|Ahead of print
|A comprehensive review on vitiligo and its pharmacotherapy: Recent trends and future challenges
Asmaa Moafa1, Fahad Khalawi2, Nagaraja Sreeharsha3
1 Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Asha 31982, Saudi Arabia
2 Postgraduate Student, Collage of Pharmacy, Jazan University, Saudi Arabia
3 Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Asha 31982, Saudi Arabia; Professor, Department of Pharmaceutics, Vidya Siri College of Pharmacy, Bengaluru, Karnataka, India
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|Date of Submission||09-Dec-2020|
|Date of Acceptance||11-Dec-2020|
|Date of Web Publication||21-Jan-2021|
Approximately 1% of population in the world is affected by an intriguing skin depigmentation disorder, vitiligo. Typically, a vitiligo lesions are seen as white milky, nonscaly patches with separate edges. Vitiligo is caused by a selective loss of epidermal melanocytes. In vitiligo, there is impaired melanocyte regeneration and/or multiplication. Although the proportion of the population affected by this disease is very low, the disease is associated with a lot of social stigmas. This defect has an important effect on the life of the patient and still a persistent load.
Keywords: Depigmentation, epidemiology and dermatology, vitiligo
|How to cite this URL:|
Moafa A, Khalawi F, Sreeharsha N. A comprehensive review on vitiligo and its pharmacotherapy: Recent trends and future challenges. Int J Med Oral Res [Epub ahead of print] [cited 2021 Feb 25]. Available from: http://www.ijmorweb.com/preprintarticle.asp?id=307581
| Different Types of Vitiligo Conditions|| |
Segmental type vitiligo (SV) has a characteristic unilateral distribution. The findings suggest that this type of vitiligo is due to nonautoimmune factors and shows a quick stabilization. However, few cases to further progression of later stages have been reported. In general, an early of vitiligo is seen in cases of SV compared with nonsegmental vitiligo. SV has been further classified based on the occurrence of lesions on the body parts.
Face segmental type vitiligo
This classification was determined by differentiating the spread lesion figure in 257 Korean patients with SV on the face and was further subdivided into six subtypes as type 1a, 1b, 2, 3, 4, and 5. The most frequent subset is Type 1a, which is usually seen in the large section of the face at the left halve. Type 1a initiates on the right halve of the midline on the brow, leading to the core of the brow, further spreading horizontally and descending, which looks like a reversed V-shaped pattern. Type 1b is located on the left or right side of the forehead with frequent signs of poliosis. Type 2 lesions look like an arch pattern initiating from the otic region down to the midline region of the philtrum. In category 3, pigmentation is removed and initiates at one side of the bottom lip extend descending and somewhat laterally at neck direction. Category 4 firmly mimics category 1, but does not cross the central line (not same as type 1a) and is exclusively located on the right halve of the face. Finally, category 5 includes the right orbital zone, which can be seen as spreading to the temporal area.
Trunk segmental type vitiligo
Again, this subset is further subclassified as Type 1–6. In category I, II, and III, the top part of the trunk is affected, whereas in category IV and V, the central section of the trunk is affected and the bottom section of the trunk is affected in category VI. The most common SV is Type 3, which is seen as “trigon shape,” which can be noticed on the top trunk in opposition to the central line of the top thorax.
| Nonsegmental Vitiligo|| |
The most common form of vitiligo is characterized by symmetrical and two-sided white spots. These macules have a typical tendency for symmetrical distribution. NSV lesions are typically disperse regular above the whole body or bilateral scattered in an acrofacial design. Contrary to SV, in NSV, hairs of the body usually do not undergo depigmentation, although there is a possibility of hair depigmentation with disease progression. The NSV includes many variants.
This most common form of vitiligo with characteristic milky-white spots presents on numerous pieces of the body, always in a symmetrical design. The most common initiation point of the disease is usually fingers, hands, and face. Pigmentation removal of scars is the most common indicator of Koebner's phenomenon (i.e., initiation of the diseases due to mechanical forces such as friction or usual pressure by wearing cloth or everyday tasks). Koebner's phenomenon is thought to be responsible for the onset of so-termed isomorphic pigmentation-removed lesions.
In acrofacial vitiligo, depigmentation is often located on the face, head, hands, and feet. A characteristic is the depigmentation of the distant finger and facial cavities. Later, it can proceed to more body parts as well and causes the typical generalized vitiligo. This type of vitiligo is further recurrent in late-onset cases like in adulthood.
Universal vitiligo or vitiligo universalis
A rare type of vitiligo is the most extensive form of the vitiligo that is usually seen in adulthood. Universal vitiligo corresponds to all pigmentation removal of the skin. As the name suggests, “Universalis” means when pigmentation removal is effectively throughout the body (80%–90% of body skin), few pigmentations can be remains available i.n., hair partially spared. This diagnosis can be challenging in an individual with fair skin, while in the individual with dark skin, it can be easily diagnosed.
Apart from these classes of vitiligo, some other subsets also exist, namely, mixed vitiligo, bilateral segmental vitiligo, multisegmental vitiligo, focal vitiligo, mucosal vitiligo, and contact or occupational vitiligo.
The presence of segmental vitiligo and nonsegmental vitiligo simultaneously in a patient has been called mixed vitiligo, and in case the two SV lesions are in attendance on both body sides, it is termed as bilateral segmental vitiligo. If 2 clear segments on the same side are attending, it can be termed multi segmental vitiligo. While, Focal vitiligo is an the presence of a little, isolated hypopigmented lesion, that neither fits into a typical segmental dispensation, nor does it evolves into NSV even after a duration of 1 or 2 years. Mucosal vitiligo typically mention to the include of the oral and/or genital mucosa.
| Existing Pharmacotherapy for Vitiligo|| |
Vitiligo is a complex autoimmune disease that affects an individual physically by causing skin disfiguration and ocular and auditory anomalies. A personalized approach is required for the management of vitiligo along with due consideration to several factors (vitiligo time periods, effect, skin type, area, gender, age, included areas, social life, and cultural influences). It has been observed that some regions, such as the face, always respond well to medicine while other body parts, namely, hands and feet remain unaffected. To date, there is no therapeutic remedy for vitiligo; however, current pharmacotherapeutic approaches can lead to significant improvement of vitiligo lesions.
The pharmacotherapy for the management of vitiligo intents to achieve the following three goals [Figure 1]:
- Ceasing vitiligo development
- Allowing complete natural coloring of lesional regions
- Preventing recurrence.
| Ceasing the Disease Progression|| |
Systemic corticosteroids have been shown to quickly stop spreading disease and to make a natural color. Oral prednisolone in low doses (0.3 mg/kg) to be taken every day for 2 months along with a large dose of methylprednisolone (8 mg/kg) taken intravenously for consecutive 3 days. In addition, this regime has resulted in the induction of some repigmentation in almost 70% of the cases as well. Oral mini pulse of betamethasone or dexamethasone at a dose of 5 mg, two times a week, on consecutive 2 days for 3–6 months has also resulted in cessation of the disease progression. However, the cases of repigmentation in this therapy have been low. However side effects, namely increased weight, insomnia, acne, agitation, menstrual disturbance, and high blood pressure, can occur.
Minocycline has anti-inflammatory, immunomodulatory, and free radical scavenging properties that encouraged the clinicians to use it in the management of vitiligo. 100 mg every day of minocycline has been found to halt the progression of vitiligo.
Narrowband ultraviolet B
Two times a week, treatment with narrowband ultraviolet B (NB-UVB) has been found to be efficient to stop disease development and also has the major advantage of supporting more effective natural color of disease lesions. In addition, melanocyte differentiation and melanin production are also induced by NB-UVB. The first-line therapy for extensive, progressive vitiligo is NB-UVB. This therapy has been found to be safe and can be administered safely to children and pregnant or lactating females. The therapy should be gradually optimized, with an aggressive approach. The initiation of the therapy is done at a low and safe dose of 200 mJ, administered twice or thrice a week with an increment of 10% to 20% of dose. The appearance of the symptomatic-free, light-pink erythema of the skin, which lasts for 24 h, is considered to be the optimal dose, and thereafter, therapy is continued at the same dose till erythema disappears.
| Repigmentation of Lesional Areas|| |
Topical steroids are useful for little, localized regions, and sill one of the gold standard therapies for vitiligo. Children, in particular patients with dark skin with lesions on the face, respond to topical steroids more improved than old age patient, fair skin patients. Local side effects of cream steroids include atrophy, striae, telangiectases, perioral dermatitis, and glaucoma (when used around the eyes). When choosing a cream corticosteroid, the site of the lesion and age of the patient need to be taken into consideration. Potent corticosteroids can be used for treating lesions on the body, whereas topical corticosteroids with less potency should be selected for the face, neck, and intertriginous regions and lesions in children. Daily or two times a day used with “days off” in a cyclic pattern is the possible regimens (e.g., 1-week use, then 1 week without for, 6 months, or application for 5 days followed by 2 days without).
Topical calcineurin inhibitors
Creams calcineurin inhibitors (tacrolimus 0.03%/0.1% and pimecrolimus 1%) have been shown to be safe and effective in children's vitiligo, especially on the head and neck, in patients with the disease for <5 years, on intertriginous and genital skin, in facial segmental disease, in dark-skinned patients, on lesions on the head and neck (especially segmental facial type), and in patients with a Fitzpatrick skin type of 3–4. Children are nine times as likely as adults to get a good response. They are less effective in acral lesions and adults. Avoidance of application over atypical pigmented lesions is recommended. Two times daily use is required for effective results. Topical calcineurin inhibitors are deemed to be the first-line therapy for facial vitiligo of childhood by the Vitiligo European Task Force.
Topical Vitamin D
Calcipotriene is a Vitamin D analogous that is not effective for vitiligo individually, but is assistant helpful when taken with creams corticosteroids (e.g., betamethasone) for facial and body vitiligo in childhood or NB-UVB.
Phototherapy is a beneficial therapeutic option for widespread vitiligo, especially in pediatric patients. Efficacy in childhood is two-fold, with stabilization of vitiligo being the first endpoint, which is achieved in 80% of children, and natural color being the secondary endpoint for children with generalized vitiligo.
Apart from the above, few general points are to be taken care of in the management of vitiligo-
- Avoiding Koebnerizing factors (friction, trauma) may help reduce the activation factors that progress new pigmentation removal
- Good sun protection with sunscreens or clothing prevents sunburn on pigmented removal regions
- Diet rich in Vitamin B12, Vitamin B9, Vitamin C, Vitamin D, Vitamin E, and zinc enhances the effect of the therapy for vitiligo. Oral herbal supplements of Phyllanthus emblica fruit extract, Ginkgo biloba, Polypodium leucotomos, Piperine, Green tea, and epigallocatechin-3-gallate also help improve the effectiveness of vitiligo therapy.
Potential emerging pharmacotherapy for vitiligo: Future research is now focused on three principle approaches:
Decreasing stress on melanocytes
This approach has been based on the fact that in vitiligo patients, elevated reactive oxygen species (ROS) levels and reduced levels of catalase enzyme in the epidermis lesional skin of vitiligo patients have been observed. Thus, using anti-oxidants or any agent that can reduce the ROS level seems to be a potential candidate for the management of vitiligo. Pseudocatalase is one such drug, which has been evaluated in the past in combination with phototherapy. Topical treatment with pesudocatalase cream results in decreased ROS levels., Some clinical studies have been reported, wherein phototherapy along with a supplement (antioxidant or ROS reducing agent) has been found to promising. G. biloba, and P. leucotomos with NB-UVB are some of the phytopharmaceuticals which have been proved to be effective in the management of disease. Various antioxidants, namely, α-lipoic acid, Vitamin C, Vitamin E, and polyunsaturated fatty acids with and without phototherapy, have also been proven to be effective in vitiligo.
Regulation of the autoimmune response
Immunomodulators are being explored to treat skin disorders, especially in conditions that involve the interplay of various immune factors. It has been reported that stressed melanocytes in vitiligo releases heat shock protein, HSP70i, thereby stimulating an innate inflammatory response in the skin. Found that mutated protein, HSP70i, exhibited low immunogenicity and seems to induce tolerance, thereby averting the initiation of the disease. Antibodies and small-molecule inhibitors that can target interferon-γ, CXCL10, and the CXCL10 receptor, CXCR3, are being explored for the management of vitiligo and are under clinical evaluation. Janus kinase (JAK)-STAT inhibitors are other important targets that are being explored for vitiligo. Oral tofacitinib, JAK 1/3 inhibitor, has been reported to provide a therapeutic effect in a generalized vitiligo patient. Tofacitinib has been approved by the Food and Drug Administration (FDA) for rheumatoid arthritis. Another JAK inhibitor, Ruxolitinib, which has JAK 1/2 selectivity, and is FDA approved for the treatment of myelofibrosis and polycythemia vera, has been found to induce repigmentation. [20,21] However, oral consumption of these immunosuppressants makes a patient more prone to a number of other diseases and side effects. Thereby, scientists now intend to develop topical formulations of these immunosuppressants. Interestingly, it has been found that inhibition of HMG-CoA reductase correspondingly inhibits the function of STAT1. These findings have prompted the evaluation of statins, namely, atorvastatin and simvastatin in the management of vitiligo.
Stimulating melanocyte regeneration
γ-melanocyte-stimulating hormone (α-MSH) is a hormone that is essential for the synthesis of melanin. Afamelanotide, an analog of a-MSH, is also being explored clinically for vitiligo. Patients with generalized vitiligo were administered a subcutaneous implant of afamelanotide along NB-UVB. It was found that a combination of NB-UVB and afamelanotide resulted in quicker and augmented total repigmentation compared to photo-monotherapy of NB-UVB. This is one of the most promising potential candidates for vitiligo treatment. Defective WNT signaling is the hallmark for vitiligo. WNT signaling is a critical step in the differentiation of melanocyte during its synthesis. Ex vivo studies suggest it to be a potential target for vitiligo therapy. The use of selective sunscreens is a very interesting approach that is being explored for vitiligo. In a small clinical trial, subjects were topical administered a 1% dimethicone formulation. Dimethicone is known to selectively block sunlight below 300 nm wavelength, thereby allowing nbUVB range (~311–312 nm) to penetrate and exert its therapeutic effect. However, large clinical trials need to be conducted to establish the effect of selective sunscreens [Table 1].
| Conclusion|| |
Vitiligo is a complex chronic disease with an interplay of inflammatory-immune-activation-driven factors, without a conclusive treatment at present. Vitiligo is associated with a social stigma and affects the quality of the life of the patient immensely. The current pharmacotherapy, which involves the usage of drugs alone or in combination with phototherapy, has been able to either halt or reduce the disease progression and to a certain extent in promoting depigmentation. However, most of these approaches can result in a relapse of the disease. Hence, exploring novel targets for treating vitiligo becomes pertinent. Many new targets and drug candidates are under clinical trials and some of the candidates have shown promising results. This has increased the hope of developing a therapeutic candidate for vitiligo that can treat the disease completely. For this to achieve large, multicentered clinical trials for these drug candidates need to be carried out.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982
Source of Support: None, Conflict of Interest: None
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