligo by altering signal transduction events. However, the authors note that computer-assisted prediction shows that the mutation also creates an epitope with a lower antigenicity. Therefore, they propose that this SNP may function by providing protection against an autoimmune process. (10)
Another hypothesis of melanocyte destruction suggests it may be an end result of metabolic and biochemical dysregu-lation. Keratinocytes and melanocytes may have innate biochemical abnormalities, particularly in the metabolism of biopterins and catechols, which increase susceptibility to reactive oxygen species and immunologic cytotoxicity. (5), (11) The oxidative stress hypothesis is supported by studies that found an imbalance in oxidative-reduction (redox) status in peripheral blood mononuclear cells in vitiligo patients, which represents the redox status of the epidermis. (11) Additionally, elevated levels of hydrogen peroxide [H.sub.2] [O.sub.2] can be found in the epidermis of vitiligo patients along with lower levels of the antioxidant catalase. (12), (13) Some have proposed that vitiligo is a systemic disease of redox imbalance that manifests with cutaneous lesions. (11)
It is possible that oxidative stress induces an immune reaction that ultimately induces melanocyte death. It has been reported that stress such as overexposure to ultraviolet (UV) light, contact with bleaching phenols, emotional stress, and mechanical injury can precipitate vitiligo. Melanocytes from vitiligo lesions have also been shown to express increased amounts of heat shock protein (HSP) 70 as compared to normal melanocytes. Heat shock proteins are expressed by cells under stress, act as chaperones, and prevent cells from undergoing apoptosis. Heat shock protein 70 in particular is unique in that it is secreted by live cells and, once it is released, enhances the antigen uptake of dendritic cells (DCs), activates the DCs, and ultimately stimulates a T-cell immune response. By chaperoning proteins and peptides out of the cells, and perhaps secreting melanosomes with (HSP) 70, it is postulated that the combination of HSP70 with these antigens induces an immune reaction against melanocytes. A recent study took this concept further by using a mouse model of autoimmune vitiligo induced by gene gun vaccination with melanocyte antigens. They showed that including human and mouse-derived inducible HSP70 in the protocol increased and accelerated depigmentation. (14) HSP70 may link the biochemical/metabolic hypothesis with the autoimmune hypothesis of vitiligo. An increased level of oxidative stress in vitiligo melanocytes may get translated into an immune response.
The neural hypothesis of vitiligo is based on observations of segmental vitiligo. Segmental vitiligo is a unique form of vitiligo. It manifests in a dermatomal, rather than Blaschkoid, distribution and is therefore postulated to involve segmental nerves that innervate affected areas. In 1 study, segmental vitiligo lesions were found to have 3 times the level of cutaneous blood flow of normal contralateral skin. Because sympathetic nerves induce vasoconstriction as they control blood flow to the skin, it is thought that vitiligo may be mediated by inadequate sympathetic innervation. This hypothesis is supported by a finding that the sympathetic nerves in vitiligo lesions have an abnormally increased adrenoceptor response to oxidative stress. (15) Segmental vitiligo does not Koebnerize, does not increase in size after the first year, and is relatively recalcitrant to treatment. Understanding the possible difference in pathogenesis may allow for development of more effective treatments. (16)
Topical corticosteroids are a standard treatment option to decrease inflammation. Because they are often associated with side effects such as atrophy, striae, and telangiectasia, they are not recommended for large lesions or areas of the body that are more susceptible to side effects such as the face. Systemic corticosteroids have reported success in rapidly progressing vitiligo. (17) However, due to adverse effects and inconsistent response, steroid monotherapy has long been viewed as a less than ideal treatment. Studies have found that one can often reap more benefit from these drugs by combining them with phototherapy. For example, a randomized left-right comparison study showed that topical fluticasone combined with UVA phototherapy was better than either alone. (18)
Topical Calcineurin Inhibitors
Topical calcineurin inhibitors (TCIs) include pimecrolimus (Elidel[R]) and tacrolimus (Protopic[R]). Topical calcineurin inhibitors target T cells, inhibiting the synthesis of inflammatory cytokines such as interleukins (IL) (including IL-2, 4, 5, and 10), interferon-gamma and tumor necrosis factor-alpha (TNF-[alpha]). They achieve this at the level of gene expression by inhibiting dephosphorylation of the transcription factor NFAT, nuclear factor of activated T cells. (19), (20) The calcineurin inhibitors can produce T-cell inhibition at levels similar to that of corticosteroids. This was shown by an in vitro study by Winiski et al that demonstrated pimecrolimus inhibits T cell activation in the same potency range as topical dexamethasone and betamethasone-17-valerate. (19,21) The TCIs are an attractive alternative because they do not have an effect on keratinocytes or fibroblasts as corticosteroids do, avoiding complications such as poor wound healing or skin atrophy. This makes them excellent candidates for sensitive areas such as the face. Because of their large molecular weight, the TCIs have limited systemic absorption, making them better candidates than steroids for the treatment of mucous membranes and areas with thin skin. (19)
Both tacrolimus and pimecrolimus have shown promise as topical treatments, with the majority of clinical studies focusing on tacrolimus. Lepe et al conducted a randomized, double blind trial of 20 pediatric patients with an average age of 9.5 years (ranging from 4-17 years) by treating 2 lesions of similar size and time of evolution in a variety of body locations for 2 months with tacrolimus 0.1% ointment and clobetasol proprionate 0.05% ointment. They concluded that tacrolimus was as effective as clobetasol, with a mean repigmentation of 41% and 49%, respectively. (22) Studies of combined therapies indicate that TCIs may increase the efficacy of phototherapy such as narrow band UVB and 308-nm ex-cimer laser treatments. (23,24) Because of evidence that transplant recipients on oral calcineurin inhibitors have increased rates of squamous cell carcinomas (SCCs), questions have been raised about risks of carcinoma with topical calcineurin inhibitors. Further studies have shown that this risk of cancer may not be simply due to immune suppression, as was originally thought. There is evidence that the systemic calcineurin inhibitors decrease the ability of keratinocytes in the skin to repair UV-induced DNA damage and inhibit UV-in-duced apoptosis. (25) Long-term studies on the risks of topical TCIs are necessary.
Phototherapy has been a cornerstone of vitiligo treatment since at least the 1950s, and is particularly effective for generalized vitiligo. The mode of action is believed to be through 2 mechanisms. Ultraviolet radiation inhibits the activation of T cells, Langerhans cells, and other components of the immune system. Ultraviolet light induces migration of melanocytes from perilesional skin and perifollicular melanocytes. There is a known collection of melanoblasts in the outer root sheath, and it has been shown that UV treatment induces these melanocytes to migrate into and undergo maturation in what becomes visibly pigmented areas.
The use of sunlight and sensitizing agents, such as naturally occurring psoralens, reportedly dates back to 1400 BC. Modern dermatologists were using topical and oral psoralens from plant extracts in combination with sunlight or UV lamps in the 1940s. The term PUVA was first used in 1974 when dermatologists began treatment with 8-methoxypsoralen (8-MOP) and UV therapy in the 320-nm to 420-nm range (UVA). (28) PUVA has been used for psoriasis since 1974 and for vitiligo since 1976. (29) It remained the mainstay of vitiligo treatment for many years despite some significant drawbacks. Acute side effects include erythema, burns, scaling, itching, epidermal thickening, and nausea with systemic therapy. Long-term adverse effects include solar elastosis, lentigines, actinic keratosis, and skin cancer, especially SCC. (30), (31)
The first 1380 patients treated for psoriasis were monitored in the PUVA Follow-Up Study which showed that long-term exposure to PUVA increased the risk of SCC in a dose-dependent manner. This study found that by 1989, approximately 13 years after beginning treatments, SCC developed in 1 quarter of patients exposed to high levels of PUVA. (29) An analysis of these patients in 1996 showed that 237 of them had developed 1422 cutaneous SCCs. The authors also concluded that the impact on basal cell carcinoma (BCC) risk was far less, only substantially increasing in patients who had received very high levels of PUVA (more than 337 treatments). (32) A recent meta-analysis of 8 studies has further confirmed the risks of SCC. They found that patients, primarily treated for psoriasis, exposed to high-dose PUVA had a 14-fold higher rate of SCC than patients who were treated with low-dose PUVA. (33) Although it has been more commonly reported in psoriasis patients, there have been at least 3 case reports of PUVA-related skin cancer in patients treated for vitiligo. (30)
Narrowband ultraviolet B therapy (NBUVB) was introduced in 1997 as a further refinement of broadband UVB therapy at 280 to 320 nm. The mechanism of action is similar to UVA therapy except that it uses light of a restricted wavelength peaking at 311 nm, does not require sensitizing agents in order to be effective, and results in lower levels of cumulative radiation doses. Since its introduction, several studies have indicated that NBUVB is superior to PUVA therapy due to its equivalent or better efficacy with reduced side effects and lower risk of subsequent skin cancer. A recent randomized double-blind trial by Yones et al in 2007 confirmed this finding by comparing systemic PUVA to NBVB therapy. The study found 64% of the patients in the NBUVB group saw greater than 50% improvement, compared to only 36% of those in the PUVA group. The color of the repigmented skin was also found to be different between the 2 groups. All NBUVB patients had excellent color match, whereas only 44% of the PUVA group had excellent color match. Psoralen plus UVA therapy seemed to induce a darker repigmentation than was present in unaffected skin, which was considered cosmetically unsatisfactory. In addition, the study also found fewer adverse affects in the NBUVB group: 96% of patients in the PUVA versus 68% in the NBUVB group experienced erythema, and 32% of the patients in the PUVA group had to change from 8-methoxypsoralen (MOP) to 5-MOP due to severe nausea. (31)
To set appropriate expectations, physicians should be aware that certain areas of the body respond better to NBUVB treatment than others. In general, the face and neck seem to respond the best, while the hands and lower limbs have the greatest failure rate. One study evaluated the variants influencing clinical response in 60 patients treated with NBUVB, and found that 68% of patients’ facial lesions had complete repigmentation as compared to only 29% of lower limb lesions. (34)
Narrowband UVB Microphototherapy
A technique called NBUVB microphototherapy, using the BIOSKIN[R] device, was introduced for patients who have less than 20% body surface area involvement. The device generates a beam of light filtered for the NBUVB spectrum that has a shutter to regulate exposure time and different conical hoods (ranging from 1-5 cm in diameter) to permit different sized areas of exposure. It allows for the UVB exposure to be limited to well-defined patches, permits different doses to be delivered to different lesions, and reduces the cumulative dosage of radiation. (35) This method has been shown to be useful in patients with less generalized vitiligo, providing comparable efficacy with less exposure risk. One study treated 734 patients who had less than 30% body surface area involvement. Treatments of once every 2 weeks over 12 months resulted in 69% of the patients achieving normal pigmentation on 75% of the areas that were treated.
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