Vogt-Koyanagi-Harada disease (Harada disease)

Key Points at a Glance

Highlights of This Disease

• Vogt-Koyanagi-Harada disease (VKH disease) is a T-cell-mediated autoimmune disease against melanocyte-associated antigens.
• In Japan, it accounts for 6.8–9.2% of uveitis cases and predominantly affects pigmented individuals in their 20s to 50s.
• Onset with acute bilateral vision loss and exudative retinal detachment, sometimes accompanied by headache, tinnitus, vitiligo, and hair loss.
• Shows characteristic clinical features according to four stages (prodromal, uveitic, chronic, and recurrent).
• Acute-phase steroid pulse therapy followed by tapering over at least 6 months is key to visual prognosis.
• Inadequate treatment can lead to serious complications such as cataract, secondary glaucoma, and choroidal neovascularization.
• Cases have been reported where COVID-19 infection or vaccination triggers the onset or exacerbation of Harada disease.

1. What is Vogt-Koyanagi-Harada disease?

Vogt-Koyanagi-Harada disease (VKH disease, Harada disease) is defined as an autoimmune disease characterized by bilateral granulomatous panuveitis with or without extraocular symptoms ¹⁾. The main lesion is in the choroid, and the autoimmune reaction affects melanocytes in the iris, ciliary body, retina, meninges, inner ear, and skin ¹⁾.

In 1906, Vogt and in 1929, Koyanagi independently reported a disease characterized by chronic anterior uveitis, alopecia, vitiligo, and hearing loss. In the same year, Harada reported posterior uveitis with cerebrospinal fluid pleocytosis and exudative retinal detachment. In 1932, Babel combined both and named it “Vogt-Koyanagi-Harada disease.”

Epidemiology

Harada disease is more common in people of color, such as Hispanics, Asians, Native Americans, Middle Easterners, and Indians⁴⁾. It is rare in sub-Saharan Black Africans. In Japan, it accounts for 6.8–9.2% of all uveitis cases. In the United States, it accounts for only 1–4%.

In one study (n=65), 78% of patients were Hispanic, 10% were Asian, and 74% were female⁴⁾. The average age at onset was 32 years, with the majority in their 20s to 50s⁴⁾. In Japanese patients, approximately 80% are HLA-DR4 positive, strongly suggesting a genetic predisposition.

Q What races and age groups are most commonly affected by Harada disease?

A

It is more common in people of color (Hispanic, Asian, Native American, etc.) in their 20s to 50s, with a tendency for women to be affected more often than men. One study found that 74% were women, and the average age at onset was 32 years ⁴⁾. In Japan, it accounts for about 7–9% of all uveitis cases.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The symptoms of Harada disease vary depending on the disease stage. Following a systematic course from before onset can aid in diagnosis.

• Prodromal symptoms (prodromal phase): Headache, fever, orbital pain, nausea, dizziness, and photophobia persist for about 3 to 5 days. Hypersensitivity of the scalp, hair, and skin may also be noticed ⁴⁾.
• Ocular symptoms (uveitic phase): Rapid bilateral vision loss. One eye may be affected first, but in 94% of cases, it progresses to both eyes within 2 weeks. Accompanied by eye pain, redness, photophobia, and floaters.
• Systemic symptoms (uveitic to chronic phase): Sensorineural hearing loss, tinnitus, and dizziness tend to appear early from the onset ⁴⁾. Meningeal irritation signs such as headache and neck stiffness also occur early.
• Skin symptoms (chronic phase and later): Vitiligo may appear on the face, hands, shoulders, lower back, etc., starting 2 to 3 months after onset ⁴⁾. Poliosis and alopecia are also often observed. In Japan, the frequency of skin symptoms is reported to be about 20%.

Clinical Findings

The clinical findings of Vogt-Koyanagi-Harada disease change according to the four disease stages.

Prodromal Stage

Extraocular symptoms precede: Headache, fever, tinnitus, vertigo, and meningeal irritation signs are predominant.

Ocular symptoms are mild: The stage when mild hyperemia of the optic disc begins to appear.

Uveitis stage

Serous retinal detachment: Multiple serous detachments of the posterior pole due to choroidal thickening. In severe cases, it may appear bullous.

Optic disc hyperemia and edema: Inflammatory findings of the posterior pole.

Anterior chamber and vitreous inflammation: As the disease progresses, it presents as panuveitis.

Chronic phase (convalescent stage)

Sunset-glow fundus: A characteristic fundus appearance due to depigmentation of the choroid.

Sugiura sign: Limbal corneal depigmentation. This is the earliest depigmentation finding, appearing about one month after onset.

Vitiligo, poliosis, and alopecia: Systemic skin symptoms become apparent.

Recurrent phase

Granulomatous anterior uveitis: Koeppe nodules, Busacca nodules, mutton-fat keratic precipitates, posterior synechiae.

Iris atrophy and depigmentation: The iris appears thin and atrophic.

Complications: Cataract, secondary glaucoma, choroidal neovascularization⁴⁾.

Q What is "sunset glow fundus"?

A

It refers to a condition where the fundus appears bright reddish-orange due to depigmentation of choroidal melanocytes. This is a characteristic finding in the chronic phase of Vogt-Koyanagi-Harada disease and often appears within a few months after treatment. It is also included as one of the diagnostic criteria.

3. Causes and Risk Factors

Autoimmune Mechanism

The etiology of Vogt-Koyanagi-Harada disease is not fully understood, but an autoimmune reaction against tyrosinase family proteins expressed by melanocytes plays a major role ²⁾. T cell-mediated immune responses (activation of Th1 and Th17 cells) cause inflammation in melanocyte-rich tissues (choroid, meninges, inner ear, skin) ¹⁾.

Genetic Predisposition

An association with HLA-DR4 subtypes such as HLA-DRB10405 has been established. A systematic review identified HLA-DRB10404, *0405, and *0410 as risk suballeles, and *0401 as a protective suballele ⁸⁾. Associations with immune response-related genes such as the IL-23 receptor have also been suggested ¹⁾.

Environmental Triggers (Viruses, Vaccines)

Infections and vaccinations have been reported to trigger the onset or exacerbation of Vogt-Koyanagi-Harada disease in genetically susceptible individuals.

• VKH disease after COVID-19 infection: A 29-year-old female developed VKH-like serous retinal detachment and optic nerve edema one month after SARS-CoV-2 infection ²⁾. Similar to various autoimmune diseases occurring after COVID-19, molecular mimicry is suspected as the mechanism ²⁾.
• VKH disease after COVID-19 vaccine: A 46-year-old female developed bilateral granulomatous uveitis two days after the first dose of mRNA COVID-19 vaccine (Pfizer-BioNTech), and met the diagnostic criteria for complete VKH disease four days after the second dose ⁷⁾. Cerebrospinal fluid examination revealed pleocytosis (57 cells/μL, 96% lymphocytes) ⁷⁾.
• Influenza vaccine-associated Vogt-Koyanagi-Harada disease: A case has been reported in a 30-year-old Filipino man positive for HLA-DR4 who developed the disease 2 days after influenza vaccination, with molecular mimicry or immune response to the adjuvant considered as possible mechanisms⁸⁾. He had previously experienced vision loss for one week after receiving the same vaccine⁸⁾.
• HPV vaccine-associated Harada-like uveitis: A case has been reported in which a patient developed bilateral vision loss, choroidal thickening, and macular edema 10 days after the third dose of the quadrivalent HPV vaccine, which resolved spontaneously without systemic steroids⁶⁾. Molecular mimicry-induced inflammatory autoimmune reaction to vaccine components has been suggested⁶⁾.
• Epstein-Barr virus and cytomegalovirus: These viral infections may act as triggers in genetically susceptible individuals⁹⁾.

Daily care and precautions

Harada disease is an autoimmune disease. Currently, there is no definitive prevention method. However, it is important to pay attention to the following points.

• If symptoms such as vision loss, eye pain, headache, or tinnitus appear suddenly, please see an ophthalmologist immediately.
• If you have been diagnosed with Harada disease, we recommend consulting your ophthalmologist or primary care physician before receiving a vaccination.
• Do not reduce or discontinue your medication on your own while undergoing steroid treatment. This increases the risk of recurrence.

4. Diagnosis and Examination Methods

Diagnostic Criteria

The revised diagnostic criteria established by the International Vogt-Koyanagi-Harada Disease Committee in 2001 are still used today.

Type	Criteria
Complete type	Meets all criteria 1 to 5
Incomplete type	Meets criteria 1 to 3 and either 4 or 5
Suspected case (ocular-only type)	Meets only criteria 1–3

Criterion 1: No history of penetrating ocular trauma or surgery before onset of uveitis Criterion 2: No clinical or laboratory evidence suggesting other diseases Criterion 3: Bilateral ocular lesions (early: serous retinal detachment, diffuse choroiditis; late: sunset glow fundus, Sugiura sign, etc.) Criterion 4: Neurological and auditory findings (meningeal irritation, tinnitus, cerebrospinal fluid pleocytosis) Criterion 5: Skin findings (alopecia, poliosis, vitiligo) — do not appear before onset of ocular disease

Imaging and functional tests

• Fluorescein fundus angiography (FFA): In the acute phase, delayed choroidal filling followed by multiple pinpoint leaks → late-phase dye pooling into serous detachment. In the chronic phase, “moth-eaten” pigment changes.
• Indocyanine green angiography (ICG): In the early to mid phase, hypofluorescent dark spots at the posterior pole (more numerous than FFA findings). In the active phase, late-phase hypofluorescence replaced by hyperfluorescence. Useful for confirming diagnosis and evaluating treatment response⁵⁾.
• Optical coherence tomography (OCT): Depicts subretinal fluid, multiloculated septa, and marked choroidal thickening. Essential for early diagnosis of Vogt-Koyanagi-Harada disease. Quantitative assessment of choroidal thickness using EDI-OCT is useful⁹⁾.
• Ultrasound (B-scan): Confirms diffuse choroidal thickening, serous retinal detachment, and absence of posterior scleritis (to differentiate from posterior scleritis).
• Full-field electroretinography (ERG): Diffuse amplitude reduction in both scotopic and photopic phases during the chronic phase. Used to evaluate retinal dysfunction.
• Cerebrospinal fluid (CSF) examination: Early pleocytosis (lasting up to 8 weeks) and elevated protein. Important for excluding infection and confirming diagnosis.
• HLA class II testing: Approximately 80% of Japanese patients with Harada disease are HLA-DR4 positive. However, about 25% of healthy Japanese individuals are also HLA-DR4 positive, so specificity is low.

Differential Diagnosis

The main diseases to be differentiated are listed below.

• Sympathetic ophthalmia: The presence or absence of a history of penetrating ocular trauma or intraocular surgery is decisive.
• Posterior scleritis: Confirm T-sign on ultrasound.
• Ocular syphilis: Can present with ocular and systemic findings very similar to Vogt-Koyanagi-Harada disease. RPR, FTA-ABS, and CSF VDRL testing are mandatory before starting steroids ³⁾. Cases have been reported where steroids were administered for VKH-like symptoms and later diagnosed as syphilis ³⁾.
• Sarcoidosis, intraocular lymphoma, posterior scleritis, idiopathic uveal effusion syndrome, acute posterior multifocal placoid pigment epitheliopathy, and others are also considered in the differential diagnosis.

Q Why is syphilis testing necessary for diagnosing Harada disease?

A

Ocular syphilis can present with almost the same syndrome as Harada disease, including uveitis, retinal detachment, tinnitus, and headache³⁾. Since administering steroids for syphilis can worsen the condition, serum syphilis tests (RPR, FTA-ABS) and cerebrospinal fluid tests (VDRL) must be performed before starting steroids³⁾.

5. Standard treatment

The treatment goal for Vogt-Koyanagi-Harada disease is rapid suppression of acute inflammation and prevention of transition to the chronic recurrent phase. Early and sufficient steroid therapy is key to not missing the “window of opportunity” for treatment ⁵⁾.

Systemic steroid therapy (first-line treatment)

Acute phase: Steroid pulse therapy

In fresh cases early after onset, high-dose intravenous steroid therapy (pulse therapy) is common. Methylprednisolone (mPSL) 500–1,000 mg/day or dexamethasone 100 mg/day is infused intravenously over 1–3 hours for 3 days. This is performed after confirming the absence of systemic infection or contraindications. It may also be indicated during pregnancy, but non-fluorinated steroids (mPSL, prednisolone) are preferred over fluorinated steroids (dexamethasone, betamethasone) which have higher placental transfer ⁹⁾.

Tapering phase: Long-term oral steroid administration

After pulse therapy or from the acute phase, oral prednisone/prednisolone is started at 1–1.5 mg/kg/day (maximum 100–200 mg/day)⁹⁾. After maintaining the initial dose for 2–4 weeks, it is tapered very slowly and discontinued over 6 months or more.

A standard prescription example is shown below.

Period	Dose
2 days each	200 mg → 150 mg → 100 mg → 80 mg/day
4 days	60 mg/day
10 days	40 mg/day
2 weeks	30 mg/day
Every 4 weeks	20 mg → 15 mg → 10 mg → 5 mg/day
Final 4 weeks	5 mg/day every other day

Regarding the relationship between treatment duration and recurrence, it has been reported that patients who received treatment for less than 6 months had a significantly higher recurrence rate of 58.8% compared to those treated for 6 months or more (recurrence rate 11.1%)⁴⁾.

Immunosuppressive drugs (steroid-sparing therapy and recurrence prevention)

A systematic review of steroid monotherapy reported that 44% of patients experienced recurrence and 59% developed sunset glow fundus⁵⁾, indicating that long-term addition of immunosuppressive therapy is often necessary.

• Cyclosporine A: Neoral 3 mg/kg/day (for a body weight of 60 kg, 180 mg/day in two divided doses). Regular monitoring of trough levels (minimum blood concentration) is essential. Monitor renal function, liver function, and blood pressure.
• Methotrexate (MTX): 25 mg orally or by injection once weekly. Its steroid-sparing effect is established⁵⁾.
• Mycophenolate mofetil (MMF): 1.5 g twice daily orally (3 g/day). In a prospective study of MMF combined with steroids, 93% of eyes maintained 20/20 vision at a mean follow-up of 37 months, and recurrent anterior uveitis and progression of sunset glow fundus were suppressed in all patients⁵⁾.
• Azathioprine: 1–2.5 mg/kg/day.

In a subanalysis of the FAST Uveitis Trial for non-infectious uveitis (including 93 cases of Vogt-Koyanagi-Harada disease, total 216 cases), the treatment success rates (steroid-sparing inflammatory control at 6 months) were comparable between MTX and MMF. Some analyses indicate that MTX achieved steroid-sparing control in 74% and MMF in 53% at 6 months⁵⁾.

Local Treatment

At the time of recurrence, anterior segment inflammation is often predominant, making local therapy important.

• Steroid eye drops: Rinderon 0.1% eye drops 3 times daily
• Mydriatic eye drops: Mydrin P eye drops once daily (to prevent posterior synechiae)
• Intravitreal triamcinolone injection: May be used as an adjunct to systemic steroid therapy⁸⁾.

Biologic agents (refractory/recurrent cases)

• Infliximab: A TNF-α inhibitor. Reports indicate efficacy in corticosteroid-resistant refractory cases¹⁾.
• Adalimumab: Also a TNF-α inhibitor. Used for refractory cases¹⁾.
• Rituximab: A B-cell depleting agent. Reports exist for use in refractory/recurrent cases.

Precautions and side effects in treatment

• Abrupt discontinuation of steroids can lead to withdrawal syndrome (inflammation relapse, adrenal insufficiency), so absolutely avoid self-judgment dose reduction or discontinuation.
• Be aware of side effects associated with long-term steroid administration (diabetes, hypertension, osteoporosis, peptic ulcer, psychiatric symptoms, steroid cataract, steroid glaucoma), and perform blood and urine tests before treatment.
• MTX and MMF are not FDA-approved (off-label for uveitis), which may cause insurance coverage issues.
• Cyclosporine requires caution regarding susceptibility to infections, renal dysfunction, and hepatic dysfunction, and regular trough level monitoring is necessary.
• During pregnancy, many immunosuppressive drugs are teratogenic, so collaboration with obstetrics and rheumatology departments is essential ⁹⁾.

Q How long does the treatment period last?

A

Steroid administration should be tapered over at least 6 months. The recurrence rate when discontinued within less than 6 months is 58.8%, which is significantly higher than the 11.1% rate when continued for 6 months or more ⁴⁾. When immunosuppressive drugs are added, longer-term continuation is often necessary.

6. Pathophysiology and Detailed Pathogenesis

T Cell-Mediated Autoimmune Reaction

The core pathogenesis of Harada disease is a Th1 and Th17 cell-mediated autoimmune reaction targeting melanocyte-associated antigens (such as tyrosinase, tyrosinase-related protein, and 75 kDa protein) ¹⁾. In individuals with genetic susceptibility (e.g., HLA-DRB1*0405), environmental triggers such as viral infection are thought to initiate the process ²⁾.

Histopathological Features

In the acute phase, granulomatous inflammation extends throughout the full thickness of the choroid. Diffuse lymphocytic infiltration with clusters of epithelioid cells and multinucleated giant cells is observed. Granulomas formed between the retinal pigment epithelium and Bruch’s membrane are known as Dalen-Fuchs nodules, which are relatively specific pathological findings in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Immunohistochemically, uveal infiltration consisting of T cells and HLA-DR-positive macrophages is demonstrated, and non-dendritic CD1-positive cells are present near choroidal melanocytes. In the chronic phase, the inflammation transitions to non-granulomatous type.

Pathophysiology of Each Disease Stage

• Prodromal stage: Viremia-like reaction and inflammatory spread to the meninges. Headache and nausea due to increased intracranial pressure occur.
• Uveitic phase: Choroidal thickening due to diffuse T-cell infiltration of the choroidal stroma and retinal pigment epithelium damage. Serous fluid accumulates in the subretinal space due to impaired or disrupted retinal pigment epithelium pump function, leading to serous retinal detachment.
• Chronic phase: Destruction and reduction of melanocytes cause choroidal depigmentation, resulting in a sunset glow fundus. Residual retinal pigment epithelium degeneration creates a “moth-eaten” appearance.
• Recurrent phase: Recurrent granulomatous inflammation in the depigmented choroidal stroma. Inflammation becomes predominant in the anterior segment, forming Koeppe nodules, mutton-fat keratic precipitates, and posterior synechiae. Choroidal neovascularization often occurs during this phase⁴⁾.

Mechanism of vaccine-associated Harada disease

Regarding the onset of Vogt-Koyanagi-Harada disease after vaccination, proposed mechanisms include molecular mimicry between vaccine peptides and choroidal self-peptides, immune complex deposition due to delayed-type hypersensitivity, and immune reactions to adjuvants (such as aluminum salts)⁸⁾. In mRNA vaccines, viral proteins may be detected in the blood 1 to 5 days after vaccination⁷⁾, and it is speculated that this may enhance pre-existing autoimmune activation⁷⁾.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

Methotrexate vs MMF in the FAST Uveitis Trial

The FAST trial (NCT01829295) is a large-scale RCT that randomly compared MTX (25 mg orally once weekly) and MMF (1.5 g twice daily) for non-infectious intermediate, posterior, and panuveitis. In a sub-analysis of 93 VKH disease cases (49 in the MTX group, 44 in the MMF group), acute Harada disease showed greater visual improvement and foveal thickness reduction with MMF (both P<.05)⁵⁾. However, there was no statistically significant difference in treatment success rates between the two groups, and MTX and MMF were considered to have equivalent efficacy as steroid-sparing immunosuppressive agents⁵⁾.

Prospects for Biologics

The use of infliximab, adalimumab, and rituximab for refractory and recurrent cases is accumulating¹⁾. However, large-scale RCT data are scarce, and their indication for Harada disease has not been established. Reports indicate that decreased function of CD4⁺CD25⁺ regulatory T cells (Tregs) correlates with disease activity in Harada disease¹⁾, and Treg-enhancing therapy is attracting attention as a future research target.

Update of Diagnostic Criteria

Several groups have successively proposed new diagnostic criteria incorporating optical coherence tomography (OCT) and ICG angiography, stratified by early and late stages⁵⁾. Standardization of VKH-specific OCT biomarkers (e.g., hyperreflective foci, quantitative choroidal thickness) is still in the research phase.

Management of VKH During Pregnancy

Reports on VKH management during pregnancy indicate that steroid pulse therapy for VKH disease in the third trimester, followed by a tapering course of oral prednisolone over 1.5 months or more, is safe and effective, with most patients showing no recurrence of uveitis after delivery ⁹⁾. However, because many immunosuppressive drugs are teratogenic, treatment options during pregnancy are limited, and individualized management by a multidisciplinary team is necessary ⁹⁾.

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8. References

1. Hussain A, Khurana R. Vogt-Koyanagi-Harada Syndrome: A Diagnostic Conundrum. Cureus. 2021;13(12):e20138. doi:10.7759/cureus.20138

2. Yepez JB, Murati FA, Petitto M, et al. Vogt-Koyanagi-Harada Disease Following COVID-19 Infection. Case Rep Ophthalmol. 2021;12:804-808. doi:10.1159/000518834

3. Abdelnabi M, Rimu A, Siddiqui S, Mora B, Guerin C. Ocular syphilis mimicking Vogt-Koyanagi-Harada syndrome: a diagnostic dilemma. Proc (Bayl Univ Med Cent). 2023;36(3):380-382. doi:10.1080/08998280.2023.2187184

4. Tayal A, Daigavane S, Gupta N. Vogt-Koyanagi-Harada Disease: A Narrative Review. Cureus. 2024;16(4):e58867. doi:10.7759/cureus.58867

5. Acharya NR, Rathinam SR, Thundikandy R, et al. Outcomes in Patients With Vogt-Koyanagi-Harada Disease From the First-Line Antimetabolites for Steroid-Sparing Treatment Uveitis Trial. Am J Ophthalmol. 2024;267:100-111. doi:10.1016/j.ajo.2024.06.004. PMID:38909740.

6. Kong K, Ding X, Ni Y. Resolution of Harada disease-like uveitis after quadrivalent human papillomavirus vaccination: a case report. Hum Vaccin Immunother. 2022;18(1):e1953349. doi:10.1080/21645515.2021.1953349

7. De Domingo B, López M, Lopez-Valladares M, et al. Vogt-Koyanagi-Harada Disease Exacerbation Associated with COVID-19 Vaccine. Cells. 2022;11:1012. doi:10.3390/cells11061012

8. Murtaza F, Pereira A, Mandelcorn MS, Kaplan AJ. Vogt-Koyanagi-Harada disease following influenza vaccination. Am J Ophthalmol Case Rep. 2022;26:101516. doi:10.1016/j.ajoc.2022.101516

9. Sundararaju U, Subramanian S, Rajakumar HK. Steroid pulse therapy for VKH during pregnancy: a safe and effective option? Orphanet J Rare Dis. 2025;20:366. doi:10.1186/s13023-025-03916-9