NON-SURGICAL TREATMENT OF VITILIGO

 

TREATMENT:

Treatment of vitiligo is often difficult and frustrating, both for the patient as well as the physician. Many modalities have been and continue to be used. The following therapies and their efficacy will be discussed:

topical corticosteroids;

topical immunomodulators;

phototherapy including PUVA, topical PUVA,

UVB and monochromatic excimer laser or light, as well as microphototherapy;

surgical options including autologous mini-punch grafting;

blister roof grafting, and epidermal cell transplantation.

The issue of bleaching accomplished by hydroquinone, monobenzone, or Q switched ruby laser will also be addressed. In determining efficacy of treatment, greater than 75% repigmentation is considered a cosmetically acceptable level of repigmentation.

Medical: Topical Corticosteroids Topical corticosteroids are often used as therapy for vitiligo. A meta-analysis in 1998 found that class 3 and 4 corticosteroids resulted in more than 75% repigmentation of 56% of segmental vitiligo patients and 55% of generalized vitiligo patients.2 In 1999, the same group made an attempt to establish evidence based guidelines for treatment of vitiligo in children and adults. Another meta-analysis of the literature was performed, which again showed that class 3 corticosteroids are the most effective and safest therapy for segmental vitiligo.1 The next group of patients includes those who have localized vitiligo. Focal vitiligo has a good prognosis in that it is more amenable to topical therapy and we have found good results with high potent topical steroids which should be applied once daily with a steroid holiday for at least one week each month to prevent tachyphylaxis. Newer topical steroids like mometasone furoate and fluticasone propionate offer a high safety: efficacy ratio and can be used for longer duration. One can wait for upto three months for repigmentation to appear and thereafter treatment may be continued till maximal repigmentation. Repigmentation has been achieved after application of potent topical corticosteroids. Clobetasol propionate is applied once or twice daily for 2 months. Scheduled treatment may be resumed after a break of 2 to 16 weeks. Patients should be monitored for signs of atrophy and telangiectasia especially while treating facial lesions. Intertriginous areas should be avoided. Ocular lesions should be checked every month when treating the eye-lids. Higher strength hydrocortisone should be preferred for children.

Systemic Corticosteroids: Those patients with actively progressing disease and those with widespread lesions are candidates for systemic medical therapy and we prefer to use systemic steroids in the form of betamethasone oral mini pulse therapy (OMP). After baseline investigations, essential prior to giving oral steroids, oral betamethasone is given in a dose of 5 mg (2.5 mg for children) on two consecutive days each week. The patient is assessed every two weeks initially and monthly thereafter to look for any side effects of steroids and to note any improvement in the lesions. One can wait for upto three months for repigmentation to appear which is usually perifollicular and perilesional. Betamethasone is continued till complete or maximal repigmentation is achieved and therapy should not be discontinued abruptly as the repigmentation may be reversed. Systemic steroids have a dual role in that they suppress the autoimmune damage and halt progression of the disease and thereafter induce pigmentation. In our experience, OMP with betamethasone is not associated with any significant side effects and the only adverse effect that we have encountered is weight gain, though without cushingoid features. The rate of cure is universally proportional to the duration of the disease.

Photochemotherapy: Psoralens have been used for many years in the treatment of Vitiligo. Presently, photochemotherapy with these furocoumarine compounds is the most effective from of treatment for Vitiligo. The trimethyl psoralen (troxsalen, TMP) 8-methoxy-psoralen (Methoxalen, 8-MOP) and psoralen (PS) are all effective and promote the repigmentation of the vitiliginous areas of skin. However 8-MOP is associated with more marked phototoxicity in amelanotic areas. To achieve repigmentation in up to 50 to 70 percent patients, long-term therapy of over 100 to 200 (over 12 to 24 months) treatment sessions with either oral 8-MOP or TMP and well controlled sunlight exposures or UV-A sources appear to be equally effective, while Bleeten5 observes that natural sunlight appears to be more effective than artificial sources of ultraviolet light.Treatment may have to be continued for at least three months and in some, over a number of years. Treatment must be continous; if interrupted, the partially repigmented patches may lose the pigment, But those macules that completely filled in should stay with about 85 percent surety. Repigmentation may not be complete and the partially treated areas may appear more bizarre. The response is slow and dark skinned patients respond better than fair-skinned individuals. Results are poor on the hands and feet, and over bony prominences. Focal Vitiligo responds better than generalized Vitiligo (i.e. it responds to 100 treatments or less, whereas generalized Vitiligo requires as many as 200 treatments). Most patients who are responding do not develop new areas of pigment loss. The appearance of new or enlarged macules indicate the possible beginning of treatment failure. The emphasis in treatment should be directed towards restoring normal color of socially interactive areas (face, chest, arms and lower lips). The face, neck, chest, stomach, back, upper arms and legs are the best criteria for assessing the degree of repigmentation. Areas that respond poorly include the lips (mucosa), distal dorsal hands, tips of fingers, toes, areas of bony prominences, palms, soles, nipples and gums. Ophthalmic examination prior to initiation of therapy, at 6 months and at 1 year are recommended. The eyes should be shielded from ultraviolet rays for eight hours with opaque glasses.

Systemic PUVA: Photochemotherapy (PUVA) was originally developed in the 1940's by an Egyptian physician for the treatment of vitiligo. It has subsequently been used for many different cutaneous disorders. Repigmentation with PUVA is widely variable and rarely is 100% achieved. In general, dark skin types have better repigmentation that paler skin types. Usually, one to three years of treatment are needed for optimal results, which is one of the drawbacks.6 PUVA has the highest rates of adverse effects among nonsurgical treatments, such as nausea, vomiting, phototoxic reactions and a theoretical increased long-term cutaneous malignancy risk. For these reasons, this method is not being used as often for vitiligo, particularly in the United States. PUVA therapy is indicated in a vitiliginous patient who is prepared to commit to 100 to 300 treatments, is above 10 years of age, there is no history of photosensitivity, and involvement is not limited to the unresponsive mucosal or digital areas. Pregnant or lactating women or aphakic patients are not included in therapy. Starting with 0.6mg/kg trimethyl psoralen (troxsalen, TMP) and 2J/cm2 UVA increase UVA dose by 0.5 to l.0J/ cm2 per treatment gradually, increasing to 1.5J/cm2 till one of the following occurs:

(a) mild phototoxicity of Vitiligo skin,

(b)perifollicular macules of repigmentation

(c) significant pigment darkening of uninvolved normal skin develops.

No Response by the Twenty-fifth Treatment Increase TMP to 0.9mg/kg and temporarily decrease UVA dose. If response still not adequate after 15 to 25 more treatments substitute 8-methoxy psoralen 0.3 mg /kg for TMP. Reduce UVA dose to 2J/cm2 per treatment. If still no response in 25 more treatments, treat with 0.3 mg/kg 8 MOP plus 0.6 mg/kg TMP and if still no response in 15 to 25 more treatments abandon the treatment as a failure. If there is marked phototoxic response and loss of pigment despite continued therapy, stop phototherapy for 2 to 4 weeks. Resume treatment at lower UVA doses (subthermal leves). Chronic phototoxicity may result in loss of repigmentation.

TOPICAL PUVA: Topical PUVA is an attempt to limit the area that becomes photosensitized and avoid some of the effects of systemic psoralen. This method also has side effects, including erythema, blistering and hyperpigmentation of normal, adjacent skin. When topical PUVA was compared to narrowband UVB in the treatment of generalized vitiligo, the therapies were found to be comparable, but narrowband UVB had fewer adverse effects and less cumulative UVB dose. Topical (localized) treatment of Vitiligo is indicated in adults and children over 2 years who have pigment loss of less than 20% to 25% of body surface. Topical psoralens are highly phototoxic and should be used only with patients who can clearly comply with the rigor required to minimize the risk of phototoxicity which can manifest as intense erythema and bullae formation. The stock 8-MOP solution is diluted with cetaphil or petrolatum to make a 0.1 % solution. However, once the disease is stable, repigmentation of cosmetically important sites can be enhanced with topical PUVA. We use psoralen in 1:10 dilution to be applied thrice weekly on alternate days and weekends off. It should be applied with an applicator or cotton swab to the lesion and the borders should be protected with petrolatum and a sunscreen. Exposure to UVA or sunlight should be carried out 45 minutes (30 to 90 minutes) after application two to three times a week. UVA exposure dose should be 0.12 or 0.25 J/cm2, increased gradually by 0.12 or 0.25 J/ cm2. We recommend one minute sunlight exposure and an increase gradually to ten minutes. In pigmented patients we have raised the concentration gradually 0.6% over resistant areas. We have used 8 M. 0. P. incorporated with a sunscreen P. A. B. A. 1% concentration without inducing severe phototoxicity. The patient is clearly instructed to wash the treated area thereafter with soap and water, apply sunscreen and if feasible wear clothing to cover that site. Repigmentation may take 20-30 exposures to begin with and maximal improvement may take upto 150-300 exposures. Puvasol: Psoralens and sunlight exposure. TMP (0.6 to 0.9 mg/kg) is the preferred drug for skin types I to III; 8. MOP (0.3 to 0.6 mg/kg) appears to be beneficial to patients with Skin type IV to VI. Two hours after ingestion of psoralens, the patient is exposed to measured periods of natural sunlight, starting with an initial exposure of 15 minutes and gradually increased to a maximum of one hour (both sides). Maximum solar radiation is received between 11 AM to 3 P. M. The patient should be treated twice initially for 2-4 weeks, followed if needed by three times weekly schedule. A persistent faint erythema is desired. Marked erythema should be avoided, since subsequent Koebnerization may cause reversal of repigmentation. Thus when erythema occurs, artificial UVA dose or sunlight exposure should be held constant or reduced. Improvement usually manifests as perifollicular pigmentation due to activation of the amelanocytic reservoir of the hair follicle causing depigmentation which enlarges. In addition there is slow repigmentation starting from the margin. Other studies have shown that melanocytes may be increased in number and appear free in the dermis. Usually disease of the face beings to respond after 25 treatments and elsewhere after 50 treatments. The recommended dose of methoxsalen is 0.6 mg. per kilogram body weight, to be taken on alternate days on an empty stomach preferably with a glass of milk in a single dose to be followed two hours later by exposure to sunlight, as peak blood levels of 8-MOP are reached three hours after ingestion.

Recommended Dose Men between 51 to 65 Kgs. between 66 to 80 Kgs. 30 mgs. 40 mgs. or 3 tablets 4 tablets Women between 30 to 50 Kgs. between 51 to 65 Kgs. 20 mgs. 30 mgs. or 2 tablets 3 tablets Children Upto 30 Kgs. between 30 to 50 Kgs. 10 mgs. 20 mgs. or 1 tablet 2 tablets Irradiation or Solar Exposure: Only in case of oral treatment, the following exposure schedules are recommended depending on the skin types. The best exposure time is when the sun is at its zenith, between 11.00 a. m. and 3.00 p. m. The patient must be lying down. If the patient has a tendency to sleep, someone must wake him or the patient must use an alarm clock. It should be noted that leukodermic patches over the face, eyelids, nasal or buccal orifices or scrotum are treated only with tablets.

For leukodermic patches on the hands, simultaneous oral treatment for the above areas of the body are recommended because overexposure may give rise to severe erythema if local treatment is used. Maintenance Therapy We suggest 2 exposures per week for a few months and then 1 exposure per week for 15 to 30 minutes.

Use of Paraminal (Para Amino Benzoic Acid ) Should be applied on the periphery of the vitiligenous patch to protect the area of normal skin. Results :- With such a regimen, cosmetically acceptable repigmentary response occurs in most cases and are achieved in 75% of cases. Repigmentation may begin after a few weeks. However, significant results may take as long as six to nine months. Some cases require maintenance dosage to retain the new pigment. Toxicity Extensive clinical experience has shown that orally administered psoralen is virtually non-toxic; there are no reported cases of an adverse effect. Side effects may occur in a few patients like nausea, vomiting, etc. If symptoms occur, half the dose should be given 21/2 hours before exposure to sunrays and the remaining half dose should be given 2 hours before exposure to sunrays. Thus two oral doses can be given at an interval of half an hour. Precautions The patients should wear optical dark glasses during sun exposure which is to be kept on for 4 to 5 hours thereafter. Specific Instructions for Local / Topical Treatment Local / topical treatment with solution or ointment is used in serious renal or hepatic diseases, diabetes, blood dyscrasias or if oral treatment has not been well tolerated. Sleeplessness or irritability may be an indication of intolerance to the drug. The schedule of exposure to be followed very accurately is as follows :-

 Half a minute per day for the first week.

 One minute per day for the second week.  

Two minutes per day for the third week.

This exposure provokes usually a slight erythema (irritation blister). The exposure could be increased in duration according to the patient's tolerance. Within a few months the threshold of erythema (irritation blister) can be reached in 5-6 minutes. After every exposure the patient should cover all the treated leukodermic patches or apply ointment. These protective measures are essential as most of the local reactions are due to inadvertent exposure and additional solar radiation.

Solution : Solution should be applied one hour before exposure very gently with the brush provided. Rubbing is not necessary for the first 15 days. It is advisable to use a weaker solution by diluting 1:10 with eau de cologne(A scented liquid made of alcohol and various fragrant oils).

Ointment: Ointment is as effective as solution and is used especially for tender skins. Symptoms and Reactions In case inflammatory reaction occurs, the application should be interrupted. The inflammation can be treated in the same way as ordinary burns of the first degree.

Usually, application of calamine lotion is sufficient.

Narrowband UVB: Narrowband UVB for the treatment of generalized vitiligo in children has recently emerged as a promising therapy.

A meta-analysis in 1999 found that narrowband UVB was the most effective and safest therapy for generalized vitiligo.1 Subsequently a number of open trials in children with generalized vitiligo have been conducted, with the best results on the face and neck and in vitiligo present for a shorter duration. Hands and feet show little response. Treatment three times per week seems to have a somewhat better response than twice per week.

Microphototherapy - UVB: A variation of narrowband UVB, microphototherapy has been used to treat both segmental and non-segmental vitiligo. The beam is focused only on areas affected by vitiligo. An open trial of adults and children with both segmental and generalized vitiligo were treated with this modality. Seventy percent achieved normal pigmentation in greater than 75% of treated areas. This may be the treatment of choice in patients with <30% BSA (body surface area) involvement and the best treatment for children, as the cumulative dose of radiation is very low and non-affected skin does not become hyperpigmented.

The other modality of treatment for focal vitiligo includes topical PUVA which can be used singly or in combination with topical steroids. We have also used topical placental extract, usually in combination with topical steroids and the results have been variable, more often on the lower side of efficacy. The other form of localized vitiligo is segmental vitiligo, which is known to have a better prognosis in that it does not progress inexorably like non-segmental vitiligo. However, response to topical medical therapy in segmental vitiligo is mostly unsatisfactory as would be expected owing to its non-autoimmune etiology and these patients in our experience do best with surgical procedures. Mucosal vitiligo is another form of localized vitiligo with poor response to medical therapy, obviously due to lack of hair follicles acting as pigment reservoirs at these sites. After an initial trial of topical therapy, especially aimed at stabilizing the disease, these patients may also be recruited for surgery. Vitiligo in children is essentially managed along the same lines as an adult with a few differences. Firstly, it must be remembered that children tend to have a better prognosis and so depending on the extent and activity of the disease, the appropriate treatment should be decided. Most children were found to do fairly well with topical steroids especially those with a high safety index like mometasone furoate and fluticasone propionate. In those children(under 16 years of age) who had widespread disease, we have used oral mini pulse therapy (OMP ) with betamethasone at a dose of 2.5mg on two consecutive days each week. Results with this therapy have been largely very satisfactory and contrary to the usual belief, side effects have been noted very rarely. Patients are recruited for surgical procedures based on certain clinical criteria including123  Disease, which is stable for at least one years.  

Failure of appropriate and adequate medical therapy.  Localized vitiligo(Focal, segmental, mucosal) Stability of the disease is the most important factor, which must be ensured before undertaking surgical procedures, and it is preferable to put a graft before proceeding with the full procedure.

Surgical procedures can be followed with application of topical PUVA-SOL once the acute edema of the procedure has subsided to enhance spread of the transplanted pigment. Another important aspect in the management of vitiligo is to identify the prognostic factors in each patient as this would be essential to decide on the end point of any modality of therapy. In our experience, poor prognostic factors includes history of progression, family history of vitiligo, widespread disease, non-segmental vitiligo, acrofacial vitiligo, mucosal involvement and leukotrichia. We would also advise that all patients of vitiligo should be given sunscreens, antioxidants and options regarding cosmetic camouflage. Finally, the management of vitiligo would not be complete without good counseling, motivation and psychological support to the patient.

Topical Immunomodulators: With the introduction of topical immunomodulators (tacrolimus and pimecrolimus), many had hoped they would be a panacea for a number of cutaneous disorders, including vitiligo. A number of studies have shown their efficacy or near-efficacy to topical corticosteroids, without the attendant adverse effects, such as atrophy.14 - 16 With new concerns regarding their long-term safety, the topical immunomodulators may best be used to treat small and/or difficult areas, such as the eyelids. An interesting report of focal hypertrichosis in a child while using topical tacrolimus for vitiligo was recently described. 308-nm excimer laser treatment in vitiligo patients Recently the beneficial effect of excimer laser treatment has been reported for patients with vitiligo. The initial ultraviolet (UV) dose was 50 mJ cm2 less than the 308-nm minimal erythematous dose in vitiligo skin. The UV dose was increased at each treatment session according to the erythematous response to the previous treatment.

Laser-induced repigmentation persisted in most cases over the entire follow-up of 12 months after the end of treatment. 308-nm excimer laser therapy is effective against vitiligo. Although repigmentation occurs fastest with 3 x weekly treatment, the ultimate repigmentation initiation seems to depend entirely on the total number of treatments, not their frequency. However, treatment periods of more than 12 weeks may be necessary to obtain a satisfactory clinical repigmentation. PMID: 15888156 [PubMed - indexed for MEDLINE] Monochromatic excimer light (MEL) Monochromatic excimer light (MEL) has been used to treat adults with either segmental or generalized vitiligo. Good results were found, with 95% of patients showing some repigmentation and approximately 50% greater than 75% repigmentation. Significantly, three patients responded to MEL who had not responded to narrowband UVB in the past. The results are similar to those with excimer laser; however, MEL has the advantage of lower power density leading to reduced risk of overexposure, the possibility to treat larger areas at a time, and shorter treatment duration. These advantages may allow this method to be useful in children, however it has unknown efficacy, as no children under 15 years were treated in this study. Micropigmentation for the treatment of Vitiligo: Permanent dermal micropigmentation using a non-allergenic iron oxide pigment to cover recalcitrant areas of Vitiligo has been reported. There was a moderate fading in the first six weeks. No allergic reactions to the pigment or Koebnerization of the Vitiligo was noted. Mild complications like pain, swelling, tenderness, and slight serous oozing lasted for few hours to 9 weeks. Tattooing in Vitiligo

1) Tattooing has been used as a form of body marking since ages.

2) It can also be used scientifically as a camouflage in Vitiligo.

3) Tattooing involves insertion of inert pigment into the skin with the help of needles.

4) Tattooing can be carried out by a) Mechanical method b) Electrical method

5) Pigments that are used include different shades of

a) Brown b) Red c) Black d) White 6) They are all oxides of iron except for the white which is titanum oxide.

7) They are all inert and are analytically tested to exclude arsenic and lead.

8) Tattooing is an extremely useful modality which can be offered to patients with suitable and resistant Vitiligo, who have few patches.

9) However, since complete color match is extremely difficult it should be reserved for patients who desire immediate results e.g. marriage or for areas where darker color is natural like areola and scrotal region.

Therapeutic wounding methods Therapeutically wounding the lesion to stimulate the melanocytes from the periphery and the black hair follicles to proliferate, migrate and re-pigment the lesion, e.g. therapeutic dermabrasion, laser ablation, cryosurgery (liquid nitrogen spraying), needling, and local application of phenol or trichloroacetic acid. For vitiligo areas with at least 25%-50% of black hair, any of the therapeutic wounding methods (phenolization is the simplest and cost effective) will accelerate the process of repigmentation. The following methods have been found to be useful at certain locations.

 Dermabrasion  ultrapulse carbon dioxide laser and concomitant PUVA treatments Tsuji et21 al had equal success with 5 percent topical 5-fluorouracil cream after dermabrasion of the lesions. Mini Pulse Therapy for Vitiligo

a) Administering corticosteroids without producing side effects. This approach consists of administering relatively large dose (5mg of betamethasone/ dexamethasone, 10 tablets of 0.5mg each) as a single dose with the morning breakfast on two consecutive days per week.

b) This dose is found to control the activity of the disease process in nearly 90% of the patients having active disease.

c) Several of the patients obtained spontaneous repigmentation

d) The side effects with this treatment are mimmal and revisable.

Methyl Prednisolone mini Pulse Therapy in Vitiligo  40 -180 mg. of Methyl Prednisolone I.M. is used instead of betamethasone with less side effects.      60-80 mg prednisolone once a week.40 mg as a single dose with the morning breakfast on two consecutive days per week.  low-dose oral prednisolone23 Autoimmunity is one of the most probable pathogenesis of vitiligo. Systemic corticosteroids may arrest the progression of vitiligo and lead to repigmentation by suppressing immunity. The clinical efficacy of low-dose oral corticosteroids was assessed to minimize the side-effects in actively spreading vitiligo patients. The patients took daily doses of oral prednisolone (0.3mg/kg body weight) initially as a single oral dose after breakfast for the first 2 months. The dosage was then reduced to half the initial dose during the 3rd month and was halved again for the 4th and final month. After 4 months of treatment, 76% showed repigmentation while the arrest of progression (both repigmentation and stationary) was noted in 90% of patients. Male sex, and patients under 15 years of age showed pronounced repigmentation with statistical significance. According to this study low-dose oral prednisolone is an effective method in preventing progression and inducing repigmentation of fast-spreading vitiligo without the associated serious side-effects.

Levamisole In Vitiligo:

a) Levamisole 150 mg on two consecutive days orally for patients who have limited and slowly spreading disease

b) Levamisole has been found to control the disease in approximately 80-90% of the patients.

c) In addition it shows a variable degree of spontaneous repigmentation.

d) The extent of repigmentation can be enhanced by using topical corticosteroids.