© Springer India 2017
Evangeline B. Handog and Maria Juliet Enriquez-Macarayo (eds.)Melasma and Vitiligo in Brown Skin10.1007/978-81-322-3664-1_2727. Oral Medications in Vitiligo
(1)
Apollo Gleneagles Hospitals, WIZDERM, Greenwood Nook, Coral Isle-14 RB, 369/2 Purbachal, Kalikapur, EM Byepass, Kolkata, 700070, India
(2)
St. John’s Medical College & Hospital, Bangalore, Karnataka, India, 560034
27.1 Introduction
The exact etiopathogenesis of vitiligo is yet to be determined, and hence there is a great dilemma regarding an effective modality of treatment for vitiligo. Treatment response is often variable. Thus, patients of vitiligo having skin of color suffer a negative impact on the quality of their lives [1–7].
Over the years, a number of studies have been carried out on different treatment modalities that may give the best outcomes. These help physicians decide on a course of treatment, supported by evidence-based medicine for different forms of vitiligo. The major studies published are from India [8], Saudi Arabia [9], America [10, 11], and Europe [12, 13].
In spite of much advancement in pharmacotherapy, treatment for vitiligo still remains a challenge for physicians. With the complex interplay of etiopathogenic factors, it still remains a mystery as to which treatment option will be best for different cases of vitiligo. The various modalities of treatment range from topical to systemic and from physical to surgical. The choice of treatment needs to be individualized based on the patients’ age, extent of vitiligo, stability, side-effect profile, coexisting morbidity, and supporting evidence [10, 12, 14–19]. The various oral medications that have been used in vitiligo are discussed, together with some novel and alternative treatment modalities.
27.2 Systemic Corticosteroids
Oral corticosteroids are very effective in controlling actively spreading vitiligo when given in optimum doses and for appropriate indications. It mainly acts by suppressing of autoantibody production and inducing apoptosis of cytotoxic T cells. It halts the progression in rapidly progressing disease and also helps in repigmentation [20–23]. In the past, daily doses of corticosteroids were often used. In light of the untoward side effects like weight gain, diabetes mellitus, hirsutism, peptic ulcer, acneiform eruptions, and osteoporosis, low-dose pulse therapy regimens were tried which showed good response without the adverse effects [20].
27.2.1 Oral Pulse Therapy
This principle of administering systemic corticosteroids has shown a lot of promise in the treatment of unstable progressive vitiligo. In pulse therapy, intermittent large (suprapharmacologic) doses are administered to enhance the therapeutic effect and reduce the side effects of a particular drug. It was pioneered in India by Pasricha [22].
As an adjunct to phototherapy, Rath et al. observed that the highest repigmentation was seen when used in combination with narrowband ultraviolet B light (NBUVB) in comparison to broadband UVB (BBUVB) and psoralen with UVA phototherapy [24].
In one study, prednisolone was given in an oral dose of 2 mg/kg once weekly in 50 patients with extensive and rapidly spreading vitiligo; 93 % of patients showed cessation of disease progression with repigmentation in 88 % of cases, with side effects developing in only three patients [25].
27.2.1.1 Oral Minipulse (OMP) Therapy
Oral minipulse therapy is usually given using dexamethasone or betamethasone, 5 mg as a single oral dose, after having breakfast on any two consecutive days of the week. This regimen has similar therapeutic response without the potential adverse effects of daily corticosteroid therapy [26, 27].
The dosage can be increased to 7.5 mg in patients with inadequate response. In children the dose can be reduced to 2.5–3.5 mg per day for two consecutive days in a week after having a thorough discussion with parents and keeping the indications and side-effect profile in mind. The mini-pulse regimen can be used in patients with other concomitant diseases like hypertension and diabetes mellitus. It is best to avoid minipulse therapy in pregnant women.
Side effects are less in comparison to daily corticosteroid therapy but can be seen nevertheless. Most common are weight gain, acneiform eruptions, gastric discomfort, hiccups, headache, and bad taste in the mouth.
The treatment is usually continued till the appearance of new lesions is halted. The dose can then be progressively reduced over a span of 6–8 months. The usual protocol is to reduce the dose of betamethasone by 1 mg every 4–6 weeks. In another study, methylprednisolone was given as OMP in doses of 0.8 mg/day along with topical fluticasone in children for a duration of 6 months. The disease was arrested in 90 % cases with repigmentation seen in 65 % cases with minimal side effects [28].
Response is usually achieved within 1–3 months in most patients. Progression of the disease is halted, and many patients achieve partial to complete repigmentation. In some cases, repigmentation may not occur at all [26, 27].
In the study conducted by Radakovik et al., 10 mg of dexamethasone minipulse was given on two consecutive days per week for up to 24 weeks in 77 patients. In 88 % of patients, progression of disease activity was stopped following 18 weeks of treatment; 69 % of patients also showed side effects like weight gain, insomnia, agitation, hypertrichosis, and menstrual disturbances [27].
In cases with rapidly progressive vitiligo, phototherapy can be started following minipulse therapy. But there is limited data regarding the efficacy of phototherapy in vitiligo when given alongside steroid minipulse therapy.
27.2.2 Intravenous Pulse Therapy
In a study by Seiter et al., methylprednisolone was administered in a dose of 8 mg/kg for three consecutive days in a month in 14 patients with generalized vitiligo. Eighty-five percent of the patients showed cessation of disease progression with repigmentation in 71 % patients. But the patients who had static disease did not show any repigmentation. The therapy was well tolerated in all except by one patient who developed intermittent arterial hypertension [29].
In another study by Nagayata, five vitiligo patients were treated with 500 mg of intravenous methylprednisolone (half-dose steroid pulse) for three consecutive days, thrice every month. The patients were evaluated using a spectrophotometer. After completion of three such monthly cycles, three out of the five patients achieved arrest of disease progression with decrease of white contrast on spectrophotometric examination [30].
Lee et al. evaluated the safety and efficacy of intravenous methylprednisolone pulse in combination with phototherapy in generalized vitiligo. Thirty-six patients were treated with intravenous methylprednisolone, 500 mg on three consecutive days followed by twice weekly treatment with PUVA. 36.1 % patients in the study achieved greater than 50 % repigmentation [31].
27.3 Immunosuppressants and Biologics
Many immunosuppressive and biologic drugs have also been tried in the treatment of vitiligo. Immunosuppressants act by inhibiting the T-cell response toward the melanocytes. They may have an adjuvant role and help in reducing the dose of corticosteroids. Of the plethora of immunosuppressives, azathioprine, cyclophosphamide, cyclosporine, and methotrexate have been tried in vitiligo with varying results [32, 33].
There is still a lot of research and study needed to determine the therapeutic potential of immunosuppressants and biologics in the treatment of vitiligo. Till such data is available, it would be prudent to keep the adverse side effect profile of these drugs in mind when it comes to treating a patient with vitiligo.
27.3.1 Azathioprine
In the study by Radmaneesh et al., 60 patients with vitiligo were randomized to receive either azathioprine (0.6–0.76 mg/kg body weight) and oral PUVA or PUVA alone for 4 months. Following treatment after 4 months, 58.4 % patients achieved a mean total repigmentation in the azathioprine and oral PUVA group compared to 24.8 % in the oral PUVA group alone. Side effects seen were minimal in both the groups during the duration of the study [32]. In view of this finding, azathioprine may be given in rapidly progressing vitiligo where corticosteroids are contraindicated.
27.3.2 Cyclophosphamide
Cyclophosphamide was also tried in a study by Gokhale et al. in a group of 33 vitiligo patients. With 100 mg given daily, some repigmentation was seen in 29 patients with side effects being cytopenia, hair loss, and nausea [34]. Some studies have also shown the efficacy of cyclophosphamide along with oral minipulse of corticosteroids and methotrexate (7.5 mg weekly) in rapidly spreading vitiligo [22, 33].
27.3.3 Cyclosporine
Cyclosporine was tried in six patients in a dose of 6 mg/kg daily. Five patients showed little to no pigmentation after several months of therapy. Side effects seen were hypertension and renal dysfunction [35].
27.3.4 Antitumor Necrosis Factor-α (Anti-TNF-α)
An open-label pilot study was carried out by Rigopuolos on four patients with progressive non-segmental vitiligo to assess the therapeutic efficacy of etanercept. It was given weekly in a dose of 50 mg for 12 weeks followed by 25 mg weekly for another 4 weeks. The patients tolerated the drug well but there was no repigmentation [36].
In another case report, a patient with ankylosing spondylitis and progressive non-segmental vitiligo was treated with infliximab in doses of 350 mg intravenously at weeks 0, 2, and 6 and then on alternate weeks for a total span of 10 months. After 6 months, partial or complete repigmentation was seen in all or most spots with a halt in the progression of vitiligo [37]. But one point that needs to be kept in mind is that non-segmental vitiligo may itself be induced by anti-TNF-α agents [38].
27.4 Oral Psoralens
Since ancient time, UV light-based therapy has been used in the treatment of vitiligo. Psoralens are naturally occurring tricyclic furocoumarins in plants. In ancient India and Egypt, medical writings mention the use of Ammi majus [39] and Psoralea corylifolia plants [40] on whitish skin patches followed by exposure to sunlight. The active ingredients were later found out to be 8-methoxypsoralen, 5-methoxypsoralen, and 8-isoamyleneoxypsoralen [41].
In 1948, modern photochemotherapy was introduced by El-Mofty [42], who purified the topical and oral psoralens. When it was discovered that psoralens were maximally activated with UVA light of 360 mm wavelength [43, 44], fluorescent black lamps were used by investigators in combination with psoralens and the use of PUVA chemotherapy began [45]. PUVA is effective in causing repigmentation of vitiligo lesions as shown by many studies [43, 46].
The most commonly used psoralen is 8-methoxypsoralen (8-MOP). This is of plant origin but synthetic preparations are also available. TMP (4, 5, 8 trimethyl psoralen) is from a synthetic preparation which is less phototoxic after oral administration but is also less effective. 5-MOP is another naturally occurring psoralen in citrus fruits, celery, and parsley leaves. This is less erythmogenic by oral route and also does not lead to the development of intolerance reactions or adverse gastrointestinal effects. The time taken to achieve therapeutic levels in blood for psoralens varies with the type and amount of food [47].
The most common dosing schedule used is by giving 8-MOP at 0.4–0.6 mg/kg, after food intake, followed by exposure to sunlight after 2 h on alternate days in a week. Though 8-MOP and TMP can both be used, the latter is often utilized as it is less phototoxic [48]. The most suitable time for sun exposure is usually between 10:30 to 11:30 am and 3:30 to 4:30 pm, but these can be modified to suit the patients’ schedule. It changes as per the geographic location of the subject, based on the latitude and longitude and also the position of the sun during that specific part of the year.
The duration of exposure is gradually increased from 5 to 15 min in a stepwise manner or till the appearance of mild erythema. The UVA doses range from 0.25 to 2 J/cm2 initially with increments of 0.2–0.5 J/cm2 every session, until erythema develops or a maximum dose is reached. A maximum of 6 J/cm2 was cited by one study [27, 49–51]. In another study, the exposure was increased by 20 % instead of a fixed increase, with the end point remaining the same [52]. Therapy should be stopped if there is no response after 6 months or 50 treatments. Maximum number of treatments has been suggested to be a maximum of 150–200 sittings.
Studies comparing UVA-based therapy with narrowband phototherapy have shown that NB-UVB may be better in comparison to PUVA [53].
There are quite a few limitations associated with psoralen-based photochemotherapy. Oral administration of psoralens can lead to nausea and vomiting. The exposure to UVA needs to be done within 2 h of ingestion. The absorption of the drug is also variable depending on the type of food taken prior to the drug. Post therapy, photo-protection is needed for the skin and the eyes to prevent damage. Also UVA penetrates deeper in comparison to UVB; thus, incorrect administration can lead to painful blistering of the skin which can be severe enough to warrant a cessation of therapy. At the same time, there is poor color match and psoralens are only moderately effective in vitiligo [54].
Psoralen based therapy is also contraindicated in children less than 10 years of age for skin type 1 and less than 16 years for skin type 2. This is because of their increased susceptibility to ocular and cutaneous damage especially if they have concomitant risk factors for developing malignant melanoma [55]. No studies are available for patients of darker skin belonging to Fitzpatrick skin type IV, V, or IV.
Past history of non-melanoma skin cancer is not an absolute contraindication, but alternative therapies may be tried in patients with other important risk factors [55].
27.5 Khellin-Based Photochemotherapy
Another type of photochemotherapy using khellin as a photosensitizer has also been tried. Khellin (5, 8-dimethoxy-2-methyl-4,5-furo-6,7 chromone) is a furanchrome, derived as an extract from the plant Ammi visnaga and is used in conjunction with UVA phototherapy [7, 56, 57] This treatment is also known as KUVA. The main advantage of this regimen is the lack of phototoxicity. Thus, it can be used with natural sunlight even as a daily regimen. Its efficacy is limited because up to 30 % of patients can present with liver toxicity in the form of cytolysis. It is used at a dose of 100 mg orally given 2 h before treatment. Notwithstanding its usefulness, the efficacy and safety profile of oral khellin-based therapies in comparison to PUVA or other treatment modalities has not been studied extensively, and available data is limited.
27.6 Other Systemic Treatments in Vitiligo
27.6.1 Antioxidants
Keeping in mind the role of cellular oxidative stress in the progression of vitiligo, antioxidants have been tried in the treatment of vitiligo [58]. Pseudocatalase, vitamin E, vitamin C, ubiquinone, lipoic acid, Polypodium leucotomos, catalase⁄superoxide dismutase combination, and Ginkgo biloba are antioxidants that have been used alone or, more frequently, in combination with phototherapy [12].
Open trials have suggested that oral administration of single or multiple antioxidants stopped the progression of vitiligo and also promoted repigmentation [59].
Vitamin E has been reported to enhance recovery of skin lipid peroxidation following PUVA therapy according to few randomized clinical trials [60]. A study by Dell’Anna et al. has demonstrated a reduction in the requirement of UV dosages after administration of a mixture of α-lipoic acid, vitamin E, and vitamin C. It also helped to enhance repigmentation [61].
Polypodium leucotomos is a fern found in South America with a wide application in the treatment of diseases like vitiligo, melasma, psoriasis, and sunlight-induced damage. It has antioxidant, photosensitizing and immunomodulator actions that showed good results on concomitant administration with PUVA or UVB [62]. In a study by Middelkamp-Hup et al., 50 patients were enrolled in a double-blind randomized study wherein they received 250 mg of the extract thrice daily along with twice weekly treatment with NBUVB. After 25–26 weeks, 44 % of patients receiving the extract showed repigmentation in the head and neck area which was significantly more, in comparison to controls (27 % only); other areas like trunk, extremities, hands and feet had poorer response Repigmentation was higher in the patients who received NB-UVB along with leucotomos extract [62].
Another novel agent, Gingko biloba, is a traditional Chinese herb. It is a polyphenol compound having anti-inflammatory, immunomodulatory, and antioxidant properties and has shown promising results in the treatment of vitiligo. In a study by Parsad et al., 52 patients were enrolled in a randomized controlled study and were treated with either 40 mg of Gingko biloba extract or placebo thrice daily. After 6 months of therapy, 80 % of vitiligo patients had cessation of disease activity compared to 36.6 % of controls. Also 40 % of patients showed up to 75 % repigmentation compared to only 9 % of controls [63].
In another study by Szczurko et al., 12 patients were treated for 12 weeks with 120 mg extract, and all had arrest of disease progression [64]. The anti-inflammatory action of Gingko biloba leads to a reduction in the cyclooxygenase activity with a reduction in IL-8 and vascular endothelial growth factor in response to TNF-α [65]. The most common side effect seen was gastric discomfort [64]. An important side effect is coagulopathy; hence, this drug should be used with caution in patients on anticoagulants [66]. However, the number of patients enrolled in this study was limited. A definite consensus cannot be reached on the long-term safety profile and further studies are warranted [63–66].
27.7 Newer and Alternative Treatments in Vitiligo [67]
Vitiligo has been increasingly recognized as a disorder of autoimmune destruction of melanocytes [68–70]. Still, controversy exists regarding its true etiopathogenesis. A number of hypotheses have been put forward like immune dysregulation, neurogenic factors, catecholamine-mediated cytotoxicity, and oxidative stress [71, 72]. Over the years, a number of compounds have been experimentally tried in the treatment of vitiligo. Some have shown good results while others have had equivocal responses. In light of the enigmatic pathophysiology of vitiligo, research continues to discover newer and novel systemic treatment modalities for vitiligo.
27.7.1 L-Phenylalanine
L-Phenylalanine (l-Phe) is an essential amino acid and a precursor to tyrosine in the melanin biosynthetic pathway. It has been explored as a treatment option in vitiligo along with ultraviolet phototherapy. It has been hypothesized that metabolism and uptake of phenylalanine is defective in vitiligo [72, 73]. Phenylalanine appears to be beneficial in vitiligo, unrelated to its role in the melanin synthesis pathway.
It has also been hypothesized that l-Phe may interfere with the antibody production in vitiligo [74, 75].
In a study by Siddiqi et al., 149 patients of vitiligo were treated with l-Phe for 18 months. Patients were divided into three groups. Group I received l-Phe (100 mg/kg body weight) with UVA phototherapy twice weekly. Group II received l-Phe alone and group III did not receive any treatment. They found that 71.2 % of the patients in group I had repigmentation up to 77 % in comparison to no pigmentation seen in groups II and III [76].
In another study by Antoniou et al., patients received oral l-Phe and UVA phototherapy in one group and oral and topical l-Phe along with UVA phototherapy in another group. In both, 75 % repigmentation was seen [74].
In two other studies, 50 mg/kg of l-Phe was given to patients along with UVA phototherapy and repigmentation ranging from 85 to 95 % after 6–8 months [77, 78].
It can be thus concluded that l-Phe limits the antibody attack on melanocytes while UVA induces repigmentation. Thus l-Phe may be tried in vitiligo in conjunction with UVA phototherapy, and the evidence is supported by quite a few randomized clinical trials.
27.7.2 Vitamin B12 and Folic Acid
It has been seen that there is decreased serum levels of vitamin B12 and folic acid in vitiligo [79, 80].
An association between vitiligo and pernicious anemia has also been noticed [81, 82]. This has led researchers to study the role of vitamin B12 and folic acid supplementation in the management of vitiligo.
Montes et al. reported that among 15 vitiligo patients, 73.3 % had folic acid deficiency, 33.3 % had vitamin B12 deficiency, and 26.6 %6 had vitamin C deficiency. On daily supplementation, repigmentation was seen in all patients and a halt in the progression of disease in 80–100 % patients, over a span of 2 years [83]. In a study by Juhlin and Olsson of 100 vitiligo patients on oral supplementation with vitamin B12 and folic acid along with phototherapy with either sunlight or UVB, repigmentation was seen in 52.2 % cases with halt in progression of vitiligo over a span of 3–6 months [84].
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