Vitiligo

Table of contents :
VITILIGO
INTRODUCTION
EPIDEMIOLOGY
QUALITY OF LIFE
ETIOLOGY AND PATHOGENESIS
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CLINCAL FEATURES
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CLINICAL MARKERS OF DISEASE ACTIVITY
SEVERITY SCORING
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STABILITY OF VITILIGO
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Koebner’s Phenomenon
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DISEASE ASSOCIATION
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DISEASE COMPLICATIONS
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DIAGNOSIS
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DIFFERENTIAL DIAGNOSIS
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MANAGEMENT
TOPICAL THERAPIES
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Systemic therapy
PHOTOTHERAPY AND COMBINATION THERAPIES
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PSORALEN AND ULTRAVIOLET A
NARROWBAND ULTRAVIOLET B
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TARGETED ULTRAVIOLET B PHOTOTHERAPY
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COMBINATION THERAPIES
PSYCHOLOGICAL INTERVENTIONS
COSMETICS
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DEPIGMENTATION THERAPY
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SURGICAL THERAPIES
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EMERGING THERAPIES
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THANK YOU

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VITILIGO

INTRODUCTION Vitiligo is a common autoimmune disease of the skin that causes depigmentation through T-cellmediated destruction of melanocytes. Pathogenesis is multifactorial, including genetic predisposition, autoimmunity, and environmental factors. Vitiligo can cause significant social stigma, with serious implications for mental health.

EPIDEMIOLOGY The prevalence of vitiligo in general population is around 0.5– 2%. Almost half of the patients first develop this disease before 20 years of age. Men and women are affected equally.

QUALITY OF LIFE Numerous studies show that patients with vitiligo feel stigmatized, have low self-esteem with poor body image, and suffer a considerable psychosocial burden. Thus, vitiligo may have a significant impact on quality of life, and patients reportedly have mental impairment similar to psoriasis and atopic dermatitis. Differences in Dermatology Life Quality Index (DLQI) scores have been noted in various cultural groups, which may reflect different social stigmas of having the disease.

ETIOLOGY AND PATHOGENESIS It is thought that instead of one particular theory, a combination of all these hypotheses effectively explains the pathogenesis of vitiligo (the convergence theory). Autoimmune theory Genetic susceptibility Dysregulated innate and adaptive immune response Increased oxidative stress

Antibodies to human melanocytes Self destruction of melanocytes theory Neurogenic theory Melanocyte specific cytotoxic CD8+ T cells

The autoimmune/autoinflammatory theory is currently the leading hypothesis and is supported by strong evidence. The association with vitiligo has demonstrated a shared underlying genetic susceptibility to other autoimmune diseases . A combination of deregulated innate and adaptive immune responses has been proposed in vitiligo.

It has also been proposed that increased oxidative stress may trigger the process of ‘haptenation’ by increasing the levels of surrogate substrates of tyrosinase resulting in the formation of highly immunogenic neoantigens in vitiligo Antibodies to normal human melanocytes have been detected using a specific immunoprecipitation assay , and may have a cytolytic effect on melanocytes .

Accumulating evidence supports a major aetiological role for melanocyte‐specific cytotoxic T cells in coordinating the targeted autoimmune tissue destruction of melanocytes in progressive vitiligo . Both helper and cytotoxic T cells from progressing margins generate predominantly type 1 cytokines. This theory is supported by the fact that various effective treatment options in vitiligo have an immunosuppressive effect on the activation and maturation of T cells (e.g. local steroids and topical immunomodulators).

The selfdestruction theory of Lerner hypothesis was based on the clinical features of vitiligo and on experimental studies of cutaneous depigmentation by chemical compounds that have a selective lethal effect on functional melanocytes : these compounds can produce a leukoderma indistinguishable from idiopathic vitiligo. In vivo, repeated frictional trauma to perilesional skin in non‐ segmental vitiligo has been shown to induce detachment and death of melanocytes (‘melanocytorrhagy’) . A neurogenic mechanism has been suggested whereby it has been hypothesized that a compound released at peripheral nerve endings in the skin could have a toxic effect on melanocytes.

Genetics A genetic factor is undoubtedly involved in vitiligo. Approximately 30% of patients have a positive family history and vitiligo has been reported in monozygotic twins . Genome‐wide association studies have identified several susceptibility loci for generalized vitiligo, each responsible for a small part of the genetic risk. The exception is TYR , which encodes the enzyme tyrosinase, which is not a component of the immune system but catalyses melanin biosynthesis within the melanocyte and is a major autoantigen in generalized vitiligo.

CLINCAL FEATURES LOCALIZED

GENERALIZED

1. FOCAL 2. SEGMENTAL 3. MUCOSAL

1.VULGARIS 2.ACROFACIAL 3.MIXED 4.UNIVERSAL

Typically, vitiligo lesions are asymptomatic, white, nonscaly macules and patches with distinct margins that fluoresce when illuminated by Wood lamp examination. Vitiligo lesions may involve any part of the body, usually with a symmetrical distribution . The disease can start at any site of the body, although the face, as well as acral and genital locations, are often the initial sites.

Acrofacial vitiligo is reportedly more common in adults and typically involves the hands, feet, and face, particularly the orifices. This form may evolve to typical generalized vitiligo. Vitiligo universalis is a rare form of widespread disease. It is usually seen in adults, although cases in children have been reported. The form is named “universalis” because it affects a large proportion of the body, frequently defined as greater than 80% of the body surface area. Despite this widespread involvement, hairs may be spared.

In Mucosal vitiligo, the oral and/or genital mucosae are primarily involved . Focal vitiligo consists of small, isolated macules or patches in one area , but not clearly in a segmental distribution. The segmental variant of vitiligo is seen in 10% to 15% of vitiligo patients who present . It is characterized by a unilateral and segmental, or blockshaped, distribution of the lesions .

Typically, a single contiguous segment is involved, although 2 or more segments with ipsilateral or contralateral distribution have been described. Mixed vitiligo is a rare form of vitiligo that refers to the occurrence of a clear example of segmental vitiligo plus additional macules or patches that do not fit the segment.

These additional patches may be remote from the segmental involvement and are bilateral and symmetrical, affecting the contralateral side. In segmental vitiligo, there is frequently early involvement of the follicular melanocyte reservoir, resulting in poliosis. The disease usually spreads over the segment within 6 to 12 months, and then stabilizes. Although this may initially be difficult to distinguish from focal vitiligo, the rapid progression of segmental disease usually makes it clear within a few weeks to months.

CLINICAL MARKERS OF DISEASE ACTIVITY

SEVERITY SCORING STABILITY OF VITILIGO KOEBNER’s PHENOMENON ACTIVE VITILIGO

SEVERITY SCORING Various severity assessment scores have been proposed for vitiligo such as VASI (Vitiligo Area Scoring Index), VES (Vitiligo Extent Scale),and VETF (Vitiligo European Task Force) scoring system. All are validated and have merits and demerits that can be read in detail from individual references.

VASI is a commonly employed tool to assess the response to phototherapy. The total body surface area in vitiligo is calculated in terms of hand units. One hand unit (which encompasses the palm plus the volar surface of all digits) is equivalent to 1% of the total body surface area. The degree of depigmentation is estimated as follows:

100%—complete depigmentation—total absence of pigmentation 90%—specks of pigment present 75%—depigmented area exceeds the pigmented area 50%—depigmented and pigmented areas are equal 25%—pigmented area exceeds depigmented area 10%—only specks of depigmentation are present.

The VASI for each body region is determined by the product of the area of vitiligo in hand units and the extent of depigmentation within each hand unit measured patch. VASI=∑ [HandUnits]×[ResidualDepigmentation] all body sites

Disease activity also has been partially quantified through scoring systems such as the vitiligo disease activity score (VIDA), which relies on patient recall, and the Koebner phenomenon in vitiligo score (K-VSCOR), which is focused on clinical signs .

STABILITY OF VITILIGO Stability refers to the arrest of the disease activity and is defined for vitiligo as the absence of new lesions, no extension of pre-existing lesions, and the absence of Koebner’s Phenomenon . Spontaneous or treatment-induced repigmentation and positive minigrafting with lack of depigmentation at the donor site are other criteria for the stable disease. Duration for which activity should remain halted for being defined as stable is a matter of debate and is defined variably in the literature, ranging from as less as 6 months to as long as 2 years.

Stability can be global, when it pertains to overall stability of the disease, or it can be lesional, when the activity of a particular vitiligo patch is studied and its activity is segregated from the rest of the lesions in the same individual. IADVL Task Force for standard guidelines of care for dermatosurgical procedures states that the absence of “new lesions, extension of pre-existing lesions and KP” for a 1 year duration satisfy the criteria for stability.

Active vitiligo is characterized by inflammatory, trichrome, and confetti-like lesions, ill-defined hypopigmented borders, and KP. The presence of KP also correlates with greater body surface area involvement and a poor response to treatment. Vitiligo disease activity (VIDA) score was proposed way back in 1999 to assess the disease activity in vitiligo and is still commonly used to assess the same .

Koebner’s Phenomenon The Koebner phenomenon, also called the isomorphic response, describes the observation that depigmentation occurs readily at the site of skin trauma in patients with active vitiligo. This can be recognized as linear marks of depigmentation where the skin has been scratched, lacerated, or burned, or nonlinear macules and patches at the site of known skin injury, such as erosions and abrasions

The K-VSCOR uses the Koebner phenomenon and anatomical location of lesions to determine disease activity in vitiligo patients. It is based on the presence or absence of vitiligo lesions at 6 different areas of the body (forehead + scalp areas, eyelids, wrists, genital + belt areas, knees and tibial crests) as well as disease duration. The K-VSCOR ranges from 0 to 56, with 56 corresponding to the highest likelihood of having the Koebner phenomenon, which serves as an indicator of disease activity in the clinic. Further validation is needed to predict the extension of lesions over a longer period of time.

Trichrome vitiligo is characterized by blurring of lesional borders because of the presence of a hypopigmented zone between the depigmented and normally pigmented border. This results in the appearance of 3 distinct colors: the depigmented skin, normally pigmented skin, and hypopigmented skin . This pattern is associated with active, rapidly spreading vitiligo.

Confetti-like depigmentation consists of multiple small macules of depigmentation clustered together, often at the edge of existing vitiligo lesions . Multiple scattered macules of confetti depigmentation in vitiligo identifying this sign as an important marker of disease activity. Inflammatory vitiligo is a very rare form of vitiligo characterized by the presence of erythema, scale, and itch at the border of hypopigmented or depigmented lesions . This inflammatory phase is typically transient, lasting just a few weeks to months but rapidly progressing to involve large areas of the body.

Hypochromic vitiligo (vitiligo minor): a form of vitiligo (NSV) that seems to be limited to dark‐sknined individuals . The term ‘minor’ refers to the partial defect in pigmentation . The relation to true vitiligo is supported by pathological examination and its coexistence with conventional vitiligo macules.

Follicular vitiligo - leukotrichia in absence of depigmented epidermis. Blue vitiligo- Vitiligo in areas of post inflammatory dermal pigmentation .

DISEASE ASSOCIATION Type 1 Diabetes Autoimmune thyroiditis Pernicious anemia Addison disease Lupus Alopecia areata Halo Nevi Autoimmune CTDs - SLE, RA, DM,SS

Up to 20% of vitiligo patients have at least 1 additional autoimmune disease, and most of these patients (13% to 19%) have autoimmune thyroid disease. This increased risk has prompted some to advocate testing TSH in all patients with vitiligo, because the pretest probability of finding a positive result is higher in this patient population.

DISEASE COMPLICATIONS Melanocytes are found not only in the epidermis of the skin, but also in the mucous membranes, hair follicles, uveal tract, retinal pigment epithelium, membranous labyrinth of the inner ear, heart, and meninges of the brain. Typically, these sites are spared in vitiligo patients, with the exception of hair follicles, which can be involved when present within lesions. However, some studies report hearing changes in vitiligo patients, with sensorineural hearing loss present with a wide range of prevalence (20% to 60%), depending on the study.

Ocular abnormalities have been reported in vitiligo patients as well, including pigment changes, scarring, and even uveitis in up to 5% of patients. Vogt-Koyanagi-Harada syndrome (VKHS) and Alezzandrini syndrome represent severe, rare forms of vitiligo that affect organs other than the skin. VKHS results in skin depigmentation with prominent poliosis, as well as hearing loss, visual changes, meningitis, and flu-like symptoms. Alezzandrini syndrome is characterized by segmental vitiligo (unilateral depigmentation) on the face with poliosis, plus ipsilateral hearing loss and visual changes.

DIAGNOSIS CLINICAL EXAMINATION AND DERMOSCOPY LAB TESTING HISTOLOGY

1. CLINICAL EXAMINATION The diagnosis of vitiligo is usually a clinical one, as there is usually no need for additional laboratory or histologic testing to confirm the diagnosis. On physical examination it is important to differentiate vitiligo from its segmental variant, as these 2 forms have different clinical course, prognosis, and treatment responses. Wood lamp examination in a dark room is helpful in differentiating the depigmentation of vitiligo from hypopigmentation seen in other diseases

Additional clinical signs that may help with the diagnosis of vitiligo are the presence of multiple halo nevi and poliosis. The presence of repigmentation can be recognized as perifollicular pigmented macules from pigmented hairs at hair-bearing sites or convex patterns of pigment at lesional borders in glabrous skin . Hair-bearing sites without poliosis repigment easily, whereas glabrous skin and lesions containing mostly white hairs respond poorly.

2.DERMOSCOPIC FINDINGS

Star burst appearance Comet tail

Micro koebner’s

Sago grain appearance

Intro perilesional erythema

Perifollicular depigmentation

Perifollicular Repigmentation

2. LAB TESTING Because vitiligo is associated with other autoimmune diseases such as thyroid diseases, clinicians should consider laboratory testing for these other diseases when patients’ symptoms warrant them. Complete blood count and antinuclear antibody testing can be considered in the context of light sensitivity, as phototherapy is a standard in vitiligo treatment.

3. HISTOLOGY When the presentation is unusual, biopsy may help to rule out other disorders of pigment abnormalities that fall within the differential diagnosis . IHC for melanocyte markers : MELAN A , MITF,HMB 45,DOPA stains

DIFFERENTIAL DIAGNOSIS

MANAGEMENT TOPICAL THERAPIES PHOTOTHERAPY AND COMBINATION THERAPY PSYCHOLOGICAL INTERVENTION COSMETICS DEPIGMENTATION THERAPY SURGICAL THERAPIES

TOPICAL THERAPIES Topical therapies may be used as monotherapy when there is limited surface involvement (less than 5% BSA) Two main classes of topical drugs are used in vitiligo: topical steroids and topical calcineurin inhibitors. The advantages of topical corticosteroids are good efficacy, ease of application, high compliance rate, and low cost. The drawbacks of topical corticosteroids are their side effects, which include skin atrophy, telangiectasia, hypertrichosis, acneiform eruptions, and striae, as well as increased intraocular pressure (exacerbation of glaucoma) when used around the eyes.

Advantages of topical calcineurin inhibitors include their good efficacy and excellent safety profile. They can be used on areas that are not ideal for steroids, such as on the face, neck, intertriginous areas, and on children. The combination of light therapy with topical calcineurin inhibitors increases their efficacy . Topical tacrolimus can be used as maintenance therapy in patients who achieved repigmentation through other methods.

Topical VIT D analogs Topical Prostaglandins - bimatoprost 0.03% Are some of the other topical drugs used.

Systemic therapy Corticosteroids - oral mini pulse therapy Anti inflammatory antibiotic - Minocycline Statins - Simvastatin Immunosuppressives

PHOTOTHERAPY AND COMBINATION THERAPIES Because of its efficacy, ease of use, and relatively good safety profile, full-body phototherapy should be considered the first treatment option in patients with more than 5% of the body surface area affected, especially if the disease is rapidly spreading . For those with more limited, focal disease, targeted phototherapy can be considered because of its very high efficacy. However, phototherapy is time-consuming and devices may not be readily accessible to all patients.

Phototherapy has been administered using different sources Oral or topical psoralen plus ultraviolet A (PUVA) Broadband ultraviolet B Narrowband ultraviolet B (nbUVB) Targeted phototherapy with excimer laser.

PSORALEN AND ULTRAVIOLET A PUVA is no longer first-line therapy for vitiligo, and has been largely replaced by nbUVB. However, PUVA may be considered in patients who fail to repigment with other modalities. Like other methods of phototherapy, PUVA is typically administered 2 or 3 times weekly.

NARROWBAND ULTRAVIOLET B nbUVB has largely replaced other modalities because of its efficacy and better safety profile. It provides 2 particular benefits: (a) repigmentation and (b) stabilization, which is important in those who have active disease.

Treatment with nbUVB should be 2 to 3 times weekly, starting with a dose of 200 millijoules (mJ) with an increase of 10% to 20% increments until reaching the minimal erythema dose, which corresponds to the lowest dose resulting in asymptomatic, visible erythema on depigmented skin that lasts less than 24 hours. A total of 9 to 12 months or more of treatment is required to achieve full repigmentation, with at least 6 months of therapy before determining that the disease is nonresponsive.

TARGETED ULTRAVIOLET B PHOTOTHERAPY Targeted UVB phototherapy is achieved using excimer lasers and lamps. They reportedly are equally effective, although excimer lamp induces more erythema. Because of their small treatment size, targeted phototherapy is indicated in patients with limited, focal vitiligo (less than 5% of the body surface area affected with stable disease). Targeted phototherapy is also reportedly the treatment that achieves highest efficacy for segmental vitiligo in its early phase (ie, disease onset of less than 6 months to 1 year). It is also reportedly safe and effective for long-term treatment of pediatric vitiligo patients

COMBINATION THERAPIES In the most recent update of the Cochrane review, combination therapies using any type of light were considered the most effective treatment for vitiligo. The combination of oral steroid pulse therapy, such as dexamethasone on weekends or prednisone on alternate days, with light therapy is reportedly helpful in controlling rapidly spreading vitiligo until phototherapy achieves a therapeutic dose

PSYCHOLOGICAL INTERVENTIONS The psychological impact of vitiligo includes poor self-perception, low quality of life, poor interpersonal relationships, depression, and anxiety. Thus, psychological interventions such as cognitive-behavioral therapy and hypnosis have been shown to improve quality of life, reduce anxiety, improve coping with disease, and even enhance repigmentation in vitiligo. Importantly, adolescents with vitiligo are uniquely susceptible to social pressure and stigma, and thus should be screened for psychological impairment and referred for management.

COSMETICS Cosmetic camouflage, especially on visible areas such as the face and the hands, can improve quality of life in patients with vitiligo. There are now several water-resistant camouflage dyes and creams that are available with a wide range of color and shades covering all skin types.

DEPIGMENTATION THERAPY Ever since the observation that monobenzyl ether of hydroquinone potently induced and exacerbated vitiligo in exposed individuals, it has been used as a treatment for vitiligo to depigment the skin, removing the remaining pigment and evening out the tone. In fact, it is the only FDA–approved medical therapy for vitiligo. It can be prescribed as a 20% topical cream to be applied 1 to 2 times daily.

It can take 1 to 2 years for complete depigmentation, and it even affects areas remote from the site of application, so it cannot be used for just local depigmentation. Hair, eyes, and other locations where melanocytes are found are typically spared during depigmentation therapy with monobenzone. Even though this is a drastic and permanent approach to therapy, patients are typically happy with the result. They must be counseled that their skin will be sun-sensitive for the rest of their lives, and sun protection must be strictly followed

SURGICAL THERAPIES Surgical therapies for vitiligo can be very successful; however, a key part of surgical therapy is patient selection. Surgery in vitiligo should be reserved for patients with highly stable disease, which has been defined as the absence of new or growing lesions for 1 to 2 years. Segmental vitiligo patients are well suited for this approach because their disease stabilizes quickly, but those who do not have this variant have much-less-successful outcomes.

Several techniques for surgical treatment exist for vitiligo, which can broadly be divided into tissue grafting and cellular grafting. Tissue grafts include thin and ultrathin split-thickness skin grafts, suction blister epidermal grafts, mini punch grafts, and hair follicle grafts. These approaches all use solid-tissue grafts whose size is matched to the donor site in a 1:1 ratio. Cellular grafts include noncultured epidermal cell suspension, cultured “pure” melanocytes, cultured epithelial grafts, and autologous noncultured extracted hair follicle suspension. These approaches A transplant suspensions of keratinocytes and melanocytes and can cover larger surface areas with up to a 1:10 ratio of donor-to-recipient .

Each technique has advantages and disadvantages. In general, tissue grafts are easier to perform than cellular grafts, but are limited by the need to harvest tissue in a 1:1 ratio to the donor site. Split-thickness grafting is easy and inexpensive, but frequently results in color mismatch and occasional failure of the graft to take. Punch grafting is easy to perform and inexpensive but should be used in limited areas because of frequent side effects, such as cobblestoning, which describes healing at the recipient site with raised grafts that are visible and palpable, like cobblestones on a path. Blister grafting gives better cosmetic results without cobblestoning, but it is timeconsuming and may be more difficult to perform because of handling and placement of the very thin blister roof graft.

Because of their improved donor-to-recipient-site ratio, excellent outcomes in percent repigmentation and color match, as well as improved healing, cellular grafts are becoming the first-line in surgical management of stable vitiligo . The most commonly used technique, the melanocyte keratinocyte transplant procedure, creates a suspension of keratinocytes and melanocytes from donor epidermis that is enzymatically digested and mechanically disrupted into a single cell suspension. It is usually conducted in 2 steps.

EMERGING THERAPIES In small case studies and series, JAK inhibitors have been reported to promote repigmentation of vitiligo patients, including oral tofacitinib, oral ruxolitinib, and topical ruxolitinib. One example that has been tested in vitiligo patients is afamelanotide, an α-melanocyte–stimulating hormone analog, which, in conjunction with nbUVB, increased the rate and extent of repigmentation in vitiligo patients.

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