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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 40  |  Issue : 2  |  Page : 78-84

Hints from the skin beneath: Vitiligo in Vogt–Koyanagi–Harada disease


1 Department of Internal Medicine, School of Medical Sciences, Hospital USM, Universiti Sains Malasia, Kelantan, Malaysia
2 Department of Dermatology, Hospital Pulau Pinang, Penang, Malaysia
3 Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

Date of Submission25-Oct-2021
Date of Decision13-Mar-2022
Date of Acceptance12-Apr-2022
Date of Web Publication10-Jun-2022

Correspondence Address:
Dr. Jo Anne Lim
Department of Internal Medicine, School of Medical Sciences, Hospital USM, Universiti Sains Malaysia, Kelantan
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ds.ds_23_22

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  Abstract 


Vogt–Koyanagi–Harada disease (VKHD) is a major vision-threatening autoimmune disease. One of its associated features is vitiligo. Little study has been done on the association between vitiligo and the disease activity of VKHD. The authors searched available literature on the relationship between vitiligo and ophthalmic disease activity in VKHD in terms of pathogenesis, clinical presentations, risk factors as well as disease activity. Among the findings is that early treatment of VKHD may be associated with full recovery. The reversal of poliosis and vitiligo is associated with the remission of uveitis, but the reverse does not hold true, whereby the worsening of vitiligo may not reflect the worsening of uveitis. It is also found that there may be an association between immunotherapy and Vogt–Koyanagi–Harada-like disease. In summary, vitiligo is an immune-mediated cutaneous manifestation which may contribute to diagnostic and treatment strategies in VKHD. Future research on genetic differences in vitiligo is still needed and may contribute to specific monitoring and therapeutic approach in this disease.

Keywords: Autoimmune disease, uveitis, vitiligo, Vogt–Koyanagi–Harada disease


How to cite this article:
Lim JA, Tan WC, Nor NM. Hints from the skin beneath: Vitiligo in Vogt–Koyanagi–Harada disease. Dermatol Sin 2022;40:78-84

How to cite this URL:
Lim JA, Tan WC, Nor NM. Hints from the skin beneath: Vitiligo in Vogt–Koyanagi–Harada disease. Dermatol Sin [serial online] 2022 [cited 2022 Aug 13];40:78-84. Available from: https://www.dermsinica.org/text.asp?2022/40/2/78/347097




  Introduction Top


Vogt–Koyanagi–Harada disease (VKHD) is an autoimmune disease which causes the destruction of melanocytes of the ophthalmic, integumentary, audio-vestibular, and the central nervous system. The most important manifestations include bilateral diffuse granulomatous panuveitis, choroiditis, and characteristic fluid accumulation under the retina causing retinal detachment. This may be accompanied by neurological, auditory, and dermatological symptoms. VKHD is most common among patients with colored skin.[1]

Cutaneous manifestations in VKHD include vitiligo, alopecia, and poliosis. Over the past two decades, new evidence has surfaced regarding the association between uveitis and these cutaneous signs. However, vitiligo is still considered one of the most variable features.[2] The authors intend to search the currently available literature on the association between vitiligo and uveitis in VKHD from the standpoint of pathogenesis, clinical manifestations, and the significance of these dermatological signs in guiding optimal treatment strategies.


  Materials and Methods Top


Review methods

A literature review was performed through searches of publications in PubMed, Web of Science, Scopus with the title of “VKH,” “Harada,” and keyword of “vitiligo” and “uveitis” in the article, with English or translated full text available up to the year 2020. The final reference list was formed on the basis of relevance to the scope of this review.


  Results Top


Pathophysiology

VKHD is a disease caused by systemic granulomatous hypersensitivity response to pigmented cells in the body.[3] The most widely accepted pathogenesis is an autoimmune aggression against melanocyte after a trigger, e.g., a viral infection. Also known as “systemic vitiligo,” the T-cell-mediated immune response against melanocytes occurs in a few target organs, i.e., the eyes, inner ears, meninges, hair, and skin.[4] It is an antigen-specific inflammatory mechanism against tyrosinase-related protein 1 and tyrosinase-related protein 2 causing pigmented cell destruction.[4]

In the acute granulomatous process of the uveitis stage, histopathological examinations found that there are similar findings in the thickened uveal tract and affected vitiliginous skin of VKHD patients. This includes the presence of cellular infiltrate composed of T-lymphocytes, in particular CD4+ T-cells and macrophages which contain melanin granules.[5]

Recent studies have found that VKHD is associated with a few genes. This includes the genetic risk factors for immune-mediated diseases, i.e., IL-23R,[6] as well as the VKHD-specific risk factors HLA-DR4, HLA-DR53, HLA-DQ4, HLA-DQw7, and HLA-DRB1.[7],[8],[9] The latest genome-wide association study (GWAS) provided a source for genome-wide level analysis and revealed several non-HLA genes associated with VKHD. This includes the IL-23R/C1orf141 and ADO/ZNF365/EGR2 loci.[10],[11] Besides, immune response dysfunction and environmental factors were also found to be associated with the development of VKHD.[4] These factors lead to Th1 and Th17 cell activations directed against the melanocytes, resulting in a multisystemic acute autoimmune response.[4] Increase in expression of a few pro-inflammatory cytokines, i.e., osteopontin,[12] nucleotide-binding oligomerization domain (NOD1/NOD2),[13] and Th lymphocyte subset analysis,[14] had been linked to patients with active VKHD. The tests for these pro-inflammatory cytokines may be potential biomarkers for the monitoring of disease activity in future.

Throughout our literature search, it is worth noting that there were reported cases of metastatic melanoma and other types of cancer which developed Vogt–Koyanagi–Harada (VKH)-like disease after being treated with immunotherapy, in particular the checkpoint inhibitor therapies as well as BRAF and MEK inhibitors [Table 1].[8],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28] Out of the 19 reported cases to date, 18 were malignant melanoma cases. Most of these patients recovered from the VKH-like illness with steroid therapy, and the majority had complete remission toward the malignancy up to the date of reporting. According to Gambichler et al., the occurrence of VKHD in immune checkpoint inhibitor (ICI)-treated melanoma patients is associated with good remission. This may be a strong predictor when monitoring the efficacy of ICI therapy on melanoma patients in future.[28] Since immunotherapy is believed to be the main focus in the next era of cancer treatment, this is an area worthy of further research.
Table 1: Vogt–Koyanagi–Harada disease-like features in patients after immunotherapy

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Additionally, interferon-alpha treatment in hepatitis,[29],[30] hepatitis B vaccination,[31] Bacillus Calmette–Guerin vaccination,[32] yellow fever vaccination,[33] influenza A viral infection,[34] and even COVID-19 infection[35] had also been linked to the induction of this disease spectrum.

Clinical manifestations

Uveitis in VKHD is generally divided into four stages, i.e., prodromal, acute uveitis, chronic convalescent, and recurrent stage. In the prodromal stage, patients may manifest symptoms resembling viral illness, e.g., fever, headaches, retro-orbital pain, and photosensitivity. Systemic symptoms, such as auditory (e.g., tinnitus, vertigo, and hyperacusis), neurological (meningismus, malaise, nausea, abdominal pain, and neck stiffness), or a combination of these factors, may also be present.

This is followed by the acute uveitic stage which is associated with blurred vision, uveitic changes, and even serous retinal detachments. The chronic or convalescent stage occurs weeks later and lasts for months. It is associated with poliosis, vitiligo, and choroidal depigmentation. Subsequently, if the disease progresses to the recurrent stage, it will present as anterior granulomatous uveitis, and may be associated with complications such as glaucoma, cataract, and subretinal neovascularization.

The majority of cutaneous manifestations arise after the uveitis attack, i.e., at the convalescent stage.[1],[36],[37] However, a small proportion of patients presented with integumentary signs prior to uveitis.[17],[38],[39] Some of these reported cases were a result of vitiliginous scarring caused by skin injuries (Koebner's phenomenon).[40],[41]

Vitiligo presents as smooth, nonitchy white opaque depigmented skin patches. The proposed contributing etiology includes genetic, autoimmunity, autonomic nervous system dysfunction, and oxidative stress. It can be divided into segmental, nonsegmental (symmetrical or bilateral), and mixed vitiligo. Nonsegmental vitiligo has been associated with a higher incidence of autoimmune disease, thus when encountering such patients, diseases of decreased pigmentation should not be taken lightly.[42]

Systemic and nonsystemic vitiligo had been reported to be different in terms of distribution.[43],[44] From reported cases, VKHD-associated vitiligo predominantly involves the face, back (especially in the pediatric age group), and upper limbs (adult) [Supplementary Material 1]. This is different from the common site of non-VKHD vitiligo which mainly involves the face and lower extremities.[45],[46] However, practically, distinguishing vitiligo in VKHD from non-VKHD is not an important element for VKHD diagnosis.

Sugiura's sign or “perilimbal vitiligo” has been reported as the earliest depigmentation to occur in VKHD, presenting as early as 1 month after the uveitis stage.[4] With the presence of this sign, an early confirmation of the diagnosis can be made. This could be one of the possible reasons that VKHD-related vitiligo tends to locate near to the eyes.

Studies have shown that vitiligo develops in a wide range of 10%–90% of VKHD patients,[5],[47] whereas 1%–5% of patients attending a vitiligo clinic is in association with concurrent VKHD.[48],[49]

Male and older age at onset of VKHD patients have been associated with an increased risk for vitiligo.[50] The presence of vitiligo and other associated signs plays an important role in categorizing VKHD. According to the most widely used Revised Diagnostic Criteria of VKHD by the International Nomenclature Committee, the disease is divided into “complete,” “incomplete,” or “probable.”[37] Bilateral uveitis and all extraocular finding, i.e., dermatological, neurological/auditory involvement must be present in a complete VKHD. For incomplete VKHD, either neurological/auditory findings or integumentary findings are required. “Probable VKHD” involves uveitis without extraocular manifestations.

”Categorizing” and “staging” the disease allow for the planning of different treatment strategies and may be associated with different prognoses. A better final visual acuity has been associated with a younger age of onset,[50],[51],[52] absence of posterior synechiae, absence of hearing loss and cutaneous manifestations,[53] early high-dose steroid therapy,[50] early immunomodulatory therapy,[52],[54] and those with less complications (i.e., cataract, glaucoma, choroidal neovascularization, and subretinal fibrosis).[50],[51],[52],[53] Thus, early detection of this disease is of utmost importance.

Reversal of poliosis and vitiligo has been associated with the remission of uveitis in VKHD.[55] This suggests the restoration of normal immune homeostasis and is linked to a better prognosis.[55],[56] The complete reversal of vitiligo and poliosis was reported in 27% of VKHD patients after systemic corticosteroid therapy.[55] Interestingly, the reverse does not hold true whereby the worsening of vitiligo may not reflect the worsening of uveitis.[22],[57] An overview of the cases regarding cutaneous signs and VKH disease is summarized in [Table 2].
Table 2: Cases which described the relationship between cutaneous signs and ocular symptoms in Vogt–Koyanagi–Harada disease

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Significance of vitiligo in Vogt–Koyanagi–Harada disease management

Vitiligo in a patient is sometimes neglected because of the perception that it does not directly lead to physical dysfunctionality. Uveitis, on the other hand, may cause visual impairment leading to significant morbidity. However, apart from the cosmetic aspects and stigmatization on a patient's psychological well-being,[50],[59],[60] understanding the relationship between vitiligo and uveitis in VKHD may allow clinicians to improve certain clinical aspects as listed below.

Cutaneous clue for early diagnosis of Vogt–Koyanagi–Harada disease

To date, there are no specific histological or serological confirmatory tests for VKHD. Clinical diagnosis is based on history, physical findings, assessments with ophthalmic imaging aided by ultrasonography, cerebrospinal fluid analysis, magnetic resonance imaging, and electrophysiological test. It can sometimes be misdiagnosed as primary angle-closure glaucoma,[61] optic neuritis, idiopathic panuveitis, anterior ischemic optic neuropathy, Alezzandrini syndrome, Waardenburg syndrome, piebaldism, drug-induced hypopigmentation, or even diabetic papillopathy.[58],[62] In some reported cases, vitiligo appeared as clues which prompted the diagnosis of VKHD and early treatment, which are associated with better outcomes.[50],[52],[62],[63]

Treatment for VKHD consists mainly of immunosuppressive drugs such as corticosteroids, ciclosporin, methotrexate, and azathioprine among other treatments. Additionally, topical steroid and calcineurin inhibitors may be prescribed for pediatric cases.[57] Recent studies showed a trend toward prompt, aggressive high-dose corticosteroid with faster resolution of inflammatory signs.[5],[36] Immunomodulatory therapy is indicated if a patient is intolerant or responded inadequately to corticosteroid. The latest evidence even suggested that early dual therapy (within 2–3 weeks from the onset) may modify the disease outcome to achieve a curative state.[64]

Decision on treatment: Escalation versus de-escalation

Systemic immunomodulatory treatments carry the risks of multiple side effects. Decisions for treatment escalations or de-escalation often depend on the disease activity of the uveitis. To date, the only reliable cutaneous findings associated with the improvement of VKHD are the reversal of poliosis and vitiligo.[55],[56] This should probably give a clue toward treatment de-escalation.

On the contrary, worsening of vitiligo during treatment de-escalation is acceptable as long as intraocular inflammatory activity remains static. There were reported cases of patients whose vitiligo worsened but uveitis remained inactive after stopping systemic immunomodulatory therapies.[22],[57] Slow tapering of the immunosuppressant medications with frequent ophthalmology follow-up is warranted in these clinical scenarios. Personal experience from the authors has shown that tapering down systemic steroid medication when vitiligo is worsening is safe and does not cause the worsening of uveitis or its recurrence.

Future research

Vitiligo and uveitis seem to be mutually associated in the pathogenesis and pathophysiology of VKHD. However, the present evidence is limited to case reports and case series. It seems that vitiligo in VKHD is still an under-researched clinical sign. Future research should focus on possible genetic and immunological aspect of vitiligo (such as in the GWAS)[65] with VKHD and the possible different diagnostic and therapeutic approaches. The different treatment responses from various forms of VKHD with or without vitiligo may also be a potential field of research. Understanding the relation between these two conditions is vital for optimal treatment strategies.


  Conclusion Top


Vitiligo is an immune-mediated cutaneous manifestation which may contribute to diagnostic and treatment strategies in VKHD. The reversal of poliosis and vitiligo is associated with the remission of uveitis, but the reverse does not hold true, whereby the worsening of vitiligo may not reflect the worsening of uveitis. There may also be an association between immunotherapy and VKH-like disease. Future research on genetic differences in vitiligo is still needed and may contribute to specific monitoring and therapeutic approach in this disease.

Ethical approval and consent to participate

The Institutional Review Board ethical approval is not required at our institutions for a review article which does not directly involve any patient.

Acknowledgments

We sincerely thank Mdm Lee Jong Koh for critical reading and useful comments on this manuscript.

Financial support and sponsorship

The publication fee was sponsored by USM Short-Term Grant (304/PPSP/6315594). The funder had no role in study design, methodology/data collection/analysis/interpretation, or manuscript preparation.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Material Top






 
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