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Classifications

Harrison's Part

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Inheritance

1

Multifactorial/polygenic

Vitiligo has a complex, non-Mendelian inheritance pattern involving approximately 50 genetic risk loci interacting with environmental triggers.

Show evidence (2 references)

PMID:28317533 SUPPORT Human Clinical

"Vitiligo reflects simultaneous contributions of multiple genetic risk factors and environmental triggers. Genomewide association studies have discovered approximately 50 genetic loci contributing to vitiligo risk."

GWAS studies confirm polygenic inheritance with ~50 loci.

PMID:28317533 SUPPORT Human Clinical

"the concordance of vitiligo was 23% in monozygotic twins, underscoring the importance of non-genetic factors as well as genetic factors in vitiligo pathogenesis"

Twin studies show only ~23% monozygotic-twin concordance (with heritability ~50%), directly supporting the non-Mendelian, multifactorial model in which genetic risk interacts with environmental triggers rather than fully determining disease.

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Subtypes

3

Non-Segmental Vitiligo (NSV)

Most common form, characterized by symmetrical depigmented patches on both sides of the body. Includes generalized, acrofacial, and universal variants.

Show evidence (4 references)

PMID:20540698 SUPPORT Human Clinical

"Non segmental vitiligo (NSV) is the most common form of the disease: it is usually progressive and may be associated with familiarity and autoimmunity."

The reference confirms that Non-Segmental Vitiligo (NSV) is the most common form of vitiligo.

PMID:22237197 SUPPORT Human Clinical

"Generalized vitiligo was the most common type (n=132, 57.4%) followed by focal (n=53, 23%) and acro-facial vitiligo (n=16, 7%)."

This reference identifies generalized vitiligo as the most common, which is a subtype of NSV, supporting the statement.

PMID:33431938 SUPPORT Human Clinical

"Non-segmental vitiligo (NSV) is the most common type of vitiligo, which is characterized by chronic and progressive loss of melanocytes."

The reference directly states that NSV is the most common type of vitiligo.

+ 1 more reference

Segmental Vitiligo (SV)

Patches are restricted to one side of the body or one area, such as a limb or the face. Typically has an earlier onset and progresses for a few years before stabilizing.

Show evidence (2 references)

PMID:28317524 SUPPORT Human Clinical

"Segmental vitiligo is characterized by its early onset, rapid stabilization, and unilateral distribution."

The provided description is consistent with the characterization of segmental vitiligo mentioned in the literature.

PMID:35094387 SUPPORT Human Clinical

"Mixed vitiligo (MV) is the coexistence of segmental vitiligo (SV) and non-segmental vitiligo (NSV)...As compared to SV, MV had significantly lower mean age of onset of segmental component (SC) (13.33 ± 9.01 vs. 15.70 ± 8.60 years, P = 0.03) and significantly higher proportion of patients with..."

The text mentions segmental vitiligo and supports characteristics such as early onset.

Mixed Vitiligo

A combination of segmental and non-segmental types occurring simultaneously or sequentially in the same individual.

Show evidence (2 references)

PMID:17241584 SUPPORT Human Clinical

"OBSERVATION: We report four more cases of mixed vtiligo, segmental with generalized type"

The provided literature discusses cases where segmental and generalized vitiligo occur together in the same individual, which supports the existence of mixed vitiligo.

PMID:34780118 SUPPORT Human Clinical

"The overlaps between segmental vitiligo (SV) and nonsegmental vitiligo (NSV) suggest the underlying features of SV, which may be helpful for treating SV...The clinical and immunological similarities between SV and M-NSV presented a deeper autoimmune understanding of SV."

This reference discusses overlaps and similarities between segmental and non-segmental vitiligo but does not specifically confirm the simultaneous or sequential occurrence in the same individual.

C

Comorbidities

Major Depressive Disorder <-> Vitiligo

?

Discussions and Knowledge Gaps

1

A large longitudinal cohort supports vitiligo-to-MDD and MDD-to-vitiligo associations, but what accounts for them? Does an acquired, cell-state-specific inflammatory program involving p38-alpha/MAPK14 precede and help cause both conditions, or are the associations better explained by psychosocial effects of visible skin disease, healthcare surveillance, treatment, nonspecific inflammatory burden, shared pleiotropic genetic liability, or parallel disease-specific mechanisms? Is MAPK14 necessary in homologous causal cell states, or merely a cross-tissue bioinformatic marker?

KNOWLEDGE GAP OPEN gap_vitiligo_mdd_shared_immune_dysregulation

Attached to

pathophysiology#Autoimmune Reaction pathophysiology#IFN-gamma-CXCL9/CXCL10 Chemokine Axis pathophysiology#Oxidative Stress pathophysiology#Innate Immune Activation

A UK primary-care cohort found that incident MDD preceded recorded vitiligo (adjusted HR 1.64) and incident vitiligo preceded recorded MDD (HR 1.31 before age 30 and 1.22 at age 30 or older). That establishes a temporal epidemiologic signal, not biological mediation. The study did not measure disease severity, and treatment and healthcare-contact effects remain possible. The cross-disease transcriptomic study is weaker mechanistic evidence: it compared separate MDD and vitiligo expression datasets, used only 15 vitiligo samples and 15 healthy samples in discovery, inferred immune signatures from bulk profiles, and used permissive differential-expression thresholds. It did not analyze an explicitly ascertained comorbid cohort or paired tissues from the same participants. The study did use independent disease-specific GEO validation sets, but discriminator performance does not establish a shared cell state or mediator. Mouse serotonergic-neuron genetics supports p38-alpha in a stress-related behavioral model; a larger human MDD study found no advantage for the tested losmapimod regimen after a smaller prematurely terminated study had favored treatment. Patient-derived nonsegmental-vitiligo keratinocytes and cultured mouse melanocytes support pan-p38 activity in skin models, not MAPK14 specificity. These compartment-, species-, and assay-specific results are compatible with parallel p38 use and do not establish a shared human MAPK14 mechanism. Conversely, bidirectional Mendelian randomization found no significant directional causal effect between generalized vitiligo and broad mental-disorder phenotypes, including depression. That design does not test shared pleiotropic genetic liability. A claims study found a mental-health profile largely comparable to atopic dermatitis. The gap is therefore the mediator and its specificity; the evidence does not justify a new vitiligo pathophysiology node, MAPK14 biomarker, or conserved mechanism module. A candidate pair-level record is curated in com_Major_Depressive_Disorder__Vitiligo.

Proposed experiments

Adjudicate temporal immune, psychosocial, and surveillance mediation

prospective longitudinal multimodal cohort study

exp_vitiligo_mdd_longitudinal_mediation

Prospectively enroll treatment-naive active nonsegmental-vitiligo-only, incident MDD-only, comorbid, and matched control groups. Reassess structured MDD diagnoses, symptom trajectories, vitiligo subtype, activity, extent and visibility, medication, healthcare utilization, autoimmune disease, smoking, BMI, socioeconomic factors, stress, stigma, and quality of life. At repeated visits profile circulating immune cells by single-cell transcriptomics plus surface proteins and measure cell-type-specific phospho-p38 and cytokines; collect paired lesional and nonlesional skin only from consenting vitiligo participants. Follow the single-disease groups for onset of the second condition and use prespecified time-varying mediation models.

Readouts

Incident second condition and within-person disease trajectories

pathophysiology#Autoimmune Reaction

Adjudicated incident MDD in vitiligo-only participants and incident vitiligo in MDD-only participants, with repeated measures of both diseases.

Interpretation: Establishes temporal order and distinguishes prediction of transition from cross-sectional correlation.

Cell-state-resolved p38 and inflammatory program

pathophysiology#Autoimmune Reaction

Phospho-p38, cytokines, and single-cell immune states in blood, aligned to lesional and nonlesional skin states.

Interpretation: Tests whether a homologous acquired state precedes both transitions rather than following disease or treatment.

Controls

Matched disease-free controls under equal surveillance

Controls matched on age, sex, site, healthcare-contact schedule, and major measured confounders.

Single-disease comparator groups

Vitiligo-only and MDD-only groups permit direction-specific analyses; atopic dermatitis is an optional visible-inflammatory-skin comparator.

Decision criterion

Support a shared acquired mediator only if the same prespecified cell-state-specific p38 program precedes onset of the second condition in both directions, tracks both outcomes within person, and mediates risk after psychosocial, treatment, autoimmune, and surveillance covariates. Prefer a psychosocial explanation if visibility, stigma, or distress predicts MDD without that program; prefer surveillance bias if equalized follow-up materially attenuates the association; classify p38 as a marker if it appears only after disease or treatment.

Would support

pathophysiology#Autoimmune Reaction Major_Depressive_Disorder:pathophysiology#Neuroinflammation

Test cell-specific MAPK14 necessity and rescue in both disease arms

human cell-specific causal perturbation and rescue study

exp_vitiligo_mdd_mapk14_cell_epistasis

Build matched human systems comprising autologous melanocyte-keratinocyte-cytotoxic T-cell skin cultures and iPSC-derived serotonergic neurons with supporting glia from active nonsegmental-vitiligo-only, MDD-only, comorbid MDD-vitiligo, and matched disease-free control donors. First map phospho-p38 to specific cell states and upstream ligands. Then compare MAPK14 CRISPR interference or knockout with a selective p38-alpha inhibitor, non-targeting and vehicle arms, and rescue with CRISPR-resistant wild-type versus kinase-dead MAPK14. Challenge skin cultures with oxidative stress and IFN-gamma-driven immune attack and neural cultures with stress/inflammatory ligands; use blinded, preregistered analysis.

Perturbations

MAPK14 genetic and pharmacologic loss of function

pathophysiology#Autoimmune Reaction

Cell-type-restricted MAPK14 CRISPR perturbation and selective p38-alpha inhibition in skin, immune, neural, and glial compartments.

Wild-type versus kinase-dead MAPK14 rescue

pathophysiology#Oxidative Stress

Isogenic rescue separates on-target catalytic dependence from editing artifacts and scaffold effects.

Readouts

Melanocyte injury and immune attack

pathophysiology#Autoimmune Reaction

Melanocyte apoptosis and survival, cytotoxic T-cell killing, and CXCL9/CXCL10 pathway readouts.

Serotonergic stress response

Major_Depressive_Disorder:pathophysiology#Monoamine Deficiency

Serotonin-transporter surface localization and uptake, cytokine release, neuronal activity, and cell viability.

Controls

Isogenic non-targeting and vehicle controls

Same donor, differentiation batch, ligand exposure, and assay schedule.

Compartment-restricted perturbation controls

Perturb MAPK14 separately in melanocytes, keratinocytes, T cells, neurons, and glia to resolve cell of action.

Decision criterion

A shared causal node requires a reproducible upstream state plus MAPK14 catalytic necessity in both arms, phenotypic rescue by wild-type but not kinase-dead MAPK14, and cross-donor replication. Different upstream signals or causal compartments support parallel context-specific uses of p38 rather than one shared circuit; loss of association after perturbation controls or failure to alter either phenotype classifies MAPK14 as a correlated marker.

Would support

pathophysiology#Autoimmune Reaction Major_Depressive_Disorder:pathophysiology#Monoamine Deficiency

Show evidence (12 references)

PMID:30528503 SUPPORT Human Clinical

"Compared with the referent cohort (n = 6,137,696), patients with vitiligo (n = 7104) that were <30 years of age at diagnosis had a higher risk of developing MDD than patients ≥30 years of age (hazard ratio 1.31, 95% CI 1.14-1.50, P < .0001 vs 1.22, 95% CI 1.08-1.37, P = .001, respectively)."

The large adjusted cohort establishes the age-stratified vitiligo-to-MDD temporal association but cannot identify its mediator.

PMID:42418414 SUPPORT Computational

"These findings primarily serve to generate hypotheses regarding shared mechanisms and prioritize targets for subsequent experimental validation."

The authors explicitly limit the cross-disease MAPK14 result to hypothesis generation.

PMID:42418414 SUPPORT Computational

"For MDD, the GSE98793 dataset was utilized, which includes 192 whole blood samples: 64 from healthy controls, 128 from patients with MDD, using the GPL570 platform for sequencing. For vitiligo, the GSE65127 and GSE53146 datasets were integrated using the R package ‘sva’ to correct batch effects...."

The analysis combined separate disease datasets and had only 15 vitiligo and 15 healthy samples, rather than paired samples from a comorbid cohort.

+ 9 more references

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Pathophysiology

7

Melanocyte Destruction

Autoimmune-mediated destruction where the immune system targets melanocytes, leading to loss of skin pigment.

Melanocyte CL:0000148 CD8+ T Lymphocyte CL:0000625

Show evidence (5 references)

PMID:33200838 SUPPORT Human Clinical

"Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction...self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo...CD8(+) cytotoxic T lymphocytes finally execute the killing of melanocytes."

The literature describes the autoimmune-mediated destruction of melanocytes involving CD8+ T lymphocytes, consistent with the provided statement.

PMID:31209143 SUPPORT Human Clinical

"Vitiligo is an autoimmune skin disease mediated by autoreactive CD8(+) T cells that destroy the pigment-producing cells of the epidermis, melanocytes, leading to areas of depigmentation."

The reference confirms the autoimmune-mediated destruction mechanism, mentioning both CD8+ T lymphocytes and melanocytes.

PMID:25184918 SUPPORT Human Clinical

"The main histopathological finding in vitiligo is the total absence of functioning melanocytes in the lesions, while the inflammatory cells most commonly found on the edges of the lesions are CD4+ and CD8+ T lymphocytes."

The literature supports the involvement of CD8+ T lymphocytes and the destruction of melanocytes in vitiligo.

+ 2 more references

Genetic Predisposition

A complex interplay of multiple genes contributes to susceptibility to vitiligo.

Show evidence (4 references)

PMID:28317533 SUPPORT Human Clinical

"Vitiligo reflects simultaneous contributions of multiple genetic risk factors and environmental triggers. Genomewide association studies have discovered approximately 50 genetic loci contributing to vitiligo risk."

The literature clearly states that multiple genetic risk factors contribute to vitiligo, aligning with the statement's claim of a complex interplay of genes.

PMID:28206724 SUPPORT Human Clinical

"Contrary to the Northern part of Europe but likewise to the Mediterranean area, the frequency of the CAT genotypes in Sicily is equally distributed. Out of all CAT genotypes, only CAT-89 T/T frequency was found to be significantly higher amongst vitiligo patients than controls."

The study mentions the association of specific gene polymorphisms with vitiligo, supporting the notion of a genetic predisposition.

PMID:29704874 SUPPORT Human Clinical

"The viewpoint that vitiligo is not caused only by predisposing mutations, or only by melanocytes responding to chemical/radiation exposure, or only by hyperreactive T cells, but rather results from a combination of aetiologic factors that impact melanocyte viability, has certainly stood the test of time."

The convergence theory supports the idea that multiple genetic and environmental factors contribute to vitiligo.

+ 1 more reference

Autoimmune Reaction

Vitiligo often coexists with other autoimmune disorders, such as thyroid disease, suggesting a common autoimmune etiology.

Show evidence (5 references)

PMID:25838868 SUPPORT Human Clinical

"Vitiligo is an acquired dermatological disease frequently associated with autoimmune thyroid disorders...Currently, the autocytotoxic and the autoimmune theories are the most accredited hypothesis"

The article indicates a strong association between vitiligo and autoimmune thyroid disorders, supporting a common autoimmune etiology.

PMID:26769615 SUPPORT Human Clinical

"Vitiligo in children is a distinct subset of vitiligo and differs from adult vitiligo... The most commonly associated autoimmune disease is thyroiditis."

The reference confirms a frequent coexistence of vitiligo and autoimmune thyroid disorders, supporting the common autoimmune etiology theory.

PMID:26724277 SUPPORT Human Clinical

"Vitiligo can also be associated with several autoimmune diseases, including autoimmune thyroid diseases, alopecia areata, and halo nevi."

This reference indicates the association of vitiligo with multiple autoimmune diseases, further supporting the shared autoimmune etiology.

+ 2 more references

Oxidative Stress

Increased oxidative stress in the skin may contribute to melanocyte vulnerability and destruction.

Show evidence (4 references)

PMID:36980277 SUPPORT Human Clinical

"Oxidative stress is considered to play a crucial role in activating consequent autoimmune responses related to vitiligo."

The literature supports the statement that increased oxidative stress in the skin contributes to melanocyte vulnerability and destruction.

PMID:33098225 SUPPORT Human Clinical

"Hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA) were significantly higher in patients than controls (p-value < .001, <.001, respectively); on the other hand, total antioxidant capacity (TAC) was significantly lower in patients than controls (p-value = .001)"

This study supports the idea that oxidative stress biomarkers are elevated in vitiligo patients, contributing to melanocyte vulnerability.

PMID:33346939 SUPPORT Human Clinical

"Apoptosis is most widely studied cell death pathways in vitiligo...new types of regulated cell death including necroptosis, pyroptosis, and ferroptosis may also participate in the pathogenesis of vitiligo."

This supports the involvement of oxidative stress-induced mechanisms in melanocyte death.

+ 1 more reference

IFN-gamma-CXCL9/CXCL10 Chemokine Axis

IFN-gamma induces keratinocyte production of CXCL9 and CXCL10 chemokines, which recruit CXCR3-positive CD8+ T cells to skin. These cytotoxic T cells mediate melanocyte destruction via perforin/granzyme and Fas-FasL pathways. Elevated serum CXCL9/CXCL10 correlate with disease activity.

keratinocyte CL:0000312 CD8+ T cell CL:0000625

response to type II interferon GO:0034341 leukocyte chemotaxis GO:0030595

skin epidermis UBERON:0001003

IL-15 and Tissue-Resident Memory T Cells

IL-15 promotes survival and cytotoxic function of CD8+ tissue-resident memory T cells (TRM) in skin, maintaining local immune surveillance and contributing to disease persistence and relapse. Serum IL-15 is elevated and correlates with disease extent.

CD8+ tissue-resident memory T cell CL:0000625

skin epidermis UBERON:0001003

Innate Immune Activation

DAMP-driven activation of plasmacytoid dendritic cells and conventional dendritic cells promotes type I interferon signaling, antigen presentation, and licensing of Th1/cytotoxic immunity. NK cells and innate lymphoid cells participate in bridging innate to adaptive immune responses.

dendritic cell CL:0000451 natural killer cell CL:0000623

skin epidermis UBERON:0001003

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

12

Cardiovascular 1

Dry Eye Disease OCCASIONAL Keratoconjunctivitis sicca HP:0001097

Show evidence (1 reference)

PMID:37919864 SUPPORT Human Clinical

"Dry eye disease is the most reported ocular abnormality in vitiligo."

Systematic review of ocular findings identifies dry eye disease as the most frequent ocular comorbidity.

Ear 1

Sensorineural Hearing Loss OCCASIONAL Sensorineural hearing impairment HP:0000407

Show evidence (4 references)

PMID:35274365 SUPPORT Human Clinical

"A 2.2-fold increased risk of developing SNHL was found in patients with vitiligo. Proper referral to otologists for early screening and closer follow-up of SNHL should be considered for patients with vitiligo, especially for patients with older age."

Large population-based cohort study (13,048 vitiligo patients) demonstrates significantly increased risk of SNHL.

PMID:37062442 SUPPORT Human Clinical

"Bilateral SNHL was found in 28 (25.0%; 95%CI 17.9%-32.1%) patients and in 1 (4.3%) control (p = 0.019)."

Cross-sectional study finds bilateral SNHL in 25% of NSV patients, with 5.4% meeting criteria for immune-mediated inner ear disease.

PMID:37062442 SUPPORT Human Clinical

"Six cases (5.4%; 95%CI 2.7%-8.0%) presented bilateral SNHL of unexplained aetiology, and anti-Hsp70 antibody positivity, fulfilling the diagnostic criteria for IMIED."

Substantiates the description's ~5% figure - 5.4% of non-segmental vitiligo patients met diagnostic criteria for immune-mediated inner ear disease (unexplained bilateral SNHL plus anti-Hsp70 positivity), supporting an autoimmune cochlear mechanism.

+ 1 more reference

Eye 1

Uveitis OCCASIONAL HP:0000554

Inflammation of the uveal tract of the eye

Show evidence (1 reference)

PMID:37919864 SUPPORT Human Clinical

"several small studies have found potential links to uveitis and glaucoma."

Systematic review of ocular findings in vitiligo identifies potential links to uveitis.

Integument 1

Increased Sensitivity To Sunlight FREQUENT Cutaneous photosensitivity HP:0000992

Other 8

Depigmented Patches VERY_FREQUENT Hypopigmented skin patches HP:0001053

Symmetrically distributed, well-demarcated white macules or patches

Sequelae: Increased Sensitivity To Sunlight

Show evidence (4 references)

PMID:25572727 SUPPORT Human Clinical

"Vitiligo is an acquired cutaneous disorder of pigmentation... Recent data provide strong evidence supporting an autoimmune pathogenesis of vitiligo."

The review characterizes vitiligo as an acquired cutaneous disorder of pigmentation, supporting depigmented patches as its defining lesion; it does not quantify the frequency band.

PMID:35166101 SUPPORT Human Clinical

"Vitiligo is a skin disorder characterized by selective loss of melanocytes resulting in circumscribed, depigmented macules and patches... its effects can be psychological, leading to stigmatization and suicidal ideation."

Confirms that selective melanocyte loss produces circumscribed depigmented macules and patches, the phenotype curated here.

PMID:17250545 SUPPORT Human Clinical

"Vitiligo is the most common depigmenting disorder, which affects 0.5-1% of the worldwide population, causing disfigurement and serious disturbances in well being."

The Vitiligo European Task Force consensus identifies vitiligo as the most common depigmenting disorder, supporting depigmentation as its cardinal manifestation.

+ 1 more reference

Premature Hair Whitening FREQUENT Poliosis HP:0002290

Especially noticeable in dark-haired individuals

Show evidence (1 reference)

PMID:26769615 SUPPORT Human Clinical

"Vitiligo in children is a distinct subset of vitiligo and differs from adult vitiligo. Characteristic features include family history of autoimmune or endocrine disease, higher incidence of segmental vitiligo, development of early or premature graying, increased incidence of autoantibodies and..."

The excerpt lists 'development of early or premature graying' as a characteristic feature of vitiligo in children, supporting the statement that premature hair whitening is occasionally associated with vitiligo.

Associated Autoimmune Disorders FREQUENT

Such as thyroid disease, type 1 diabetes, rheumatoid arthritis, etc.

Show evidence (4 references)

PMID:34104234 SUPPORT Human Clinical

"The association with chronic thyroiditis is based on common autoimmune background and excessive reactive oxygen species that destroy melanocytes and thyrocytes (oxidative stress hypothesis)..."

This reference discusses the association of vitiligo with chronic autoimmune thyroiditis, supporting the statement that vitiligo is frequently associated with autoimmune disorders.

PMID:35637045 SUPPORT Human Clinical

"Vitiligo and Graves' disease were also diagnosed in this cohort but affected few patients."

This reference indicates that vitiligo is associated with autoimmune disorders like Graves' disease and Hashimoto's disease, supporting the statement.

PMID:37405428 SUPPORT Human Clinical

"The most frequent autoimmune disorders in patients with vitiligo were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, Addison's disease, and systemic sclerosis (SSc)."

This reference provides evidence that vitiligo is frequently associated with various autoimmune disorders, supporting the statement.

+ 1 more reference

Depression/Anxiety FREQUENT

Related to altered appearance and social stigma

Show evidence (5 references)

PMID:33170870 SUPPORT Human Clinical

"The general prevalence of anxiety among vitiligo patients was equal to 35.8%."

Systematic review and meta-analysis of 15 studies finds anxiety prevalence of 35.8% in vitiligo patients, supporting FREQUENT frequency classification.

PMID:32013982 SUPPORT Human Clinical

"Depression and Anxiety are common psychiatric disorders in vitiligo patients."

The study confirms that depression and anxiety are common in vitiligo patients.

PMID:16405601 SUPPORT Other

"We review the psychosocial effects of vitiligo, how patients deal with them and the psychiatric morbidity in vitiligo patients."

The study acknowledges the psychosocial effects and psychiatric morbidity in vitiligo patients but does not specify the frequency as occasional.

+ 2 more references

Koebner Phenomenon HP:6000933

Show evidence (3 references)

PMID:39606817 SUPPORT Human Clinical

"Vitiligo vulgaris was the most common form, with increased leukotrichia and the Koebner phenomenon."

Review of late-onset vitiligo identifies the Koebner phenomenon as a prominent clinical feature.

PMID:38768496 SUPPORT Human Clinical

"The variables were studied: age at onset, sex, hereditary family history, personal history of thyroid diseases, time of evolution, classification, Köebner phenomena, mucosal vitiligo, halo nevus, premature graying and the presence of other dermatoses."

Childhood vitiligo study includes Koebner phenomenon as a standard clinical variable assessed in 574 pediatric patients.

PMID:37992390 SUPPORT Human Clinical

"At the periphery of the lesion, unstable vitiligo usually shows up as a diffuse border, trichrome pattern, micro-Koebner/comet tail phenomenon, satellite lesions, or a tapioca sago pattern."

Dermoscopy review identifies micro-Koebner phenomenon as a dermatoscopic sign of active vitiligo.

Halo Nevi OCCASIONAL

Show evidence (2 references)

PMID:26724277 SUPPORT Human Clinical

"Vitiligo can also be associated with several autoimmune diseases, including autoimmune thyroid diseases, alopecia areata, and halo nevi."

Review identifies halo nevi as a condition associated with vitiligo.

PMID:38768496 SUPPORT Human Clinical

"The variables were studied: age at onset, sex, hereditary family history, personal history of thyroid diseases, time of evolution, classification, Köebner phenomena, mucosal vitiligo, halo nevus, premature graying and the presence of other dermatoses."

Childhood vitiligo study systematically tracks halo nevi as an associated dermatologic finding in pediatric patients.

Skin depigmentation Vitiligo HP:0001045

Show evidence (1 reference)

PMID:30911977 SUPPORT Human Clinical

"common acquired depigmenting skin disease characterized by a progressive loss of functional melanocytes"

This review defines vitiligo as an acquired depigmenting skin disease from progressive loss of melanocytes.

Leukotrichia White hair HP:0011364

Show evidence (1 reference)

PMID:19911140 SUPPORT Human Clinical

"depigmented macules or patches on the skin, the mucous membranes and/or white hair"

This review notes vitiligo can affect hair, producing white hair (leukotrichia).

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Genetic Associations

10

NALP1 (Associated)

Show evidence (2 references)

PMID:17637824 SUPPORT Human Clinical

"This study confirms genetic association of generalized vitiligo with variation in NALP1, which contains at least two independent risk signals."

The study identified and confirmed a genetic association between generalized vitiligo and variations in the NALP1 gene. This supports the statement.

PMID:28317533 SUPPORT Human Clinical

"the vitiligo-associated causal SNPs constitute haplotypes of missense variants in almost complete linkage disequilibrium, which together synergize to result in constitutive gain of NLRP1 function and thus activation of interleukin-1 beta"

Fine-mapping of the NLRP1 (NALP1) locus shows the causal vitiligo-associated missense SNPs produce constitutive gain of NLRP1 inflammasome function driving IL-1 beta activation, giving a functional mechanism for the NALP1 genetic association.

TYR (Associated)

Gene: TYR hgnc:12442

Show evidence (3 references)

PMID:20410501 SUPPORT Human Clinical

"We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase."

The study identified a significant association between generalized vitiligo and a genetic locus containing the TYR gene.

PMID:32838589 SUPPORT Human Clinical

"The tyrosinase levels were significantly elevated in patients. The TT genotype was the most prevalent one in the patients... MiRNA 196a-2 C/T (11614913) gene polymorphism and the elevated serum tyrosinase levels might be related to the pathogenesis of vitiligo and may affect its therapeutic response."

Elevated serum tyrosinase levels in vitiligo patients suggest a genetic association involving the TYR gene with vitiligo.

PMID:28317533 SUPPORT Human Clinical

"For TYR, encoding tyrosinase, a key melanogenic enzyme and the major vitiligo autoimmune antigen, the vitiligo-associated SNPs are protective"

TYR encodes tyrosinase, the major vitiligo autoimmune antigen; its vitiligo-associated coding SNPs are protective, explaining the inverse TYR genetic relationship between vitiligo and melanoma risk.

PTPN22 (Associated)

Gene: PTPN22 hgnc:9652

Show evidence (2 references)

PMID:21515266 SUPPORT Human Clinical

"The PTPN22 locus is one of the strongest risk factors outside of the major histocompatability complex that associates with autoimmune diseases...vitiligo"

The literature specifically mentions that PTPN22 is associated with vitiligo as part of its association with several autoimmune diseases.

PMID:28164884 SUPPORT Human Clinical

"Several studies have demonstrated the association of protein tyrosine phosphatase, non-receptor type 22 +1858C-->T polymorphism with vitiligo... limited ethnic-based studies... In conclusion, protein tyrosine phosphatase, non-receptor type 22 +1858 T allele predisposes European individuals to vitiligo."

This source confirms the association but notes that the genetic association is specific to the European population and not found in the Asian population, suggesting partial support.

MC1R (Associated)

Gene: MC1R hgnc:6929

Show evidence (2 references)

PMID:20197744 SUPPORT Human Clinical

"Genome-wide association studies (GWAS) have unveiled single nucleotide polymorphisms (SNPs) or genetic variants in MC1R, TPCN2, ASIP, KITLG, NCKX5, TYR, IRF4, OCA2, and TYRP1 pigmentation genes."

This reference provides evidence of an association between the MC1R gene and vitiligo.

PMID:33757175 SUPPORT Human Clinical

"MC1R was found as a key gene in vitiligo and involved in the melanogenesis."

This reference identifies MC1R as a key gene involved in vitiligo, providing further support for its genetic association.

HLA-A (Associated)

Gene: HLA-A hgnc:4931

Show evidence (1 reference)

PMID:17243956 SUPPORT Human Clinical

"Meta-analysis showed a significantly increased frequency of HLA-A2 in vitiligo among cases [OR = 2.07, 95% confidence interval (CI) 1.67-2.58]."

The meta-analysis strongly suggests an association between HLA-A2, a specific allele of HLA-A, and vitiligo.

HLA-DRB1 (Associated)

Gene: HLA-DRB1 hgnc:4948

Show evidence (2 references)

PMID:34686989 SUPPORT Human Clinical

"In this study, we have evaluated the association and role of HLA-DRB4*01:01, -DRB1*07:01, and -DQB1*03:03:2 genes in different clinical subtypes of Vitiligo in the Iranian population."

The study discusses the association of different HLA-DRB1 allelic genes, including HLA-DRB1, with vitiligo.

PMID:20526339 SUPPORT Human Clinical

"Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles..."

The findings of the genome-wide association study indicate an association of HLA-DRB1 alleles with vitiligo.

IFIH1 (Associated)

Gene: IFIH1 hgnc:18873

Show evidence (1 reference)

PMID:22561518 SUPPORT Human Clinical

"IFIH1 (P = 4.91 × 10(-15))"

Large-scale GWAS meta-analysis identified IFIH1 as a vitiligo susceptibility locus at genome-wide significance, encoding an immunoregulatory protein involved in innate immune sensing.

BACH2 (Associated)

Gene: BACH2 hgnc:14078

Show evidence (1 reference)

PMID:22561518 SUPPORT Human Clinical

"BACH2 (P = 2.53 × 10(-8))"

GWAS meta-analysis identified BACH2 as a vitiligo susceptibility locus at genome-wide significance. BACH2 encodes an immunoregulatory transcription factor involved in immune cell development.

IRF4 (Associated)

Gene: IRF4 hgnc:6119

Show evidence (1 reference)

PMID:27723757 SUPPORT Human Clinical

"Twenty-three new loci achieved genome-wide significance (P < 5 × 10−8) for association with vitiligo and demonstrated subsequent replication; of these, 21 are completely novel (FASLG, PTPRC, PPP4R3B, BCL2L11, FARP2-STK25, UBE2E2, FBXO45-NRROS, PPP3CA, IRF4, SERPINB9, CPVL, NEK6, ARID5B"

GWAS meta-analysis names IRF4 among the 23 new vitiligo risk loci reaching genome-wide significance with replication.

FOXP3 (Associated)

Gene: FOXP3 hgnc:6106

Show evidence (1 reference)

PMID:33181260 SUPPORT Human Clinical

"FOXP3 mRNA and protein levels were significantly decreased (p < 0.001) in GV Tregs compared to controls"

This study found that FOXP3 expression is significantly reduced in regulatory T cells of vitiligo patients, and identified FOXP3 promoter polymorphisms associated with disease susceptibility.

💊

Medical Actions

6

Topical Corticosteroid

Action: topical corticosteroid therapy Ontology label: Topical Corticosteroid Therapy NCIT:C122078

Common first-line treatment to reduce inflammation and potentially stimulate repigmentation.

Show evidence (4 references)

PMID:19178066 SUPPORT Human Clinical

"Topical corticosteroids are one of the oldest and most useful treatments for dermatologic conditions... evidence of effectiveness exists only for select conditions, such as psoriasis, vitiligo..."

The use of topical corticosteroids as a treatment for vitiligo is supported, indicating it as a common and effective treatment option.

PMID:38477910 SUPPORT Human Clinical

"Evidence supports the use of... topical corticosteroids... as effective therapeutics for vitiligo..."

The recommendations include topical corticosteroids as a first-line treatment for vitiligo in pediatric, adolescent, and young adult patients.

PMID:33350506 SUPPORT Human Clinical

"The mainstay of treatment for unstable vitiligo has been topical agents (corticosteroids, calcineurin inhibitors)..."

This article highlights topical corticosteroids as a primary treatment for vitiligo, supporting the statement.

+ 1 more reference

JAK Inhibitor Therapy

Action: JAK inhibitor therapy Ontology label: Immunosuppressive Therapy NCIT:C15261

Agent: ruxolitinib CHEBI:66919

Targeting the IFN-gamma-JAK/STAT signaling pathway with JAK inhibitors (e.g., topical ruxolitinib) represents a leading therapeutic strategy. Often combined with narrowband UVB phototherapy to enhance repigmentation efficacy.

Phototherapy

Action: radiation therapy Ontology label: Radiation Therapy NCIT:C15313

UVB light or PUVA treatment can stimulate melanocyte regeneration and pigment production.

Show evidence (4 references)

PMID:27638438 SUPPORT Human Clinical

"Acting on multiple steps in vitiligo pathogenesis, narrowband ultraviolet B is one of the few therapies that can effectively induce stabilization and stimulate repigmentation."

The article supports the use of narrowband UVB for stimulating repigmentation in vitiligo.

PMID:28317529 SUPPORT Human Clinical

"The most potent stimulus for repigmentation is the UV light."

This reference directly supports that UV light, including UVB, is a potent stimulus for repigmentation in vitiligo.

PMID:20149899 SUPPORT Human Clinical

"There have been many treatments to cure vitiligo such as use of steroid creams, PUVA (psoralen and ultraviolet A light), narrow band UVB (ultraviolet B), various surgical techniques, vitamin D analogues and pseudocatalase."

It lists both PUVA and narrowband UVB as standard treatments for vitiligo.

+ 1 more reference

Skin Graft

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

can be used for stable vitiligo.

Show evidence (5 references)

PMID:38038734 SUPPORT Human Clinical

"For patients with stable vitiligo who have not achieved satisfactory results with medical treatments, the melanocyte-keratinocyte transplantation procedure (MKTP) is a viable option."

MKTP is a type of autologous non-cultured cellular grafting procedure used for treating stable vitiligo.

PMID:37000977 SUPPORT Human Clinical

"Surgical therapies are effective methods to treat resistant stable vitiligo, with each method having advantages and disadvantages."

This study compares ultrathin skin grafting (UTSG) and suction blister epidermal grafting (SBEG), both of which are skin grafting methods used to treat stable vitiligo.

PMID:34169570 SUPPORT Human Clinical

"Cultured epidermal autografts (CEA) are surgical therapeutic alternatives for patients with stable vitiligo resistant to conventional medical treatments."

CEA is mentioned as an option for treating stable vitiligo, indicating the use of skin grafting.

+ 2 more references

Melanocyte Transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

can be used for stable vitiligo.

Show evidence (3 references)

PMID:12709002 SUPPORT Human Clinical

"This surgical treatment gives its best results in segmental and focal vitiligo, even with large affected areas, and in at least 50% of patients with generalized vitiligo."

This implies that melanocyte-keratinocyte transplantation can be effective for stable vitiligo.

PMID:28445194 SUPPORT Human Clinical

"Cultured autologous melanocyte transplantation (CMT) is an effective treatment for stable vitiligo."

This confirms the use of melanocyte transplantation for stable vitiligo.

PMID:35457678 SUPPORT Human Clinical

"Both the development of new techniques and modifications to the already available treatment of cell and tissue transplantation give hope to numerous patients around the world."

Surgical treatments including melanocyte transplantation are viable for stable vitiligo according to the literature.

Monobenzone Cream

Action: Pharmacotherapy NCIT:C15986

Agent: monobenzone CHEBI:34380

Treatment with monobenzone cream to remove remaining pigment in cases of extensive vitiligo.

Show evidence (2 references)

PMID:3168334 SUPPORT Human Clinical

"When large areas of skin are involved or when the patient is unresponsive to therapy, serious consideration should be given to depigmentation with monobenzone (Benoquin)."

This supports the use of monobenzone cream for removing remaining pigment in cases of extensive vitiligo.

PMID:21054565 SUPPORT Human Clinical

"If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation...Our review revealed that...Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent and has few side-effects."

The reference supports the use of monobenzone (MBEH) for depigmentation in extensive vitiligo cases.

🌍

Environmental Factors

3

UV Exposure

Curation note: the evidence collected under this entry is entirely therapeutic ultraviolet phototherapy rather than an environmental exposure, so this arguably belongs under treatments rather than environmental. Kept here pending a curator decision; its pathograph link is modelled as protective accordingly.

Promotes the repigmentation process in some cases, but can exacerbate the contrast in others.

Show evidence (3 references)

PMID:29124690 SUPPORT Human Clinical

"This chapter focuses on the use of ultraviolet light in vitiligo as an established therapeutic option."

The reference suggests that UV light is used to treat vitiligo, which implies it can promote repigmentation. However, it does not address the exacerbation of contrast.

PMID:34245476 SUPPORT Human Clinical

"Targeted phototherapy with EL demonstrated better repigmenting efficacy than TUVB in vitiligo."

This reference supports UV exposure aiding in repigmentation but does not discuss exacerbating contrast.

PMID:34806278 SUPPORT Human Clinical

"Patients received Nb-UVB three times per week for 6 months... 90% of lesions showed variable degrees of repigmentation and 10% showed increase in size, indicating increased activity of the disease."

UVB treatments result in repigmentation in most cases, though some lesions increased in size, indicating potential exacerbation.

Mechanism Target:

PROTECTS_AGAINST Skin depigmentation — Therapeutic ultraviolet phototherapy opposes the depigmented phenotype by driving repigmentation, stimulating melanocyte precursors out of the follicular reservoir to repopulate lesional skin. The target is the depigmentation phenotype rather than the melanocyte-destruction process, because repopulation after destruction is what the cited evidence measures; phototherapy's separate immunomodulatory action on the autoreactive attack is not evidenced here.

Show evidence (1 reference)

PMID:34245476 SUPPORT Human Clinical

"Targeted phototherapy with EL demonstrated better repigmenting efficacy than TUVB in vitiligo."

Reports repigmenting efficacy for targeted ultraviolet phototherapy in vitiligo, an effect opposing the melanocyte loss this node describes.

Stress

Psychological stress is implicated in the exacerbation or onset of the disease.

Show evidence (3 references)

PMID:26057504 SUPPORT Human Clinical

"Psychological stressors should be considered as potential disease triggers in vitiligo patients."

The study identifies psychological stressors as potential triggers for the onset of vitiligo.

PMID:37481827 SUPPORT Model Organism

"Psychological stress triggers onset and development of vitiligo in humans."

A restraint-stress mouse model shows psychological stress promotes vitiligo-related depigmentation, supporting stress as a disease trigger; the cited study is a mouse-model (plus in vitro) investigation, not a human study.

PMID:31986193 SUPPORT Human Clinical

"Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo."

The data supports the notion that stress is a precipitating factor in vitiligo development.

Mechanism Target:

TRIGGERS Oxidative Stress — Pointed at the oxidative stress node rather than at melanocyte destruction, because that is the step this entry models as making melanocytes vulnerable and it is the plausible entry point for a systemic stressor. The animal item is what gives that target choice any molecular purchase: restraint stress lowers cutaneous OGG1, the glycosylase that repairs oxidative guanine damage, which is this node's own currency. The intermediates are still recorded as unknown, because that chain was traced in mice whose depigmentation was chemically induced, and no human sentence here follows stress to any molecular step. Both human items are graded partial for the same reason from opposite directions: one is a recommendation from a study with no comparison group, the other a cross-sectional difference.

Show evidence (3 references)

PMID:26057504 SUPPORT Human Clinical

"Psychological stressors should be considered as potential disease triggers in vitiligo patients."

Concludes that psychological stressors should be considered as potential disease triggers in affected patients. A recommendation about what to consider, from a questionnaire study without a comparison group, which is why it is partial rather than support.

PMID:31986193 SUPPORT Human Clinical

"Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo."

Reports significantly higher perceived stress in affected individuals than in those without the disease. A cross-sectional difference, which cannot separate stress as cause from stress as consequence of a visible skin disease.

PMID:37481827 SUPPORT Model Organism

"restraint stress aggravated anxiety-like behaviors and increased levels of macrophage migration inhibitory factor (MIF) and corticosterone in the circulation, accompanied with decreasing the expression of cutaneous 8-oxoguanine DNA glycosylase (OGG1) in depigmentation mice"

The only sentence in this link that reaches a molecule: restraint stress lowers cutaneous OGG1, the glycosylase that excises oxidised guanine, which is a step in the oxidative handling this node holds. Partial because the model is a mouse whose depigmentation was induced chemically, so the finding converges on the human claim without establishing it.

Chemical Exposure

Certain phenolic compounds and other chemicals can induce or exacerbate vitiligo.

Show evidence (3 references)

PMID:36433836 SUPPORT Human Clinical

"In the binary logistic regression model, household chemicals/colored toothpaste use...and an occupational exposure to phenol/catechol derivatives were significantly associated with vitiligo (three to fourfold increase)."

The study identifies phenol derivatives as significant risk factors for the development of vitiligo.

PMID:33039241 SUPPORT Human Clinical

"Chemicals like Monobenzyl Ether of Hydroquinone (MBEH) and 4-Tertiary Butyl Phenol (4-TBP) have been widely recognized to induce clinical lesions that resemble vitiligo."

The study demonstrates that phenol-based compounds can induce vitiligo-like lesions.

PMID:28317525 SUPPORT Human Clinical

"these chemicals have been used therapeutically in patients with severe vitiligo to depigment their remaining skin and improve their appearance...these chemicals appear to induce melanocyte autoimmunity"

The study mentions the use of chemicals, including phenols, to induce vitiligo for therapeutic purposes, supporting the role of phenolic compounds in inducing or exacerbating vitiligo.

Mechanism Target:

TRIGGERS Melanocyte Destruction — The best-evidenced exposure in this tranche, and the only one with a quantified effect: phenol and catechol derivatives carry a three- to fourfold increase in a case-control study. The intervening step is recorded as known because one cited sentence names it, describing these chemicals as appearing to induce melanocyte autoimmunity, which is the route to the destruction this node holds. That sentence also carries the resemblance claim, so a third item asserting only resemblance would have added a citation without adding a claim and was left on the exposure rather than the link.

Show evidence (2 references)

PMID:36433836 SUPPORT Human Clinical

"In the binary logistic regression model, household chemicals/colored toothpaste use...and an occupational exposure to phenol/catechol derivatives were significantly associated with vitiligo (three to fourfold increase)."

Case-control study finding household chemicals and occupational exposure to phenol and catechol derivatives significantly associated with the disease, at a three- to fourfold increase.

PMID:28317525 SUPPORT Human Clinical

"Because chemical-induced depigmentation is clinically and histologically indistinguishable from nonchemically induced vitiligo, and because these chemicals appear to induce melanocyte autoimmunity"

One continuous clause carrying both halves of the claim: that chemically induced depigmentation cannot be told apart from the disease, and that these chemicals appear to induce melanocyte autoimmunity, which is the intervening step between the exposure and the destruction at this node.

🔬

Biochemical Markers

2

Autoantibodies to Melanocytes (Elevated)

Show evidence (1 reference)

PMID:17289548 SUPPORT Human Clinical

"The frequent association of vitiligo with autoimmune diseases, together with studies demonstrating that vitiligo patients can have autoantibodies and autoreactive T lymphocytes against pigment cells supports the theory that there is an autoimmune involvement in the aetiology of the disease."

The abstract does mention that vitiligo patients can have autoantibodies against pigment cells, supporting the notion that autoantibodies to melanocytes are present. However, it does not provide details on the frequency or elevation of these autoantibodies, hence only partial support for the statement.

Inflammatory Cytokines (Elevated)

Context: Lesional skin

Show evidence (2 references)

PMID:35096274 SUPPORT Human Clinical

"Since the significant changes of chemokines have been documented in vitiligo in many recent studies, it has been suggested that ROS-mediated chemotactic signals are not only the biomarkers of disease progression and prognosis but also are involved in the pathogenesis of vitiligo by facilitating..."

Documents altered chemokine (a cytokine subfamily) levels in vitiligo and their role in trafficking immune cells to lesional skin. Partial because the review addresses chemokines specifically rather than inflammatory cytokines as a whole.

PMID:22099450 SUPPORT Human Clinical

"Recent research in vitiligo suggests that various local triggers alert the skin immune innate system and may precede adaptive immune responses targeting melanocytes."

This reference points out that inflammatory mechanisms are active in vitiligo, particularly involving inflammatory cytokines.

📊

Prevalence

1

Worldwide

Point Prevalence 500.0–2000.0 per 100,000 >1 in 1,000

The worldwide prevalence of vitiligo ranges from 0.5% to 2%, making it the most frequent cause of depigmentation globally.

Show evidence (3 references)

PMID:25596811 SUPPORT Human Clinical

"Vitiligo, an acquired pigmentary disorder of unknown origin, is the most frequent cause of depigmentation worldwide, with an estimated prevalence of 1%."

Lancet Seminar reports estimated global prevalence of 1%.

PMID:38768496 SUPPORT Human Clinical

"The worldwide prevalence ranges from 0.5% to 2%, and in children from 0% to 2.16%."

Childhood vitiligo study confirms the 0.5-2% range.

ORPHA:3435 SUPPORT Other

"NON RARE IN EUROPE: Vitiligo"

Orphanet classifies vitiligo as non-rare in Europe, consistent with prevalence estimates of 0.5-2%.

📊

Related Datasets

5

Transcriptomic profiling of vitiligo patients shows polar immune dysregulation in involved and uninvolved skin geo:GSE298871

Background: Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being FDA-approved. Although vitiligo is primarily regarded as a Th1/IFN-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. Objective: To obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. Results: Robust inflammatory dysregulation was captured not only in lesional, but also nonlesional vitiligo skin relative to healthy controls.

human BULK RNA SEQ n=17

PMID:40513622

Identified by GEO DataSets index search for Vitiligo (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Single-Cell Transcriptomics Reveals Peripheral Immune Responses in Non-Segmental Vitiligo geo:GSE231794

Vitiligo is a common autoimmune depigmented dermatology due to the destruction of melanocytes. Much evidence suggests that vitiligo is associated with systemic immune activation. Previous studies have focused on immune cell infiltration in and around lesion areas, while few studies have investigated the cell types and function of circulating immune cells in peripheral blood. We collected peripheral blood from five patients with progressive non-segmental vitiligo (PV) and three healthy controls (HC).Single-cell RNA sequencing(scRNA-seq) is used to investigate the mechanisms of peripheral immune responses in vitiligo patients.

human SINGLE CELL RNA SEQ n=8

PMID:38077333

Identified by GEO DataSets index search for Vitiligo (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Increased expression of LOC100506314 in T cells from patients with vitiligo and contributed to the pathogenesis of vitiligo geo:GSE205751

The aim of this study was to investigate the differential expression of long non-coding RNAs (lncRNAs) in T cells from patients with vitiligo and their roles in the pathogenesis of vitiligo. The expression profiles of the RNA transcripts in T cells from three patients with vitiligo and three controls were conducted using microarray analysis. These aberrantly-expressed genes were further validated using T cells from 41 patients with vitiligo and 28 controls. The biologic function of the specific lncRNAs was investigated using transfection, RNA pull-down assay plus proteomic approach and Western blotting.

human MICROARRAY n=6

PMID:37731844

Identified by GEO DataSets index search for Vitiligo (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Exome sequencing data for 40 cases of alopecia areata and vitiligo ega:EGAS00001003831

Sequencing of independent unrelated cases of alopecia areata (total/ universal) and vitiligo (>10%, affected family member). DNA obtained from blood

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Vitiligo"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Immune control of functional memory CD8 T cells in normal-appearing vitiligo skin ega:EGAS50000001317

This study aimed to characterize immune cell states in nonlesional (NL) and perilesional (PL) skin of patients with vitiligo using single-cell RNA sequencing. Shared CD8⁺ T cell clusters were detected in both regions, with PL-derived cells enriched for immune activation pathways and NL skin showed stronger infiltration of regulatory T cells. These findings reveal functional T cell heterogeneity in vitiligo and highlight regulatory mechanisms that may limit depigmentation in NL skin.

human SINGLE CELL RNA SEQ

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Vitiligo"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

{ }

Source YAML

click to show

name: Vitiligo
creation_date: '2025-12-04T16:57:31Z'
description: An autoimmune skin disorder characterized by the loss of skin pigmentation due to the destruction of melanocytes.
category: Complex
parents:
- Autoimmune Disease
- Skin Disorder
inheritance:
- name: Multifactorial/polygenic
  description: Vitiligo has a complex, non-Mendelian inheritance pattern involving approximately 50 genetic risk loci interacting with environmental triggers.
  evidence:
  - reference: PMID:28317533
    reference_title: "Genetics of Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitiligo reflects simultaneous contributions of multiple genetic risk
      factors and environmental triggers. Genomewide association studies have
      discovered approximately 50 genetic loci contributing to vitiligo risk.
    explanation: GWAS studies confirm polygenic inheritance with ~50 loci.
  - reference: PMID:28317533
    reference_title: "Genetics of Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the concordance of vitiligo was 23% in monozygotic twins, underscoring
      the importance of non-genetic factors as well as genetic factors in
      vitiligo pathogenesis
    explanation: Twin studies show only ~23% monozygotic-twin concordance (with heritability ~50%), directly supporting the non-Mendelian, multifactorial model in which genetic risk interacts with environmental triggers rather than fully determining disease.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_low: 500.0
  rate_high: 2000.0
  percentage: 0.5-2
  notes: >-
    The worldwide prevalence of vitiligo ranges from 0.5% to 2%, making it
    the most frequent cause of depigmentation globally.
  evidence:
  - reference: PMID:25596811
    reference_title: "Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitiligo, an acquired pigmentary disorder of unknown origin, is the
      most frequent cause of depigmentation worldwide, with an estimated
      prevalence of 1%.
    explanation: Lancet Seminar reports estimated global prevalence of 1%.
  - reference: PMID:38768496
    reference_title: "Prognostic factors in childhood vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The worldwide prevalence ranges from 0.5% to 2%, and in children from
      0% to 2.16%.
    explanation: Childhood vitiligo study confirms the 0.5-2% range.
  - reference: ORPHA:3435
    reference_title: "NON RARE IN EUROPE: Vitiligo"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NON RARE IN EUROPE: Vitiligo"
    explanation: Orphanet classifies vitiligo as non-rare in Europe, consistent with prevalence estimates of 0.5-2%.
has_subtypes:
- name: Non-Segmental Vitiligo (NSV)
  description: Most common form, characterized by symmetrical depigmented patches on both sides of the body. Includes generalized, acrofacial, and universal variants.
  evidence:
  - reference: PMID:20540698
    reference_title: "Vitiligo: pathogenetic hypotheses and targets for current therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Non segmental vitiligo (NSV) is the most common form of the disease: it is usually progressive and may be associated with familiarity and autoimmunity.'
    explanation: The reference confirms that Non-Segmental Vitiligo (NSV) is the most common form of vitiligo.
  - reference: PMID:22237197
    reference_title: "Clinical pattern of vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Generalized vitiligo was the most common type (n=132, 57.4%) followed by focal (n=53, 23%) and acro-facial vitiligo (n=16, 7%).
    explanation: This reference identifies generalized vitiligo as the most common, which is a subtype of NSV, supporting the statement.
  - reference: PMID:33431938
    reference_title: "Association of GZMB polymorphisms and susceptibility to non-segmental vitiligo in a Korean population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Non-segmental vitiligo (NSV) is the most common type of vitiligo, which is characterized by chronic and progressive loss of melanocytes.
    explanation: The reference directly states that NSV is the most common type of vitiligo.
  - reference: PMID:37062442
    reference_title: "Prevalence of immune-mediated inner ear disease in non-segmental vitiligo: A cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concomitance of autoimmune disease in vitiligo patients demands the investigation of immune-mediated inner ear disease (IMIED) as a cause of SNHL in NSV.
    explanation: The reference indicates the association of autoimmune conditions with NSV, characterizing it as a common subtype.
- name: Segmental Vitiligo (SV)
  description: Patches are restricted to one side of the body or one area, such as a limb or the face. Typically has an earlier onset and progresses for a few years before stabilizing.
  evidence:
  - reference: PMID:28317524
    reference_title: "Segmental Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Segmental vitiligo is characterized by its early onset, rapid stabilization, and unilateral distribution.
    explanation: The provided description is consistent with the characterization of segmental vitiligo mentioned in the literature.
  - reference: PMID:35094387
    reference_title: "Clinicodemographic features of mixed vitiligo: a case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mixed vitiligo (MV) is the coexistence of segmental vitiligo (SV) and non-segmental vitiligo (NSV)...As compared to SV, MV had significantly lower mean age of onset of segmental component (SC) (13.33 ± 9.01 vs. 15.70 ± 8.60 years, P = 0.03) and significantly higher proportion of patients with more than 1% body surface involvement by SC (66.2% vs. 51.5%, P = 0.03)
    explanation: The text mentions segmental vitiligo and supports characteristics such as early onset.
- name: Mixed Vitiligo
  description: A combination of segmental and non-segmental types occurring simultaneously or sequentially in the same individual.
  evidence:
  - reference: PMID:17241584
    reference_title: "Mixed vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'OBSERVATION: We report four more cases of mixed vtiligo, segmental with generalized type'
    explanation: The provided literature discusses cases where segmental and generalized vitiligo occur together in the same individual, which supports the existence of mixed vitiligo.
  - reference: PMID:34780118
    reference_title: "New insights into segmental vitiligo: A clinical and immunological comparison with nonsegmental vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The overlaps between segmental vitiligo (SV) and nonsegmental vitiligo (NSV) suggest the underlying features of SV, which may be helpful for treating SV...The clinical and immunological similarities between SV and M-NSV presented a deeper autoimmune understanding of SV.
    explanation: This reference discusses overlaps and similarities between segmental and non-segmental vitiligo but does not specifically confirm the simultaneous or sequential occurrence in the same individual.
pathophysiology:
- name: Melanocyte Destruction
  description: Autoimmune-mediated destruction where the immune system targets melanocytes, leading to loss of skin pigment.
  cell_types:
  - preferred_term: Melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  - preferred_term: CD8+ T Lymphocyte
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:33200838
    reference_title: "Mechanisms of melanocyte death in vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction...self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo...CD8(+) cytotoxic T lymphocytes finally execute the killing of melanocytes.
    explanation: The literature describes the autoimmune-mediated destruction of melanocytes involving CD8+ T lymphocytes, consistent with the provided statement.
  - reference: PMID:31209143
    reference_title: "The Role of Memory CD8(+) T Cells in Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is an autoimmune skin disease mediated by autoreactive CD8(+) T cells that destroy the pigment-producing cells of the epidermis, melanocytes, leading to areas of depigmentation.
    explanation: The reference confirms the autoimmune-mediated destruction mechanism, mentioning both CD8+ T lymphocytes and melanocytes.
  - reference: PMID:25184918
    reference_title: "Vitiligo--Part 2--classification, histopathology and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The main histopathological finding in vitiligo is the total absence of functioning melanocytes in the lesions, while the inflammatory cells most commonly found on the edges of the lesions are CD4+ and CD8+ T lymphocytes.
    explanation: The literature supports the involvement of CD8+ T lymphocytes and the destruction of melanocytes in vitiligo.
  - reference: PMID:35653192
    reference_title: "Multimodal analyses of vitiligo skin identify tissue characteristics of stable disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is an autoimmune skin disease characterized by the destruction of melanocytes by autoreactive CD8+ T cells.
    explanation: This source directly mentions the destruction of melanocytes by CD8+ T cells.
  - reference: PMID:18460889
    reference_title: "Autoimmune etiology of generalized vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is characterized by progressive skin depigmentation resulting from an autoimmune response targeting epidermal melanocytes...Type I cytokine-mediated immunity to melanocytes in vitiligo involves T cells reactive with melanosomal antigens...
    explanation: The source elaborates on the autoimmune nature of vitiligo, involving T cells and targeting melanocytes.
- name: Genetic Predisposition
  description: A complex interplay of multiple genes contributes to susceptibility to vitiligo.
  evidence:
  - reference: PMID:28317533
    reference_title: "Genetics of Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo reflects simultaneous contributions of multiple genetic risk factors and environmental triggers. Genomewide association studies have discovered approximately 50 genetic loci contributing to vitiligo risk.
    explanation: The literature clearly states that multiple genetic risk factors contribute to vitiligo, aligning with the statement's claim of a complex interplay of genes.
  - reference: PMID:28206724
    reference_title: "Vitiligo susceptibility and catalase gene polymorphisms in Sicilian population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Contrary to the Northern part of Europe but likewise to the Mediterranean area, the frequency of the CAT genotypes in Sicily is equally distributed. Out of all CAT genotypes, only CAT-89 T/T frequency was found to be significantly higher amongst vitiligo patients than controls.
    explanation: The study mentions the association of specific gene polymorphisms with vitiligo, supporting the notion of a genetic predisposition.
  - reference: PMID:29704874
    reference_title: "The convergence theory for vitiligo: A reappraisal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The viewpoint that vitiligo is not caused only by predisposing mutations, or only by melanocytes responding to chemical/radiation exposure, or only by hyperreactive T cells, but rather results from a combination of aetiologic factors that impact melanocyte viability, has certainly stood the test of time.
    explanation: The convergence theory supports the idea that multiple genetic and environmental factors contribute to vitiligo.
  - reference: PMID:33278065
    reference_title: "An update on Vitiligo pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The complex interplay between non-immunological and immunological factors in vitiligo is key for the development of the disease.
    explanation: This underscores the multifactorial nature of vitiligo, consistent with the statement's emphasis on a complex genetic interplay.
- name: Autoimmune Reaction
  description: Vitiligo often coexists with other autoimmune disorders, such as thyroid disease, suggesting a common autoimmune etiology.
  evidence:
  - reference: PMID:25838868
    reference_title: "Oxidative stress and immune system in vitiligo and thyroid diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is an acquired dermatological disease frequently associated with autoimmune thyroid disorders...Currently, the autocytotoxic and the autoimmune theories are the most accredited hypothesis
    explanation: The article indicates a strong association between vitiligo and autoimmune thyroid disorders, supporting a common autoimmune etiology.
  - reference: PMID:26769615
    reference_title: "Vitiligo in Children: A Birds Eye View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo in children is a distinct subset of vitiligo and differs from adult vitiligo... The most commonly associated autoimmune disease is thyroiditis.
    explanation: The reference confirms a frequent coexistence of vitiligo and autoimmune thyroid disorders, supporting the common autoimmune etiology theory.
  - reference: PMID:26724277
    reference_title: "Vitiligo: Pathogenesis, clinical variants and treatment approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo can also be associated with several autoimmune diseases, including autoimmune thyroid diseases, alopecia areata, and halo nevi.
    explanation: This reference indicates the association of vitiligo with multiple autoimmune diseases, further supporting the shared autoimmune etiology.
  - reference: PMID:20578892
    reference_title: "Shared genetic relationships underlying generalized vitiligo and autoimmune thyroid disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Generalized vitiligo is an autoimmune disease of skin pigmentation that is associated with increased prevalence of other autoimmune diseases, particularly autoimmune thyroid disease.
    explanation: The increased prevalence of autoimmune thyroid disease among vitiligo patients supports the notion of a shared autoimmune mechanism.
  - reference: PMID:11681494
    reference_title: "Autoimmune aspects of vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In brief, the disease is frequently associated with other disorders which have an autoimmune origin such as autoimmune thyroiditis and insulin-dependent diabetes mellitus.
    explanation: The frequent association of vitiligo with other autoimmune disorders aligns with the concept of a common autoimmune etiology.
- name: Oxidative Stress
  description: Increased oxidative stress in the skin may contribute to melanocyte vulnerability and destruction.
  evidence:
  - reference: PMID:36980277
    reference_title: "The Role of Oxidative Stress in Vitiligo: An Update on Its Pathogenesis and Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Oxidative stress is considered to play a crucial role in activating consequent autoimmune responses related to vitiligo.
    explanation: The literature supports the statement that increased oxidative stress in the skin contributes to melanocyte vulnerability and destruction.
  - reference: PMID:33098225
    reference_title: "Support for increased cardiovascular risk in non-segmental vitiligo among Egyptians: A hospital-based, case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA) were significantly higher in patients than controls (p-value < .001, <.001, respectively); on the other hand, total antioxidant capacity (TAC) was significantly lower in patients than controls (p-value = .001)
    explanation: This study supports the idea that oxidative stress biomarkers are elevated in vitiligo patients, contributing to melanocyte vulnerability.
  - reference: PMID:33346939
    reference_title: "The fate of melanocyte: Mechanisms of cell death in vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Apoptosis is most widely studied cell death pathways in vitiligo...new types of regulated cell death including necroptosis, pyroptosis, and ferroptosis may also participate in the pathogenesis of vitiligo.
    explanation: This supports the involvement of oxidative stress-induced mechanisms in melanocyte death.
  - reference: PMID:37230937
    reference_title: "Increased anti-oxidative action compensates for collagen tissue degeneration in vitiligo dermis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found that the expression levels of collagen-related genes and anti-oxidative enzymes were upregulated in vitiligo-derived fibroblasts.
    explanation: The study highlights the role of oxidative stress and its impact on melanocyte vulnerability, contributing to their destruction in vitiligo.
- name: IFN-gamma-CXCL9/CXCL10 Chemokine Axis
  description: IFN-gamma induces keratinocyte production of CXCL9 and CXCL10 chemokines, which recruit CXCR3-positive CD8+ T cells to skin. These cytotoxic T cells mediate melanocyte destruction via perforin/granzyme and Fas-FasL pathways. Elevated serum CXCL9/CXCL10 correlate with disease activity.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: CD8+ T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: response to type II interferon
    term:
      id: GO:0034341
      label: response to type II interferon
  - preferred_term: leukocyte chemotaxis
    term:
      id: GO:0030595
      label: leukocyte chemotaxis
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
- name: IL-15 and Tissue-Resident Memory T Cells
  description: IL-15 promotes survival and cytotoxic function of CD8+ tissue-resident memory T cells (TRM) in skin, maintaining local immune surveillance and contributing to disease persistence and relapse. Serum IL-15 is elevated and correlates with disease extent.
  cell_types:
  - preferred_term: CD8+ tissue-resident memory T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
    description: Specifically tissue-resident memory (TRM) phenotype with CD69+CD103+ markers
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
- name: Innate Immune Activation
  description: DAMP-driven activation of plasmacytoid dendritic cells and conventional dendritic cells promotes type I interferon signaling, antigen presentation, and licensing of Th1/cytotoxic immunity. NK cells and innate lymphoid cells participate in bridging innate to adaptive immune responses.
  cell_types:
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
phenotypes:
- category: Dermatological
  name: Depigmented Patches
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Depigmented patches
    term:
      id: HP:0001053
      label: Hypopigmented skin patches
  sequelae:
  - target: Increased Sensitivity To Sunlight
  evidence:
  - reference: PMID:25572727
    reference_title: "Vitiligo: symptoms, pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is an acquired cutaneous disorder of pigmentation... Recent data provide strong evidence supporting an autoimmune pathogenesis of vitiligo.
    explanation: The review characterizes vitiligo as an acquired cutaneous disorder of pigmentation, supporting depigmented patches as its defining lesion; it does not quantify the frequency band.
  - reference: PMID:35166101
    reference_title: "Vitiligo in the City of Bukavu ( Democratic Republic of Congo)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is a skin disorder characterized by selective loss of melanocytes resulting in circumscribed, depigmented macules and patches... its effects can be psychological, leading to stigmatization and suicidal ideation.
    explanation: Confirms that selective melanocyte loss produces circumscribed depigmented macules and patches, the phenotype curated here.
  - reference: PMID:17250545
    reference_title: "The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is the most common depigmenting disorder, which affects 0.5-1% of the worldwide population, causing disfigurement and serious disturbances in well being.
    explanation: The Vitiligo European Task Force consensus identifies vitiligo as the most common depigmenting disorder, supporting depigmentation as its cardinal manifestation.
  - reference: PMID:23796814
    reference_title: "Cumulative life course impairment in vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo is an acquired, idiopathic skin disease characterized by the mostly progressive loss of the inherited skin color leading to white patches... The disease burden includes stigmatization, depression, impaired quality of life, lack of self-confidence, embarrassment and self-consciousness.
    explanation: Describes progressive loss of inherited skin color leading to white patches, supporting the depigmented-patch phenotype.
  notes: Symmetrically distributed, well-demarcated white macules or patches
- category: Dermatological
  name: Premature Hair Whitening
  frequency: FREQUENT
  description: >-
    Premature graying of scalp hair, eyebrows, or eyelashes. Leukotrichia
    within vitiligo lesions (white hairs in depigmented patches) reflects
    destruction of hair follicle melanocyte reservoir and indicates poorer
    prognosis for repigmentation.
  phenotype_term:
    preferred_term: Poliosis
    term:
      id: HP:0002290
      label: Poliosis
  evidence:
  - reference: PMID:26769615
    reference_title: "Vitiligo in Children: A Birds Eye View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo in children is a distinct subset of vitiligo and differs from adult vitiligo. Characteristic features include family history of autoimmune or endocrine disease, higher incidence of segmental vitiligo, development of early or premature graying, increased incidence of autoantibodies and poor response to topical PUVA.
    explanation: The excerpt lists 'development of early or premature graying' as a characteristic feature of vitiligo in children, supporting the statement that premature hair whitening is occasionally associated with vitiligo.
  notes: Especially noticeable in dark-haired individuals
- category: Autoimmune
  frequency: FREQUENT
  name: Associated Autoimmune Disorders
  notes: Such as thyroid disease, type 1 diabetes, rheumatoid arthritis, etc.
  evidence:
  - reference: PMID:34104234
    reference_title: "Vitiligo and chronic autoimmune thyroiditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The association with chronic thyroiditis is based on common autoimmune background and excessive reactive oxygen species that destroy melanocytes and thyrocytes (oxidative stress hypothesis)...
    explanation: This reference discusses the association of vitiligo with chronic autoimmune thyroiditis, supporting the statement that vitiligo is frequently associated with autoimmune disorders.
  - reference: PMID:35637045
    reference_title: "Additional autoimmune diseases associated with type 1 diabetes in children and adolescents: A French single-center study from 2014 to 2021."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vitiligo and Graves' disease were also diagnosed in this cohort but affected few patients.
    explanation: This reference indicates that vitiligo is associated with autoimmune disorders like Graves' disease and Hashimoto's disease, supporting the statement.
  - reference: PMID:37405428
    reference_title: "Association of vitiligo with multiple cutaneous and extra-cutaneous autoimmune diseases: a nationwide cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most frequent autoimmune disorders in patients with vitiligo were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, Addison's disease, and systemic sclerosis (SSc).
    explanation: This reference provides evidence that vitiligo is frequently associated with various autoimmune disorders, supporting the statement.
  - reference: PMID:16420246
    reference_title: "HLA class II haplotype DRB1*04-DQB1*0301 contributes to risk of familial generalized vitiligo and early disease onset."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Familial clustering of vitiligo is not uncommon, and patients and their relatives are at increased risk for a specific complex of other autoimmune diseases.
    explanation: This reference indicates that vitiligo is associated with a higher risk of other autoimmune diseases, supporting the statement.
- category: Ophthalmologic
  frequency: OCCASIONAL
  name: Uveitis
  notes: Inflammation of the uveal tract of the eye
  evidence:
  - reference: PMID:37919864
    reference_title: "Ocular findings in vitiligo and recommendations for dermatologists."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several small studies have found potential links to uveitis and
      glaucoma.
    explanation: Systematic review of ocular findings in vitiligo identifies potential links to uveitis.
  phenotype_term:
    preferred_term: Uveitis
    term:
      id: HP:0000554
      label: Uveitis
- category: Psychological
  frequency: FREQUENT
  name: Depression/Anxiety
  description: >-
    Depression and anxiety are common in vitiligo patients. Pooled prevalence
    of anxiety is approximately 36%. Related to altered appearance, social
    stigma, and reduced quality of life.
  notes: Related to altered appearance and social stigma
  evidence:
  - reference: PMID:33170870
    reference_title: "Vitiligo and anxiety: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The general prevalence of anxiety among vitiligo patients was equal to
      35.8%.
    explanation: Systematic review and meta-analysis of 15 studies finds anxiety prevalence of 35.8% in vitiligo patients, supporting FREQUENT frequency classification.
  - reference: PMID:32013982
    reference_title: "Evaluating prevalence of depression, anxiety and hopelessness in patients with Vitiligo on an Iranian population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Depression and Anxiety are common psychiatric disorders in vitiligo patients.
    explanation: The study confirms that depression and anxiety are common in vitiligo patients.
  - reference: PMID:16405601
    reference_title: "Psychosocial effects of vitiligo."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: We review the psychosocial effects of vitiligo, how patients deal with them and the psychiatric morbidity in vitiligo patients.
    explanation: The study acknowledges the psychosocial effects and psychiatric morbidity in vitiligo patients but does not specify the frequency as occasional.
  - reference: PMID:37975615
    reference_title: "Exploring genetic associations between vitiligo and mental disorders using Mendelian randomization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Although a large number of existing studies have confirmed that people with vitiligo are prone to mental disorders...
    explanation: This study indicates a susceptibility to mental disorders in vitiligo patients but does not specify the frequency as occasional.
  - reference: PMID:32064670
    reference_title: "Quality of life, emotion dysregulation, attention deficit and psychiatric comorbidity in children and adolescents with vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most important finding of this study is that anxiety disorders are more prominent than depression in childhood vitiligo.
    explanation: This study highlights the prominence of anxiety disorders and depression in children with vitiligo but does not specify the frequency as occasional.
- name: Increased Sensitivity To Sunlight
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Increased Sensitivity To Sunlight
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
- category: Dermatological
  name: Koebner Phenomenon
  description: >-
    Development of new depigmented patches at sites of skin trauma, friction,
    or injury. The Koebner phenomenon is a sign of active disease and is
    observed in a substantial proportion of vitiligo patients. It is used
    clinically to assess disease activity.
  phenotype_term:
    preferred_term: Koebner Phenomenon
    term:
      id: HP:6000933
      label: Koebner Phenomenon
  evidence:
  - reference: PMID:39606817
    reference_title: "Late-Onset Vitiligo: Epidemiology, Clinical Characteristics, and Management Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitiligo vulgaris was the most common form, with increased
      leukotrichia and the Koebner phenomenon.
    explanation: Review of late-onset vitiligo identifies the Koebner phenomenon as a prominent clinical feature.
  - reference: PMID:38768496
    reference_title: "Prognostic factors in childhood vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variables were studied: age at onset, sex, hereditary family
      history, personal history of thyroid diseases, time of evolution,
      classification, Köebner phenomena, mucosal vitiligo, halo nevus,
      premature graying and the presence of other dermatoses.
    explanation: Childhood vitiligo study includes Koebner phenomenon as a standard clinical variable assessed in 574 pediatric patients.
  - reference: PMID:37992390
    reference_title: "Dermatoscopic Patterns in Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the periphery of the lesion, unstable vitiligo usually shows up as a
      diffuse border, trichrome pattern, micro-Koebner/comet tail phenomenon,
      satellite lesions, or a tapioca sago pattern.
    explanation: Dermoscopy review identifies micro-Koebner phenomenon as a dermatoscopic sign of active vitiligo.
- category: Otolaryngologic
  name: Sensorineural Hearing Loss
  frequency: OCCASIONAL
  description: >-
    Vitiligo patients have a 2.2-fold increased risk of developing
    sensorineural hearing loss (SNHL) due to destruction of melanocytes in
    the stria vascularis of the cochlea. Bilateral SNHL is found in
    approximately 25% of non-segmental vitiligo patients, with ~5% meeting
    criteria for immune-mediated inner ear disease.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:35274365
    reference_title: "Association between sensorineural hearing loss and vitiligo: a nationwide population-based cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 2.2-fold increased risk of developing SNHL was found in patients with
      vitiligo. Proper referral to otologists for early screening and closer
      follow-up of SNHL should be considered for patients with vitiligo,
      especially for patients with older age.
    explanation: Large population-based cohort study (13,048 vitiligo patients) demonstrates significantly increased risk of SNHL.
  - reference: PMID:37062442
    reference_title: "Prevalence of immune-mediated inner ear disease in non-segmental vitiligo: A cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bilateral SNHL was found in 28 (25.0%; 95%CI 17.9%-32.1%) patients and
      in 1 (4.3%) control (p = 0.019).
    explanation: Cross-sectional study finds bilateral SNHL in 25% of NSV patients, with 5.4% meeting criteria for immune-mediated inner ear disease.
  - reference: PMID:37062442
    reference_title: "Prevalence of immune-mediated inner ear disease in non-segmental vitiligo: A cross-sectional study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six cases (5.4%; 95%CI 2.7%-8.0%) presented bilateral SNHL of unexplained
      aetiology, and anti-Hsp70 antibody positivity, fulfilling the diagnostic
      criteria for IMIED.
    explanation: Substantiates the description's ~5% figure - 5.4% of non-segmental vitiligo patients met diagnostic criteria for immune-mediated inner ear disease (unexplained bilateral SNHL plus anti-Hsp70 positivity), supporting an autoimmune cochlear mechanism.
  - reference: PMID:26724277
    reference_title: "Vitiligo: Pathogenesis, clinical variants and treatment approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sensorineural hearing loss was reported in several vitiligo patients
      due to a reduction in the number of melanocytes contained in the
      membranous labyrinth of the inner ear.
    explanation: Review confirms the pathogenesis of SNHL in vitiligo relates to melanocyte loss in the cochlea.
- category: Ophthalmologic
  name: Dry Eye Disease
  frequency: OCCASIONAL
  description: >-
    The most commonly reported ocular abnormality in vitiligo, reflecting
    melanocyte involvement in ocular structures.
  phenotype_term:
    preferred_term: Dry eye disease
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:37919864
    reference_title: "Ocular findings in vitiligo and recommendations for dermatologists."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dry eye disease is the most reported ocular abnormality in vitiligo.
    explanation: Systematic review of ocular findings identifies dry eye disease as the most frequent ocular comorbidity.
- category: Dermatological
  name: Halo Nevi
  frequency: OCCASIONAL
  description: >-
    Depigmented ring surrounding melanocytic nevi (Sutton nevi), reflecting
    autoimmune response against melanocytes within the nevus. Frequently
    associated with vitiligo, especially in children.
  evidence:
  - reference: PMID:26724277
    reference_title: "Vitiligo: Pathogenesis, clinical variants and treatment approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitiligo can also be associated with several autoimmune diseases,
      including autoimmune thyroid diseases, alopecia areata, and halo nevi.
    explanation: Review identifies halo nevi as a condition associated with vitiligo.
  - reference: PMID:38768496
    reference_title: "Prognostic factors in childhood vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variables were studied: age at onset, sex, hereditary family
      history, personal history of thyroid diseases, time of evolution,
      classification, Köebner phenomena, mucosal vitiligo, halo nevus,
      premature graying and the presence of other dermatoses.
    explanation: Childhood vitiligo study systematically tracks halo nevi as an associated dermatologic finding in pediatric patients.
- name: "Skin depigmentation"
  category: Dermatological
  description: "Vitiligo produces acquired, progressive cutaneous depigmentation from loss of functional melanocytes."
  phenotype_term:
    preferred_term: "Skin depigmentation"
    term:
      id: HP:0001045
      label: "Vitiligo"
  evidence:
  - reference: PMID:30911977
    reference_title: "Childhood Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "common acquired depigmenting skin disease characterized by a progressive loss of functional melanocytes"
    explanation: "This review defines vitiligo as an acquired depigmenting skin disease from progressive loss of melanocytes."
- name: "Leukotrichia"
  category: Dermatological
  description: "Leukotrichia (white hair within vitiligo lesions) is a characteristic feature of vitiligo."
  phenotype_term:
    preferred_term: "Leukotrichia"
    term:
      id: HP:0011364
      label: "White hair"
  evidence:
  - reference: PMID:19911140
    reference_title: "Vitiligo in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "depigmented macules or patches on the skin, the mucous membranes and/or white hair"
    explanation: "This review notes vitiligo can affect hair, producing white hair (leukotrichia)."
biochemical:
- name: Autoantibodies to Melanocytes
  presence: Elevated
  evidence:
  - reference: PMID:17289548
    reference_title: "Autoantibody responses to melanocytes in the depigmenting skin disease vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The frequent association of vitiligo with autoimmune diseases, together with studies demonstrating that vitiligo patients can have autoantibodies and autoreactive T lymphocytes against pigment cells supports the theory that there is an autoimmune involvement in the aetiology of the disease.
    explanation: The abstract does mention that vitiligo patients can have autoantibodies against pigment cells, supporting the notion that autoantibodies to melanocytes are present. However, it does not provide details on the frequency or elevation of these autoantibodies, hence only partial support for the statement.
- name: Inflammatory Cytokines
  presence: Elevated
  context: Lesional skin
  evidence:
  - reference: PMID:35096274
    reference_title: "The Promising Role of Chemokines in Vitiligo: From Oxidative Stress to the Autoimmune Response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Since the significant changes of chemokines have been documented in vitiligo in many recent studies, it has been suggested that ROS-mediated chemotactic signals are not only the biomarkers of disease progression and prognosis but also are involved in the pathogenesis of vitiligo by facilitating the innate and adaptive immune cells, especially melanocyte-specific T cells, trafficking to the lesional areas of vitiligo.
    explanation: Documents altered chemokine (a cytokine subfamily) levels in vitiligo and their role in trafficking immune cells to lesional skin. Partial because the review addresses chemokines specifically rather than inflammatory cytokines as a whole.
  - reference: PMID:22099450
    reference_title: "Vitiligo as an inflammatory skin disorder: a therapeutic perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Recent research in vitiligo suggests that various local triggers alert the skin immune innate system and may precede adaptive immune responses targeting melanocytes.
    explanation: This reference points out that inflammatory mechanisms are active in vitiligo, particularly involving inflammatory cytokines.
genetic:
- name: NALP1
  association: Associated
  evidence:
  - reference: PMID:17637824
    reference_title: "Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This study confirms genetic association of generalized vitiligo with variation in NALP1, which contains at least two independent risk signals.
    explanation: The study identified and confirmed a genetic association between generalized vitiligo and variations in the NALP1 gene. This supports the statement.
  - reference: PMID:28317533
    reference_title: "Genetics of Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the vitiligo-associated causal SNPs constitute haplotypes of missense
      variants in almost complete linkage disequilibrium, which together
      synergize to result in constitutive gain of NLRP1 function and thus
      activation of interleukin-1 beta
    explanation: Fine-mapping of the NLRP1 (NALP1) locus shows the causal vitiligo-associated missense SNPs produce constitutive gain of NLRP1 inflammasome function driving IL-1 beta activation, giving a functional mechanism for the NALP1 genetic association.
- name: TYR
  gene_term:
    preferred_term: TYR
    term:
      id: hgnc:12442
      label: TYR
  association: Associated
  evidence:
  - reference: PMID:20410501
    reference_title: "Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase.
    explanation: The study identified a significant association between generalized vitiligo and a genetic locus containing the TYR gene.
  - reference: PMID:32838589
    reference_title: "Factors affecting vitiligo response to treatment: do MiRNA 196a2C/T gene polymorphism and serum tyrosinase levels have any role?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The tyrosinase levels were significantly elevated in patients. The TT genotype was the most prevalent one in the patients... MiRNA 196a-2 C/T (11614913) gene polymorphism and the elevated serum tyrosinase levels might be related to the pathogenesis of vitiligo and may affect its therapeutic response.
    explanation: Elevated serum tyrosinase levels in vitiligo patients suggest a genetic association involving the TYR gene with vitiligo.
  - reference: PMID:28317533
    reference_title: "Genetics of Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For TYR, encoding tyrosinase, a key melanogenic enzyme and the major
      vitiligo autoimmune antigen, the vitiligo-associated SNPs are protective
    explanation: TYR encodes tyrosinase, the major vitiligo autoimmune antigen; its vitiligo-associated coding SNPs are protective, explaining the inverse TYR genetic relationship between vitiligo and melanoma risk.
- name: PTPN22
  gene_term:
    preferred_term: PTPN22
    term:
      id: hgnc:9652
      label: PTPN22
  association: Associated
  evidence:
  - reference: PMID:21515266
    reference_title: "Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The PTPN22 locus is one of the strongest risk factors outside of the major histocompatability complex that associates with autoimmune diseases...vitiligo
    explanation: The literature specifically mentions that PTPN22 is associated with vitiligo as part of its association with several autoimmune diseases.
  - reference: PMID:28164884
    reference_title: "Association of protein tyrosine phosphatase, non-receptor type 22 +1858C→T polymorphism and susceptibility to vitiligo: Systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Several studies have demonstrated the association of protein tyrosine phosphatase, non-receptor type 22 +1858C-->T polymorphism with vitiligo... limited ethnic-based studies... In conclusion, protein tyrosine phosphatase, non-receptor type 22 +1858 T allele predisposes European individuals to vitiligo.
    explanation: This source confirms the association but notes that the genetic association is specific to the European population and not found in the Asian population, suggesting partial support.
- name: MC1R
  gene_term:
    preferred_term: MC1R
    term:
      id: hgnc:6929
      label: MC1R
  association: Associated
  evidence:
  - reference: PMID:20197744
    reference_title: "Genetics of pigmentation and melanoma predisposition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genome-wide association studies (GWAS) have unveiled single nucleotide polymorphisms (SNPs) or genetic variants in MC1R, TPCN2, ASIP, KITLG, NCKX5, TYR, IRF4, OCA2, and TYRP1 pigmentation genes.
    explanation: This reference provides evidence of an association between the MC1R gene and vitiligo.
  - reference: PMID:33757175
    reference_title: "Identification of key genes and evaluation of immune cell infiltration in vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MC1R was found as a key gene in vitiligo and involved in the melanogenesis.
    explanation: This reference identifies MC1R as a key gene involved in vitiligo, providing further support for its genetic association.
- name: HLA-A
  gene_term:
    preferred_term: HLA-A
    term:
      id: hgnc:4931
      label: HLA-A
  association: Associated
  evidence:
  - reference: PMID:17243956
    reference_title: "Association of vitiligo with HLA-A2: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Meta-analysis showed a significantly increased frequency of HLA-A2 in vitiligo among cases [OR = 2.07, 95% confidence interval (CI) 1.67-2.58].
    explanation: The meta-analysis strongly suggests an association between HLA-A2, a specific allele of HLA-A, and vitiligo.
- name: HLA-DRB1
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  association: Associated
  evidence:
  - reference: PMID:34686989
    reference_title: "Contribution of HLA class II genes, DRB4*01:01, DRB1*07:01, and DQB1*03:03:2 to clinical features of Vitiligo disease in Iranian population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, we have evaluated the association and role of HLA-DRB4*01:01, -DRB1*07:01, and -DQB1*03:03:2 genes in different clinical subtypes of Vitiligo in the Iranian population.
    explanation: The study discusses the association of different HLA-DRB1 allelic genes, including HLA-DRB1, with vitiligo.
  - reference: PMID:20526339
    reference_title: "Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles...
    explanation: The findings of the genome-wide association study indicate an association of HLA-DRB1 alleles with vitiligo.
- name: IFIH1
  gene_term:
    preferred_term: IFIH1
    term:
      id: hgnc:18873
      label: IFIH1
  association: Associated
  notes: MDA5 (melanoma differentiation-associated gene 5), involved in innate immune sensing and type I interferon signaling. Associated with vitiligo susceptibility in GWAS studies.
  evidence:
  - reference: PMID:22561518
    reference_title: "Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IFIH1 (P = 4.91 × 10(-15))
    explanation: Large-scale GWAS meta-analysis identified IFIH1 as a vitiligo susceptibility locus at genome-wide significance, encoding an immunoregulatory protein involved in innate immune sensing.
- name: BACH2
  gene_term:
    preferred_term: BACH2
    term:
      id: hgnc:14078
      label: BACH2
  association: Associated
  notes: BTB and CNC homology 2, transcription regulator involved in immune cell development and function. GWAS-identified risk locus for vitiligo and other autoimmune diseases.
  evidence:
  - reference: PMID:22561518
    reference_title: "Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BACH2 (P = 2.53 × 10(-8))
    explanation: GWAS meta-analysis identified BACH2 as a vitiligo susceptibility locus at genome-wide significance. BACH2 encodes an immunoregulatory transcription factor involved in immune cell development.
- name: IRF4
  gene_term:
    preferred_term: IRF4
    term:
      id: hgnc:6119
      label: IRF4
  association: Associated
  notes: Interferon regulatory factor 4, involved in immune regulation and pigmentation. Associated with vitiligo susceptibility.
  evidence:
  - reference: PMID:27723757
    reference_title: "Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twenty-three new loci achieved genome-wide significance (P < 5 × 10−8) for association with vitiligo and demonstrated subsequent replication; of these, 21 are completely novel (FASLG, PTPRC, PPP4R3B, BCL2L11, FARP2-STK25, UBE2E2, FBXO45-NRROS, PPP3CA, IRF4, SERPINB9, CPVL, NEK6, ARID5B
    explanation: GWAS meta-analysis names IRF4 among the 23 new vitiligo risk loci reaching genome-wide significance with replication.
- name: FOXP3
  gene_term:
    preferred_term: FOXP3
    term:
      id: hgnc:6106
      label: FOXP3
  association: Associated
  notes: Forkhead box P3, master regulator of regulatory T cells. Implicated in vitiligo pathogenesis through impaired immune regulation.
  evidence:
  - reference: PMID:33181260
    reference_title: "Association of FOXP3 and GAGE10 promoter polymorphisms and decreased FOXP3 expression in regulatory T cells with susceptibility to generalized vitiligo in Gujarat population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FOXP3 mRNA and protein levels were significantly decreased (p < 0.001) in GV Tregs compared to controls
    explanation: This study found that FOXP3 expression is significantly reduced in regulatory T cells of vitiligo patients, and identified FOXP3 promoter polymorphisms associated with disease susceptibility.
environmental:
- name: UV Exposure
  notes: >-
    Curation note: the evidence collected under this entry is entirely
    therapeutic ultraviolet phototherapy rather than an environmental exposure,
    so this arguably belongs under treatments rather than environmental. Kept
    here pending a curator decision; its pathograph link is modelled as
    protective accordingly.
  influences_mechanisms:
  - target: Skin depigmentation
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Therapeutic ultraviolet phototherapy opposes the depigmented phenotype by
      driving repigmentation, stimulating melanocyte precursors out of the
      follicular reservoir to repopulate lesional skin. The target is the
      depigmentation phenotype rather than the melanocyte-destruction process,
      because repopulation after destruction is what the cited evidence
      measures; phototherapy's separate immunomodulatory action on the
      autoreactive attack is not evidenced here.
    evidence:
    - reference: PMID:34245476
      reference_title: "Is targeted UVB as effective as excimer light phototherapy in treatment of vitiligo?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Targeted phototherapy with EL demonstrated better repigmenting efficacy than TUVB in vitiligo."
      explanation: >-
        Reports repigmenting efficacy for targeted ultraviolet phototherapy in
        vitiligo, an effect opposing the melanocyte loss this node describes.
  description: Promotes the repigmentation process in some cases, but can exacerbate the contrast in others.
  evidence:
  - reference: PMID:29124690
    reference_title: "Impact of Ultraviolet Light on Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This chapter focuses on the use of ultraviolet light in vitiligo as an established therapeutic option.
    explanation: The reference suggests that UV light is used to treat vitiligo, which implies it can promote repigmentation. However, it does not address the exacerbation of contrast.
  - reference: PMID:34245476
    reference_title: "Is targeted UVB as effective as excimer light phototherapy in treatment of vitiligo?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Targeted phototherapy with EL demonstrated better repigmenting efficacy than TUVB in vitiligo.
    explanation: This reference supports UV exposure aiding in repigmentation but does not discuss exacerbating contrast.
  - reference: PMID:34806278
    reference_title: "Assessment of changes in color and size of vitiligo lesions during treatment with narrow band ultraviolet B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients received Nb-UVB three times per week for 6 months... 90% of lesions showed variable degrees of repigmentation and 10% showed increase in size, indicating increased activity of the disease.
    explanation: UVB treatments result in repigmentation in most cases, though some lesions increased in size, indicating potential exacerbation.
  exposure_term:
    preferred_term: UV light exposure
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
- name: Stress
  influences_mechanisms:
  - target: Oxidative Stress
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Pointed at the oxidative stress node rather than at melanocyte
      destruction, because that is the step this entry models as making
      melanocytes vulnerable and it is the plausible entry point for a
      systemic stressor. The animal item is what gives that target choice
      any molecular purchase: restraint stress lowers cutaneous OGG1, the
      glycosylase that repairs oxidative guanine damage, which is this node's
      own currency. The intermediates are still recorded as unknown, because
      that chain was traced in mice whose depigmentation was chemically
      induced, and no human sentence here follows stress to any molecular
      step. Both human items are graded partial for the same reason from
      opposite directions: one is a recommendation from a study with no
      comparison group, the other a cross-sectional difference.
    evidence:
    - reference: PMID:26057504
      reference_title: "Vitiligo disease triggers: psychological stressors preceding the onset of disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Psychological stressors should be considered as potential disease triggers in vitiligo patients."
      explanation: >-
        Concludes that psychological stressors should be considered as
        potential disease triggers in affected patients. A recommendation
        about what to consider, from a questionnaire study without a
        comparison group, which is why it is partial rather than support.
    - reference: PMID:31986193
      reference_title: "The relationship between stress and vitiligo: Evaluating perceived stress and electronic medical record data."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo."
      explanation: >-
        Reports significantly higher perceived stress in affected individuals
        than in those without the disease. A cross-sectional difference, which
        cannot separate stress as cause from stress as consequence of a
        visible skin disease.
    - reference: PMID:37481827
      reference_title: "Restraint stress promotes monobenzone-induced depigmentation in mice via the activation of glucocorticoid receptor/macrophage migration inhibitory factor signaling pathway."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "restraint stress aggravated anxiety-like behaviors and increased levels of macrophage migration inhibitory factor (MIF) and corticosterone in the circulation, accompanied with decreasing the expression of cutaneous 8-oxoguanine DNA glycosylase (OGG1) in depigmentation mice"
      explanation: >-
        The only sentence in this link that reaches a molecule: restraint
        stress lowers cutaneous OGG1, the glycosylase that excises oxidised
        guanine, which is a step in the oxidative handling this node holds.
        Partial because the model is a mouse whose depigmentation was induced
        chemically, so the finding converges on the human claim without
        establishing it.
  description: Psychological stress is implicated in the exacerbation or onset of the disease.
  evidence:
  - reference: PMID:26057504
    reference_title: "Vitiligo disease triggers: psychological stressors preceding the onset of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Psychological stressors should be considered as potential disease triggers in vitiligo patients.
    explanation: The study identifies psychological stressors as potential triggers for the onset of vitiligo.
  - reference: PMID:37481827
    reference_title: "Restraint stress promotes monobenzone-induced depigmentation in mice via the activation of glucocorticoid receptor/macrophage migration inhibitory factor signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Psychological stress triggers onset and development of vitiligo in humans.
    explanation: A restraint-stress mouse model shows psychological stress promotes vitiligo-related depigmentation, supporting stress as a disease trigger; the cited study is a mouse-model (plus in vitro) investigation, not a human study.
  - reference: PMID:31986193
    reference_title: "The relationship between stress and vitiligo: Evaluating perceived stress and electronic medical record data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo.
    explanation: The data supports the notion that stress is a precipitating factor in vitiligo development.
  exposure_term:
    preferred_term: Psychological stress exposure
    term:
      id: XCO:0001265
      label: stress
- name: Chemical Exposure
  influences_mechanisms:
  - target: Melanocyte Destruction
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The best-evidenced exposure in this tranche, and the only one with a
      quantified effect: phenol and catechol derivatives carry a three- to
      fourfold increase in a case-control study. The intervening step is
      recorded as known because one cited sentence names it, describing these
      chemicals as appearing to induce melanocyte autoimmunity, which is the
      route to the destruction this node holds. That sentence also carries
      the resemblance claim, so a third item asserting only resemblance would
      have added a citation without adding a claim and was left on the
      exposure rather than the link.
    evidence:
    - reference: PMID:36433836
      reference_title: "Role of chemical exposure in the incidence of vitiligo: a case-control study in Tunisia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the binary logistic regression model, household chemicals/colored toothpaste use...and an occupational exposure to phenol/catechol derivatives were significantly associated with vitiligo (three to fourfold increase)."
      explanation: >-
        Case-control study finding household chemicals and occupational
        exposure to phenol and catechol derivatives significantly associated
        with the disease, at a three- to fourfold increase.
    - reference: PMID:28317525
      reference_title: "Chemical-Induced Vitiligo."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Because chemical-induced depigmentation is clinically and histologically indistinguishable from nonchemically induced vitiligo, and because these chemicals appear to induce melanocyte autoimmunity"
      explanation: >-
        One continuous clause carrying both halves of the claim: that
        chemically induced depigmentation cannot be told apart from the
        disease, and that these chemicals appear to induce melanocyte
        autoimmunity, which is the intervening step between the exposure and
        the destruction at this node.
  description: Certain phenolic compounds and other chemicals can induce or exacerbate vitiligo.
  chemicals:
  - Phenol
  evidence:
  - reference: PMID:36433836
    reference_title: "Role of chemical exposure in the incidence of vitiligo: a case-control study in Tunisia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the binary logistic regression model, household chemicals/colored toothpaste use...and an occupational exposure to phenol/catechol derivatives were significantly associated with vitiligo (three to fourfold increase).
    explanation: The study identifies phenol derivatives as significant risk factors for the development of vitiligo.
  - reference: PMID:33039241
    reference_title: "Chemical induced pathognomonic features observed in human vitiligo are mediated through miR-2909 RNomics pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Chemicals like Monobenzyl Ether of Hydroquinone (MBEH) and 4-Tertiary Butyl Phenol (4-TBP) have been widely recognized to induce clinical lesions that resemble vitiligo.
    explanation: The study demonstrates that phenol-based compounds can induce vitiligo-like lesions.
  - reference: PMID:28317525
    reference_title: "Chemical-Induced Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: these chemicals have been used therapeutically in patients with severe vitiligo to depigment their remaining skin and improve their appearance...these chemicals appear to induce melanocyte autoimmunity
    explanation: The study mentions the use of chemicals, including phenols, to induce vitiligo for therapeutic purposes, supporting the role of phenolic compounds in inducing or exacerbating vitiligo.
  exposure_term:
    preferred_term: Chemical exposure
    term:
      id: ECTO:0000231
      label: exposure to chemical
treatments:
- name: Topical Corticosteroid
  description: Common first-line treatment to reduce inflammation and potentially stimulate repigmentation.
  evidence:
  - reference: PMID:19178066
    reference_title: "Choosing topical corticosteroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Topical corticosteroids are one of the oldest and most useful treatments for dermatologic conditions... evidence of effectiveness exists only for select conditions, such as psoriasis, vitiligo...
    explanation: The use of topical corticosteroids as a treatment for vitiligo is supported, indicating it as a common and effective treatment option.
  - reference: PMID:38477910
    reference_title: "Expert Recommendations on Use of Topical Therapeutics for Vitiligo in Pediatric, Adolescent, and Young Adult Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Evidence supports the use of... topical corticosteroids... as effective therapeutics for vitiligo...
    explanation: The recommendations include topical corticosteroids as a first-line treatment for vitiligo in pediatric, adolescent, and young adult patients.
  - reference: PMID:33350506
    reference_title: "Vitiligo: an update on systemic treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mainstay of treatment for unstable vitiligo has been topical agents (corticosteroids, calcineurin inhibitors)...
    explanation: This article highlights topical corticosteroids as a primary treatment for vitiligo, supporting the statement.
  - reference: PMID:20445292
    reference_title: "Topical treatment in vitiligo and the potential uses of new drug delivery systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Topical therapy is employed as first-line treatment in localized vitiligo. Currently, several topical agents are available... corticosteroids...
    explanation: Topical corticosteroids are mentioned as a first-line treatment, aligning with the provided statement.
  treatment_term:
    preferred_term: topical corticosteroid therapy
    term:
      id: NCIT:C122078
      label: Topical Corticosteroid Therapy
- name: JAK Inhibitor Therapy
  description: Targeting the IFN-gamma-JAK/STAT signaling pathway with JAK inhibitors (e.g., topical ruxolitinib) represents a leading therapeutic strategy. Often combined with narrowband UVB phototherapy to enhance repigmentation efficacy.
  notes: Addresses the core IFN-gamma-CXCL9/CXCL10 chemokine axis that recruits cytotoxic T cells to skin.
  treatment_term:
    preferred_term: JAK inhibitor therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
- name: Phototherapy
  description: UVB light or PUVA treatment can stimulate melanocyte regeneration and pigment production.
  evidence:
  - reference: PMID:27638438
    reference_title: "Phototherapy: The vitiligo management pillar."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Acting on multiple steps in vitiligo pathogenesis, narrowband ultraviolet B is one of the few therapies that can effectively induce stabilization and stimulate repigmentation.
    explanation: The article supports the use of narrowband UVB for stimulating repigmentation in vitiligo.
  - reference: PMID:28317529
    reference_title: "Repigmentation through Melanocyte Regeneration in Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most potent stimulus for repigmentation is the UV light.
    explanation: This reference directly supports that UV light, including UVB, is a potent stimulus for repigmentation in vitiligo.
  - reference: PMID:20149899
    reference_title: "Current remedies for vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There have been many treatments to cure vitiligo such as use of steroid creams, PUVA (psoralen and ultraviolet A light), narrow band UVB (ultraviolet B), various surgical techniques, vitamin D analogues and pseudocatalase.
    explanation: It lists both PUVA and narrowband UVB as standard treatments for vitiligo.
  - reference: PMID:34806278
    reference_title: "Assessment of changes in color and size of vitiligo lesions during treatment with narrow band ultraviolet B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'OBJECTIVE: To study whether the colorimeter and point counting technique can be used as objective methods in monitoring vitiligo lesions during treatment with Nb-UVB...'
    explanation: The study demonstrates the effectiveness of narrowband UVB in increasing the melanin index, indicating pigment production in vitiligo lesions.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
- name: Skin Graft
  description: can be used for stable vitiligo.
  evidence:
  - reference: PMID:38038734
    reference_title: "Practical guidelines for the treatment of vitiligo with the melanocyte-keratinocyte transplantation procedure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For patients with stable vitiligo who have not achieved satisfactory results with medical treatments, the melanocyte-keratinocyte transplantation procedure (MKTP) is a viable option.
    explanation: MKTP is a type of autologous non-cultured cellular grafting procedure used for treating stable vitiligo.
  - reference: PMID:37000977
    reference_title: "Ultrathin Skin Grafting Versus Suction Blister Epidermal Grafting in the Treatment of Resistant Stable Vitiligo: A Self-Controlled Comparative Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Surgical therapies are effective methods to treat resistant stable vitiligo, with each method having advantages and disadvantages.
    explanation: This study compares ultrathin skin grafting (UTSG) and suction blister epidermal grafting (SBEG), both of which are skin grafting methods used to treat stable vitiligo.
  - reference: PMID:34169570
    reference_title: "Cultured epidermal autografts for treatment of stable vitiligo: Quantitative analysis of color matching with surrounding normally pigmented skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cultured epidermal autografts (CEA) are surgical therapeutic alternatives for patients with stable vitiligo resistant to conventional medical treatments.
    explanation: CEA is mentioned as an option for treating stable vitiligo, indicating the use of skin grafting.
  - reference: PMID:22994670
    reference_title: "Smashed skin grafting or smash grafting - a novel method of vitiligo surgery."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A number of new therapeutic options for vitiligo have become available...One among them is the smashed skin grafting or simply smash grafting
    explanation: This reference discusses smash grafting as a method used in vitiligo treatment.
  - reference: PMID:27274556
    reference_title: "Management of vitiligo patients with surgical interventions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Medical treatments are usually reasonably effective for nonstable vitiligo patches; however, for vitiligo patches that have been stable for a substantial period of time, surgical intervention should be considered.
    explanation: It supports the use of surgical interventions, including skin grafting, for stable vitiligo.
  context: Stable vitiligo
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Melanocyte Transplantation
  description: can be used for stable vitiligo.
  evidence:
  - reference: PMID:12709002
    reference_title: "Melanocyte-keratinocyte cell transplantation for stable vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This surgical treatment gives its best results in segmental and focal vitiligo, even with large affected areas, and in at least 50% of patients with generalized vitiligo.
    explanation: This implies that melanocyte-keratinocyte transplantation can be effective for stable vitiligo.
  - reference: PMID:28445194
    reference_title: "Successful Treatment of Stable Vitiligo by Low-Density Cultured Autologous Melanocyte Transplantation Combined With Narrowband Ultraviolet B Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cultured autologous melanocyte transplantation (CMT) is an effective treatment for stable vitiligo.
    explanation: This confirms the use of melanocyte transplantation for stable vitiligo.
  - reference: PMID:35457678
    reference_title: "Surgical Treatment of Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both the development of new techniques and modifications to the already available treatment of cell and tissue transplantation give hope to numerous patients around the world.
    explanation: Surgical treatments including melanocyte transplantation are viable for stable vitiligo according to the literature.
  context: Stable vitiligo
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
- name: Monobenzone Cream
  description: Treatment with monobenzone cream to remove remaining pigment in cases of extensive vitiligo.
  evidence:
  - reference: PMID:3168334
    reference_title: "Vitiligo."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: When large areas of skin are involved or when the patient is unresponsive to therapy, serious consideration should be given to depigmentation with monobenzone (Benoquin).
    explanation: This supports the use of monobenzone cream for removing remaining pigment in cases of extensive vitiligo.
  - reference: PMID:21054565
    reference_title: "Depigmentation therapies for normal skin in vitiligo universalis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation...Our review revealed that...Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent and has few side-effects.
    explanation: The reference supports the use of monobenzone (MBEH) for depigmentation in extensive vitiligo cases.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: monobenzone
      term:
        id: CHEBI:34380
        label: monobenzone
review_notes: >-
  Vitiligo is an acquired disorder of skin pigmentation characterized by the
  development of white patches due to loss of melanocytes. The depigmented
  patches and premature hair whitening are the defining features, alongside a
  frequent association with other autoimmune conditions and a substantial
  psychosocial impact. Curation caveat: several phenotype frequency bands in
  this entry were originally set from typical clinical presentation rather than
  from quantitative evidence, contrary to
  docs/frequency-evidence-guidelines.md. Bands that could not be tied to a
  quantitative source are being progressively removed or re-sourced; treat any
  remaining unsourced band as provisional.
disease_term:
  preferred_term: vitiligo
  term:
    id: MONDO:0008661
    label: vitiligo
discussions:
- discussion_id: gap_vitiligo_mdd_shared_immune_dysregulation
  prompt: >-
    A large longitudinal cohort supports vitiligo-to-MDD and
    MDD-to-vitiligo associations, but what accounts for them? Does an acquired,
    cell-state-specific inflammatory program involving p38-alpha/MAPK14 precede
    and help cause both conditions, or are the associations better explained by
    psychosocial effects of visible skin disease, healthcare surveillance,
    treatment, nonspecific inflammatory burden, shared pleiotropic genetic
    liability, or parallel disease-specific mechanisms? Is MAPK14 necessary in
    homologous causal cell states, or merely a cross-tissue bioinformatic
    marker?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Autoimmune Reaction
  - pathophysiology#IFN-gamma-CXCL9/CXCL10 Chemokine Axis
  - pathophysiology#Oxidative Stress
  - pathophysiology#Innate Immune Activation
  rationale: >-
    A UK primary-care cohort found that incident MDD preceded recorded vitiligo
    (adjusted HR 1.64) and incident vitiligo preceded recorded MDD (HR 1.31
    before age 30 and 1.22 at age 30 or older). That establishes a temporal
    epidemiologic signal, not biological mediation. The study did not measure
    disease severity, and treatment and healthcare-contact effects remain
    possible. The cross-disease transcriptomic study is weaker mechanistic
    evidence: it compared separate MDD and vitiligo expression datasets, used
    only 15 vitiligo samples and 15 healthy samples in discovery, inferred
    immune signatures from bulk profiles, and used permissive
    differential-expression thresholds. It did not analyze an explicitly
    ascertained comorbid cohort or paired tissues from the same participants.
    The study did use independent disease-specific GEO validation sets, but
    discriminator performance does not establish a shared cell state or
    mediator. Mouse serotonergic-neuron genetics supports p38-alpha in a
    stress-related behavioral model; a larger human MDD study found no advantage
    for the tested losmapimod regimen after a smaller prematurely terminated
    study had favored treatment. Patient-derived
    nonsegmental-vitiligo keratinocytes and cultured mouse melanocytes support
    pan-p38 activity in skin models, not MAPK14 specificity. These
    compartment-, species-, and assay-specific results are compatible with
    parallel p38 use and do not establish a shared human MAPK14 mechanism.
    Conversely, bidirectional Mendelian randomization found no significant
    directional causal effect between generalized vitiligo and broad
    mental-disorder phenotypes, including depression. That design does not test
    shared pleiotropic genetic liability. A claims study found a mental-health
    profile largely comparable to atopic dermatitis. The gap is therefore the
    mediator and its specificity; the evidence does not justify a new vitiligo
    pathophysiology node, MAPK14 biomarker, or conserved mechanism module. A
    candidate pair-level record is curated in
    com_Major_Depressive_Disorder__Vitiligo.
  evidence:
  - reference: PMID:30528503
    reference_title: "Vitiligo and major depressive disorder: A bidirectional population-based cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with the referent cohort (n = 6,137,696), patients with vitiligo (n = 7104) that were <30 years of age at diagnosis had a higher risk of developing MDD than patients ≥30 years of age (hazard ratio 1.31, 95% CI 1.14-1.50, P < .0001 vs 1.22, 95% CI 1.08-1.37, P = .001, respectively)."
    explanation: >-
      The large adjusted cohort establishes the age-stratified
      vitiligo-to-MDD temporal association but cannot identify its mediator.
  - reference: PMID:42418414
    reference_title: "Bioinformatics analysis reveals the characteristics of immune microenvironment in major depressive disorder and vitiligo."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "These findings primarily serve to generate hypotheses regarding shared mechanisms and prioritize targets for subsequent experimental validation."
    explanation: >-
      The authors explicitly limit the cross-disease MAPK14 result to hypothesis
      generation.
  - reference: PMID:42418414
    reference_title: "Bioinformatics analysis reveals the characteristics of immune microenvironment in major depressive disorder and vitiligo."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "For MDD, the GSE98793 dataset was utilized, which includes 192 whole blood samples: 64 from healthy controls, 128 from patients with MDD, using the GPL570 platform for sequencing. For vitiligo, the GSE65127 and GSE53146 datasets were integrated using the R package ‘sva’ to correct batch effects. The combined datasets included 15 healthy samples and 15 vitiligo samples, using the GPL570 and GPL14951 platforms for sequencing."
    explanation: >-
      The analysis combined separate disease datasets and had only 15 vitiligo
      and 15 healthy samples, rather than paired samples from a comorbid cohort.
  - reference: PMID:42418414
    reference_title: "Bioinformatics analysis reveals the characteristics of immune microenvironment in major depressive disorder and vitiligo."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Differentially expressed genes (DEGs) between disease and control groups were identified using the R package ‘limma’, applying a threshold of |log2FC| > 0 and P-value < 0.05."
    explanation: >-
      The permissive nonzero fold-change and nominal P-value screen limits the
      specificity of the candidate-gene intersection.
  - reference: PMID:42418414
    reference_title: "Bioinformatics analysis reveals the characteristics of immune microenvironment in major depressive disorder and vitiligo."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "It should be noted that these ssGSEA scores represent inferred immune signatures from bulk RNA-seq data, rather than direct measurements of actual immune cell abundances."
    explanation: >-
      The immune-cell results are computational enrichment scores rather than
      measured cell abundances.
  - reference: PMID:42418414
    reference_title: "Bioinformatics analysis reveals the characteristics of immune microenvironment in major depressive disorder and vitiligo."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Two independent GEO datasets (GSE52790 and GSE80009) were utilized as external validation sets to examine the consistency and stability of these findings."
    explanation: >-
      Independent disease-specific datasets strengthen the candidate-marker
      screen relative to discovery alone, but ROC-style discriminatory
      validation does not establish a shared cell state, p38 activity,
      mediation, or causality.
  - reference: DOI:10.1111/exd.14979
    reference_title: "Exploring genetic associations between vitiligo and mental disorders using Mendelian randomization"
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "In our findings, none of the rigorous bidirectional MR analyses uncovered a significant causal association."
    explanation: >-
      The null result constrains genetically instrumented disease-to-disease
      effects between generalized vitiligo and a broad depression phenotype; it
      does not test shared pleiotropic liability and leaves acquired and
      clinically defined MDD-subgroup mechanisms unresolved.
  - reference: PMID:41781039
    reference_title: "Prevalence and comparative risk of mental health disorders in persons with vitiligo: a retrospective matched cohort study using claims data with expert-informed case validation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mental health comorbidity profile was largely comparable to that of atopic dermatitis, whereas more pronounced differences were observed in comparisons with psoriasis."
    explanation: >-
      A dermatologic comparator confirms mental-health burden but challenges
      the specificity of a vitiligo-specific shared immune mechanism.
  - reference: PMID:21835346
    reference_title: "Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Social defeat stress produced social avoidance (a model of depression-like behaviors) and reinstatement of cocaine preference (a measure of addiction risk) in wild-type mice, but not in mice having p38α MAPK selectively deleted in serotonin-producing neurons of the dorsal raphe nucleus."
    explanation: >-
      Cell-specific mouse genetics supports a p38-alpha stress pathway in
      serotonergic neurons, not a human MDD-vitiligo bridge.
  - reference: PMID:24699061
    reference_title: "Evaluation of antidepressant properties of the p38 MAP kinase inhibitor losmapimod (GW856553) in Major Depressive Disorder: Results from two randomised, placebo-controlled, double-blind, multicentre studies using a Bayesian approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A subsequent study, Study 009 (n=128), designed using a Bayesian approach based on a prior derived from Study 574, showed no advantage for losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = 1.11; 95% credible interval, -0.22, 2.50). Biomarker data showed no significant changes. In conclusion 7.5 mg BID losmapimod was not effective in MDD."
    explanation: >-
      The larger human MDD study and its biomarkers were null, although a
      smaller prematurely terminated study had favored treatment. A single
      regimen, duration, and selected MDD population without demonstrated
      biomarker modulation is a narrow pharmacologic constraint, not a
      refutation of cell-specific MAPK14 activity or a shared acquired mediator.
  - reference: PMID:20085492
    reference_title: "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."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In keratinocytes from perilesional vitiligo skin, we observed high levels of activated p38, NF-kB p65 subunit, p53, and Smac/DIABLO proteins."
    explanation: >-
      Patient-derived keratinocytes from 12 people with nonsegmental vitiligo
      support a skin-compartment pan-p38 signal. The cultured-cell study does
      not resolve MAPK14 from other p38 isoforms or connect the signal to MDD.
  - reference: PMID:18575770
    reference_title: "Minocycline protects melanocytes against H2O2-induced cell death via JNK and p38 MAPK pathways."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Also, H2O2 treatment activates JNK and p38 MAPK, and executive caspase 3 in B10BR cells."
    explanation: >-
      p38-family activation in oxidatively stressed mouse melanocytes supplies
      separate plausibility but is neither MAPK14-specific nor evidence of a
      shared human mechanism.
  proposed_experiments:
  - experiment_id: exp_vitiligo_mdd_longitudinal_mediation
    name: Adjudicate temporal immune, psychosocial, and surveillance mediation
    description: >-
      Prospectively enroll treatment-naive active nonsegmental-vitiligo-only,
      incident MDD-only, comorbid, and matched control groups. Reassess
      structured MDD diagnoses, symptom trajectories, vitiligo subtype,
      activity, extent and visibility, medication, healthcare utilization,
      autoimmune disease, smoking, BMI, socioeconomic factors, stress, stigma,
      and quality of life. At repeated visits profile circulating immune cells
      by single-cell transcriptomics plus surface proteins and measure
      cell-type-specific phospho-p38 and cytokines; collect paired lesional and
      nonlesional skin only from consenting vitiligo participants. Follow the
      single-disease groups for onset of the second condition and use
      prespecified time-varying mediation models.
    experiment_type:
      preferred_term: prospective longitudinal multimodal cohort study
    readouts:
    - name: Incident second condition and within-person disease trajectories
      target: pathophysiology#Autoimmune Reaction
      description: >-
        Adjudicated incident MDD in vitiligo-only participants and incident
        vitiligo in MDD-only participants, with repeated measures of both
        diseases.
      interpretation: >-
        Establishes temporal order and distinguishes prediction of transition
        from cross-sectional correlation.
    - name: Cell-state-resolved p38 and inflammatory program
      target: pathophysiology#Autoimmune Reaction
      description: >-
        Phospho-p38, cytokines, and single-cell immune states in blood, aligned
        to lesional and nonlesional skin states.
      interpretation: >-
        Tests whether a homologous acquired state precedes both transitions
        rather than following disease or treatment.
    controls:
    - name: Matched disease-free controls under equal surveillance
      description: >-
        Controls matched on age, sex, site, healthcare-contact schedule, and
        major measured confounders.
    - name: Single-disease comparator groups
      description: >-
        Vitiligo-only and MDD-only groups permit direction-specific analyses;
        atopic dermatitis is an optional visible-inflammatory-skin comparator.
    decision_criterion: >-
      Support a shared acquired mediator only if the same prespecified
      cell-state-specific p38 program precedes onset of the second condition in
      both directions, tracks both outcomes within person, and mediates risk
      after psychosocial, treatment, autoimmune, and surveillance covariates.
      Prefer a psychosocial explanation if visibility, stigma, or distress
      predicts MDD without that program; prefer surveillance bias if equalized
      follow-up materially attenuates the association; classify p38 as a marker
      if it appears only after disease or treatment.
    would_support:
    - pathophysiology#Autoimmune Reaction
    - Major_Depressive_Disorder:pathophysiology#Neuroinflammation

  - experiment_id: exp_vitiligo_mdd_mapk14_cell_epistasis
    name: Test cell-specific MAPK14 necessity and rescue in both disease arms
    description: >-
      Build matched human systems comprising autologous
      melanocyte-keratinocyte-cytotoxic T-cell skin cultures and iPSC-derived
      serotonergic neurons with supporting glia from active
      nonsegmental-vitiligo-only, MDD-only, comorbid MDD-vitiligo, and matched
      disease-free control donors. First map phospho-p38 to specific cell states
      and upstream ligands. Then compare MAPK14 CRISPR interference or knockout
      with a selective p38-alpha inhibitor, non-targeting and vehicle arms, and
      rescue with CRISPR-resistant wild-type versus kinase-dead MAPK14. Challenge
      skin cultures with oxidative stress and IFN-gamma-driven immune attack and
      neural cultures with stress/inflammatory ligands; use blinded,
      preregistered analysis.
    experiment_type:
      preferred_term: human cell-specific causal perturbation and rescue study
    perturbations:
    - name: MAPK14 genetic and pharmacologic loss of function
      target: pathophysiology#Autoimmune Reaction
      description: >-
        Cell-type-restricted MAPK14 CRISPR perturbation and selective
        p38-alpha inhibition in skin, immune, neural, and glial compartments.
    - name: Wild-type versus kinase-dead MAPK14 rescue
      target: pathophysiology#Oxidative Stress
      description: >-
        Isogenic rescue separates on-target catalytic dependence from editing
        artifacts and scaffold effects.
    readouts:
    - name: Melanocyte injury and immune attack
      target: pathophysiology#Autoimmune Reaction
      description: >-
        Melanocyte apoptosis and survival, cytotoxic T-cell killing, and
        CXCL9/CXCL10 pathway readouts.
    - name: Serotonergic stress response
      target: Major_Depressive_Disorder:pathophysiology#Monoamine Deficiency
      description: >-
        Serotonin-transporter surface localization and uptake, cytokine release,
        neuronal activity, and cell viability.
    controls:
    - name: Isogenic non-targeting and vehicle controls
      description: >-
        Same donor, differentiation batch, ligand exposure, and assay schedule.
    - name: Compartment-restricted perturbation controls
      description: >-
        Perturb MAPK14 separately in melanocytes, keratinocytes, T cells,
        neurons, and glia to resolve cell of action.
    decision_criterion: >-
      A shared causal node requires a reproducible upstream state plus MAPK14
      catalytic necessity in both arms, phenotypic rescue by wild-type but not
      kinase-dead MAPK14, and cross-donor replication. Different upstream
      signals or causal compartments support parallel context-specific uses of
      p38 rather than one shared circuit; loss of association after perturbation
      controls or failure to alter either phenotype classifies MAPK14 as a
      correlated marker.
    would_support:
    - pathophysiology#Autoimmune Reaction
    - Major_Depressive_Disorder:pathophysiology#Monoamine Deficiency
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  - classification_value: IMMUNE_RHEUMATOLOGIC
references:
- reference: DOI:10.25259/ijdvl_793_2023
  title: 'Differential expression of serum CXCL9 and CXCL10 levels in vitiligo patients and their correlation with disease severity and stability: A cross-sectional study'
  findings: []
- reference: DOI:10.3390/ijms24119749
  title: Etiopathogenesis and Emerging Methods for Treatment of Vitiligo
  findings: []
- reference: DOI:10.3390/ijms25084409
  title: 'Pathogenesis of Alopecia Areata and Vitiligo: Commonalities and Differences'
  findings: []
- reference: DOI:10.3390/jcm12185861
  title: Serum Inflammatory and Oxidative Stress Markers in Patients with Vitiligo
  findings: []
- reference: DOI:10.3390/jcm13175225
  title: 'Vitiligo: From Pathogenesis to Treatment'
  findings: []
- reference: DOI:10.3390/life15050684
  title: 'Comprehensive Overview of Cytokine Interplay in Vitiligo: A Decade of Meta-Analyses Systematically Reviewed'
  findings: []
datasets:
- accession: geo:GSE298871
  title: Transcriptomic profiling of vitiligo patients shows polar immune dysregulation in involved and uninvolved skin
  description: 'Background: Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being FDA-approved. Although vitiligo is primarily regarded as a Th1/IFN-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. Objective: To obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. Results: Robust inflammatory dysregulation was captured not only in lesional, but also nonlesional vitiligo skin relative to healthy controls.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 17
  publication: PMID:40513622
  notes: Identified by GEO DataSets index search for Vitiligo (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE231794
  title: Single-Cell Transcriptomics Reveals Peripheral Immune Responses in Non-Segmental Vitiligo
  description: Vitiligo is a common autoimmune depigmented dermatology due to the destruction of melanocytes. Much evidence suggests that vitiligo is associated with systemic immune activation. Previous studies have focused on immune cell infiltration in and around lesion areas, while few studies have investigated the cell types and function of circulating immune cells in peripheral blood. We collected peripheral blood from five patients with progressive non-segmental vitiligo (PV) and three healthy controls (HC).Single-cell RNA sequencing(scRNA-seq) is used to investigate the mechanisms of peripheral immune responses in vitiligo patients.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 8
  publication: PMID:38077333
  notes: Identified by GEO DataSets index search for Vitiligo (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE205751
  title: Increased expression of LOC100506314 in T cells from patients with vitiligo and contributed to the pathogenesis of vitiligo
  description: The aim of this study was to investigate the differential expression of long non-coding RNAs (lncRNAs) in T cells from patients with vitiligo and their roles in the pathogenesis of vitiligo. The expression profiles of the RNA transcripts in T cells from three patients with vitiligo and three controls were conducted using microarray analysis. These aberrantly-expressed genes were further validated using T cells from 41 patients with vitiligo and 28 controls. The biologic function of the specific lncRNAs was investigated using transfection, RNA pull-down assay plus proteomic approach and Western blotting.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 6
  publication: PMID:37731844
  notes: Identified by GEO DataSets index search for Vitiligo (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003831
  title: Exome sequencing data for 40 cases of alopecia areata and vitiligo
  description: Sequencing of independent unrelated cases of alopecia areata (total/ universal) and vitiligo (>10%, affected family member). DNA obtained from blood
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Vitiligo"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000001317
  title: Immune control of functional memory CD8 T cells in normal-appearing vitiligo skin
  description: This study aimed to characterize immune cell states in nonlesional (NL) and perilesional (PL) skin of patients with vitiligo using single-cell RNA sequencing. Shared CD8⁺ T cell clusters were detected in both regions, with PL-derived cells enriched for immune activation pathways and NL skin showed stronger infiltration of regulatory T cells. These findings reveal functional T cell heterogeneity in vitiligo and highlight regulatory mechanisms that may limit depigmentation in NL skin.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Vitiligo"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'

📚

References & Deep Research

References

6

DOI:10.25259/ijdvl_793_2023

Differential expression of serum CXCL9 and CXCL10 levels in vitiligo patients and their correlation with disease severity and stability: A cross-sectional study