After a Medline literature search, there were 15 research articles about tacrolimus ointment for vitiligo since Smith first reported the application of tacrolimus ointment for the treatment of vitiligo in 2002 until February 2006. Among them, there were 14 articles about the clinical efficacy of tacrolimus ointment in the treatment of vitiligo.
1.Status of treatment
1.1 Adult vitiligo
In the searchable literature, Smith [1] was the first to report that tacrolimus ointment could treat vitiligo in 2002. He found that tacrolimus ointment could treat not only atopic dermatitis but also vitiligo when he treated a 33-year-old patient with atopic dermatitis with 0.1% tacrolimus ointment. The patient suffered from both atopic dermatitis and vitiligo, especially at the margins of the vitiligo. After 2 months of treatment with 0.1% tacrolimus ointment, not only did the atopic dermatitis improve significantly, but the white patches of skin at the site of atopic dermatitis showed pigmentation, and 90% of the white patches regained color after 18 months of treatment. 2002 Grimes et al [2] treated two adult vitiligo patients with topical 0.1% tacrolimus ointment, one patient was 24 years old and had the disease for 15 years, and applied 0.1% tacrolimus Tanghetti applied 0.1% tacrolimus ointment topically to 15 cases of vitiligo, and after 1.5 months of treatment, 13 patients showed hyperpigmentation, and 3 of them had >75% recovery of pigmentation. The authors found that the patients with better efficacy also received sun exposure while being treated with tacrolimus ointment. The authors concluded that tacrolimus ointment has a synergistic effect with UV light in the treatment of vitiligo.
1.2 Vitiligo in children
Kanward et al [4] applied 0.03% tacrolimus ointment topically to treat 22 Indian children with vitiligo. The mean age of the patients was 7.2+1.4 years, 13 boys and 9 girls; 12 cases of common vitiligo, 9 cases of restricted vitiligo and 1 case of stepwise vitiligo with a mean duration of 8+3 months. All patients were treated with 0.03% tacrolimus ointment topically twice daily for 12 weeks. At the end of the course of treatment, 19 patients showed varying degrees of pigmentation in the leukoplakic areas and 3 cases showed no change. Among the 19 patients who developed pigmentation, 11 patients had pigmentation exceeding 75% of the lesion area, 5 patients had pigmentation of 50-75% of the lesion area, and 3 patients had pigmentation of less than 50% of the lesion area. Only three patients experienced pruritus or burning sensation during the treatment, and no other adverse effects were observed. The authors concluded that topical application of tacrolimus ointment is effective in the treatment of vitiligo in children.Silverberg [5] et al. applied 0.03% tacrolimus ointment to treat 57 children with vitiligo, 26 children were treated with 0.03% ointment and 31 children were treated with 0.1% ointment.After 3 months of treatment, it was found that 34 of 38 children with head and neck vitiligo (89% ) lesions showed hyperpigmentation, and 20 (63%) of the 32 children with vitiligo of the trunk and extremities showed hyperpigmentation. It was found that children with segmental vitiligo responded better to tacrolimus ointment treatment, especially the facial lesions had the best effect on tacrolimus ointment topical treatment with an efficiency of 94%. The authors concluded that tacrolimus ointment is effective in the treatment of vitiligo in children, especially head and neck vitiligo.
1.3 Tacrolimus combined with phototherapy for vitiligo
Several studies have confirmed the effectiveness of 308nm excimer laser for vitiligo and tacrolimus topical for vitiligo, so how effective is the combination of both, Passeron et al [6] conducted a study. 14 patients with 43 white spots were randomized into two groups A and B. Group A had 23 white spots and was treated with a combination of 308nm laser irradiation and 0.1% tacrolimus ointment topical. The initial dose of 308 nm laser was 50 mJ/cm2, and the dose was increased by 50 mJ/cm2 for every 2 irradiations, twice a week; 0.1% tacrolimus ointment was applied topically twice a day. 20 white spots in group B were treated with 308 nm laser irradiation only. After 3 months of treatment, all white spots in group A (23 spots) showed hyperpigmentation, while 17 spots in group B (20 spots) showed hyperpigmentation. 16 (70%) of the spots in group A had hyperpigmentation areas greater than 75%, while only 4 (20%) of the spots in group B had hyperpigmentation areas greater than 75%. This result showed that the combination of 308nm laser irradiation and 0.1% tacrolimus ointment was significantly better than 308nm laser irradiation alone in the treatment of vitiligo, indicating a synergistic effect between the two in the treatment of vitiligo. This result also proved that topical tacrolimus ointment is effective in the treatment of vitiligo.Adam et al [7] also observed the excimer laser combined with topical tacrolimus ointment in the treatment of vitiligo using a self double-blind placebo-controlled method. A total of 6 patients with 24 symmetrical white patches were treated with randomized topical application of 0.1% tacrolimus ointment or placebo twice a day, and concurrent application of excimer laser three times a week for 10 weeks. The results showed that 50% of the lesions in the tacrolimus ointment plus excimer laser group re-colored more than 75%, while only 20% of the lesions in the placebo plus excimer laser group re-colored more than 75%, and the time of appearance of hyperpigmentation was found to be earlier in the tacrolimus group than in the placebo group.
1.4 Controlled study with glucocorticoid-based ointments
Lepe [8] conducted a controlled study of the efficacy of 0.1% tacrolimus ointment versus 0.05% clobetasol propionate ointment in the treatment of vitiligo using a double-blind randomized controlled approach. A total of 20 patients were treated with a 2-month course of treatment using a self-randomized control method. At the end of treatment, 49.3% of lesions in the clobetasol propionate ointment group and 41.3% in the tacrolimus ointment group showed hyperpigmentation, with no statistically significant difference in efficacy between the two. However, in the clobetasol propionate ointment group, three patients showed skin atrophy and two lesions showed capillary dilation. This study suggests that 0.1% tacrolimus ointment is almost as effective as 0.05% clobetasol propionate ointment in the treatment of vitiligo in children. Since tacrolimus ointment does not produce side effects such as skin atrophy and capillary dilation when applied topically, tacrolimus ointment is a good choice for the treatment of vitiligo in children and vitiligo in sensitive skin or some special areas such as eyelids.
2.Treatment mechanism
2.1 Immunological mechanism
The pathogenesis of vitiligo is still unknown. Autoimmunity is currently the main doctrine, although a lot of research has been conducted in this area, but the exact mechanism is still unclear, such as whether the autoimmune reaction is cellular or humoral immunity, is it a systemic or local immune reaction? These questions relate to the treatment of vitiligo. Although these questions are still difficult to determine, it can be determined that there may be localized immunological abnormalities in the skin of vitiligo patients, judging from the ability of topical topical corticosteroid treatment of vitiligo to stop the progression of vitiligo.
Tacrolimus is an immunosuppressant whose mechanism of action is by binding to calmodulin thereby blocking the gene transcription of some lymphokines. In terms of its pharmacological action, its treatment of vitiligo should be effective. Because it can inhibit the local abnormal immune response and stop the development of vitiligo. Therefore, for progressive vitiligo, topical application of Tacrolimus can stop the development of vitiligo. So how to explain the recovery of pigmentation after the application of tacrolimus treatment? One reason may be that after topical tacrolimus application, the abnormal local immune response to the lesions disappears, allowing the residual melanocytes to continue to grow and proliferate, or the melanocytes in the hair follicles to wander into the epidermis, divide, proliferate and then produce pigment. But there may be other immunological mechanisms.Grimes [9] recently treated 19 patients with vitiligo with 0.1% tacrolimus ointment topically. The levels of IFN-r, TNF-a,IL-10 in the patients’ leukoplakic areas and in the uninvolved skin around the leukoplakic areas were measured before and after treatment. After 24 weeks of treatment, 17 patients showed varying degrees of pigment recovery, with 13 patients (68%) showing >75% pigment recovery. IFN-r, TNF-a, and IL-10 were found to be significantly higher in vitiligo patients compared to normal subjects in the leukoplakic areas and in the skin surrounding the leukoplakic areas,
After 24 weeks of topical treatment with 0.1% tacrolimus ointment, TNF-a was significantly reduced, while IFN-r and IL-10 did not change significantly. This study suggests that local cytokine imbalance in vitiligo lesions may play an important role in the pathogenesis of vitiligo, and that the recovery of pigmentation in vitiligo areas with topical tacrolimus ointment may be related to the inhibition of local TNF-a by tacrolimus.
2.2 The keratinocyte pathway theory
Keratinocytes and melanocytes are the two main cells in the epidermis, and they are adjacent to each other and have a close anatomical relationship. Many previous studies have found that keratin-forming cells have an important effect on melanocytes. Could the topical application of tacrolimus, which restores pigmentation to the white areas of vitiligo, also be via the keratin-forming cell pathway? This was confirmed by a recent study.Lan
et al [10] found that after adding tacrolimus to keratin-forming cells cultured in vitro for a period of time, the supernatant significantly promoted the growth of melanocytes in vitro, but had no effect on melanin synthesis or melanocyte wandering. The study also confirmed that the addition of tacrolimus to in vitro cultured keratinocytes resulted in a significant increase in stem cell factor (SCF) in the supernatant. Previous studies have confirmed that topical skin application of SCF can cause skin hyperpigmentation [11] and confirmed that UV irradiation increases the release of SCF from human keratinocytes, and suggested that UV-induced hyperpigmentation may be caused by the release of SCF from keratinocytes thereby promoting melanocyte proliferation [12]. Therefore, Lan et al. suggested that tacrolimus may promote melanocyte proliferation by stimulating the release of SCF from keratinocytes. This may be one of the mechanisms by which topical tacrolimus is able to restore pigmentation.
It has been shown that melanoblast (MB) cells in the middle and lower part of the hair follicle and in the sheath of the hair root outside the follicle are the main source of melanocytes for pigmentation recovery in vitiligo. lan et al. also demonstrated that the supernatant of keratinocytes cultured in vitro with tacrolimus for a period of time significantly promoted the growth of melanocytes in vitro, but not for melanin synthesis and melanocyte wandering were not affected. The mechanism of MB migration from the hair follicle to the epidermis is unknown, and the process of MB migration involves the degradation and reconstruction of extracellular matrix such as gliadin and fibronectin, matrix metalloproteinases (MMPs), and the formation of a new cellular matrix.
metalloproteinases (MMPs) are very important. Several studies have found significantly enhanced expression of MMPs in tissues during tissue reconstruction and cell wandering, and found significantly enhanced expression of MMPs in malignant melanoma metastases [13]. Studies have demonstrated that keratin-forming cells synthesize and secrete MMPs, mainly MMP-1, MMp- and MMP-9. Lan et al. similarly demonstrated that the supernatant of keratin-forming cells cultured in vitro with the addition of tacrolimus for a period of time significantly stimulated the upregulation of MMp-9 activity. Therefore, it can be speculated that when topical tacrolimus is applied topically, it can directly enhance the activity of MMPs, which can create a favorable microenvironment for melanocytes or melanoblasts to wander, thus promoting the recovery of pigmentation in vitiligo white areas.
2.3 Direct action on melanocytes
The biological effects of tacrolimus on melanocytes were recently investigated by Kang et al. It was found that tacrolimus inhibited the growth of melanocytes cultured in vitro, but was able to promote pigmentation, and it was found that tacrolimus promoted pigmentation of melanocytes by stimulating the activity and expression of tyrosinase. It was also found that tacrolimus was able to promote melanocyte wandering. The results of this study are of great significance for understanding the mechanism of action of tacrolimus in the treatment of vitiligo.
3, the current problems in the study of topical tacrolimus for vitiligo
Although the topical treatment of vitiligo with tacrolimus has been successful in recent years and has attracted interest and attention, there are still problems in this area of research in the following aspects.
3.1 Lack of placebo-controlled studies: Most of the current literature on tacrolimus topical treatment of vitiligo are case reports of tacrolimus topical treatment of vitiligo, some are tacrolimus combined with other therapies for vitiligo, there is not yet a rigorous tacrolimus vs placebo-controlled study.
3.2 Disease course Vitiligo is divided into progressive and quiescent stages. In general, the goals and methods of treatment vary in different periods of vitiligo. There are no reports in the literature on the observed efficacy of tacrolimus in treating vitiligo in different periods. Understanding the efficacy of tacrolimus in treating vitiligo in different periods is important to understand the mechanism of tacrolimus in treating vitiligo.