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Keywords:

  • vitiligo;
  • repigmentation;
  • depigmentation;
  • therapy;
  • medical;
  • surgical

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

Treatment for vitiligo is difficult and prolonged. Nevertheless, at present considerable knowledge accumulated during several decades on the pathogenic mechanisms, revealed important clues for designing new strategies to improve vitiligo depigmentation. With available medical therapies, high repigmentation percentages mostly on facial and neck lesions are achieved, although they are less effective on trunk and limbs and poor on the acral parts of the extremities. Narrow band UVB and psoralens and UVA are the two most important treatments for generalized vitiligo affecting more than 10–20% of the cutaneous surface, and topical corticosteroids, or calcineurin inhibitors are the most valuable treatments for localized vitiligo. Persistence of achieved regimentation is variable and an undefined percentage of patients may have variable recurrence. When vitiligo becomes refractory, surgical methods may improve depigmentation as effectively as with medical therapy; in segmental (unilateral) or long standing, non-segmental (bilateral) stable vitiligo, repigmentation with surgical methods is usually permanent.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

Considerable research done throughout several decades have enlightened the darkness of vitiligo etiology with numerous publications on diverse pathogenic mechanisms acting during pigment loss, although certain unknown factors involved in depigmentation are yet to be determined.

Pathogenesis. Vitiligo has been reported in 0.1–2% of various global populations (Majumder, 2000) and 20–30% of patients report vitiligo in first or second degree relatives. Genetic data support a non-Mendelian, multi-factorial, polygenic inheritance (Grimes, 2004). Diverse pathogenic mechanisms have been proposed (Westerhof and d’Ischia, 2007), with alterations of cellular and humoral immunity (Kemp et al., 2001; Ongenae et al., 2003), oxidative stress (Schallreuter et al., 1991, 1994), cathecholamines (Orecchia, 2000), a pigment cell structural aberration (Boissy et al., 1991), melanocytorrhagia (Cario-Andre et al., 2007), epidermal cytokines (Moretti et al., 2002), metabolic dysregulations (Dell’anna and Picardo, 2006), and also a convergence hypothesis with simultaneous defects. The recent finding of DNA sequence variants in the NALP1 region associated with the risk of several epidemiologically associated autoimmune and auto-inflammatory diseases with vitiligo (Jin et al., 2007), may open a new avenue for additional findings in the pathogenesis of vitiligo (Taieb, 2007). Based upon these findings, the prevailing hypothesis is that genetically affected individuals are increasingly prone to damage affecting melanocytes, which evokes an immune response targeting melanocytes antigens leading to depigmentation. For therapeutic interventions this pathogenic approach identifies two phases: one to halt the disease and another one for stimulating repigmentation. In addition, two forms of vitiligo are commonly observed: 1) non-segmental (bilateral) vitiligo with a chronic, progressive and unpredictable course, where immune alterations seem to dominate the pathogenic scenario, and 2) segmental (unilateral) vitiligo developing at an earlier age, having a shorter course, where stabilization and no further progress is frequently seen (Hann and Nordlund, 2000).

Although based upon clinical findings it is not possible to determine the presence or absence of remaining pigment cells, non-melanized melanocytes have been found microscopically in long standing disease (Tobin et al., 2000), but also in spite of appropriate therapy vitiligo may continue its natural course (Luger and Paul, 2007).

The melanocyte reservoir. Melanocytes must be present somehow in vitiligo lesions to induce repigmentation during therapy. Early work, showed amelanotic melanocytes in the external root sheath of hair follicles (Staricco, 1959); further studies with psoralens and UVA (PUVA) therapy, demonstrated DOPA negative, non-dendritic pigment cells along the external root sheath of hair follicles which migrated towards the epidermis, and gradually transformed into mature, dendritic, tyrosinase positive melanocytes repopulating the basal cell layer; a melanocyte reservoir in the hair follicle was then postulated and confirmed thereafter (Cui et al., 1991; Ortonne et al., 1979). Additional work documented the presence of small, dendritic, tyrosinase negative and c-kit positive melanocytes found mostly around the follicular ostium (Grichnik et al., 1996); later on, melanocyte stem cells were also described in the bulge area near the insertion of the hair follicle muscle, tightly bound to hair cycling (Loomis et al., 2008). These immature melanocytes at different stages of development may be stimulated to originate repigmentation when needed (Figure 1); in addition, numerous pigment cells not destroyed during depigmentation and those at the border of depigmented lesions, may also reproduce or migrate to depigmented skin but as a less effective mechanism.

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Figure 1.  Perifollicular repigmentation. The most important mechanism of repigmentation in vitiligo is depicted in this illustration with pigmentation spreading 2-4 mm around the follicular units. Affected areas usually become fully repigmented when perifollicular pigmented spots undergo coalescence.

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When treating 125 patients with 352 vitiligo patches, 194 (55%) showed the following repigmentation patterns: 1) perifollicular, of which the majority 127 (65.5%) were on systemic and 35 (18%) on topical PUVA; 2) diffuse, in 98 (27.8%) patches, 66 (67.3%) of which were on topical steroids; 3) marginal, in 15 patches, of which the majority (80%) were on systemic PUVA and topical calcipotriol (Parsad et al., 2004).

Therapy and anatomical location. Repigmentation of the face and neck have the maximum response within relatively short time and constitute the so called ‘bland areas’; next, proximal extremities and trunk respond effectively although not as well as facial skin, constituting the ‘intermediate areas’; lastly, in acral parts of the extremities or ‘hard areas’ repigmentation is difficult to achieve. The variable amount of hair follicles and melanocytes in diverse skin areas together with other unknown factors could explain this repigmentation outcome.

Vitiligo area measurement. The lack of a universal method for evaluation of the affected vitiligo areas makes difficult to asses the validity of therapeutic success when comparing results of different series (Mahmoud et al., 2008); most articles use a percentage scale for improvement from 0 to 100%, which has an important subjective component. When digital measurement softwares are used, they are not specified, and in addition they are designed for different purposes other than for measuring vitiligo areas. Two important methods, the Vitiligo Area Scoring Index (VASI) (Hamzavi et al., 2004) designed to measure vitiligo areas, and the Dermatology Life Quality Index (DLQI) to estimate the subjective improvement as seen by vitiligo patients (Kent and al-Abadie, 1996; Ongenae et al., 2005), will add significant value in future studies.

Randomized, controlled, double blind studies are scarce and many articles are open label, retrospective or case reports; however, information derived from such studies illustrate on the tendency of certain treatments. Lastly, the purpose of this review is to present an update on the most valuable information about medical and surgical therapies for vitiligo, although complete and permanent repigmentation may not be achieved in every patient.

Vitiligo therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

Depigmentation in vitiligo should be initially treated with medical therapy. When therapy fails in spite of appropriate interventions, vitiligo may become refractory and stable and surgical therapy with transplantation of melanocytes in selected patients may be indicated.

Medical therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

As a general rule, although not defined by evidence based findings or validated for every medication, topical therapy for vitiligo is usually recommended when depigmentation is less that 10–20% of the skin surface (Grimes and Billips, 2000; Menchini et al., 2004; Morison, 2000), and systemic therapy when exceeding these limits; but when topical therapy of small areas fails, systemic treatment may be indicated. Repigmentation is slow and patients should be adviced about compliance and patience. Follow up visits should be around 2–3 months apart.

Medical therapy will be divided in the following categories: 1) corticosteroids, 2) immunomodulators, 3) ultraviolet radiation; 4) lasers; 5) alternate therapy; 6) depigmentation and 7) psychological support and camouflage. Selection of a specific therapy depends on effectiveness supported by evidence based information and according to the dermatologist’s experience since diverse treatments may offer comparable results.

Alternate therapy should be tried when therapeutic failures to first line treatments occur.

Corticosteroids

In addition to their actions in inflammation, corticosteroids can suppress the immune system by decreasing immunoglobulin and complement. In vitiligo, a reduction in antibody-mediated cytotoxicity against pigment cells has been observed following treatment with systemic steroids (Rezaei et al., 2007).

Topical corticosteroids

This is a first line therapy for localized vitiligo, recommended for facial and/or small lesions and in children. Low potency steroids such as hydrocortisone may be useful, but a meta–analysis including randomized controlled trials of 29 patient series showed that corticosteroids class 3 and 4 were the most effective for localized vitiligo (Njoo et al., 1998). Although most recent publications propose 0.05% clobetasol propionate as an important therapy, topical potent and ultrapotent corticosteroids should be limited to 2–4 months to avoid local side effects (atrophy, telangiectasia, striae) and percutaneous absorbtion with chronic adrenal insufficiency (Levin and Maibach, 2002); alternating regimes with less potent steroids could minimize side effects. If no response, therapy should be stopped after 3–4 months. A more recent evidence-based analysis disclosed that the best option was topical steroids, followed by topical immunomodulators (Forschner et al., 2007). Several studies illustrate on the efficacy of topical cosrticosteroids (Table 1).

Table 1.   Repigmentation efficacy of topical corticosteroids and topical corticosteroids versus calcineurin inhibitors
Topical corticosteroids
 StudyNo. of patientsRepigmentation % or estimatedRemarks
  1. n.s., non-significant; F.V., facial vitiligo; N.F.V., non-facial vitiligo; pts, patients.

Therapy
 Clobetasol prop 0.05%Kumari, 198475a) 80% of pts >90% F.V. b) 40% of pts >90% N.F.VOpen, non-controlled study
 Clobetasol prop 0.05%Handa et al., 2001232207 (89% of pts) >50% and >75%Retrospective study plus sunlight exposure
 Potent & very potent Cockayne et al., 200210 children 25 adults10 (100% of pts) 100% 9 (36% of pts) 100%Open retrospective study
 Moderate & high potent Kwinter et al., 2007101 children64% of 70 pts. 100%Retrospective 29% of pts abnormal cortisol
Comparative therapy
 Clobestasol prop 0.05%  Tacrolimus 0.1%Lepe et al., 200320 2049.3% 41.3% (n.s.)Randomized, double blind study
 Clobetasol prop. 0.05%  Pimecrolimus 1%Coskun et al., 200510Similar results on both sidesProspective left/right comparative study
Systemic corticosteroids

The only indication is vitiligo of rapid course; a reduction in complement-mediated cytotoxicity by autoantibodies to melanocytes has been observed (Mahmoud et al., 2008). Small daily doses of prednisolone (0.3 mg/kg body weight) in 81 vitiligo patients, resulted in 87.7% arrest of progression and 70.4% repigmentation (Kim et al., 1999). Similar results were observed with 5 mg betamethasone on two consecutive days per week (Pasricha and Khaitan, 1993), or with similar pulses of 10 mg dexamethasone (Radakovic-Fijan et al., 2001).

Immunomodulators

Initial observations suggested that tacrolimus inhibits T-cell activation by down-regulating the transcription of genes encoding proinflammatory cytokines IL-2, IL-3, IL-4, IL-5, interferon (IFN), tumor necrosis factor (TNF) and granulocyte-macrophage colony–stimulating factor (GM-CSF) in T cells (Lawrence, 1998); also, in a controlled study, significantly increased expression of IFN-gamma, TNF-α and IL-10 in vitiligo skin with subsequent lower post-treatment expression of TNF-α was found, suggesting that cytokine imbalance plays a role in vitiligo depigmentation (Grimes, 2004). In addition, proliferation of both melanocytes and melanoblasts, as well as significantly enhanced stem cell factor (SCF) in vitro, and metalloproteinase-9 (MMP-9) activity -which is involved in cell migration- occur with tacrolimus-treated keratinocyte supernatants; these findings suggest the effects of tacrolimus on melanocyte growth and migration during repigmentation (Kang and Choi, 2006; Lan et al., 2005).

Although it has been suggested that UVR treatment is not necessary to achieve repigmentation with tacrolimus (Sardana et al., 2007), excimer laser has been claimed to enhance the pigmentary response (Ostovari et al., 2006). Pimecrolimus has also been successfully used in vitiligo although sometimes with conflicting results (Day and Lin, 2008). Its mechanism of action should be similar to that of tacrolimus.

Selectivity in their mode of action, absence of skin atrophy and lack of significant systemic absorption are the advantages of the topical calcineurin inhibitors compared with topical corticosteroids. However, the FDA required labeling of both tacrolimus and pimecrolimus with a black box warning regarding a possible cancer risk. Currently, patients are advised against over exposure to natural or artificial sunlight. Local burning is common; acne in a patient with facial vitiligo (Bakos and Bakos, 2007) and hyperpigmentation of a patch of vitiligo (De and Kanwar, 2008) have been reported with tacrolimus. At present the therapeutic efficacy of tacrolimus and pimecrolimus in vitiligo is confined to case studies and larger, controlled studies are warranted (Sehgal et al., 2008). Different studies describe the efficacy of calcineurin inhibitors (Figures 2 and 3) (Tables 2 and 3).

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Figure 2.  Focal vitiligo before tacrolimus. A 6-yr-old boy with vitiligo of the distal half of the penis developed depigmentation 8 months before consultation. No other lesions were present.

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Figure 3.  Focal vitiligo after tacrolimus. The same patient of Figure 2 as observed 6 months after treatment with 0.1% tacrolimus ointment twice daily, disclosing around 80% repigmentation. This therapy may be a good option for genital areas where ultraviolet light treatment and corticosteroids are not recommended.

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Table 2.   Repigmentation efficacy of the calcineurin inhibitor tacrolimus alone, with NB UVB, versus placebo, and versus pimecrolimus
Calcineurin inhibitors
TherapyStudyNo. of patientsRepigmentation % or estimatedRemarks
  1. pts, patients.

Tacrolimus 0.1%Grimes et al., 2002  64 of 6 pts 50–75% 1 pt. 100%Case reports
Tacrolimus 0.1%Grimes, 2004 1917 (68% of pts) >75%Controlled study
Tacrolimus 0.03% facial Tacrolimus 0.1% non-facialFai et al., 2007110 (403 lesions)42% of lesions >50%: 73% in facial vitiligo 68% non-facial vitiligoNon-controlled study Disappointing in genital areas
Tacrolimus 0.03% & 0.1%Silverberg et al., 2004 57 children89% of pts head/neck 63% of pts trunk/extr.Non-controlled study Pts had partial repigmentation
Tacrolimus & NB UVB versus  Placebo & NB UVBMehrabi and Pandya, 2006  9   9No significant differencesRandomized, placebo controlled, double blind study
Tacrolimus versus pimecrolimus occlusive therapyHartmann et al., 2008  188% versus 73%Case report Left/right comparative
Table 3.   Repigmentation efficacy of the calcineurin inhibitor pimecrolimus
Calcineurin inhibitors
TherapyStudyNo. of patientsRepigmentation % or estimatedRemarks
  1. pts, patients.

Pimecrolimus 1%Sendur et al., 2006193 pts excellent 4 pts moderate 11 pts mild/minimalNon-controlled study
Pimecrolimus 1% non-facial lesionsDawid et al., 200620No difference with placeboLeft/right comparative study
Pimecrolimus 1% facial lesionsMayoral et al., 2007 872.5%Retrospective study
Pimecrolimus 1%Seirafi et al., 20073085.7% trunk, 75% face, 70% elbowsNon-controlled study
Pimecrolimus 1%Boone et al., 20072672.9% head and neckPilot, non-controlled study
Pimecrolimus 1%Souza Leite and Craveiro Leite, 2007 2100% genital lesionsCase reports

Ultraviolet radiation

Ultraviolet radiation (UVR), both in the range of UVB and UVA, are first line modalities for vitiligo affecting more than 10–20% of the skin surface. The effects of UVR are twofold:

Immunosuppression to halt melanocyte destruction

Previous evidence suggests that UVB can induce T-regulatory (suppressor) cell activity. Released IL10 may be important for the differentiation and activation of T-regulatory cells which may suppress autoimmune conditions (Ponsonby et al., 2005). A higher suppressive effect has been observed with narrow band (NB) UVB as compared with broad band UVB on systemic immune responses (El-Ghorr and Norval, 1997). In addition to immunosuppression (Pathak and Fitzpatrick, 1992), sera from patients after PUVA contain higher levels of basic fibroblast growth factor (bFGF), SCF and hepatocyte growth factor, which may create a favourable environment for re-growth of melanocytes (Wu et al., 2007).

Stimulation of the number of melanocytes, and melanocyte migration

In vitiligo, a significantly lower expression of GM-CSF, SCF, and bFGF have been found compared with partially affected or unaffected skin (Moretti et al., 2002). UVR increases the number of residual melanocytes most probably by enhancing melanocyte growth factors such as bFGF and endothelin-1 (ET-1) (Abdel-Naser et al., 2006; Hirobe, 2005). The activation of stem cells in the hair follicle and interfollicular epidermis, -which could escape the immune destruction mechanisms since they do not express melanocyte differentiation markers-, could provide differentiated melanocytes for repigmentation (Osawa et al., 2005). In addition, an immortal melanoblast line, melb-a cells, has been shown to secrete metalloproteinase 2 (MMP2) in culture, with significant migration in response to PUVA. Lastly, alpha MSH is also involved in the up-regulation of MMP2 expression (Lei et al., 2002).

Photochemotherapy

Oral PUVA (Psoralens and UVA 320–400 nm)

Micronized 8-methoxy-psoralen 0.2–0.4 mg/kg, is given 1–1½ h before 320–400 nm UVA stimulation with 1–2 Joules per cm2 (J/cm2) and it is increased according to the patient’s response. Treatment is done 2–3 times weekly and patients must wear UVA-blocking glasses following treatment (Drake et al., 1996a). A broad-spectrum sunscreen and appropriate clothing after therapy are recommended (Roelandts, 1991). Children under 12 yrs of age should not be treated. With 5-methoxy-psoralen similar results and less gastric side effects occur (Hann et al., 1991). Repigmentation with this therapy is described in different publications (Table 4).

Table 4.   Repigmentation efficacy of photochemotherapy with oral PUVA alone, and oral PUVA versus azathioprine
Photochemotherapy
TherapyStudyNo. of patientsRepigmentation % or estimatedRemarks
  1. pts, patients.

Oral PUVAKwok et al., 2002978 pts complete, 59 moderate and 30 minimal10 yr retrospective 57 relapsed in 1 yr
Oral PUVATallab et al., 200532Overall repigmentation 59.4%Non-controlled study Poor on hands, feet, periorificial
Oral PUVAVussuki et al., 20062860% of pts partial repigmentationProspective, non-controlled study Mean number/treatments: 84.2
Oral PUVA & azathioprine versus PUVA aloneRadmanesh and Saedi, 20066058.4% PUVA & azathioprine, 24.8% PUVA aloneControlled, randomized trial Azathioprine enhances PUVA efficacy

The most common complication with PUVA is over-dosage and severe burning (Suliman and Abdolmoneim, 2005). Twelve patients undergoing PUVA therapy developed second degree burns affecting 5–25% of the body surface without sequelae (Herr et al., 2007). Keratosis in vitiligo patches have seldom been reported (Hassab-El-Naby et al., 2006); a ‘confetti-like’ depigmentation occurred in a patient treated with PUVA (Bhatnagar et al., 2007b), which we have observed in one of our patients (Figure 4). This side effect could more frequent that estimaded because it can be confused with developing new vitiligo lesions.

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Figure 4.  Idiopathic guttate hypomelanosis-like (IGH) depigmentation post PUVA. This 16-yr-old girl had generalized, non-segmental (bilateral) vitiligo since age 10. The patient received PUVA during 2 yrs with 100% improvement on facial areas and near to 90% recovery on limbs. While receiving PUVA she progressively developed numerous IGH-like depigmented spots on the previously repigmented areas of the extremities as depicted on the right leg. Therapy was discontinued and lesions remained unchanged for the next 3 yrs.

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Topical PUVA (Psoralens and UVA 320–400 nm)

Application of 0.1–0.01% 8-methoxy-psoralen in ethanol or hydrophilic petrolatum to vitiligo skin is done 15 to 30 min before UVA with a dose of 0.12–0.25 J/cm2, 1–3 times weekly, which is gradually increased until mild erythema develops.

In a study of 73 patients with topical PUVA, seven patients (9%) had 100% repigmentation, 26 (36%) had 50% or greater repigmentation, 29 (40%) had less than 50% pigment return, and 11 (15%) had no effect; repigmentation was observed in 56% of facial lesions (Grimes et al., 1982).

PUVAsol (Psoralens and UVA 290–400 nm solar spectrum)

Trimethyl-psoralen at a dose fo 0.3 mg/kg, is administered 2–4 h before 10–15 min sun exposure, increasing 5 min per treatment until developing slight erythema (Drake et al., 1996b). Out of 100 adults and 18 children with vitiligo, 61 of the adult patients had more than 80% repigmentation and 18 more had 50–80% recovery; all children had more than 80% improvement (Theodoridis et al., 1976). Sunlight overexposure and lack of adequate parameters make this therapy unreliable.

Phototherapy

NB UVB (311 nm)

This UVR has become an important therapy for vitiligo since first introduced a decade ago (Westerhof and Nieuweboer-Krobotova, 1997), substituting PUVA therapy in many patients. Since no oral psoralen is used, ocular or gastrointestinal side effects are non-existent. NB UVB is initiated with 0.1 mJ/cm2 followed by 20% increments on a weekly basis according to response. Increasing doses of NB UVB during therapy are frequently tolerated by patients, suggesting photoadaptation of vitiliginous skin (Rivard et al., 2007). It has been claimed as the UV treatment of choice for vitiligo (Njoo et al., 1998; Westerhof and Nieuweboer-Krobotova, 1997). Several studies show important repigmentation rates (Figure 5) (Table 5).

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Figure 5.  NB UVB therapy. This 33-yr-old woman has had generalized non-segmental (bilateral) vitiligo for the past 10 yrs. After 155 sessions of NB UVB therapy delivered during a period of 2 yrs, about 90% improvement on the affected areas of chest and abdomen has been achieved. Repigmentation (dotted line), discloses a better response on the medial aspect of the treated area.

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Table 5.   Repigmentation efficacy of NB UVB phototherapy (311 nm)
Phototherapy
TherapyStudyNo. of patientsRepigmentation % or estimatedRemarks
  1. S.V., segmental vitiligo; N.S.V., non-segmental vitiligo; T. PUVA, topical PUVA; CDLQI, Children Dermatology Life Quality Index; pts, patients.

Two groups of pts. a) T. PUVA & NB UVB b) NB UVB alone Westerhof and Nieuweboer-Krobotova, 1997a) 28 pts T. PUVA, 78 pts NB UVB b)175 pts NB UVBa) In 13 pts. some repig. In 52 pts. some repig. b) >75%: In 5 pts after 3 months In 32 pts after 12 months Before and after trial NB UVB efficient as T PUVA with fewer side effects
NB UVBNjoo et al., 2000a51 childrenIn 53% of pts >75%CDLQI improved as repigmentation progressed
NB UVBBrazzelli et al., 200510 childrenIn 5 pts >75% In 3 pts 25–75%Non-controlled
NB UVBKanwar and Dogra, 200520 childrenIn 15 pts marked In 4 pts moderate In 1 pt mild Prospective, non-controlled study
NB UVBChen et al., 200572In 9 pts 75–100% In 24 pts 50–75% In 20 pts 25–50%Retrospective study
NB UVBBrazzelli et al., 200760100% In 68% of pts (face) In 57% of pts (neck) In 50% of pts (trunk)Non-controlled study
NB UVBSitek et al., 200731In 5 pts <75%, 2 yrs after therapy Suggest <50% persistency of repigmentation
NB UVBNicolaidou et al., 200770 detection of predictive factors, stabilityIn 34.4% of pts (face) In 7.4% of pts (body) >75% repigmentationNon-controlled study Better prognosis in facial lesions, phototypes III–V, and early response
NB UVBAnbar et al., 2006b150 90% N.S.V. 10% S.V.N.S.V In 48% of pts marked In 27% of pts moderate In 25% of pts mild S.V. only mild Non-controlled study Vitiligo type, location and duration are predictive factors

Keratoacanthoma in a vitiligo lesion after NB UVB phototherapy has been described as a rare event (Brazzelli et al., 2006); long term effects of NB UVB have yet to be determined.

Targeted UVB microphototherapy (300–320 nm, peak at 311 nm)

A focused beam of broad band UVB light with a 311 nm peak, 2–3 times per week, has been reported as an alternative to NB UVB and PUVA for localized vitiligo. From 734 patients, 510 (69.48%) achieved >75% repigmentation of treated areas and 112 were totally repigmented; other 155 patients (21.12%) achieved 50–75% repigmentation and 69 (9.40%) showed <50% repigmentation (Menchini et al., 2003). When 0.05% betamethasone dipropionate cream is combined with 311-nm NB UVB microfocused phototherapy, the highest repigmentation rates are achieved (Lotti et al., 2008).

Broadband UVA (320–400 nm)

Ultraviolet A without psoralen, has also been used three times weekly in a controlled, comparative and randomized trial in 20 selected patients; after 48 sessions over 16 weeks with 15 J/cm2, >60% repigmentation was observed in 50% suggesting UVA as an alternate therapy for vitiligo (El-Mofty et al., 2006).

Comparison Studies

PUVA versus NB UVB

Recent studies to evaluate PUVA versus NB UVB seem to disclose some advantages in favor of the latter with higher repigmentation rates and better color matching (Table 6).

Table 6.   Repigmentation efficacy of combination therapy with PUVA versus NB UVB
Photochemotherapy versus phototherapy
TherapyStudyNo. of patientsRepigmentation % or estimatedRemarks
  1. pts, patients.

PUVA versus NB UVBParsad et al., 200669In 9 pts 75–100% PUVA In 14 pts 50–75% PUVA In 13 pts 75–100% NB UVB In 10 pts 50–75% NB UVBRetrospective study NB UVB better color matching
PUVA versus NB UVBBhatnagar et al., 2007a25 PUVA 25 NB UVBNB UVB superior in disease stability and repigmentationOpen prospective study and evaluation with VIDA scoring
PUVA versus NB UVBYones et al., 200756In 16 of 25 pts >50% with NB UVB In 9 of 25 pts >50% with PUVADouble-blind randomized study Better color matching with NB UVB
NB UVB versus excimer laser

The effectiveness of NB UVB phototherapy was compared with the 308-nm monochromatic excimer light (MEL) in 21 vitiligo patients with symmetrical lesions on opposite sides, treated twice weekly for 6 months in a randomized, investigator-blinded and half-side comparison design. At the end of the study six lesions (37.5%) treated with 308-nm MEL and only one lesion (6%) treated with NB UVB achieved excellent repigmentation suggesting that 308-nm MEL is more effective and faster than NB UVB (Casacci et al., 2007).

Lasers

Helium–neon laser

With the low-energy 632.8 nm helium–neon laser (He–Ne) in vitiligo in vitro studies revealed that its effects may be related to a significant increase in bFGF release from both keratinocytes and fibroblasts and nerve growth factor release from keratinocytes. In a recent study with two melanoblast cell lines stimulated with He-Ne laser, mobility was enhanced in immature cells, whereas melanogenesis was promoted in more differentiated melanoblasts (Lan et al., 2006). In 30 patients with segmental vitiligo treated with 3.0 J/cm2, after an average of 16 treatment sessions, 1–2 times weekly, >50% repigmentation was observed in 60% of patients (Yu et al., 2003).

Excimer laser

The 308-nm excimer laser produces faster repigmentation rates than any other medical method so far reported. In a clinical trial with 187 patients in 20 sessions at different week frequencies, repigmentation was faster when treatment was delivered 2–3 times/week with head and neck showing the best response (Shen et al., 2007).

In a similar, prospective, controlled clinical trial of 14 patients during 12 weeks randomly assigned to receive excimer treatment once, two or three times per week, repigmentation depended on the total number of treatments rather than on their frequency (Hofer et al., 2005). In a retrospective review of 97 patients with stable vitiligo with a total of 221 vitiligo patches treated with excimer, 50.6% of patches showed >75% repigmentation, 25.5% had 100% and facial lesions >50% repigmentation (Hadi et al., 2006).

In regard to location, 25 patients with generalized or localized vitiligo with 85 lesions at different body sites were treated; after 10 weeks, >75% repigmentation was found in 7/28 (25%) of lesions on the face, trunk, arm, and/or leg (high-responder areas), versus 1/43 (2%) of lesions on the elbow, wrist, dorsum of the hand, knee, and foot (low-responder areas), suggesting that the therapeutic effect depends mainly on vitiligo location (Hofer et al., 2006). Furthermore, in a smaller group of nine patients and data from literature review, similar results were found and excimer laser was suggested as a therapy for facial lesions (Greve et al., 2006).

To summarize, in a recent review, the 308-nm excimer laser demonstrated its efficacy and good tolerance for localized vitiligo. Repigmentation seems to be faster than with NB UVB, except in extremities and bony prominences. Since no data for skin cancer risk are available caution is adviced (Passeron and Ortonne, 2006).

Alternate and adjuvant therapies

Phenylalanine

Phenylalanine (Phe) has been claimed to act as an inhibitor of cytolitic antibodies and with sunlight it stimulates migration of melanocytes (Cormane et al., 1985, 1986;Kuiters et al., 1986). Phe is given orally in a dose of 50 mg/kg, 30 min to 1 h before plus 2–12 J/cm2 UVA exposure (PheUVA) (Drake et al., 1996a). The efficacy of Phe was assessed in an open trial with 149 patients during 18 months, and in another small double-blind trial with 32 patients, during 6 months; repigmentation up to 77% in the open and 60% in the blind trial were observed (Siddiqui et al., 1994). In a retrospective study on 41 patients who received PheUVA 5 yrs previously, from 25 evaluable patients, only 11 (44%) had permanent repigmentation (Greiner et al., 1994).

In a non-controlled retrospective survey of 193 patients treated with oral (50 or 100 mg/kg daily) and topical (10% gel) plus 30 min of sun exposure, a good response with 56.7% repigmentation was achieved; improvement was 90.3% for the face, 42.8% for the trunk, and 37.1% for the limbs (Camacho and Mazuecos, 1999). With the addition of 0.025% clobetasol propionate at night, >75% repigmentation in 68.5% of 70 patients was observed (Camacho and Mazuecos, 2002). Contraindications include phenylketonuria, impaired liver and kidney function, malignant skin disease, pregnancy, breast-feeding, previous arsenic exposure or radiotherapy, and autoimmune disorders. This method could be an alternative when other therapies failed or are not indicated.

Vitamin D-3 analogs
Calcipotriol and tacalcitol

Because of defective calcium homeostasis in depigmented skin (Schallreuter and Pittelkow, 1988), the vitamin D-3 analogs calcipotriol and taclacitol have been used topically in vitiligo, where modulation of the local immune response on specific T cell activation occurs; they also influence melanocyte maturation and differentiation and up-regulate melanogenesis through pathways activated by specific ligand receptors, such as ET receptor and c-kit (Birlea et al., 2008). Different trials suggest the efficacy of vitamin D-3 analogs, although their real value in vitiligo still remains controversial (Table 7).

Table 7.   Repigmentation efficacy of vitamin D-3 analogs calcipotriol and tacalcitol alone or versus NB UVB, PUVA and versus placebo
Vitamin D-3 analogs
TherapyStudyNo. of patientsRepigmentation % or estimatedRemarks
  1. pts, patients.

Calcipotriol & NB UVB versus NB UVB aloneArca et al., 2006a) 15 pts NB UVB & calcipotriol b) 25 pts NB UVB No statistically significant differenceRandomized controlled trial
Calcipotriol & NB UVBGoktas et al., 200624 pts NB UVB & calcipotriol on right sideIn NB UVB & calcipotriol 51% In NB UVB 39%Open label left and right comparative study Calcipotriol enhances NB UVB
Calcipotriol alone versus Calcipotriol & PUVAAmeen et al., 2001a) 26 pts calcipotriol b) 4 pts calcipotriol & PUVA a) In 17 pts 30–100% b) In 3 of 4 pts good response Open label prospective study
Calcipotriol & NB UVB versus placebo & NB UVBHartmann et al., 200510No difference found between the 2 groupsComparative controlled clinical trial
Tacalcitol & NB UVB versus NB UVB aloneLeone et al., 200632Combined treatment was superiorOpen label, randomized, prospective study
Polypodium leucotomos

Polypodium leucotomos (PLe) is derived from a Central America fern, and has been found to have immunomodulator properties; it is able to modulate the immune response after trauma, inhibiting Th2 pathway activation (Navarro-Zorraquino et al., 2007); PLe has also been shown to display an inhibitory effect on the polyclonal proliferative response of PBMC to T lymphocyte mitogens that interact with cytoplasmic membrane molecules (Rayward et al., 1997).

In a randomized controlled trial, 50 patients with vitiligo vulgaris received 250 mg oral PLe or placebo three times daily, combined with NB UVB twice weekly for 25–26 weeks; repigmentation was higher in the PLe group in the head and neck areas (44% versus 27%); trunk and extremities had little improvement (6 and 4% respectively). Although an additional effect with NB UVB was observed (Middelkamp-Hup et al., 2007), more studies are necessary to ascertain the validity of PLe in vitiligo.

Khellin

Khellin (Khe) is a furochromone, used in the past as a coronary vasodilator. An oral dose of 50–100 mg is given 2 h before UVA exposure from 5 to 15 J/cm2 depending on the patient’s skin type. Khe is activated by UVA and has been shown to stimulate melanocyte proliferation and melanogenesis in vitro (Carlie et al., 2003).

Early work in a double blind study with Khe and sunlight exposure in 30 patients showed an important repigmentation response stimulating further research (Abdel-Fattah et al., 1982).

In a group of 28 patients treated with UVA, >70% repigmentation was achieved in 41% of the patients who had received 100–200 treatments, a success rate comparable to therapy with psoralen, but seven patients had a mild elevation of liver transaminases and therapy was discontinued (Ortel et al., 1988). More recently, in a retrospective study of 28 patients, from 17 patients who received oral therapy with Khe, seven (41%) had >70% repigmentation after a mean of 194 treatments (Hofer et al., 2001). The possibility of permanent liver damage has discouraged the routine use of oral Khe.

When a topical 2% solution of Khe for vitiligo was tested in a two side comparative study versus placebo with sunlight exposure up to 90 min, three times weekly for 4 months in four patients, no significant differences was detected (Orecchia and Perfetti, 1992). However, when topical Khe and UVA (KUVA) and PUVA for vitiligo were compared in a pilot study in 33 patients, repigmentation rates were similar, but KUVA required more sessions and higher UVA doses (Valkova et al., 2004). In our hands, a 3% Khe emulsion with 5–10 min of daily sunlight exposure has shown remarkable repigmentation properties over a period of several months, particularly on facial and neck lesions and without side effects (Figures 6 and 7). Nevertheless, controlled, double blind, randomized studies should be done to establish the efficacy of this therapy (Falabella, R., Barona, M.I., personal communication).

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Figure 6.  Non-segmental vititigo before topical Khellin. This 42-yr-old woman of Hispanic descent has had vitiligo for the past 5 yrs, affecting facial areas exclusively. Topical treatment with unknown medications did not induce significant repigmentation.

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Figure 7.  Non-segmental vititigo after topical Khellin. Same patient as depicted in Figure 6, discloses near to 100% repigmentation 1 yr after topical 3% Khellin emulsion plus sunlight exposure for 10–15 min daily.

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5-Fluorouracil

In an open label study, topical 5% 5-Fluorouracil (5-FU) was used twice daily under occlusion for 7–9 days after superficial dermabrasion, in 28 patients with vitiligo; in 18 (64%) subjects complete or almost complete repigmentation occurred, and in five others (18%) partial repigmentation was observed (Tsuji and Hamada, 1983), but scarring, uneven hyperpigmentation, or infection make this therapy impractical and not recommended.

A combination treatment with erbium:YAG laser resurfacing and topical 5-FU in periungual vitiligo in nine patients was assessed in a prospective left-right comparative study; a mean overall improvement of 47.8% versus 1.1% in the control group was seen, suggest this method as an option for periungueal vitiligo; morbidity and pain are important limitations (Anbar et al., 2006a).

Pseudocatalase

Accumulation of hydrogen peroxide (H2O2) accompanied by low catalase levels and high concentrations of 6- and 7-biopterin are toxic for melanocytes in vitiligo epidermis (Schallreuter et al.,1991), but H2O2 can be removed effectively with pseudocatalase leading to successful repigmentation (Schallreuter et al., 2001). A modified pseudocatalase-KUS (PC-KUS) cream for vitiligo repigmentation was assessed in 59 patients by comparing Dead Sea bathing and sunlight with PC-KUS or placebo cream. Initiation of repigmentation was observed after 10–16 days with the combination treatment (Schallreuter et al., 2002); however, in another trial with pseudocatalase mousse applied twice daily to the hands and face of vitiligo patients with twice-weekly sub-erythemogenic NB UVB phototherapy, no repigmentation was observed (Patel et al., 2002). More recently, with NB UVB activated PC-KUS in a non-controlled, retrospective study in 71 children with vitiligo, >75% repigmentation was achieved in 66/71 patients on the face/neck, 48/61 on the trunk, and 40/55 on the extremities but not on hands/feet (Schallreuter et al., 2008). Well controlled, double blind studies are necessary to ascertain the real value of pseudocatalase in vitiligo.

Catalase and dismutase superoxide

The efficacy of a combination of catalase/dismutase superoxide gel was compared with topical 0.05% betamethasone in a randomized, matched-paired, double-blind trial in 25 patients with stable vitiligo, evaluated by digital morphometry. After 10 months of therapy, repigmentation occurred equally, suggesting that both treatments have a similar efficacy for repigmenting vitiligo. No side effects were observed (Sanclemente et al., 2008). More studies to confirm these findings are warranted.

Antioxidant therapy

Folic acid, vitamin B12 and sun exposure were used in an open label study for a minimal period of 3–6 months in 100 hundred patients with vitiligo during summer and UVB irradiation in winter; improvement occurred in 52 patients and total repigmentation was observed in six others (Juhlin and Olsson, 1997). Further work in 27 patients with stable vitiligo was done in two randomized groups with NB UVB alone or NB UVB combined with vitamin B12 and folic acid for 1 yr. Although repigmentation was notable on face, trunk and extremities it was minimal on hands and feet, and vitamin B12 and folic acid did not seem to improve the effect of NB UVB (Tjioe et al., 2002).

More recently, 35 patients were treated with NB UVB and an oral antioxidant pool (AP) containing alpha-lipoic acid, vitamins C and E and polyunsaturated fatty acids, in a randomized, double-blind, placebo-controlled multicentre trial. The therapeutic response with AP and NB UVB, revealed 47% of the patients achieving >75% repigmentation against 18% in the placebo group; catalase activity increased to 114% and reactive oxygen species decreased up to 60% in PBMC. Therapy with AP significantly improves the clinical effectiveness of NB UVB by reducing oxidative stress (Dell’Anna et al., 2007). At present, antioxidants should be used as coadyuvant rather than as a first line therapies.

Human placental extracts

Melagenina, the Cuban placental extract has been evaluated previously and the biochemistry, assays for biological activity and the pharmacology studies as reported do not stand up to rigorous and acceptable scientific standards (Nordlund and Halder, 1990). We have observed many patients receiving this therapy for many months with minimal if any repigmentation, facial lesions responding somewhat better (Falabella and Barona, personal communication). In a recent trial, when a placental extract (Placentrex®) was combined with dermabrasion for vitiligo, it was not superior to dermabrasion alone (Sethi et al., 2007).

Other therapies

Tyrosine topical or systemic, cysteine, other vitamins and trace elements, clofazimine, Chinese herbal medications, ayurvedic medicine and other alternative medications have been used with variable success, but to date no scientific support is available on the real value of these treatments. In addition, some of them may originate undesirable side effects (Graham-Brown, 1992).

Depigmentation

Some selected patients with vitiligo universalis may benefit from depigmentation of unsightly residual pigmented patches on facial and exposed areas. Depigmentation may be achieved with 20% monobenzone which is first applied with a patch test for 48 h to detect hypersensitivity; then, twice daily applications are followed by depigmentation within the next 6–12 months (Nordlund, 2000) (Figures 8 and 9). Only adults with more that 50–70% depigmentation should be treated and sunlight protection is essential to prevent non-melanoma skin cancers (Ortonne et al., 1978).

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Figure 8.  Residual patches of vitiligo. This 55-yr-old woman has had universal vitiligo for 22 yrs affecting more than 70% of her skin surface. Some normally pigmented patches still remain on facial areas, mostly on both cheeks, provoking marked esthetic disfigurement.

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Figure 9.  Depigmentation after monobenzone. After topical application of 20% monobenzone daily during 8 months, noticeable depigmentation of pigmented patches as observed in Figure 8 was followed by a more normal appearance and social acceptation with subsequent improvement of her emotional distress.

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The Q-switched 755-nm alexandrite laser has also been used successfully to treat persistent pigment patches (Rao and Fitzpatrick, 2004), as well as the Q-switched ruby laser (QS-RL) (Kim et al., 2001b).

A combination therapy with topical 4-methoxyphenol (4-MP) cream and QS-RL in 16 patients with vitiligo universalis, was followed by total depigmentation with 4-MP cream in 11 patients, and four of the five non-responders became successfully depigmented with the QS-RL (Njoo et al., 2000b). Cryotherapy in 1–3 sessions 4- to 6-week apart was useful for permanent depigmentation in five patients (Radmanesh, 2000).

Psychological support and camouflage

Vitiligo provokes psychological stress in patients who are often the object of discrimination, staring, rude remarks and negative comments during interaction with other individuals (Ongenae et al., 2006; Porter and Beuf, 1991). The intensity of psychological reactions varies from patient to patient. With mild or moderate symptoms, listening to the patient’s complaints and reassurance with some advice about the possibilities of improvement are frequently helpful; nevertheless, with marked low-esteem and depression, patients should have psychiatric help. Concealing the visible disfiguring macules with clothing and cosmetics, dyes or stains is very important for patients. Tanning should be avoided since it enhances the contrast with normally pigmented skin.

Surgical therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

Until 1983, most articles referred to vitiligo as a condition treated exclusively with medical therapy. Early work with thin dermoepidermal grafts suggested that surgery had a place for vitiligo depigmentation (Behl and Bhatia, 1973). Later on, the value of grafts for vitiligo therapy was confirmed (Falabella, 1983; Koga, 1988; Suvanprakorn et al., 1985). In addition, successful grafting for repigmentation of leukoderma post burn also demonstrated that melanocytes could be successfully transplanted into depigmented skin (Falabella, 1971); (Falabella, 1984). Since then, improved procedures have provided new tools for vitiligo therapy.

Melanocytes, surgical trauma, cytokines, T cells and repigmentation

The presence of melanocytes in grafts is crucial for repigmentation induced by surgical methods as demonstrated in an elegant double-blind, placebo-controlled study, where pigment cells in an epidermal cell suspension repigmented vitiligo lesions, whereas a similar suspension without melanocytes failed to do so (van Geel et al., 2004). In addition, surgical trauma induces proinflammatory cytokines which have an effect on melanogenesis and pigment cell migration. During in-vitro experiments, increased dendricity and edema, higher levels of tyrosinase and immunoreactive b-locus protein were found when pigment cells were cultured for 2 days with prostaglandin D2 (PGD2), leukotrienes B4 – C4 – D4 – E4 (LTB4, LTC4, LTD4, LTE4), thromboxane B2 (TXB2) and 12-hydroxy eicosatetraenoic acid (HETE) (Morelli et al., 1992); similar effects were observed with prostaglandin E2 (PGE2) (Tomita et al., 1987),TGF-alpha and LTC4 (Morelli et al., 1992); moreover, bFGF, and SCF also have important effects on melanocyte migration and probably on pigment cell proliferation (Horikawa et al., 1995); endothelin-1 (ET-1) also modulates melanocyte migration (Mou et al., 2004) and elevate tyrosinase levels (Imokawa et al., 1997).

When studying punch biopsies from grafted areas in six patients with non-segmental vitiligo on days 14, 17, 21 and 28 after minigrafting and processed with MoAbs HMB-45, CD4, CD8, ICAM-1, and LFA-1, in patients not responding with repigmentation, significant numbers of cytotoxic T-lymphocytes and LFA-1 positive infiltrating cells occurred in the early phases post grafting, suggesting a cell-mediated immune response towards grafted melanocytes in active vitiligo (Abdallah et al., 2003).

An unexplained finding known as ‘satellite repigmentation’ or ‘reverse Koebner phenomenon’ has been observed in some patients with vitiligo after grafting disclosing repigmentation in the nearby areas of non-grafted skin (Agarwal et al., 2004; Laxmisha and Thappa, 2006; Malakar and Dhar, 1998), and also in contralateral non-grafted lesions (Falabella, 2005); cytokines elicited during surgical trauma could be a possible explanation.

General principles of surgical repigmentation therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

Selecting the method

Any surgical method, carried out appropriately, yields acceptable results. As an important rule, the less invasive the method, the better results will be achieved; it is also important to preserve the integrity of donor sites.

Candidates for surgical repigmentation

Several parameters should be taken into consideration with surgical procedures:

Stable vitiligo

Although not specifically defined, the longer the observation period the more accurate the concept of stability. Segmental (unilateral) vitiligo is the most stable form responding well to surgical interventions (Falabella, 2000); when bilateral vitiligo becomes stable, approximately half of the patients may also recover (Falabella et al., 1995b; Mulekar, 2003). Although it is difficult to ascertain vitiligo activity (Malakar et al., 2000), several factors suggest stability: 1) inactive lesions at least for 2 yrs; 2) spontaneous repigmentation; 3) a positive minigrafting test with 4–5 minigrafts (1.0–1.2 mm) disclosing peripheral repigmentation (Figure 10) (Boersma et al., 1995; Falabella, 2004); 4) absence of new koebnerization, including the minigrafting test donor site, although Koebner not always indicates unstable vitiligo (Mulekar et al., 2007), and has also been observed in two patients with segmental vitiligo (Mulekar et al., 2005a); 5) segmental vitiligo per se is almost synonym of stable disease.

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Figure 10.  Minigrafting test. Seven 1 mm minigrafts were implanted in the upper eyelid of this 10-yr-old boy with segmental (unilateral) vitiligo of 4 yrs duration. After 4 months and direct sunlight exposure for 10 min daily, marked repigmentation and complete coalescence of minigrafts was observed, indicating high possibilites of surgical repigmentation for the remaining depigmentation.

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Age

Preadolescents could be treated under appropriate sedation and patients beyond age 50 may be interested in surgical therapy.

Patient’s expectations

Skin appearance after surgical repigmentation is not always similar to normal skin, and results vary from patient to patient. Slight hyperpigmentation can be expected, but minor imperfections are far less important than the noticeable improvement achieved.

Depigmented versus hypopigmented lesions

The best results are seen in completely depigmented lesions of skin types III to VI; hypopigmented lesions do not repigment as well.

Methods and size of lesions

Minigrafting and suction epidermal grafting may be useful for small or medium sized lesions, but for extensive defects in vitro culture techniques or thin dermoepidermal grafts offer additional benefits (Olsson and Juhlin, 1995).

Lesions on exposed areas

Most patients are interested in treatment of lesions on exposed and visible areas. Although the dorsum of the hands and fingers are the most refractory regions, in well defined stable disease successful repigmentation is possible (Acikel et al., 2007;Falabella, 1996, 2000; Falabella et al., 1992; Kahn and Cohen, 1995).

Serial procedures

Patients may require several sessions for full recovery; small residual depigmented defects may be additionally treated with minigrafting (Falabella et al.,1995a).

Psychological aspects

Some patients with high concerns about minimal or moderate depigmentation should have a careful evaluation, to ascertain the real need for surgical treatment.

Photographic records

Photographic documentation is always recommended to evaluate the percentage and quality of repigmentation and possible side effects.

Method and donor site

The selected method depends on the surgeon’s training; non-invasive methods with little dermal manipulatetion are recommended. Donor sites should be as hidden as possible, and the gluteal region, the inner upper thigh or forearm (Laxmisha and Thappa, 2005a) may be suitable for this purpose.

Contraindications

Patients with hypertrophic scarring, a keloidal diathesis, or hyperpigmentation in previous areas of minor local burns or trauma should be carefully evaluated to avoid developing similar results with surgery.

Surgical methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

Essentially five basic methods for melanocyte transplantation have been described: 1) non-cultured epidermal suspensions; 2) thin dermo-epidermal grafts; 3) suction epidermal grafting; 4) minigrafting and punch grafting; and 5) in-vitro cultured epidermis with melanocytes or pure melanocyte suspensions. All methods provide good to excellent results and the most important factors for success are patient selection and surgeon’s expertise.

Non-cultured melanocyte suspensions

This method, reported more than 15 yrs ago has become a very useful tool for vitiligo surgery (Gauthier, 1995; Gauthier and Surleve-Bazeille, 1992; Lontz et al., 1994). The technique is performed by grafting non-cultured epidermal suspensions bearing both keratinocytes and melanocytes; suspensions are obtained by 0.25% trypsin digestion of a thin piece of donor skin; epidermal cells, including melanocytes, are injected into blisters raised by liquid nitrogen freezing, or ‘seeded’ on recipient sites denuded with superficial dermabrasion. With the addition of M2 melanocyte culture medium the cell suspension becomes enriched allowing the recovery of larger defects (Olsson and Juhlin, 1998). If hyaluronic acid is supplemented to the cell suspension, viscosity improves the attachment of cells to recipient sites (van Geel et al., 2001). It has been estimated that the minimum number of melanocytes required to produce satisfactory repigmentation is probably in the range of 210–250/mm2 (Tegta et al., 2006). Recipient sites are covered for 5–7 days with non-adherent dressings and repigmentation occurs during the following months.

To evaluate the efficacy of epidermal suspensions, 122 patients with generalized, 43 segmental and 19 with focal vitiligo were treated; excellent repigmentation occurred in 53% of generalized vitiligo patients, 84% in the segmental and 69% in the focal group (Mulekar, 2003). In another study with 142 patients with vitiligo vulgaris, 56% of patients showed excellent, 11% good, 9% fair and 24% disclosed poor repigmentation (Mulekar, 2005); three other patients with genital lesions also had successful repigmentation (Mulekar et al., 2005b).

In a group of 25 patients who failed to respond, the procedure was repeated with the addition of a low dose oral betamethasone; in 15 of 17 patients with vitiligo vulgaris and in seven of eight with segmental vitiligo good to excellent repigmentation ocurred, suggesting stabilization of vitiligo by corticosteroids (Mulekar, 2006). Recently, a shelf kit, (ReCell®), was developed and in five patients with 10 lesions on a left/right trial encouraging repigmentation was observed (Mulekar et al., 2008). Further work in 40 patients with refractory stable vitiligo (30 generalized and 10 localized), the mean percentage of repigmentation was 72%, 3–12 months after grafting and the mean DLQI score significantly decreased after treatment (van Geel et al., 2006).

An advantage of this method is that if recipient and donor sites are manipulated carefully, no scarring occurs.

The repigmentation yield is approximately 1:3 to 1:5 ratio or higher according to the dilutions used.

Thin dermo-epidermal grafts

In spite of excellent repigmentation (Behl and Bhatia, 1973) with minimal or no scarring (Kahn et al., 1993), this method has not gained popularity so far. Grafts are harvested at a depth of 0.1–0.3 mm, placed directly on recipient abraded areas next to each other and secured with surgical dressings under mild pressure for one week. Repigmentation occurs shortly during the following weeks. Acral regions as the dorsum of hands and fingers also respond with success. (Kahn and Cohen, 1995; Kahn et al., 1993). After 17 procedures in 12 patients with stable vitiligo, good to excellent repigmentation was observed in 88% procedures (Kahn and Cohen, 1998). In a case series of 21 patients with 32 stable refractory vitiligo patches, 100% repigmentation was achieved in 22 patches and 90–95% in 10 others (Agrawal and Agrawal, 1995). In 19 additional patients, excellent repigmentation was observed without scarring and the method was recommended for large areas (Olsson and Juhlin, 1997).

In a study, 13 anatomic sites of seven young male patients were treated with carbon dioxide laser resurfacing and thin skin grafts; in six patients complete repigmentation was achieved (Acikel et al., 2003).

The advantage of this method is that it can be done in one session, but a disadvantage is the 1:1 ratio yield.

A modification of this technique is the use of small 3–5 mm thinly shaved dermo-epidermal fragments inserted under very thin flaps raised by thin shaving on the recipient site; repigmentation occurs by coalescence of pigment spread (McGovern et al., 1999).

Minigrafting

This is the simplest and most commonly used surgical method for vitiligo repigmentation. Multiple perforations on recipient sites with a small 1.0–1.2 mm punch, are done 3–4 mm apart from each other; pulsed erbium: YAG may also be used to create recipient graft sites (Sachdev and Shankar, 2000). Next, minigrafts are harvested from the donor site with a similar punch and transferred to recipient sites with fine forceps or hypodermic needle (Laxmisha and Thappa, 2006); Micropore® tape applied directly on minigrafts for 2 weeks assures adequate immobilization; on difficult areas tissue glue (cyanoacrylate) can be used to immobilize individual grafts (Ghorpade, 2004). For facial lesions 1.0 mm mingrafts and for other areas 1.2 mm minigrafts are recommended. Repigmentation occurs around each minigraft up to 2–5 mm by coalescence of pigment spread (Figures 11 and 12).

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Figure 11.  Segmental vitiligo. This 32-yr-old woman has had very stable upper eyelid vitiligo for 10 yrs. No response was achieved with diverse medical treatments.

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Figure 12.  Repigmentation with minigrafting in segmental vitiligo. After a positive minigrafting test, the same patient of Figure 11 was treated with 1 mm minigrafts and around 95% repigmentation in 3 months was achieved. Notice the absence of cobblestoning with the use of very small minigrafts.

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From a group of 23 patients with 36 lesions receiving minigrafts, 19 patients showed 80–99% repigmentation in 14 lesions, 50–80% in 10 and 0–50% in 12 others, indicating a good response in vitiligo vulgaris (Boersma et al., 1995). Furthermore, 880 patients were grafted and 90–100% repigmentation was achieved in 74% of patients but a ‘polka dot’ appearance (excessive separation among grafts) in 44% of patients and colour mismatch in 34% others, were frequent side effects (Malakar and Dhar, 1999). In a study, 108 patients with refractory lip leucoderma treated with punch grafts, complete repigmentation was achieved in 72% of patients and ‘cobblestoning’ was the most common complication in 30% of patients (Malakar and Lahiri, 2004), probably because large grafts were used; failure in eight patients occurred because of herpes labialis. Lips have also responded well in eight patients with punch grafts (Babu et al., 2008). A modification of minigrafting prepared by mincing a donor piece of thin skin to produce ‘seed grafts’ delivered onto an ultrasonic abraded recipient site with additional PUVA was followed by excellent repigmentation (Tsukamoto et al., 2002).

Combination of minigrafting with NB UVB in 66 patients successful in 86% of patients, with a maximum pigment spread of 12 mm and an average of 6.5 mm, emphazising the value of UVR for enhancing repigmentation; however, 35%‘cobblestoning’ occurred, probably because 1.5 mm punches were used. (Lahiri et al., 2006).

An advantage of this method is the simple maneuvers required but small minigrafts must be used at all times to avoid ‘cobblestoning’. The repigmentation yield ratio varies from 1:10 to 1:20.

Epidermal grafting

Epidermal grafting has become very popular with different reports emphasizing excellent results. Grafts are harvested at a negative pressure of 200–300 Hg mm with different custom made suction devices (Falabella, 1984, 1996; Hann et al., 1995; Skouge and Morison, 1995); syringe or funnels have also been used (Gupta et al., 1999; Kim and Yun, 2000). Blister grafts usually develop in 2–3 h, but timing can be reduced to 30–60 min if heat is provided during suction (Peachey, 1971; Skouge and Morison, 1995). The inner aspect of the thigh and the flexor aspect of the forearm are good donor sites (Laxmisha and Thappa, 2005a). Koebner phenomenon has been reported at donor sites in generalized vitiligo (Hatchome et al., 1990).

Recipient sites are prepared by epidermis removal with liquid nitrogen freezing, superficial dermabrasion (van Geel et al., 2001), erbium YAG laser (Pai et al.,2002), CO2 laser (Hasegawa et al., 2007) or ultrapulse CO2 laser (Oh et al., 2001). Blisters grafts are transferred with a thin spatula or acetate films onto recipient sites (Albert and Shenoi, 2001) and covered with non-adherent dressings for 5 days. For lip vitiligo, (Laxmisha and Thappa, 2005b) adhesive tape (Steri Strips®) has been used to immobilize grafts. Repigmentation occurs with grafts and coalescence of pigment spread. A study in piebald patients showed that melanocytes and pigment spread horizontally from blister grafts, a mechanism that could also be valid for vitiligo (Horikawa et al., 1999). PUVA enhances repigmentation of epidermal grafts (Gupta et al., 2004; Hann et al., 1995; Skouge and Morison, 1995).

In a retrospective, uncontrolled case series and literature review of 143 patients treated with epidermal grafting, repigmentation success rates for generalized and segmental/focal vitiligo were 53 and 91% respectively (Gupta and Kumar, 2003). Epidermal grafts have been successfully used for lip vitiligo (Gupta et al., 2007); complete repigmentation was observed in 23 of 25 patients (92%), but hyperpigmentation developed in 12 subjects (Gupta et al., 2006). Delicate areas such as eyelids were treated in six patients with excellent results (Nanda et al., 2006). In a case report of segmental vitiligo with surgical failure, repigmentation was complete when NB UVB and oral corticosteroids were added to the grafting procedure (Lee et al., 2007). Chemical epilation facilitate epidermal grafting within hairy regions (Kim et al., 2001a). Reapplication of unused epidermal grafts to donor sites in eight patients, was followed by improved healing and reduced residual pigmentation (Lee et al., 2006).

Repigmentation yield is about 1:5 or higher when epidermal grafts are placed separately from each other. The main advantage is the absence of scarring in donor and recipient sites. Donor sites may be reused if necessary.

In-vitro cultured epidermis with melanocytes and melanocyte suspensions

Although at initial stages these methods have been fraught with problems due to the use of tumor promoting tetradecanoylphorbol 13-acetate (TPA) in most serum free melanocyte media, modern technology allows melanocyte culturing without these chemicals, and with well defined media optimal and exponential growth of pigment cells is achieved.

Epidermis with melanocytes

In-vitro cultured epidermis with melanocytes was initially described two decades ago for treatment of vitiligo using MCDB-153 culture medium with a fibroblast feeder layer (Brysk et al., 1989), and also with H-MEM culture medium supplemented with fetal bovine serum (Falabella et al., 1989). From a small donor skin sample, an epidermal suspension is made by 0.25% trypsin digestion and seeded in culture flasks; epidermal sheets are harvested 3 weeks later from the culture vessel and transplanted onto depigmented recipient sites previously denuded with liquid nitrogen freezing (Falabella et al., 1989), superficial dermabrasion, CO2 lasers, pulsed Erbium-YAG lasers (Kaufmann et al., 1998) (Guerra et al., 2003) or diathermo-surgery (Guerra et al., 2000). A hyaluronic artificial matrix for growing keratinocytes and melanocytes, has also been used with success (Andreassi et al., 1998; Pianigiani et al., 2005).

In a study of 32 vitiligo patients treated with cultured epidermis, repigmentation of extremities and periorificial sites was 8% and on other body sites it ranged from 88 to 96% (Guerra et al., 2000); in another trial 18 of 21 patients achieved 90% repigmentation (Guerra et al., 2003). In an experimental study, transplantation of epidermal sheet keratinocytes seeded at high density was performed; a fibroblast feeder layer helped to maintain the melanocyte number while keratinocytes were subconfluent, but failed to oppose the inhibitory influence of keratinocytes on melanocyte TRP-1 expression. These findings could explain failure of repigmentation in some patients (Phillips et al., 2001).

In two different experiments with well defined serum-free medium, keratinocytes and melanocytes were successfully co-cultured either on a chemically defined plasma polymer substrate (Beck et al., 2003), or on a silicone carrier pretreated with 20% carboxylic acid deposited by plasma polymerization, developing a neo-epidermis (Eves et al., 2008); both methods, with significant number of melanocytes could be useful in future trials for repigmentation of vitiligo.

Melanocyte suspensions

In-vitro cultured melanocyte suspensions are obtained in a similar manner with specific and defined culture media such as Ham’s F12; during subculturing, pigment cells increase in number and may be transplantated onto denuded areas at a density of 60 000–100 000 melanocytes/cm2; the suspension, evenly spread onto recipient surfaces and covered for 5–7 days provided a good cellular take (Lontz et al., 1994; Olsson and Juhlin, 1995). In 120 patients treated, 84%patients with stable localized vitiligo had 90 to 100% repigmentation, followed by 54% of patients with stable generalized vitiligo, but only 14% of patients with active generalized vitiligo had good results (Chen et al., 2004). In a similar study with 100 patients, repigmentation was 95–100% in 40 subjects and from 65 to 94% in 32 others (Olsson and Juhlin, 1995). Melanocyte suspensions kept under freezing for 6–12 months were re-cultured after thawing and transplanted in four patients; successful repigmentation suggested the enormous potential of frozen cells for future trials (Olsson et al., 1994).

Newer technologies are in progress; cultured melanocytes in serum-free medium attaching to porcine gelatin microbeads used as microcarriers, could be used in the future for treating large vitiligo areas (Liu et al., 2004). In addition, melanocytes cultured in chitosan-coated polystyrene wells started to aggregate after 2 days and grew into compact melanocyte spheroids on day 3, constituting a feasible alternative for use in autologous melanocyte transplantation for vitiligo (Lin et al., 2005). Furthermore, an in vitro study disclosed that murine fibroblasts are more potent than human fibroblasts in secreting soluble factors such as SCF, which can act directly on pigmentation or activate keratinocytes to produce basement membrane proteins or melanogenic factors (Cario-Andre et al., 2006).

Repigmentation is attained with both types of cultured melanocyte grafts several months after surgery, and PUVA contributes to provide faster and deeper repigmentation. The large population of cells obtained from a small donor site, is a great advantage for treating extensive vitiligo areas in a single session. Their future use will depend on cost effective facilities where cells from individual patients can be processed for the clinician (Ghosh et al., 2008).

Other surgical methods

Micropigmentation

This technique is useful for vitiligo lesions on mucous and mucocutaneous areas. It is accomplished by tattoing inert pigment granules into the dermis within collagen bundles and extracellularly at a depth range of 1–2 mm, delivered by multiple needles electrically driven; combinations of white, yellow, black, red and brown pigments are used (Thami, 2007).

Repigmentation of leukotrichia

Repigmentation of leukotrichia has been observed after treating vitiligo with thin dermoepidermal grafts (Agrawal and Agrawal, 1995), epidermal grafts (Hann et al., 1992), punch grafting (Malakar and Dhar, 1998) and with in vitro cultured epidermal grafts (Falabella et al., 1992). A reverse mechanism of melanocyte migration, from the repigmented epidermis towards the external root sheath and then to the hair bulb has been advocated as the explanation of repigmentation. This method should be performed in patients developing disfiguring leukotrichia.

Side effects of vitiligo surgery

Surgical procedures involve manipulation of donor and recipient sites and gentle maneuvers avoid side effects.

Infection

Although not frequently reported, aseptic techniques should always be performed to prevent bacterial infections (Gupta and Kumar, 2003); reactivation of herpes simplex (Malakar and Lahiri, 2004) is avoided with systemic antivirals.

Post-inflammatory hyperpigmentation

This effect, mostly transient, may be expected in a vast number of patients, but especially with skin phototypes IV to VI; sometimes permanent hyperpigmentation occurs and a genetic diathesis cannot be excluded. Proinflammatory cytokines (Horikawa et al., 1995; Morelli et al., 1992; Tomita et al., 1987, 1992), elicited during surgical procedures may play an important pathogenic role. Permanent hyperpigmentation in areas of previous skin trauma may be a warning against repigmentation surgery.

Uneven repigmentation

Irregular pigmentation after surgical procedures may occur, but it happens more frequently with technical errors than because of the patient’s response. In fact, sometimes surgical procedures provide better results than medical therapy (Falabella et al., 1992).

Scarring

Hypertrophic scars, thick grafts and irregular surfaces are the most frequent side effects. For dermoepidermal grafts, plain knives for shaving do not provide even graft thickness. In minigrafting, ‘cobblestoning’ is avoided with mini-punches up to 1.2 mm; larger punches may yield poor cosmetic results (Malakar and Dhar, 1999).

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References

Recent advances in the pathogenesis of vitiligo have contributed to find better treatments, and at present many affected individuals find a solution for depigmented skin either with medical or surgical therapies; however progression of the disease, and partial or lack of complete repigmentation still occurs in a good number of patients. Diverse therapies from the present armamentarium have been used with remarkable success in facial and neck lesions, moderate to good on trunk and proximal extremities, but poor or no repigmentation is accomplished on distal or acral parts and bone prominences of the extremities. For generalized bilateral vitiligo, NB UVB and PUVA are the most important therapies, whereas for localized vitiligo topical corticosteroids and calcineurin inhibitors disclose the highest efficacy. Segmental (unilateral) vitiligo responds to surgical interventions with approximately 70–100% repigmentation in 60–100% of patients, whereas in stable non-segmental (bilateral) disease around 50% of patients improve with similar repigmentation.

Future studies, with newer and more potent therapies will depend on the full knowledge of vitiligo pathogenesis.

Standardization of methods for evaluation both in regard to efficacy and patient’s quality of life are important to determine the most appropriate therapies for vitiligo.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Vitiligo therapy
  5. Medical therapy
  6. Surgical therapy
  7. General principles of surgical repigmentation therapy
  8. Surgical methods
  9. Conclusions
  10. References