Use of Tacrolimus Ointment in Vitiligo Alone or in Combination TherapyS. Berti, MD1; G. Buggiani, MD1,2; T. Lotti, MD1,2 1. Department of Pediatric Medicine, Anna Meyer Children’s Hospital of Florence, Florence, Italy2. Department of Dermatological Sciences, University of Florence, Florence, ItalyABSTRACT

Current treatments for vitiligo are largely unsatisfactory. Topical corticosteroids and phototherapy (narrow-band UVB and psoralen+UVA) are the most prescribed, however, these therapies are often not effective and have important side-effect, especially when used for a long time. Many studies have reported the efficacy and safety of tacrolimus ointment in adults and children with vitiligo, particularly when located on the head and neck. Successful treatment is possible when it is combined with other therapies, such as narrow-band UVB, microphototherapy, helium-neon laser, or narrow-band excimer laser.

Key Words: corticosteroids, phototherapy, tacrolimus, vitiligo Vitiligo, an acquired pigmentary skin disorder affecting 1% of the world’s population, is characterized by depigmented macules that correspond histologically with reduced or absent cutaneous melanocytes.1 Although the mechanism of melanocyte dysfunction and disappearance is still unclear, there are 2 major theories regarding its pathogenesis: the autoimmune theory and the autotoxicity theory.2 Current treatments, e.g., topical corticosteroids, narrow-band UVB (NBUVB), and psoralen+UVA (PUVA), are the most prescribed,3 but are not often effective, and corticosteroids aplied to the face may lead to cutaneous atrophy, telangiectasia, and ocular complications. NBUVB treatment requires expensive equipment and trained personnel, and PUVA has been associated with a risk of carcinogenesis.3 Phototherapy and corticosteroids have limited effectiveness, particularly on the acral regions.4

Immunomodulators, such as tacrolimus ointment 0.1% and 0.03% (Protopic®, Astellas), and pimecrolimus cream 1% (Elidel®, Novartis) are approved for treating atopic dermatitis in adult patients and pediatric patients over 2 years of age.2 Tacrolimus can be used as an alternative to topical steroids in many other forms of dermatitis, such as vitiligo. This ointment does not cause the atrophy, telangiectasia, or adverse ocular effects of topical corticosteroids, which has limited application to the face and intertriginous areas.1

Tacrolimus acts on T cells and mast cells, inhibiting T cell activation and the production of proinflammatory cytokines, such as Tumor Necrosis Factor (TNF), whose levels are higher in vitiligo lesional skin.5 Moreover, it prevents the release of proinflammatory mediators in mast cells by degranulation.1 Recently, the successful treatment of vitiligo with tacrolimus has been reported (See Table 1).

Xu et al.1 studied 30 vitiligo patients who were treated with tacrolimus ointment for 4 months or more. Of these, 83.3% patients showed some repigmentation at the end of 4 months. In

particular, 1 patient achieved excellent (100%) repigmentation at the end of 14 weeks, and another 2 patients exhibited 100% repigmentation at the end of 16 weeks. Of these 25 patients, repigmentation was graded as complete in 20%, moderate in 20%, mild in 23.3%, and minimal in 20%. Of the patients with segmental vitiligo of the head and neck, 80% showed the some response, but there was no statistical significance between segmental and vulgaris vitiligo. Patients who had vitiligo for more than 5 years also responded well. Repigmentation is notoriously difficult to achieve. The mean percentage of repigmentation on the head and neck was greater than that seen on the trunk and extremities. The only reported side-effect was initial burning on application in 4 patients. The study found that tacrolimus was a safe and effective therapy for vitiligo, especially when it involved the head and neck.

Reference Evidence

Xu, et al.1 83.3% (25/30) repigmentation: 12% excellent 20% complete 20% moderate 23.3% mild 20% minimal

Choi, et al.2 69.3% repigmentation: (no difference of disease location or age of onset; better response in short-duration disease)

Hartmann, et al.4

81% repigmentation on face 80% repigmentation on extremities (when in occlusion)

Table 1: Recent studies on the treatment of vitiligo with tacrolimus ointment

In 2008, Choi et al.2 studied 79 patients; 52 were treated with tacrolimus and 27 with topical corticosteroids. Topical immunomodulators were found to be as effective as topical steroids and patient response was faster than that once obtained by topical steroids. The patients studied were then divided in 3 groups according to the location of vitiligo lesions: 59 had lesions on the face, 53 on the hands, and 23 on the feet. After treatment, 38 showed repigmentation on the face, 31 on the hands, and 9 on the feet. The investigators could not find any statistically significant differences in the ratio of lesions, which showed response among these 3 groups. They further divided their study into 2 groups: long-duration (>12 months) and short-duration (<12 months). The short-duration group showed a higher rate of response that was statistically significant. There was no statistical difference between the group of younger (i.e., <18 years of age) and older (i.e., >18 years of age) patients. The faster response of topical immunomodulators may be related to their effects on melanocytes, i.e., the proliferation of melanocytes is enhanced by a tacrolimustreated keratinocyte supernatant, which is rich with stem cell factor and matrix metallopeptidase-9.2 These results coincide with those of Lepe et al.7 who, in a study of 20 patients, documented that clobetasol and tacrolimus showed more than 75% repigmentation in 5 patients. There were no statistically significant differences between these 2 treatments (p>0.05).

In a placebo-controlled 12-month prospective study of 31 vitiligo patients, Hartmann et al.4 documented the safety and efficacy of tacrolimus, even in those with disease of long-standing duration and in those who received long-term treatment. Tacrolimus may significantly improve the quality of life of affected patients. In the region beyond the face and neck, additional occlusion with polyurethane foil or hydrocolloid dressing may significantly enhance the therapeutic results and may shorten the time until the start of repigmentation. When tacrolimus

was applied occlusively, repigmentation was documented in 81% of patients with facial lesions, and in 80% of patients with lesions on the extremities.

Many studies suggest the associated use of tacrolimus with other therapeutic options to improve the rate of repigmentation.8-10 Lotti et al.8 studied 458 patients with vitiligo that affected less than 10% of their skin surface. A 311nm narrow-band microphototherapy (Bio Skin®, Cropper Medical) was given alone or in combination with topical treatment, (i.e., tacrolimus, pimecrolimus, betamethasone dipropionate 0.05%, calcipotriol, or phenylalanine cream). The investigators reported that targeted combination therapies in vitiligo were remarkably more effective than a single treatment. Fai et al.9 studied 110 patients with chronic and refractory vitiligo in a period of 30 months, and suggested that the combination of topical tacrolimus with NBUVB phototherapy as an alternative approach that could be highly effective for the treatment of refractory vitiligo located on the face, trunk, and limbs. However, longterm data and randomized controlled trials on a large number of patients are required.

The association of tacrolimus with NBUVB excimer laser has been reported to improve the repigmentation rate, but it is associated with the possibility of unexpected burns.10 Recently, an association between helium-neon laser and topical tacrolimus has been proposed to be effective without infringing on the issue of additional photocarcinogenic risk. Since the underlying repigmentation mechanisms of these 2 modalities are different, it is reasonable to propose that combining them may produce better clinical results.11 It is important to remember that NBUVB, microphototherapy, UVB narrow-band excimer laser, and helium-neon laser still have the potential to produce skin cancer. In fact they are effective for treating vitiligo, especially when combined with tacrolimus ointment. Based on the evidence, these treatment options appear to be safe and well tolerated, even though they may have carcinogenic potential, which is extremely important for children affected by vitiligo.

Silverberg et al.12 reported that the use of tacrolimus ointment is an effective alternative treatment for vitiligo in children, particularly involving head and neck areas. Kanwar et al. studied 25 Asian children with vitiligo (i.e., 54.5% had vitiligo vulgaris, 40.9% had focal vitiligo, and 4.5% had segmental vitiligo). In this study, application with topical 0.03% tacrolimus applied twice daily for 12 weeks was shown to be an effective and well-tolerated treatment. Response was graded as complete (i.e., >75% repigmentation) in 57.9% of the patients, moderate (i.e., 50%-75% repigmentation) in 26.3%, mild (i.e., <50% repigmentation) in 15.7%, and 3 patients had no response. Side-effects, such as pruritus and burn, which was noted in only 3 patients, were minimal.13

ConclusionTacrolimus ointment is effective and safe for treating vitiligo, especially when it is located on the head and neck, or when the disease is long-lasting. Childhood vitiligo can be successfully treated with tacrolimus, sparing the adverse events seen from topical corticosteroids. Although topical application is not associated with systemic immunosuppression, the long-term risk from the application of tacrolimus ointment to the skin is still unknown. Further studies with topical tacrolimus for the treatment of vitiligo with long-term follow-up are necessary to better evaluate the safety, efficacy, and stability of repigmentation, especially when associated with focused UVB microphototherapy.

ADVANCES CONTINUE IN VITILIGO TREATMENTJul 1, 2004 By: Cheryl Guttman Dermatology Times Washington - Treatment of vitiligo has advanced significantly recently, although older therapies still retain an important place in the management of this therapeutically challenging disease, says pearl E. Grimes, M.D. Speaking at the annual meeting of the American Academy of Dermatology, Dr. Grimes reviewed information about roles for topical immunomodulators, targeted light therapy, and narrowband UVB phototherapy, and discussed new information on potential risks associated with use of dihydroxyacetone-containing self-tanners and depigmentation therapy with mono-benzone cream (Benoquin).Efficacy of the topical immunomodulator tacrolimus ointment (protopic, Fujisawa Healthcare, Inc.) as a treatment for vitiligo was first reported by Dr. Grimes several years ago, and since that time other researchers have produced corroborating evidence of its benefits as a therapeutic modality for both adults and children. In addition, preliminary data suggest that pimecrolimus (Elidel, Novartis) offers similar efficacy, says Dr. Grimes, associate clinical professor of dermatology, David Geffen School of Medicine, University of California, Los Angeles, and director, Vitiligo and pigmentation Institute of Southern California.

tacrolimus most effective Findings from initial studies showed that tacrolimus was most effective for inducing repigmentation on sun-exposed areas of skin. Subsequently, however, it has been shown that a synergistic benefit can be achieved using concomitant narrowband UVB phototherapy to treat anatomic regions normally covered by clothing. Results of a recently published randomized, double-blind, split-side trial by Lepe et al. (Arch Dermatol 2003; 139:651-654) enrolling 20 children with vitiligo provided an excellent illustration of the efficacy of tacrolimus and its safety advantages. In that study, tacrolimus ointment 0.1 percent was almost as effective as clobetasol propionate 0.05 percent in inducing repigmentation. However, corticosteroid use was associated with development of skin atrophy in three patients and telangiectasia in two, while the only adverse effect associated with tacrolimus was a burning sensation in two patients."A major advantage of tacrolimus is that it is well-tolerated when used for extended periods, although there still remains a need for even longer term safety data," Dr. Grimes says. The main limitations of tacrolimus relate to aesthetics and economics. Recognizing that patients may dislike the greasy ointment base of tacrolimus and in an effort to minimize treatment cost, Dr. Grimes says she often uses tacrolimus in combination regimens. For example, she may recommend that patients use pimecrolimus cream in the morning and tacrolimus ointment in the evening, or she may start treatment with a high potency corticosteroid used once daily in the morning with tacrolimus applied only in the evening, switching to twice-daily tacrolimus treatment after four to six weeks. Since the first report describing narrowband UVB as a treatment for vitiligo by Westerhof and colleagues in 1997, several other studies have demonstrated its efficacy and safety.

"Narrowband UVB has become my treatment of choice for patients with moderate to severe vitiligo, defined as having more than 15 to 20 percent body surface area involvement," Dr. Grimes says. She reported results from her own experience using narrowband UVB to treat 95 patients. The population was 40 percent Caucasian, 35 percent Hispanic, 13 percent African American, 9 percent Asian, and 3 percent were from other ethnic groups. The mean number of treatments administered was 41, but there was a relationship between response and number of treatments received. With 15 treatments, 43 percent of patients achieved >50 percent repigmentation whereas 71 percent of patients receiving more than 50 treatments repigmented more than 50 percent.

UVB phototherapy advanced for vitiligo treatment "We have not abandoned PUVA, but narrowband UVB has the advantages of avoiding systemic side effects and the need for ocular protection while offering an excellent safety profile for use in children. However, it does require sessions three times per week to attain the maximum efficacy that can be achieved with PUVA," Dr. Grimes says. For patients with less extensive disease, targeted phototherapy offers a safe and effective treatment alternative. A variety of light units emitting at different wavelengths are available, although Dr. Grimes indicated the number one system in her practice is a combination UVA/UVB device (TheraLight) that allows for both targeted UVB phototherapy and targeted UVA with psoralen. Dr. Grimes' extensive experience treating vitiligo has also led to some clinically important observations regarding existing management modalities. For example, while depigmentation therapy with monobenzone cream continues to be an important alternative for patients who have greater than 50 percent pigment loss and who have either failed various repigmentation therapies or have no desire to undergo repigmentation, use of that modality can sometimes be associated with delayed repigmentation that is refractory to retreatment. "It seems that monobenzone knocks out melanocytes in the epidermis, but does not affect the follicular reservoir. Consequently, while these patients depigment beautifully, one to two years later, they may repigment as the follicular melanocytes become activated. Retreatment with 20 percent monobenzone is ineffective, and the pigmentation has also proven refractory to depigmentation with 40 percent monobenzone combined with chemical peels. Ultimately, treatment involves repigmentation using PUVA or narrowband UVB," Dr. Grimes says. Although treatment for vitiligo ideally produces permanent repigmentation, cosmetic camouflage remains an integral component in management. As a new caveat, however, years of experience indicate that regular use of dihydroxyacetone-containing self-tanners may lessen the response to repigmentation therapies, and new data may support that observation. "Dihydroxyacetone may inhibit repigmentation by increasing hydrogen peroxide and oxidative stress. ... We are now recommending that patients use cosmetics to camouflage areas of depigmentation,"Dr. Grimes says. Dr. Grimes has no financial interest in any of the modalities she mentioned

UVB spars with PUVA for tough vitiligoFeb 1, 2004 By: Cheryl Guttman Dermatology Times

Bangkok, Thailand - Narrow band ultraviolet B (NBUVB) phototherapy can offer a well-tolerated and effective modality for achieving repigmentation of vitiligo in Pediatric and adult Asian patients, said Natta Rajatanavin, M.D. In a recent publication [J Am Acad Dermatol 2003;49:473-6], Dr. Rajatanavin, associate professor of medicine and head of the phototherapy unit, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, and colleagues reported their experience using NBUVB as monotherapy to treat vitiligo in a series of 60 Thai patients. The subjects in their three-year retrospective study ranged in age from 11 to 61, and all were selected for NBUVB because they had failed previous topical therapy or responded insufficiently to or could not tolerate PUVA. "Based on our analyses, we consider NBUVB the treatment of choice for progressive, symmetrical vitiligo, particularly when lesions are present on the face, trunk, arms, and legs. Compared with PUVA, NBUVB seems to offer comparable efficacy and has the additional advantages of causing less hyperpigmentation of normal skin and avoiding hyperkeratosis of vitiliginous skin. For those reasons, the majority of our patients who had received prior PUVA indicated a preference for NBUVB," Dr. Rajatanavin said."However, our experience indicates that patients whose vitiligo has already failed to respond to PUVA probably represent a pre-selected group with treatment-resistant disease," she added. Of the 60 patients included in the study, two were skin type V and the rest were skin types III (25 patients) and IV (33 patients). Vitiligo was generalized in 53 individuals and localized in seven, and the body surface area of involvement ranged from <5 percent to 50 percent. Duration of disease averaged 8.2 years and varied from six months to 22 years. NBUVB sessions were scheduled twice a week on non-consecutive days and involved total body exposure using a standard dosing protocol that began with a 100 mJ/cm2 dose in all patients. The dose was raised incrementally thereafter and treatment was continued to achieve maximum repigmentation unless the patient was satisfied or failed to achieve 25 percent improvement after 40 to 50 sessions. Treatment duration ranged from five months to two years and patients received between 36 and 175 treatments. Treatment response, defined as >50 percent repigmentation, was achieved in 25 (42 percent) of the 60 patients with 20 patients (33 percent) achieving >75 percent repigmentation. Five patients had no response and disease progressed in three individuals. Analyses of factors predicting response showed that good responses were achieved in patients with symmetrical vitiligo on the face, trunk, arms, and legs. "Lesions of the face and body responded fairly quickly with progression halting within the first 10 treatments. However, many additional exposures were needed to achieve cosmetically acceptable repigmentation," Dr. Rajatanavin said. Lesions of the hands and feet rarely repigmented more than 25 percent. In addition, the rate of responders was significantly lower among the subgroup of patients who had previously failed PUVA relative to those who had received topical therapy only. Among 24 patients without a history of PUVA treatment, 16 (67 percent) responded compared with only nine (25 percent) of the 36 patients who had received PUVA. The proportion of patients who had received prior PUVA was 36 percent among responders and 77 percent among no responders. Other variables examined as potential predictors of response included disease duration, patient age, gender, and skin type, but none of those features differed significantly between responders and no responders.The dosing protocol used at Ramathibodi Hospital involved dose increases of 20 percent per treatment over the first 10 treatments followed by 10 percent increases until session 20.

Thereafter, the increments per treatment were reduced to five percent, and the dose continued to be raised until 50 percent repigmentation was achieved or the patient was satisfied. "In a limited number of other reports on NBUVB phototherapy for vitiligo, the protocols have varied with starting doses ranging anywhere between 75 and 280 J/cm2. In initiating treatment with 100 mJ/cm2, we encountered a mild phototoxic reaction, but that was restricted to persons with disease involving more than 10 percent of body surface area. Based on the safety observed in patients with less extensive disease, we now use a starting dose of 200 mJ/cm2 if the lesion is less than 10 percent of body surface area and follow our same protocol for dose increments," Dr. Rajatanavin said. The NBUVB phototherapy was generally well tolerated using that approach. No patient discontinued treatment because of adverse events, and only 10 percent of patients experienced more than mild erythema or pruritus. Nine responders continued to be seen after treatment cessation, and during follow-up extending up to two years, vitiligo remained in remission in only five patients. Among the other four individuals, vitiligo either recurred or new lesions developed between three and 24 months after NBUVB ended. Three of those patients responded to NBUVB retreatment, although more slowly than they did during the first course. There are several treatments for Vitiligo, but there is still no vitiligo cure.   Treatments include steroids, vitamins cosmetic creams, skin grafts and the modern treatment of choice is narrow band UVB phototherapy.

Mometasone cream versus pimecrolimus cream for the treatment of childhood localized vitiligo.Köse O, Arca E, Kurumlu Z.Department of Dermatology, Gülhane School of Medicine, Ankara, Turkey. okose@gata.edu.trAbstractBACKGROUND: With regard to the lack of effective treatment modalities for childhood localized vitiligo, the search for newer therapeutic agents continues.OBJECTIVE: To conduct an open, comparative trial to evaluate the clinical efficacy and safety of topical mometasone cream and pimecrolimus cream in the treatment of childhood vitiligo.METHODS: Fifty patients with childhood vitiligo were included in the study. Patients were treated for 3 months either with mometasone cream (0.1%) once daily or with pimecrolimus cream (1%) twice daily.RESULTS: Forty patients, 20 from each group, completed the study. The two drugs were found to be statistically significantly effective for diminishing lesion size (Z = 3.070,p = 0.002 andZ = 3.845,p < 0.001, respectively). There were no statistical differences between the two drugs:Z = 1.427,p = 0.154 (mometasone non-inferiority to pimecrolimus). The mean repigmentation rate was 65% in the mometasone group and 42% in the pimecrolimus group at the end of therapy. Atrophy, telangiectasia and erythema were observed in two patients (10%) in the mometasone cream group and a burning sensation and pruritus were observed in two patients (10%) in the pimecrolimus cream group; drop-out was not related to the observed adverse effects.

CONCLUSION: Mometasone cream was found to be effective in the treatment of vitiligo on any part of the body. Pimecrolimus was not effective on the body except for the face in childhood localized vitiligo.

Vitiligo treatmentsvitiligo phototherapy: effectiveness of UVB for vitiligo treatmentAmerican Academy of Dermatology. Study Confirms Effectiveness of Revolutionary Vitiligo Treatment SCHAUMBURG, IL (July 12, 2001) Imagine feeling perfectly healthy on the inside, but on the outside something looks wrong. For millions of people who suffer from vitiligo, a disease in which patients experience a complete loss of pigment in localized areas of the skin, this feeling is one they know all too well. In a new study by dermatologist Henry W. Lim, MD, chairman of the department of dermatology at Henry Ford Hospital, Detroit, Mich., the effectiveness of narrow-band UVB (NB-UVB) phototherapy as treatment for vitiligo was examined in a small sampling of patients. The results of the study are promising for this often hard-to-treat skin condition. After completing an average of 19 treatments with NB-UVB phototherapy, five of the seven vitiligo patients that participated in the study showed greater than 75 percent repigmentation. Additionally, one patient has remained repigmented 11 months after phototherapy was discontinued. "The successful repigmentation that these patients experienced is quite remarkable," explained Dr. Lim, co-author of "Narrow-Band Ultraviolet B is a Useful and Well-Tolerated Treatment for Vitiligo" published in the June 2001 issue of the Journal of the American Academy of Dermatology. "Vitiligo is a difficult skin condition to treat, and patients are often frustrated because results from some of the other current treatments are not nearly as favourable." Vitiligo is a disease in which patients have a complete loss of pigment in localized areas of the skin. These areas, often around the mouth and eyes, become completely white. As a result, vitiligo can be cosmetically disfiguring, especially for dark-skinned people. Vitiligo affects 1 percent to 2 percent of the worldwide population and about half of the people who develop it do so before the age of 20. About one fifth of those with vitiligo have a family member with this condition. Vitiligo usually affects both sides of the body, and although the cause is generally not known, it is believed to be an autoimmune process. During the twelve-month trial period, 11 patients participated in Dr. Lim s study. Therapy was administered three times a week and affected segments of the body were treated with NB-UVB, a light source that emits a very narrow spectrum of UVB, the portion of sunlight that causes sunburn. The dose of radiation was increased by 15 percent for each treatment. If mild burning, pain or blistering developed, the irradiation dose was decreased. Once the desirable 75 percent repigmentation was achieved, the frequency of treatments was tapered to twice a week for four weeks, then weekly for an additional four weeks. NB-UVB therapy has several advantages over other therapies for vitiligo. While topical corticosteroid therapy has a success rate of 56 percent, long-term use of corticosteroids can result in thinning of the skin, stretch marks, and dilation of blood vessels. Another treatment option is oral or topical psoralen plus UVA (PUVA), the latter which has a success rate of 51 percent. However, patients need to ingest or apply psoralen before getting the light treatment, and long term use of oral PUVA for another skin disease, psoriasis, has been associated with an increased incidence of skin cancer. Presently, there are only a few centres in the United States that have the capabilities for NB-UVB therapy; therefore patients undergoing this therapy have long distances

to commute. While NB-UVB therapy has been used in Europe since the mid-1980s, there has not been any evidence that it causes an increase in skin cancer "Our findings confirmed that narrow-band UVB therapy is a useful and well-tolerated treatment option for patients with vitiligo," says Dr. Lim of the American Academy of Dermatology. "Although more research needs to be conducted, the successes thus far are promising to those who suffer from the psychological and physical effects of vitiligo." cortisone steroid treatment for vitiligo still dangerousHydrocortisone steroids once used liberally in the 1980's often cause more problems than they address. Steroids may initially help for a very short time, however they have often dangerous and longer lasting side effects such thinning of the skin, dilated blood vessels, bruising, skin colour changes and hair loss. Vitiligo often flares up much worse after discontinuing steroids. Long term use of Hydrocortisone can cause liver and kidney disease and worsen psoriasis. Large amounts of Hydrocortisone are found in the Skin Cap and Blue Cap and other "zinc" sprays, hence these products can be very dangerous. Stop using the steroids and Vitiligo usually returns many times worse than it was prior to using steroids to treat the Vitiligo. vitamins, drugs and diets for vitiligoThere is no CLINICAL evidence that exists anywhere that proves vitamins, homeopathic or a special diet can improve, treat or cure Vitiligo. If you are interested in Vitamins or moisturising lotions, you are best to see your pharmacist or Dermatologist than waste your money on expensive and "unique" home made products found on the internet. If only it were that simple. Vitiligo has been known about for at least five thousand years and if any particular nutrient had been proved to be beneficial surely we would all have heard about it by now! If you really want to spend money on vitamins, go to your pharmacist and buy quality products, not home made "cures" on the internet.  UVB narrow band phototherapy for vitiligoUVB narrow band phototherapy is extremely efficient Vitiligo treatment. particularly Narrow Band UVB that promotes normal skin growth patterns. You can order our home Vitiligo phototherapy treatment here; online ordering.

Topical tacrolimus and the 308-nm excimer laser: a synergistic combination for the treatment of vitiligo.Author(s): Passeron T, Ostovari N, Zakaria W, Fontas E, Larrouy JC, Lacour JP, Ortonne JPAffiliation(s): Department of Dermatology, Hopital de l'Archet 2, Nice, France. t.passeron@free.frPublication date & source: 2004-09, Arch Dermatol., 140(9):1065-9.Publication type: Clinical Trial; Randomized Controlled TrialOBJECTIVE: To compare the efficacy of combined tacrolimus and 308-nm excimer laser therapy vs 308-nm excimer laser monotherapy in treating vitiligo. DESIGN: Comparative, prospective, randomized, intraindividual study. PATIENTS: Fourteen patients, aged 12 to 63 years, with Fitzpatrick skin types II to IV. INTERVENTION: For each patient, 4 to 10 target lesions were chosen. The treatment applied to each target lesion was randomized by drawing lots. Each lesion was treated twice a week by the 308-nm excimer laser, for a total of 24 sessions. Initial fluences were 12 mcal/cm(2) (50 mJ/cm(2)) less than the minimal erythemal dose in vitiliginous skin. Then, fluences were increased by 12 mcal/cm(2) every second session.

Moreover, topical 0.1% tacrolimus ointment was applied twice daily on target lesions receiving the combined tacrolimus and excimer laser treatment (group A). Group B target lesions received only excimer laser monotherapy. For each treated lesion, the untreated lesion on the opposite side served as the control. Tolerance was evaluated by a visual analog scale, and secondary events were recorded at each session. MAIN OUTCOME MEASURE: Treatment efficacy, which was blindly evaluated by 2 independent physicians by direct and polarized light photographs taken before and after treatment. RESULTS: Forty-three lesions were treated (23 in group A and 20 in group B). All patients completed the study. Repigmentation was observed in all group A lesions (100%) and in 17 (85%) of the 20 group B lesions. Repigmentation was not observed in the untreated lesions (control group). A repigmentation rate of 75% or more was obtained in 16 (70%) of the 23 group A lesions and in 4 (20%) of the 20 group B lesions. In UV-sensitive areas (the face, neck, trunk, and limbs, with the exception of bony prominences and extremities), 10 (77%) of 13 group A lesions had a repigmentation rate of 75% or more vs 4 (57%) of 7 group B lesions. In classically UV-resistant areas, 6 (60%) of 10 group A lesions had a repigmentation rate of 75% or more vs 0 of the 13 group B lesions. The mean number of sessions necessary for an improvement of repigmentation was 10 in group A and 12 in group B. Adverse effects have been limited, and tolerance was excellent. CONCLUSIONS: The combination treatment of 0.1% tacrolimus ointment plus the 308-nm excimer laser is superior to 308-nm excimer laser monotherapy for the treatment of UV-resistant vitiliginous lesions (P<.002). The efficacy and the good tolerance of the 308-nm excimer laser in monotherapy for treating localized vitiligo were also confirmed, but this treatment regimen should be proposed only for UV-sensitive areas.

An open randomized study to compare narrow band UVB, topical pimecrolimus and topical tacrolimus in the treatment of vitiligo.Author(s): Stinco G, Piccirillo F, Forcione M, Valent F, Patrone PAffiliation(s): Department of Clinical and Experimental Pathology and Medicine, Institute of Dermatology, University of Udine, Ospedale San Michele di Gemona, piazza Rodolone 1, 33013 Gemona del Friuli (Udine), Italy. giuseppe.stinco@uniud.itPublication date & source: 2009-11, Eur J Dermatol., 19(6):588-93. Epub 2009 Aug 4.Publication type: Comparative Study; Randomized Controlled TrialVitiligo is an acquired loss of pigmentation and its treatment remains very difficult up to date. Narrow band ultraviolet B (NB-UVB) and topical immunomodulators are included among the most innovative approaches to vitiligo. We evaluated the efficacy and tolerability of NB-UVB, topical pimecrolimus and tacrolimus in the treatment of vitiligo. Adult patients with chronic and stable vitiligo refractory to conventional therapies were enrolled in an open parallel groups study. The patients were scheduled on the basis of a computer-generated randomization into three groups: 13 patients received NB-UVB phototherapy 3 times a week, 15 patients were treated with pimecrolimus 1% cream b.i.d. and 16 patients applied tacrolimus 0.1% ointment b.i.d. All three treatment regimens were performed for 24 weeks. At baseline and every three weeks for the whole period of therapy the patients were examined through digital photographs and, at the end of the study, based on the percentage of repigmentation, treatment outcome was classified as "absent" (0), "slight" (< 25%), mild (25-49%), "moderate" (50-74%), and "excellent" (> 75%). During the whole period of the study, possible side effects were recorded. The response to

treatments varied according to the anatomical location of the lesions. No statistically significant differences in repigmentation for any anatomical site were recorded with the three treatments. The best results were obtained for lesions of the face with pimecrolimus cream and tacrolimus ointment and of the neck with NB-UVB. Statistically significant differences in repigmentation between photo-exposed and covered skin areas were recorded although the patients were asked to avoid direct UV exposition and to apply a very high protection sun screen on vitiligo lesions. All three treatments should be considered as a good option in the treatment of vitiligo. NB-UVB irradiation may represent the optimal choice in generalized vitiligo with topical immunomodulators in localized vitiligo.

Response of vitiligo to once- vs. twice-daily topical tacrolimus: a controlled prospective, randomized, observer-blinded trial.Author(s): Radakovic S, Breier-Maly J, Konschitzky R, Kittler H, Sator P, Hoenigsmann H, Tanew AAffiliation(s): Division of Special and Environmental Dermatology, Medical University of Vienna, Vienna, Austria. sonja.radakovic@meduniwien.ac.atPublication date & source: 2009-08, J Eur Acad Dermatol Venereol., 23(8):951-3. Epub 2009 Jun 2.Publication type: Randomized Controlled TrialBACKGROUND: A few studies on the treatment of vitiligo with topical tacrolimus have been published and showed promising results. However, most of these trials were uncontrolled. OBJECTIVE: This study aims to assess the response of vitiligo to once- or twice-daily treatment with 0.1% tacrolimus in a controlled, randomized, observer-blinded study. METHODS: Seventeen patients with generalized vitiligo were enrolled in this study. In each patient, two lesions were selected and randomized to treatment with either once- or twice-daily application of 0.1% tacrolimus for a total period of 6 months. In 10 patients, a third patch was left untreated to serve as a control. RESULTS: Fifteen patients with 40 target lesions completed the study. Twice-daily treatment induced excellent (> 75%) repigmentation in two lesions, moderate (> 25-50%) and poor (1-25%) repigmentation in four lesions each, and no response in five lesions. Once-daily treatment resulted in moderate repigmentation in two lesions and poor repigmentation in five lesions, whereas no effect was observed in the remaining eight lesions. One out of 10 control lesions developed moderate spontaneous repigmentation, the other nine remained unchanged. Besides the frequency of tacrolimus application, the treatment outcome was determined by the localization of the affected areas with the facial region showing the best response. CONCLUSIONS: Tacrolimus ointment appears to be an effective treatment option for facial vitiligo. A guarded prognosis is advisable for vitiliginous lesions on other localizations. Treatment must be applied twice daily for optimum response.

Time-kinetic study of repigmentation in vitiligo patients by tacrolimus or pimecrolimus.Author(s): Lubaki LJ, Ghanem G, Vereecken P, Fouty E, Benammar L, Vadoud-Seyedi J, Dell'Anna ML, Briganti S, Picardo M, Heenen M

Affiliation(s): Department of Dermatology, Hopital Erasme, Universite Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium. klubaki@ulb.ac.bePublication date & source: 2010-03, Arch Dermatol Res., 302(2):131-7. Epub 2009 Jun 23.Publication type: Randomized Controlled TrialNew topical immunomodulators have been reported to cause repigmentation of vitiligo lesions. However, time-kinetics of such repigmentation in different anatomic locations is not well known. We performed a randomized double-blind placebo control study with tacrolimus versus the vehicle and a nonrandomized control study with pimecrolimus to evaluate the time to reach significant pigmentation, its duration and extent in treated areas. Antioxidant status of serum was also assessed. Twenty patients, in the tacrolimus study, had one pair of lesions on different localizations, and 20 on face and/or upper limbs for pimecrolimus. The extent of repigmentation was evaluated by slides and mapmakings at baseline and every 4 weeks during 7 months. Adverse events were recorded. The derivatives of oxygen metabolites, the ferric reducing ability of serum and vitamin E were assessed. Three groups of patients were identified with the tacrolimus study. Eight had no significant change in response characterized by a parallel increase of repigmentation or none in treated and control areas. Nine had a better repigmentation to tacrolimus at fifth month of treatment. Three had a marked repigmentation in control areas at the end of treatment. Repigmentation was significant on the face compared to upper-limbs with pimecrolimus from fourth to seventh month. A significant reduction of oxidative stress and an increase in antioxidant capacity in serum of patients treated with topical tacrolimus was observed, while those treated with pimecrolimus did not show any significant changes but an increase in vitamin E. Our work defines three periods in repigmentation, triggering during the first 4 months, increase in pigmentation with tacrolimus and a plateau or a sustained repigmentation. The continuity of the treatment seems necessary to ensure a prolonged repigmenting effect and even an enhanced one, such as the one we observed on the face with pimecrolimus. The extent of repigmentation was more significant on the face compared to other locations probably due to differences in melanocyte density. Furthermore, we did not find any relationship between repigmentation and the duration of vitiligo. Tacrolimus was able to reduce the systemic oxidative stress independently from its repigmenting capacity. Both drugs were well tolerated.

A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo.Author(s): Lepe V, Moncada B, Castanedo-Cazares JP, Torres-Alvarez MB, Ortiz CA, Torres-Rubalcava ABAffiliation(s): Dermatology Department, Dr Ignacio Morones Prieto Hospital Central, Universidad Autonoma de San Luis Potosi, 2405 V Carranza Avenue, Zona Universitaria, 78210 San Luis Potosi, Mexico.Publication date & source: 2003-05, Arch Dermatol., 139(5):581-5.Publication type: Clinical Trial; Randomized Controlled TrialOBJECTIVE: To assess the safety and efficacy of topical 0.1% tacrolimus vs 0.05% clobetasol propionate. DESIGN: Randomized double-blind trial. SETTING: Department of Dermatology, Hospital Central Dr Ignacio Morones Prieto, San Luis Potosi, Mexico. PARTICIPANTS: From 20 children with vitiligo, 2 symmetrical lesions of about the same size and evolution time were selected. They were devoid of any topical or systemic therapy for 2 months prior to

inclusion.Interventions Treatment with topical tacrolimus and clobetasol for a 2-month period. MAIN OUTCOMES MEASURES: The grade of repigmentation was evaluated by color slides at baseline and again at every 2-week visit. The slides were analyzed by 2 clinicians unrelated to the study and by a morphometric digitalized computer program. Characteristics of pigment, time of response, symptoms, telangiectasias, and atrophy were evaluated every 2 weeks. RESULTS: Eighteen (90%) of the 20 patients experienced some repigmentation. The mean percentage of repigmentation was 49.3% for clobetasol and 41.3% for tacrolimus. Lesions in 3 patients using clobetasol presented atrophy, and 2 lesions incurred telangiectasias; tacrolimus caused a burning sensation in 2 lesions. CONCLUSIONS: Tacrolimus proved almost as effective as clobetasol propionate to restore skin color in lesions of vitiligo in children. Because it does not produce atrophy or other adverse effects, tacrolimus may be very useful for younger patients and for sensitive areas of the skin such as eyelids, and it should be considered in other skin disorders currently treated with topical steroids for prolonged periods.

Combined excimer laser and topical tacrolimus for the treatment of vitiligo: a pilot study.Author(s): Kawalek AZ, Spencer JM, Phelps RGAffiliation(s): Department of Dermatology Mount Sinai School of Medicine, New York, New York, USA.Publication date & source: 2004-02, Dermatol Surg., 30(2 Pt 1):130-5.Publication type: Clinical Trial; Randomized Controlled TrialBACKGROUND: Vitiligo is an acquired skin disorder that is characterized by well-defined, often symmetric white patches. Although current therapeutic modalities are directed toward increasing melanocyte melanin production, few treatment modalities address the immunologic nature of the disease. OBJECTIVE: To determine whether excimer laser, a known therapeutic modality, in combination with tacrolimus, a topical immunomodulator, accelerate response time and/or improve the degree of response in patients with this disorder. METHODS: Eight subjects diagnosed with vitiligo were recruited to participate in this institutional review board-approved double-blind, placebo-controlled study. Twenty-four symmetric vitiliginous patches (elbows, knees) from eight subjects received excimer laser treatment three times per week for 24 treatments or 10 weeks. Additionally, topical tacrolimus 0.1% ointment (Protopic) and placebo (Aquaphor) were applied to randomized patches (left or right) twice daily throughout the length of the trial. Vitiliginous patches were monitored with photographs at baseline, every 2 weeks, and 6 months after treatment. Biopsies were performed on subjects with significant results. RESULTS: Twenty vitiliginous patches from six subjects qualified for evaluation. Fifty percent of patches treated with combination excimer laser and tacrolimus achieved a successful response (75% repigmentation) compared with 20% for the placebo group. Subjects who responded successfully repigmented faster (19%) with combination therapy compared with excimer laser alone. Additionally, three subjects experienced transient hyperpigmentation in lesions treated with combination therapy. CONCLUSION: Combining topical immunomodulators with known phototherapeutic modalities may represent a key advancement in the treatment of disease.

Efficacy and safety of pimecrolimus cream 1% in adult patients with vitiligo: Results of a randomized, double-blind, vehicle-controlled study.Author(s): Dawid M, Veensalu M, Grassberger M, Wolff KAffiliation(s): Division of General Dermatology,Department of Dermatology,University of Vienna,Vienna General Hospital, Vienna, Austria.Publication date & source: 2006-11, J Dtsch Dermatol Ges., 4(11):942-6.Publication type: Background: Vitiligo is an acquired, pigmentary skin disorder which is disfiguring and difficult to treat. In an earlier open label study in adult patients with vitiligo, pimecrolimus cream 1% was reported to have similar efficacy as clobetasol propionate 0.05%. We performed a double-blind, intrapatient comparison of pimecrolimus cream 1% with placebo cream. Patients and methods: Twenty adult Caucasians with symmetrical vitiligo (predominantly on extremities, none in the face) were treated b.i.d. for 6 months left/right with pimecrolimus/vehicle (N = 10) or vehicle/pimecrolimus (N = 10), respectively. Primary efficacy endpoint was the size of the target lesion at month 6 and secondary efficacy endpoint was re-pigmentation. Results: Treatment with pimecrolimus cream 1% or vehicle resulted in no significant change in mean target lesion size. Modest repigmentation (1-25%) was noted with pimecrolimus at month 2 in 12 of 17 patients (vehicle: 9 of 17 patients). Afterwards, the number of patients who experienced an improvement of pigmentation steadily decreased (3 of 14 patients with pimecrolimus and 2 of 14 with placebo at month 6).Treatment was well tolerated.There were no treatment-related adverse events, no induction of skin atrophy nor any other application site side effects. Conclusion: In this group of adult patients with symmetrical vitiligo, treatment of body lesions (except face) with pimecrolimus cream 1% could not be shown to be effective.

Topical treatment and combination approaches for vitiligo: new insights, new developments.Author(s): Hossani-Madani AR, Halder RMAffiliation(s): Department of Dermatology, Howard University College of Medicine, Washington, DC 20060, USA.Publication date & source: 2010-02, G Ital Dermatol Venereol., 145(1):57-78.Publication type: ReviewDespite much research done involving elucidation of the pathogenesis of vitiligo, a precise cause is still not known. Prevalent hypotheses include the autoimmune, genetic, neural, self-destruction, growth factor deficiency, viral, and convergence theories, which have served as the basis for treatment formulation. Topical therapies have been a mainstay of vitiligo treatment, with or without phototherapy. Topical treatments used in the treatment of vitiligo include steroids, calcineurin inhibitors, vitamin D analogues, pseudocatalase, and depigmenting agents. Combination therapies are used to improve the success rate of repigmentation. In this article, we have examined randomized controlled trials utilizing topical treatments used as monotherapy or combination therapy. Although psoralen and khellin can be used as topical agents, used in conjunction with UV radiation, we have not included them in the review due to their inability to be used as monotherapy. We have also excluded less used or ineffective topical agents, such as melagenina, topical phenylalanine, topical L-DOPA, coal tar, anacarcin forte oil and topical

minoxidil. According to current guidelines, a less than two month trial of potent or very potent topical corticosteroids or topical calcineurin inhibitors may be used for therapy of localized vitiligo (<20% skin surface area). Combinations of topical corticosteroids with excimer laser and UVA seem to be more effective than steroids alone. Pseudocatalase plus NB-UVB does not seem to be more effective than placebo with NB-UVB. Combinations of vitamin D analogues have varied efficacy based on which type is used and the type of UV light. Efficacy of calcineurin inhibitor combinations also vary based on the type used and UV light combined, with tacrolimus being more effective with excimer laser. Pimecrolimus has been effective with NB-UVB and excimer laser on facial lesions, and microdermabrasion on localized areas.