Vitiligo: epidemiology and Vitiligo: epidemiology and pathophysiologypathophysiology

Torello LottiTorello Lotti

University Unit of Dermatology - University Unit of Dermatology -

University of Florence School of MedicineUniversity of Florence School of Medicine

Florence, ItalyFlorence, Italy

Vitiligo: DefinitionVitiligo: Definition Primitive acquired pigmentation Primitive acquired pigmentation

disorder with focal depigmentation of disorder with focal depigmentation of the skinthe skin

Characterized by well circumscribed Characterized by well circumscribed milky white cutaneous/mucous maculesmilky white cutaneous/mucous macules

Patches arise as a consequence of Patches arise as a consequence of destruction and/or functional destruction and/or functional inactivation of melanocytes underlying inactivation of melanocytes underlying a complex syndromea complex syndrome

Acquired (only in few cases congenital), Acquired (only in few cases congenital), often familial (23% of the cases).often familial (23% of the cases).

Vitiligo: epidemiologyVitiligo: epidemiology Vitiligo affects 0.5-4% of the World population. The disease generally begins between the ages of 2 and

40. In a Dutch study, 50% of patients reported the occurrence

before the age of 20.

Vitiligo epidemiologyVitiligo epidemiology

Incidence ranges from 0,1% to 8,8% in different country of the globe. The highest incidence of the condition has

been recorded in India, Mexico and Japan.

Descriptive epidemiology (incidence, prevalence, HANES 1 study)

Analytical epidemiology (Factors, Relative risks, odds ratio)

Clinical epidemiology (Natural history and prognosys)

Adults and children of both sex are equally affected

The greater number of reports among females is probably due to greater social consequence to woman and girls affected by this condition.

50% of patients before the age of 20 25% of patients before the age of 8

Vitiligo epidemiologyVitiligo epidemiology

Clinical classificationClinical classification

Localized Focal – one or more macules in one area but not clearly in a segmental

distribution Unilateral/segmental – one or more macules involving a unilateral

segment of the body – lesions stop abruptely at the midline Mucosal – mucous membranes alone

Generalized Vulgaris – scattered patches that are widely distributed Acrofacialis – distal extremities and face Mixed – acrofacialis and vulgaris

Universalis – complete or nearly complete depigmentation

Vitiligo: why? Vitiligo: why?

1. Loss or reduction of melanocytes

2. Reduced melanine production from melanocytes (altered tyrosinase activity, altered structure/activity of rough endoplasmic reticulum, lack of specific melanocyte receptors…)

3. Decreased melanine transfer from melanocytes to keratinocytes

4. Primary disorder of keratinocytes

Vitiligo etiopathogenesisVitiligo etiopathogenesis GENETIC PREDISPOSITIONGENETIC PREDISPOSITION

Autoimmune Susceptibility Locus (AIS1)Autoimmune Susceptibility Locus (AIS1)

AUTOIMMUNEAUTOIMMUNE Umoral mechanism -AutoantibodiesUmoral mechanism -Autoantibodies Citotoxic mechanism – Cell mediatedCitotoxic mechanism – Cell mediated

METABOLICMETABOLIC Hydrogen peroxide accumulationHydrogen peroxide accumulation Abnormal expression of Tyrosine-Related Abnormal expression of Tyrosine-Related Protein -1Protein -1

OTHERSOTHERS Viral hypothesisViral hypothesis Neuronal toxicityNeuronal toxicity

Autoimmune pathogenesisAutoimmune pathogenesis Presence of “vitiligo antibodies” in Presence of “vitiligo antibodies” in

patients patients Vitiligo is associated with several Vitiligo is associated with several

autoimmune disease (vitiligo is a autoimmune disease (vitiligo is a syndrome, not a disease…): tyroiditis (up syndrome, not a disease…): tyroiditis (up to 40%), diabetes type I (1-7%), to 40%), diabetes type I (1-7%), autoimmune gastritis, autoimmune autoimmune gastritis, autoimmune polyglandular syndromes, alopecia polyglandular syndromes, alopecia areata…areata…

Most effective therapies in inducing Most effective therapies in inducing repigmentation have also repigmentation have also immunosuppressive effects immunosuppressive effects (i.e.corticosteroids, ultraviolet, cytotoxic (i.e.corticosteroids, ultraviolet, cytotoxic drugs)drugs)

Immunotherapies for melanoma often Immunotherapies for melanoma often cause vitiligo patchescause vitiligo patches

Altered Altered antioxidant and antioxidant and

scavenger scavenger mechanismmechanism

Increased activity Increased activity of superoxide of superoxide

dismutasedismutase

High levels of epidermic 7-BHHigh levels of epidermic 7-BH44 and and

HH22OO22

Inhibition of enzyme function Inhibition of enzyme function (phenylalanine-hydroxilase and tyrosinase) (phenylalanine-hydroxilase and tyrosinase)

and and abnormal expression of Tyrosinase abnormal expression of Tyrosinase Related Protein-1 (TRP-1).Related Protein-1 (TRP-1).

impaired melanine synthesisimpaired melanine synthesis

Metabolic Metabolic pathogenesispathogenesis

A focus on keratinocytesA focus on keratinocytes

Impaired scavenging mechanisms can lead to ROS increase and subsequent melanocyte damaging

Altered function of PAR-2 receptor can impair calcium homeostasis in keratinocytes and affect melanosome intake and processing

Prignano F, Pescitelli L, Becatti M, Fiorillo C, Taddei N, Lotti Prignano F, Pescitelli L, Becatti M, Fiorillo C, Taddei N, Lotti T. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – T. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – 19th 2008 19th 2008

Betts CM, Lotti T, Prignano F. 5° Joint meeting of SSSR and Betts CM, Lotti T, Prignano F. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – 19th 2008SCUR. Otsu, Japan May 17th – 19th 2008

The focus on keratinocytesThe focus on keratinocytes

The importance of mitochondria in keratinocytes from perilesional skin and the role of oxidative stress

Prignano F, et al. Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin. J Derm Sci 2009;54:157–167

Mitochondrial alterations in Mitochondrial alterations in perilesional keratinocytesperilesional keratinocytes

Mitochondrial activity plays a crucial role in normal cell function

Mitochondrial alterations observed in perilesional keratinocytes appear to be very similar to those described in the same cell types during apoptosis

The mitochondrial damage is associated with an increase in ROS production and, hence, oxidative stress.– Prignano F, et al. J Derm Sci 2009;54:157–167

Functional alterations in vitiligo skinFunctional alterations in vitiligo skin

High levels of TNF-alpha and FasL in the depigmented epidermis (role in increasing apoptosis)– Kim NH, et al. J Invest Dermatol 2007;127:2612–7.

mRNA for TNF-α and IL-6, with an inhibitory effect on pigmentation, was increased in the epidermis from vitiligo biopsies.

This could contribute to keratinocyte apoptosis, which results in reduced release of melanogenic cytokines and in melanocyte disappearance.– Moretti S, et al. Histol Histopathol 2009:24:849-857

Functional alterations in vitiligo skinFunctional alterations in vitiligo skin

Apoptotic keratinocytes may cause a decrease in SCF synthesis, which plays an important role in melanocyte survival and proliferation

Keratinocyte apoptosis induces a decrease in the synthesis of other melanocyte growth factors, such as bFGF, resulting in melanocyte disappearance.– Lee AY, et al. Br J Dermatol

2004;151:995–1003.– Moretti S, et al. Histol Histopathol

2009:24:849-857

Functional alterations in vitiligo skinFunctional alterations in vitiligo skin

SCF and ET-1 may contribute to melanocyte survival Endothelin-1 (ET-1) mRNA seems to be significantly

reduced in lesional as compared to perilesional epidermis– Moretti S, et al. Histol Histopathol 2009:24:849-857

Functional alterations in vitiligo skinFunctional alterations in vitiligo skin

Protease-activated receptor (PAR) 2 is abundantly expressed by keratinocytes, and seems to contribute to the pigmentation process

PAR-2 impairment is seen in vitiligo, and may contribute to the epidermal pigment deficit through a reduced melanosome uptake in keratinocytes.

To date, a precise cause and effect relationship between these two conditions cannot be determined.– Moretti S, et al. Pigment Cell Melanoma Res 2009;22:335–

338

In search for more evidence: the long roadIn search for more evidence: the long road

The importance of mitochondria in keratinocytes from perilesional skin and the role of oxidative stress

The possible role of antioxidant supplementation in the treatment of vitiligo

Positive effects of the supplementation Positive effects of the supplementation of antioxidants in cultured cellsof antioxidants in cultured cells

Total Antioxidant Capacity (marker of cellular scavengingactivity)

Mitochondrial membrane depolarization (marker ofmitochondrial and cellularintegrity)

- Becatti M, Prignano F, Fiorillo C, Pescitelli L, Nassi P, Lotti T, Taddei N. The involvement of Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: Protective effects of curcumin and capsaicin. Antioxid Redox Signal. 2010, 1;13(9):1309-1321.

Future perspectivesFuture perspectives Our study group is investigating on the positive

effects of the supplementation of antioxidants in cultured cells form lesional, perilesional and healthy skin of selected vitiligo patients.

The supplementation of curcumin and capsaicin at peculiar concentrations can dramatically improve the resistance of cultured cells to oxidative stress.

Focus on keratinocytes from perilesional skin as the first actors in vitiligo pathogenesis .

Thank you for your attentionThank you for your attention

professor@ torellolotti.it