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Vogt–Koyanagi–Harada syndrome: a rheumatologic perspective
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.
... 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. ...
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.
... Thus, perhaps the true effi cacy of infl iximab is still unclear; we have found no controlled studies that have investigated the use of infl iximab as the primary treatment for AISNHL, although there have been several reports on its use for various conditions in which hearing was discussed. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] There have also been a few interesting reports suggesting the value of intratympanic administration of infl iximab. [40][41][42] To better evaluate infl iximab as a treatment option for AISNHL, a large, double-blind, placebo-controlled study is needed. ...
We conducted a retrospective study to assess the effects of infliximab, a chimeric monoclonal antibody, on hearing in patients with autoimmune sensorineural hearing loss who had previously not responded to steroid therapy and/or treatment with other immunosuppressive drugs such as methotrexate and cyclophosphamide. We reviewed the records of 8 such patients. Our objective measures of outcome were pure-tone averages at 500, 1,000, 2,000, and 3,000 Hz and speech discrimination scores. At the completion of treatment, no patient exhibited a positive response to infliximab therapy by objective measurements, and only 1 patient (12.5%) reported subjective improvement.
We report the case of a deliberate application of cyanoacrylate adhesive (commonly called "superglue") to the nose of a 9-year-old boy during a fight. The glue was successfully removed under general anesthesia without causing trauma to the nasal mucosa. To the best of our knowledge, only 1 other case of cyanoacrylate injury to the nasal cavity has been published in the literature. We also provide an algorithm to guide clinicians in the future management of this unusual circumstance.
To review current advances in the diagnosis and therapy of Vogt-Koyanagi-Harada (VKH) disease.
A new T-cell subset (Th17) may play an important role in the initiation and maintenance of inflammatory disease when stimulated by the interleukin (IL)-23, thus producing IL-17. Recent developments of new imaging techniques, such as high-resolution optical coherence tomography 3 scanner (OCT3), have allowed greater accuracy in VKH disease diagnosis. The OCT3 examinations have shown that cystoid spaces appear in the neurosensory layer (between the inner and outer segments of photoreceptors) and not in the subretinal space. This structural finding was also supported by functional studies with multifocal electroretinography that measured the photoreceptors activity. Antimetabolites (azathioprine, mycophenolate mofetil and methotrexate), T-cell inhibitors (cyclosporine and tacrolimus) and biologic agents, associated with the well known glucocorticosteroids therapy, showed good results in acute and chronic phases of the disease. Intravitreal triamcinolone and bevacizumab were reported to have encouraging results for progressive or stubborn cases of VKH disease.
To uphold visual acuity, an early, fast and accurate diagnosis is necessary, followed by an aggressive and lengthy immunosuppressive treatment.
Ultrasound biomicroscopy (UBM) is reported to be useful for the evaluation of the anterior chamber, chamber angle, and ciliary body. However, a UBM examination is diffi cult and invasive for the patient. The new Visante (Carl Zeiss Meditec, Oberkochen, Germany) imaging system using anterior segment optical coherence tomography (AS-OCT) makes it possible to visualize the anterior segment noninvasively to obtain quantitative information. We report a patient with acute angle-closure glaucoma associated with Vogt-Koyanagi-Harada (VKH) disease in whom imaging with AS-OCT was carried out to evaluate the anterior segment.
This volume covers many topics in the field of T-cell costimulation. The need for such a volume is testament to the growth of the field. From its beginning as a concept in the 1980s, we have now progressed to the point where many molecules now have functionally defined roles in T-cell costimulation. In addition, the field has progressed 'from bench to bedside'. Abatacept [cytotoxic T-lymphocyte antigen-4 (CTLA-4)-immunoglobulin (Ig) (CTLA-4-Ig)], an inhibitor of CD28-mediated T-cell costimulation, was approved for the treatment of moderate-to-severe rheumatoid arthritis in 2006 by the Food and Drug Administration and in 2007 by the European Medicines Agency. This chapter first presents a personal historical perspective on the early basic studies on the elucidation of the CD28/B7 T-cell costimulatory pathway and the discovery of CTLA-4-Ig. We next present an overview of studies of CTLA-4-Ig in preclinical animal studies. The material discussed in these first two sections is selective rather than exhaustive; their purpose is to provide context for the final section, a summary of human clinical studies performed with abatacept.
Ustekinumab is a fully human monoclonal antibody that binds with high specificity and affinity to the cytokines interleukin (IL)-12 and IL-23, thereby suppressing IL-12- and IL-23-mediated inflammation associated with psoriasis. In two large, phase III trials in patients with moderate to severe plaque psoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients (administered as two injections 4 weeks apart) than placebo recipients achieved a 75% improvement on the Psoriasis Area and Severity Index (PASI 75) score at 12 weeks. Other efficacy measures, including the physician's global assessment of clinical response at week 12, also favored ustekinumab over placebo. Psoriatic symptom control was maintained during ustekinumab maintenance therapy (administered once every 12 weeks) for up to 76 weeks. In a phase II trial in patients with active plaque psoriasis and psoriatic arthritis, signs and symptoms of arthritis and psoriatic symptom control were improved to a greater extent with ustekinumab than with placebo at 12 weeks, based on the proportion of patients achieving a 20% improvement in American College of Rheumatology response criteria (arthritis) or PASI 75 (skin symptoms). Health-related quality of life, assessed using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index, was improved to a significantly greater extent with ustekinumab than with placebo at week 12. Subcutaneous ustekinumab was generally well tolerated in clinical trials, with most treatment-emergent adverse events being of mild severity.
To report three cases of presumed Vogt-Koyanagi-Harada (VKH) disease with unilateral ocular manifestations.
This retrospective study reviewed the long-term follow-up observations of three patients who attended the uveitis clinic at Tokyo Medical University Hospital. The patients were followed for 5-16 years with systemic clinical, ophthalmologic and laboratory examinations. Ophthalmoscopic findings, extraocular manifestations, visual acuity, and response to corticosteroid administration were evaluated.
Three patients had characteristic clinical features of VKH involving only one eye, including diffuse choroiditis, serous retinal detachment, focal areas of delayed choroidal perfusion, multifocal areas of pinpoint leakage, macular oedema, and optic nerve staining. All patients received systemic corticosteroid therapy during the acute phase of the disease. During the follow-up period (5-16 years), all three patients developed sunset-glow fundus and nummular chorioretinal depigmented scars in the affected eye only, as well as systemic complications of deafness, vitiligo, and poliosis.
The clinical and laboratory features of all three patients were typical of VKH disease except for the unilateral involvement. It is important for ophthalmologists to recognize unilateral VKH disease, even though it is a rare clinical variant of the disease.
Sympathetic ophthalmia (SO) is a rare, bilateral, non-necrotizing, granulomatous uveitis that occurs after ocular trauma or surgical procedures to one eye threatening sight in the fellow eye. The pathophysiology is not clearly understood, but it appears that the disrupted integrity of the inciting eye leads to an autoimmune hypersensitivity reaction against the exposed ocular antigens in the injured eye as well as in the sympathizing eye. More recently, vitreoretinal surgery has been noted to be a risk factor for the development of SO.
Medline search for case reports of sympathetic ophthalmia with links to full text in English yielded articles for review of patient demographics, clinical presentation and examination, therapies and final visual acuity.
Eighty-six patients with SO were included in this review. Sixty-two patients were male and 24 were female with an average age of 46 years. Injuries accounted for 47% of patients while ocular surgery was reported in 44% of patients with pars plana vitrectomy occurring in 21%. Most patients reported reduced vision and presented with uveitis. Ninety-five percent of them received systemic corticosteroid therapy and 75% of patients also received immunomodulators. About 70% of patients had improved visual acuity in their sympathizing eye at their last reported evaluation.
Sympathetic ophthalmia warrants prompt evaluation and treatment to maintain a favorable visual outcome. Ocular surgeries including vitreoretinal surgery and cyclodestructive procedures have been noted to be risk factors for the development of sympathetic ophthalmia. With current medical management including corticosteroids and immunomodulators visual prognosis is relatively good.
We report a brother and a sister with Vogt-Koyanagi-Harada syndrome. The girl had all the manifestations of this condition; her brother was less severely affected. Both showed mental and growth retardation. The literature on this syndrome is reviewed.
Etiological characteristics of endogenous uveitis vary among areas and races around the world. There are few epidemiological reports on the etiology of uveitis from areas within Asia. We report statistical data on uveitis in Japan.
We reviewed all of the records of patients with endogenous uveitis who visited the Uveitis Survey Clinic of Hokkaido University Hospital in 1981 and 1994 and extended the survey to include new patients with uveitis seen over the 3-year period from 1992 to 1994.
Bechcet's disease, sarcoidosis and Vogt-Koy-anagi-Harada disease were the three most frequently diagnosed diseases in both 1981 and 1994. The proportion of patients with unclassified uveitis decreased from 38% to 30% during the 13-year period from 1981 to 1994 as a result of the establishment of new disease categories during this time. Notable additions included human T-lymphotropic virus type 1-associated uveitis and tubuloinerstitial nephritis and uveitis syndrome. Sarcoidosis is now the most frequent endogenous uveitis in our clinic.
Not only does the etiological basis of uveitis vary among ethnic groups but advances in clinical and basic research have changed the diagnostic approach to uveitis, altering the etiological profile over time.
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.
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.
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.
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.
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.
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.