Vogt-Koyanagi-Harada Disease

Vogt-Koyanagi-Harada (VKH) disease is a multisystemic autoimmune disorder that affects the eyes, central nervous system, the auditory system, and the integumentary system. An autoimmune reaction against melanocyte-associated antigens in the uvea, meninges, inner ear, skin, and hair results in various manifestations of the disease that may present at different time points during the disease course.^1,2 Four clinical phases of the disease have been described: a) the prodromal phase characterized by neurological and auditory symptoms and lymphocytic pleocytosis in the cerebrospinal fluid; b) the acute uveitic phase characterized by diffuse choroiditis that causes papilledema and exudative retinal detachments and may evolve to panuveitis; c) the convalescent phase with resolution of overt intraocular inflammation but may be associated with smoldering subclinical choroidal inflammation with depigmentation of the fundus and the integumentary changes such as vitiligo, poliosis and alopecia that may appear at this phase when timely and adequate treatment is not administered in the acute uveitic phase; d) the chronic recurrent phase characterized by uncontrolled disease with chronic recurrent granulomatous anterior uveitis and less commonly relapsing exudative retinal detachments.¹ In recent reports, two distinct phases have been defined, the initial-onset acute VKH and the chronically evolving VKH disease.^2–4 The distinction between these two forms has been reported to have diagnostic, therapeutic and prognostic significance.^2–5 In this issue of Ocular Immunology and Inflammation, we included recent studies investigating diagnostic criteria, imaging features, and treatment of VKH disease as well as brief reports of atypical cases.

The diagnosis of VKH disease is based on clinical findings; thus several sets of clinical diagnostic or classification criteria have been developed.^3,6–9 In a case-control study in Chinese patients, Wu and colleagues¹⁰ have compared the performance of three sets of criteria, including the revised diagnostic criteria (RDC) for VKH disease, which was published in 2001 following the First international Workshop on VKH disease,⁶ the Chinese Diagnostic Criteria for VKH disease (CDCV) developed by Yang and colleagues in 2018,⁷ and the Standardization of Uveitis Nomenclature (SUN) Working Group classification criteria (SUN-C) published in 2021.⁸ They reported that the sensitivity of CDCV (92.2%) was significantly higher than the sensitivities of RDC (66.7%) and SUN-C (54.3%) and showed similar results in both early and late stage VKH disease. All three criteria sets had a high specificity without any significant difference between them.¹⁰ It is important to note that the RDC set does not include imaging features other than fluorescein angiography and B-scan ultrasonography findings for early manifestations of the disease; and more importantly, defines disease categories of complete, incomplete, and probable VKH, which does not allow the diagnosis of the definitive “complete” form as these criteria mix acute and chronic signs that never occur together.¹¹ In the SUN-C set, optical coherence tomography (OCT) feature of exudative retinal detachment is included for early-stage VKH, and choroidal involvement in panuveitis is to be confirmed by enhanced depth imaging (EDI) OCT or indocyanine green angiography (ICGA).⁸ While choroidal thickening on EDI-OCT is included as a criterion of early-stage VKH in CDCV set as well, neurologic or auditory manifestations for early-stage VKH or integumentary findings for late-stage VKH, the extraocular manifestations included in both the RDC and SUN-C sets, are not required in CDCV, allowing diagnosis of VKH disease in the absence of these manifestations. In another diagnostic criteria set specifically designed for initial-onset acute VKH disease, diffuse choroiditis evidenced by ICGA and/or EDI-OCT is a sine qua non diagnostic criterion, while neurologic or auditory symptoms are defined as helpful, but not essential, diagnostic features.³

There are two reports in this issue investigating the role of OCT angiography (OCTA) in monitoring VKH disease.^12,13 Ding and colleagues retrospectively analyzed panoramic montage images of five 12 × 12 swept-source OCTA scans of both eyes of 16 patients who received corticosteroid therapy with or without immunosuppressive agents for the treatment of acute VKH disease.¹² At initial visit, while none of the eyes had superficial or deep retinal capillary plexus changes, 93.8% had scattered dark foci in both choriocapillaris and Sattler’s layers which were interpreted as true flow void based on corresponding EDI-OCT and ICGA findings. Follow-up OCTA scans in 30 eyes showed a reduction in dark foci in both layers which was consistent with a decrease in choroidal thickness, but not necessarily with the resolution of subretinal fluid.¹² The authors suggested that the widefield OCTA findings could be helpful in differentiating especially atypical VKH from other entities such as acute posterior multifocal placoid pigment epitheliopathy (APMPPE) which primarily involves the choriocapillaris at the posterior pole. They reported that their results confirmed a previous OCTA study of acute VKH which showed that multiple choriocapillaris flow void foci were reduced after treatment,¹⁴ and suggested that this imaging modality could be used as a noninvasive tool to accurately monitor response to treatment in patients with acute VKH disease.

Ben Aoun and colleagues have also investigated changes in outer retinal layers and choriocapillaris by swept source OCT and OCTA imaging in 21 patients presenting with acute VKH and followed through the convalescent stage at 3, 6, 12, and 24 months without recurrence.¹³ Choriocapillaris flow voids were found in 85.7% at initial exam. The presence of flow voids at months 6, 12, and 24 was significantly associated with poor final visual acuity. Flow voids at months 12 and 24 were also significantly associated with the presence of structural OCT outer retinal layer alterations.¹³ The predictive value of OCTA images showing impairment of choroidal flow at baseline needs to be investigated in larger longitudinal studies.

In a brief report, Fonollosa and colleagues showed that a hyper-reflective band of outer nuclear layer on OCT images in two patients, one with acute VKH disease and the other with acute sympathetic ophthalmia, progressed to complete loss of outer retinal layers and thickening of the retinal pigment epithelium after the resolution of subretinal fluid.¹⁵ In response to this brief report, Ali and colleagues reported that they observed hyper-reflective outer nuclear layer in 31% of eyes and this finding was associated with poor initial visual acuity in VKH patients.¹⁶ Although late fibrosis and ellipsoid layer loss developed more frequently in eyes with an initial hyper-reflective outer nuclear layer than in those without this finding, the difference was not statistically significant. Any clinical significance and predictive value of outer nuclear layer hyper-reflectivity in acute VKH disease remains to be clarified in further studies.

The concept of “therapeutic window of opportunity” has been put forth for initial-onset acute VKH disease, because a prompt diagnosis and early effective treatment are essential in order to prevent a chronic evolution with serious complications and visual impairment.^2,17 The outcome has been reported to depend on the phase of presentation and efficacy of initial treatment, as none of the patients who presented early in the initial-onset acute uveitic phase preceding anterior segment inflammation and treated with combined systemic corticosteroids and immunomodulatory agents as first-line treatment developed sunset glow fundus (SGF) or progressed to chronic recurrent evolution.¹⁸ Fauquier and colleagues have investigated the impact of initial management in a retrospective cohort of 50 VKH patients seen at two referral centers in France.¹⁹ The median interval between ocular symptom onset and initiation of therapy was 14.5 days, ranging from 1 to 197 days. Three patients in their cohort had SGF and 11 had cutaneous manifestations at baseline, indicating that it was a mixed cohort of acute and chronic VKH patients. All patients initially received high-dose corticosteroid therapy, given as intravenous pulses in 92%. Only five patients (10%) received immunosuppressive therapy within 6 months, 56% developed at least one relapse, 44% developed ocular complications during follow-up, and SGF was observed in 14 (28%) patients. The authors found a significant association between relapse and treatment delay of more than 26 days, but no significant association of relapse with the initial number of corticosteroid pulses.¹⁹ These results are consistent with the data reported in VKH cohorts treated with corticosteroid monotherapy or with late introduction of immunosuppressive therapy.^2,17 The rates of chronic recurrent disease and SGF have been reported to be much lower when immunosuppressive agents were used as first line in combination with corticosteroid therapy for initial-onset acute VKH disease.^2,17,18 In response to Fauquier and colleagues’ study, Khairallah and colleagues drew attention to a significant limitation arising from the use of RDC for diagnosis, mixing early and late-stage VKH in clinical cohorts.²⁰

In a Japanese multicenter retrospective study, Nakai and colleagues reported the results of adalimumab therapy in patients with chronic VKH disease who failed conventional treatment with corticosteroids and/or immunosuppressive agents.²¹ The authors reported significant reductions in subfoveal choroidal thickness, ICGA scores, and the mean daily corticosteroid dose at 6 months of adalimumab treatment. Baseline visual acuity was significantly lower in patients with SGF than those without, and there was a significant improvement only in the former group, presumably because visual acuity was better in patients without SGF and it was preserved. The reduction in subfoveal choroidal thickness was not significant in patients with SGF, which was explained by the presence of choroidal atrophy at baseline in that group. Adverse events were reported in 17% and adalimumab therapy had to be discontinued in 8.6% because of reactivation of latent tuberculosis, development of psoriasis, arthritis, or allergic reactions.²¹ While lack of a control group and initiation of adalimumab therapy at variable stages of chronicity were among the limitations of their study, reductions in ICGA scores and corticosteroid dose at six months in both patients with and without SGF suggest the beneficial effect of adalimumab therapy for chronic VKH disease. B cell depleting therapy with the anti-CD20 agent rituximab has been reported to be effective in refractory chronic recurrent uveitis associated with VKH disease, including cases refractory to anti-TNF therapy.^22–24

Souto and colleagues have investigated the health-related and vision-related quality of life in 22 patients with chronic VKH disease who were on long-term immunomodulatory treatment.²⁵ Even though the quality of life scores were worse in VKH patients than in normal controls both at baseline and at 24 months of follow-up, the scores remained stable or improved at 24 months compared to baseline; and the improvement in scores was associated with better visual function, better control of intraocular inflammation and reduced need for treatment.²⁵

There are four brief reports in this issue describing atypical cases of VKH disease. Kumar Menia and colleagues reported on the diagnostic and therapeutic challenges in an elderly woman from India who presented with bilateral panuveitis and bullous retrolental retinal detachment.²⁶ VKH disease is rare in childhood and present diagnostic and therapeutic challenges in pediatric cases. However, the outcome of VKH disease in the pediatric age group has been reported to be as good as the adult disease in children who present early in the acute uveitic phase and receive effective treatment.²⁷ Sadhu and colleagues reported the rare occurrence of VKH disease in a 4-year-old boy and reviewed the ten published cases of VKH disease in pre-school children at 3–5 years of age.²⁸ A confusing febrile illness in the prodromal phase and a missed diagnosis in the acute uveitic phase may result in a late presentation of young children with severe ocular complications and visual impairment as well as widespread integumentary changes associated with chronic VKH disease. Hassan and colleagues reported the extremely rare case of a 2-year-old girl who presented with impaired fixation, severe intraocular inflammation, extensive posterior synechiae and cataract, suggesting onset of uveitis at even an earlier age.²⁹ She was diagnosed both with VKH disease and autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome, a rare genetic disease. The authors reported that they found such a rare association in two other cases in the literature. Despite intensive therapy including adalimumab, the child developed SGF and integumentary changes.²⁹ Tobaigy and colleagues reported reversal of bilateral peripheral iris depigmentation after intensive therapy in two children, 6 and 8 years of age, with chronic VKH disease.³⁰ On the other hand, SGF observed in both cases and skin depigmentation in one of them were not reversible.³⁰

We trust that the research articles and brief reports on VKH disease included in this issue will shed more light on this intriguing disease and inspire authors to continue submitting novel data about this intriguing disease to our journal.