Article

Vogt–Koyanagi–Harada syndrome: a rheumatologic perspective

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Abstract

Vogt–Koyanagi–Harada (VKH) syndrome is an idiopathic systemic inflammatory disorder that affects various melanocyte-containing structures, including the eyes, meninges, inner ear and skin. It classically leads to bilateral chronic granulomatous diffuse uveitis, and its extraocular manifestation can include sensorineural hearing loss, meningitis, and cutaneous findings of vitiligo, poliosis (loss of hair pigment) and alopecia. Ethnicity/racial background and HLA genotype play a strong role in the pathogenesis of VKH syndrome. The inflammatory process is not completely understood, but recent studies have pointed to several potential autoantigen targets, and have also demonstrated the role IL-23 plays in inducing the differentiation of Th17 cells and the subsequent production of IL-17. The success in preserving the vision of VKH syndrome patients hinges on early diagnosis and aggressive treatment that includes immunomodulatory therapy, and as a result ophthalmologists are increasingly referring such patients to rheumatologists for management. It is therefore necessary for the rheumatologists to be familiar with VKH syndrome and its clinical aspects and management. Although the role of biologics in the treatment of VKH syndrome has yet to be investigated, it is possible that such treatments may prove beneficial, given what is currently known about the pathogenesis of the disease.

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... The differential diagnosis of VKH includes the anatomical condition of uveal effusion syndrome; infectious processes such as syphilis, herpes family viruses, toxoplasmosis, tuberculosis, or Lyme disease; malignancies such as leukemia, melanoma, or metastasis; or inflammatory diseases including sarcoidosis, Behcet's disease, and posterior scleritis. [8] The third section of VKH disease is bilateral ocular involvement either early or late occurring. The fourth and fifth components are nonocular presentations of neurological/auditory and integumentary findings such as meningismus, tinnitus, dysacusis, poliosis, vitiligo, and alopecia. ...
... The fourth and fifth components are nonocular presentations of neurological/auditory and integumentary findings such as meningismus, tinnitus, dysacusis, poliosis, vitiligo, and alopecia. [1,8] Four stages are described in VKH disease with ocular involvement mostly in acute and chronic uveitis stage. [8] According to Rao et al., "sunset glow fundus" which means pale choroidal pigmentation and perilimbal vitiligo, known as "Sugiura's sign," belong to the hallmark of chronic stage, while bullous detachment and choroidal thickening account for acute stage when comparing with other non-VKH uveitis. ...
... [1,8] Four stages are described in VKH disease with ocular involvement mostly in acute and chronic uveitis stage. [8] According to Rao et al., "sunset glow fundus" which means pale choroidal pigmentation and perilimbal vitiligo, known as "Sugiura's sign," belong to the hallmark of chronic stage, while bullous detachment and choroidal thickening account for acute stage when comparing with other non-VKH uveitis. [1,2] There is no image-related component mentioned in the revised criteria. ...
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The study aimed to present a case of ocular syphilis mimicking Vogt–Koyanagi–Harada (VKH) disease. This is an observational case report. A 59-year-old female with Sicca syndrome and rheumatoid arthritis presented to the ophthalmologic department with blurred vision of the right eye for 5 days accompanied by color sensation loss in both eyes. Bilateral disc hyperemia and serous retinal detachment at the posterior pole were noted in her both eyes by fundus examination. Fluorescein angiography revealed bilateral late dye leakage from the disc and posterior choroid. Optical coherence tomography showed bilateral subretinal fluid and choroidal thickening. The impression of her condition was VKH disease initially. However, she was later diagnosed with bilateral ocular syphilis with optic neuritis which was proved by laboratory data. After appropriate antimicrobial agent treatment, her best-corrected visual acuity, serous retinal detachment, and disc hyperemia improved. There was no recurrent intraocular inflammation even without systemic steroid or immunosuppressive therapy control during the following 1 year. Ocular syphilis can mimic many other ocular inflammatory diseases including VKH disease. It is necessary to differentiate infectious causes from inflammatory origins due to the substantially different treatment and prognosis.
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Behçet's disease and Vogt-Koyanagi-Harada (VKH) syndrome are characterized by a severe intraocular inflammation with a long course and recurrent episodes. Activated autoreactive lymphocytes are considered to be responsible for the development of this inflammation. These lymphocytes may also be involved in the perpetuation and recurrence of this inflammation if they do not properly go into apoptosis. To investigate this hypothesis, a study was carried out to evaluate the resistance of lymphocytes to apoptosis in these two uveitis entities. Blood samples were obtained from 17 patients with Behçet's disease, 15 patients with VKH syndrome, and 11 healthy individuals. Mononuclear cells were isolated by centrifugation with Ficoll-Paque and cultured in RPMI 1640 with or without phytohemagglutinin (PHA) for 9 h at 37 degrees C in an atmosphere with 5% CO( 2). The obtained cells were incubated with anti-Fas antibody for 8 h at 37 degrees C in an atmosphere with 5% CO(2). The cells were stained with annexin V/propidium iodide and finally subjected to flow cytometry. A significantly lower percentage of apoptotic lymphocytes after PHA stimulation was noted in Behçet's disease (19.7 +/- 4.1%) and VKH syndrome (20.4 +/- 6.9%) than in controls (26.1 +/- 7.3%). The percentage of apoptotic lymphocytes without PHA stimulation also tended to be lower in the patients with Behçet's disease (12.6%) and with VKH syndrome (12.8%) than in controls (14.6%), although the difference was not significant. Lymphocytes in patients with either Behçet's disease or VKH syndrome are relatively resistant to apoptosis mediated by anti-Fas antibody. These apoptosis-resistant, or long-lived, lymphocytes may be involved in the chronic and recurrent intraocular inflammation seen in these patients.
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To report almost simultaneous onset of Vogt-Koyanagi-Harada (VKH) syndrome in co-workers, friends, and neighbors. The onset of VKH syndrome in six patients was examined. Patient 1 and Patient 2 worked in the same room of an office and developed VKH syndrome 3 weeks apart from each other. Patient 3 and patient 4 were friends, lived in the same city, and developed VKH syndrome 1 month apart. Patient 5 and patient 6 lived in the same suburb and developed the syndrome 1 month apart. Almost simultaneous onset of VKH syndrome in co-workers, friends, and neighbors may suggest an exogenous factor such as viral infection in the pathogenesis.
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Vogt-Koyanagi-Harada (VKH) syndrome is a systemic condition characterized by ocular inflammatory disease as well as skin, ear, and meningeal manifestations. Patients with VKH often report tinnitus and hearing loss, but these symptoms tend to be given secondary consideration because most undergo treatment with steroids to prevent blindness resulting from granulomatous uveitis, exudative retinal detachment, and optic nerve inflammation. METHODS/STUDY DESIGN: In the current retrospective review, 24 patients with this syndrome were screened for auditory system abnormalities. All patients denied history of noise exposure or ototoxic agent exposure. The age range of the patients was 13 to 42 years. Three patients reported tinnitus and two patients reported sudden hearing loss. One patient experienced vertigo and aural fullness. Eight of 24 patients had pure-tone thresholds greater than 25 dB hearing loss at two or more frequencies. Five of 24 of these patients experienced hearing loss outside of the 95% confidence interval for published age-matched control populations. There was sloping sensorineural hearing loss at 4 kHz and above in five of 24 patients. All eight patients with hearing loss experienced some degree of hearing loss at 4 kHz or above. Three patients had mild to moderate low-frequency sensorineural hearing loss. There were no tympanometric abnormalities suggestive of conductive involvement. Abnormal acoustic reflex decay was observed in one patient. We conclude that a significant number of patients with VKH experience sensorineural hearing loss and that every patient with VKH should undergo a review of systems for auditory abnormalities and referral for audiologic testing if symptomatic. It is possible that untreated patients may experience worse symptoms.
Article
To determine whether T lymphocytes of patients with Vogt-Koyanagi-Harada (VKH) disease cross-react with peptides of melanocytes and with exogenous antigens. Cross-reactivity with melanocyte peptides, tyrosinase (tyrosinase(450-462): SYLQDSDPDSFQD) and the mimic virus peptide, i.e., cytomegalovirus envelope glycoprotein H (CMV-egH(290-302): SYLKDSDFLDAAL) was examined by a lymphocyte proliferation assay or cytokine production. The seroprevalence of various viruses was examined by a complement fixation test. To examine if the virus infections in VKH patients were latent, we measured genomic DNA of the virus using real-time polymerase chain reaction (PCR). Some of the T cells established from VKH recognized melanocyte peptides including the tyrosinase peptide as well as the CMV-egH(290-302) peptide, which had a high amino acid homology to the tyrosinase peptide. Cytomegalovirus (CMV) peptide-specific T cells showed a significant proliferation not only to CMV-egH(290-302) but also to tyrosinase(450-462). The seroprevalence of CMV was significantly higher in VKH patients. In addition, all tested samples of VKH patients were negative for CMV-DNA. These results indicate that CMV infection may stimulate the production of T cells that cross-react with tyrosinase by a mechanism of molecular mimicry. These events may be responsible for the onset of VKH disease.
Article
To determine the significance of lumbar puncture in diagnosis of Vogt-Koyanagi-Harada disease (VKH). A retrospective analysis was conducted on 116 consecutive patients diagnosed with VKH. Two additional patients who presented with acute VKH were included in the analysis. Demographic characteristics, including gender, age, and ethnicity, were extracted from the medical record. The stage of disease at presentation was documented. Pertinent laboratory results and diagnostic procedures such as lumbar puncture, fluorescein angiography, and echography that contributed to the diagnosis of VKH were collected. Lumbar puncture results for 10 patients were available. Eight of these patients presented with pleocytosis consistent with a diagnosis of VKH. Clinical features and fluorescein angiography confirmed the diagnosis in these patients. Both of the patients who did not exhibit cerebrospinal fluid (CSF) pleocytosis presented with headache, vision loss, and bilateral uveitis. Fluorescein angiography disclosed multiple foci of leakage at the retinal pigment epithelium level with accumulation of dye under the retina and disc leakage, confirming diagnosis of VKH. The utility of lumbar puncture as a diagnostic criterion for VKH should be re-evaluated given that clinical features and fluorescein angiography alone often support the diagnosis. The inherent risks and complications associated with the procedure must prompt the clinician to reserve this evaluation for atypical presentations.
Article
To delineate the historical steps associated with the genesis of the name and the definition of Vogt-Koyanagi-Harada (VKH) disease. A bibliographical review of the major publications that were relevant to the original development of the name of the clinical entity known today as Vogt-Koyanagi-Harada disease, in the historical context of the early 20th century. Three distinct time periods can be considered to be important in terms of providing a historical perspective on VKH disease. Given that the cutaneous manifestations of VKH disease are so characteristic, these could not have been missed even before the actual clinical entity of VKH was recognized in the early 20th century. Indeed, several authors, including the Arabic doctor Mohammad-al-Ghâfiqî in the 12th century as well as Jacobi, Nettelship and Tay in the 19th century, described poliosis, neuralgias and hearing disorders. Many of these cases were probably due to sympathetic ophthalmia, but some were clearly VKH cases. The second phase is characterized by the surge of articles that appeared early in the 20th century that defined the disease more precisely. A number of these authors subsequently became associated with the disease name, the first being Alfred Vogt from Switzerland, followed by Japanese researchers. Yoshizo Koyanagi was in fact not the first Japanese author to describe the disease; this honor goes to the first Japanese Professor of Ophthalmology at the University of Tokyo, Dr. Jujiro Komoto, who published in a German language journal, Klinische Monatsblätter für Augenheilkunde in 1911. Yoshizo Koyanagi published his first report in the Nippon Ganka Gakkai Zasshi 3 years later, in 1914, but it was a much later article, one published in 1929, that definitively associated his name with the disease. In this review article, Koyanagi reported 16 cases, of which six were his own cases, that beautifully illustrate the natural course of the disease. In this same time period, Einosuke Harada, in an article published in Nippon Ganka Gakkai Zasshi in 1926 that was based on several case studies, comprehensively described a syndrome that included (1) a prodromal phase of malaise and meningeal irritation; (2) bilateral uveitis of diverse intensity; (3) bilateral retinal detachments spontaneously resolving; (4) integumentary changes; (5) lymphocytosis of the spinal fluid; (6) dysacousia. It is now accepted that Vogt-Koyanagi disease and the syndrome described by Harada are one entity with a diverse clinical spectrum bearing the universally accepted name of Vogt-Koyanagi-Harada disease. The third phase and most recent phase is characterized by the rapid progress made in terms of knowledge of the physiopathology of the disease, primarily due to the development of immunological methods. The evidence accumulated to date clearly points towards an autoimmune Th1 disease directed against proteins associated with choroidal melanin. Other analytical techniques, such as indocyanine green angiography, have enabled researchers to monitor more closely the primary lesional process at the level of the choroid, and standardized diagnostic criteria have been generated in the recent past. Those who earn scientific merit in clinical medicine are the ones who are able to visualize an overview based on the synthesis of 'new' medical facts that have been made available, usually reported singly by several, unassociated authors concomitantly. This is certainly the case for Yoshizo Koyanagi and Einosuke Harada. Conversely, Alfred Vogt was primarily lucky in that he encountered and subsequently precisely described the first case in the literature.