A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing.

Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1ß, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.

Vogt Koyanagi Harada Disease In Paediatric Age Group: Clinical Characteristics, Remission, Recurrences and Complications in Asian Indian Population.

PURPOSE: To describe disease characteristics and outcomes of Vogt-Koyanagi-Harada (VKH) syndrome in paediatric patients. STUDY DESIGN: Retrospective chart analysis. METHODS: A RETROSPECTIVE: Analysis of all patients ≤16 years with VKH syndrome was done. Clinical presentations, complications, recurrences and outcomes in cases of paediatric VKH were reviewed. RESULTS: 72 eyes of 36 patients with a mean age at presentation of 13.7 ± 2.34 years were assessed. Mean duration of symptoms and follow up were 9.88 ± 17.3 weeks and 55 months respectively. Clinical signs at presentation included anterior chamber cells >2+(34/72eyes, 47.2%), granulomatous keratic precipitates (6 eyes, 8.3%), posterior synechiae (35 eyes,48.6%), disc edema (46 eyes, 63.8%), neurosensory retinal detachments (44 eyes, 61.1%) and 'sunset-glow' fundus (9 eyes, 12.5%). Best corrected visual acuity (BCVA) at the time of presentation was 1.3logMAR or a Snellens equivalent of 20/400 which improved to 0.51logMAR (Snellens equivalent of 20/63) at last follow up. Remission was achieved in 61.1% cases. More than half of our patients developed one or more complications. CONCLUSION: VKH in paediatric patients poses a challenge due to a delayed presentation and paediatric VKH patients have a worse visual acuity at the time of presentation as compared to adult age groups. Rates of remission may be low along with high risk of complications and hence there is a need for prolonged immunosuppression.

Rheumatologic manifestations in a cohort of patients with Vogt-Koyanagi-Harada disease.

OBJECTIVES: Vogt-Koyanagi-Harada Disease (VKHD) is a systemic autoimmune disorder characterized by granulomatous panuveitis. Inflammatory rheumatic diseases (IRDs) are among the differential diagnosis of VKHD. However, current knowledge on the rheumatological aspects of VKHD is still limited. We aimed to investigate the prevalence of rheumatic conditions in VKHD patients. METHODS: VKHD patients were included in the study and they were reviewed in terms of the presence of any rheumatological manifestations. RESULTS: There were 18 patients with a female preponderance (83.3%, female). Inflammatory type of peripheral joint pain (11%) and sicca symptoms (33%) were the most common rheumatological findings. The frequency of spondyloarthritis-related features such as inflammatory back pain and HLA-B27 rate was not increased. None of the patients had radiographic sacroiliitis. Anti-nuclear antibody was positive in high titres nearly in 30% of the patients and three patients had antibodies against extractable nuclear antigens. Nailfold capillaroscopy was abnormal in about one-third of the patients. Pathergy test was negative in all cohorts. While angiotensin-converting enzyme was elevated in nearly 20% of the patients, there were no abnormalities on chest X-rays. CONCLUSION: VKHD shares some features with IRDs. The common features were mostly suggestive of connective tissue disease rather than SpA or rheumatoid arthritis.

miRNAs: una nueva mirada de la enfermedad de Vogt-Koyanagi-Harada / miRNAs: a new look at Vogt-Koyanagi-Harada disease

Vogt-Koyanagi-Harada disease (VKH) is an autoimmune multisystemic syndrome that includes bilateral intraocular inflammation, associated with exudative retinal detachments, and systemic manifestations in the auditory, integumentary, and central nervous systems. The frequency of VKH disease in the world is variable, but in Santiago, Chile, it causes approximately 17% of non-infectious uveitis, an incidence 2 to 3-fold greater than in the USA or European countries. The evidence shows that the pathogenesis of VKH would be caused by cell-mediated autoimmunity directed against melanocytes present in the uveal tissue. CD4+ T lymphocytes (especially hyperactivity of Th17 and Th1 cells), B lymphocytes, cytokines (e.g., TGF-ß, IL-2, IL-6, IL-23 and INF-γ) and chemokines appear to play an important role in the development of VKH. Several lines of evidence support that the pathogenesis of uveitis observed in VKH involves an altered pattern of micro-ribonucleic acids (miRNA) expression, driving the loss of immunological tolerance. In this review, we discuss the evidence related to regulation and altered expression of miRNA associated with Vogt-Koyanagi-Harada and other autoimmune diseases. (AU)

Prevalence and causes of clinically detectable uveitic serous retinal detachment.

PURPOSE: To describe the prevalence and causes of clinically detectable uveitic serous retinal detachment (SRD). METHODS: Retrospective chart review of a large clinic-based series. RESULTS: Serous retinal detachment was present in 78 of the 2761 (2.8%) patients. Vogt-Koyanagi-Harada (VKH) disease was the most commonly identified cause (38/78, 48.7%). Less common associated etiologies included toxoplasmic retinochoroiditis (8/78, 10.3%), sarcoidosis (5/78, 6.4%), intraocular lymphoma (4/78, 5.1%), presumed tuberculosis (3/78, 3.8%), and posterior scleritis (2/78, 2.6%). Fifteen patients (19.2%) with uveitic SRD at presentation had no identifiable etiology and were labeled idiopathic or indeterminant. Thirty of the 38 patients with VKH disease (78.9%) had positive neurological and/or integumentary findings, and therefore constituted either complete or incomplete subtypes of the disease. The remaining eight (21.1%) had presumed/ocular VKH disease limited to the eye. CONCLUSION: While VKH disease by far is the most common cause of clinically detectable uveitic SRD, a number of other non-infectious and infectious inflammatory disorders were also associated with this distinctive clinical finding.

Changes in Etiology of Uveitis in a Single Center in Japan.

Purpose: We investigated the changes in etiology of uveitis at the Uveitis Clinic of Tokyo Medical University Hospital in recent years.Methods: Medical records of patients with uveitis diagnosed between 2011 and 2017 (Group A) and between 2001 and 2007 (Group B) were reviewed.Results: 1,587 patients in group A and 1,507 patients in group B were analyzed. For noninfectious uveitis, frequencies of Vogt-Koyanagi-Harada disease, intraocular lymphoma (IOL) and iridocyclitis in young girls increased, while those of sarcoidosis and Behçet's disease decreased in the recent era. For infectious uveitis, herpetic iridocyclitis, ocular toxoplasmosis, ocular syphilis, and bacterial endophthalmitis increased, while acute retinal necrosis and ocular toxocariasis decreased. Unclassified uveitis decreased, whereas infectious uveitis and IOL increased due to the availability of new diagnostic tests.Conclusion: Etiologies of uveitis have changed over the years. Further development of novel tests and diagnostic criteria would increase definitive diagnosis for unclassified uveitis. (147/150 words).

Early phase Vogt-Koyanagi-Harada Disease in Nepalese Elderly woman: A case report.

INTRODUCTION: Vogt-Koyanagi-Harada (VKH) disease is defined as an autoimmune disorder characterized by bilateral granulomatous panuveitis with systemic manifestations, such as tinnitus, vertigo, and meningism caused by melanocyte antigen-reactive T-cells. Majority of VKH patients present at the age between 20 and 50 years. VKH is uncommon in elderly and challenging to manage. VKH is one of the important differential diagnosis of bilateral pan uveitis Case: A 65 year/ female brought with chief complaint of sudden loss of vision in both eyes, headache and hearing problem for 1 month. She didn't give any history of other systemic illness, ocular surgery, ocular trauma, chronic use of medicament. Her visual acuity was hand movement with accurate projection of rays (HM) in both eyes The intraocular pressure (IOP) was 12mmHg in both eye. Slit-lamp bio microscopy revealed features of Pan uveitis in both eye. Systemic work up revealed no any other abnormalities. A diagnosis of early phase VKH was made and treated with intravenous pulse steroid therapy followed by tapering dose of oral steroid along with immunemodulator resulting in a very good visual recovery. CONCLUSION: VKH can present in elderly. immunomodulator should be considered in elderly to prevent side effect of steroid along with recurrence of inflammation.

Evolving spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors results from the WHO's pharmacovigilance database.

PURPOSE: Drug-induced uveitis is a rare but sight-threatening condition. We seek to determine the spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors (ICI). METHODS: Retrospective pharmacovigilance study based on adverse drug reactions reported within VigiBase, the WHO international pharmacovigilance database. We included deduplicated individual case safety reports (ICSRs) reported as 'uveitis' at Preferred Term level according to the Medical Dictionary for Drug Regulatory Activities between 1967 and 04/28/2019. We performed a case/non-case analysis to study if suspected drug-induced uveitis were differentially reported for each suspected treatment compared to the full database. We excluded drugs with potential indication bias. RESULTS: 1404 ICSRs corresponding to 37 drugs had a significant over-reporting signal with a median age of 57 [42-68] years and 45.7% of males. We identified five major groups of treatments: bisphosphonates (26.9%), non-antiviral anti-infectious drugs (25.4%), protein kinase inhibitors (15.5%), ICI (15.0%), and antiviral drugs (11.1%). Severe visual loss was reported in 12.1% of cases. ICI and protein kinase inhibitors were the most recently emerging signals. The time to onset between first infusion and uveitis was significantly different between groups ranging from 5 days [2-19] in the bisphosphonate group to 138.5 [47.25-263.75] in protein kinase inhibitors group (p < 0.0001). Anti-Programmed Cell death 1 represented more than 70% of ICI-induced uveitis. We identified Vogt-Koyanagi-Harada (VKH)-like syndrome as being associated with ICI use. CONCLUSIONS: The spectrum of drug-induced uveitis has changed with the evolution of pharmacopeia and the recent emergence of ICIs. VKH-like syndrome has been reported with ICI and protein kinase inhibitors therapy.

Síndrome de Vogt-Koyanagi-Harada en niños / Vogt-Koyanagi-Harada syndrome in children

Vogt-Koyanagi-Harada (VKH) syndrome is a systemic inflammatory disease that causes chronic and bilateral granulomatous panuveitis, usually described in adults. Objectives: To describe manifestations and complications of VKH in pediatric patients. Methods: Retrospectivedescriptive study upon patients <14 years-old with VKH, attended from January 1985 to July 2010 in three different centers. Results: A total of 17 patients (34 eyes) were studied; 9 (53%) female. The mean age was 10.8 years-old. Among extraocular manifestations; neurological (71%), dermatological (29%) and auditive (24%) signs were observed. Ocular findings included optic-disc involvement (94%), anterior uveitis (79%), choroiditis (77%), serous retinal detachment (71%) and vitritis (71%). Initial visual acuity (VA) was ≤0.05 in 47% of cases and ≥0.6 in 12% of patients. 71% presented complications: glaucoma (20 eyes), sinechiae (10 eyes), maculopathy (6 eyes) cataract (5 eyes) and ptisis bulbi (1 eyes). 35% received only corticosteroids and 65% inmunosupressive drugs. After treatment, 6% had VA ≤0.05 and 59% ≥0.6. Ten patients (59%) recurred: 30% compromising posterior pole, and 50% recurred >3 times. Conclusions: VKH in children is infrequent. It presents with optic-disc involvement and complications of posterior pole. It requires a high degree of suspicion, quick evaluation and early treatment, which include inmunosupressive and extended corticosteroid therapy. Nevertheless, a high rate of recurrence is seen among this group of patients. (AU)

Vogt-Koyangi-Harada en fase crónica y terapia biológica: reporte de cuatro casos / Vogt-Koyanagi-Harada in chronic phase of recurrence and biological therapy: report of four cases

Objetivo: describir cuatro casos de Vogt Koyanagi Harada (VKH), con uveítis en fase crónica de recurrencia y la respuesta a fármacos anti TNF alfa. Diseño: reporte de casos. Métodos: se realizó estudio descriptivo tipo reporte de caso, mediante recolección y análisis de historias clínicas de pacientes adultos de un centro de referencia de enfermedades autoinmunes, que cumplieran criterios diagnósticos de VKH y que estuvieran en tratamiento con terapia biológica para dicha patología. Resultados: en el presente artículo informamos una serie de cuatro casos de VKH, de los cuales todas fueron mujeres entre los 19 y 57 años, en fase crónica y de recurrencia de la enfermedad. En todos los casos existió refractariedad al uso de esteroides a dosis altas y no respuesta a inmunosupresores como ciclosporina y metotrexate, requiriéndose instauración de terapia biológica anti TNF alfa con control de su patología. Conclusiones: En el VKH en fases tardías la respuesta a altas dosis de esteroides y a inmunosupresores convencionales puede ser fallida, ante lo cual el uso de terapia biológica con fármacos anti TNF alfa y anti CD20 es una alternativa factible, requiriéndose aún mayores estudios en este campo que permitan una prescripción eficaz y segura.

Objective: to describe four cases of Vogt Koyanagi Harada (VKH) disease, in chronic and recurrence phase that were treated with anti-TNF biological therapy and their response to this therapy. Design: cases reports. Methods: We performed a descriptive, case report with clinical chart review of adult patients in a center of autoimmune diseases who met diagnostic criteria for VKH and treated with biological therapy. Results: We report four cases of VKH treated in our center of autoimmune diseases, which were all women between 19 and 57 years, in chronic and recurrence phase of disease. In all cases there was refractory to steroid use at high doses and no response to immunosuppressive treatment as cyclosporine and methotrexate, requiring introduction of anti-TNF biological therapy to control their disease. Conclusions: In chronic phases of VKH the response to high doses of steroids and conventional immunosuppressive therapy may be failed, therefore the use of biological therapy with anti-CD20 and anti-TNF alpha is a viable alternative, still requiring further study in this fi eld to enable an eff ective and safe prescription.

Poliosis circumscripta: overview and underlying causes.

Although traditionally known as "white forelock," poliosis circumscripta, defined as a localized patch of white hair in a group of hair follicles, can involve any hairy area on the body including the scalp, eyebrows, and eyelashes. Microscopically, poliosis demonstrates either decreased or absent melanin and/or melanocytes in the hair bulbs of the affected hair follicles. Classically, poliosis is known to occur in the setting of several genetic syndromes including piebaldism, Waardenburg, and tuberous sclerosis. In addition, poliosis has been described in association with various acquired conditions. These include inflammatory conditions, benign and malignant neoplastic entities that are mainly melanocytic, medications, and others. In this review, we aim to describe the different conditions where poliosis may be encountered, with the aim of helping the clinician to better evaluate any patient presenting with poliosis.

[Incidence of uveitis in the northern Kyushu region of Japan --comparison between the periods of 1996-2001 and 2003-2008].

PURPOSE: To report the clinical statistical analysis of patients with uveitis in the northern Kyushu region of Japan. SUBJECTS AND METHODS: This retrospective study involved 735 new patients with uveitis who visited the Kyushu university hospital from January 2003 to December 2008. The subjects were classified into four groups; adolescent (0-19 years), young (20-39 years), middle-aged (40-59 years) and old (60 years or older) and were compared with the results of our previous studies. RESULT: This study comprised 343 men and 392 women. The age averaged 47.2 years. Definitive diagnosis was made in 385 cases (52.4%). The most frequent clinical entity was sarcoidosis (9.8%), followed by Vogt-Koyanagi-Harada disease (7.9%), Behçet's disease (7.6%), acute anterior uveitis associated with human leukocyte antigen (HLA)-B27 (4.5%), herpetic iridocyclitis (3.1%), human T-lymphotropic virus type I associated uveitis (HU) (2.7%), and intraocular lymphoma (2.3%). The proportion of unclassified uveitis was large among females in general, and among adolescents in the four groups. The incidence of secondary glaucoma in the whole group of 735 patients with uveitis was 22.2%. Among the patients with ocular hypertension, the proportion of steroid responders was large in the adolescent group. CONCLUSION: Compared with our previous report, this study shows increasing frequency of sarcoidosis and decreasing frequency of Behçet's disease except in the young group. HU showed a decreasing incidence.

Vogt-koyanagi-harada syndrome.

PURPOSE: Vogt-Koyanagi-Harada syndrome is a bilateral, chronic, diffuse granulomatous panuveitis frequently associated with neurological, auditory, and integumentary manifestations. It is also one of the most common forms of uveitis among pigmented races including Chinese patients. METHODS: This article reviews the current developments of Vogt-Koyanagi-Harada syndrome, including epidemiology, etiology, clinical features, observational techniques, genetics, treatment, and prognosis. RESULTS: Increasing reports have been published to describe the clinical features of Vogt-Koyanagi-Harada syndrome in various ethnic populations from different parts of the world. In spite of tremendous progress in laboratory and clinical research, the etiology of Vogt-Koyanagi-Harada syndrome is still not completely known. Numerous studies indicate an autoimmune nature for this disease. A recent study has shown that Th17, a new subset of T cell, plays an important role in the initiation and maintenance of this disease. Early and aggressive systemic corticosteroids are still the mainstay of initial therapy for Vogt-Koyanagi-Harada syndrome. However, nonsteroid immunomodulatory therapy, including cyclosporine, chlorambucil, cyclophosphamide, and azathioprine have brought out encouraging results. Improved visual outcomes in patients with Vogt-Koyanagi-Harada syndrome in recent years have been reported when compared with decades ago, presumably due to the more aggressive use of immunosuppressive agents. CONCLUSION: Although the prognosis for VKH syndrome was greatly improved, future prospective, controlled, multi-center studies are needed to determine the optimal treatment regime for this disease. The IL17/23 pathway may provide a novel therapeutic target to control inflammation in VKH syndrome.

Neurological concomitants of uveitis.

AIM: To describe the prevalence and types of neurological disease that occur in association with uveitis. METHODS: Retrospective review of medical records of patients attending a tertiary referral uveitis service over a 15 year period. RESULTS: Of 1450 patients with uveitis, 115 (7.9%) had neurological disease that was considered to be causally related to the eye inflammation. The most frequent neurological associations were Vogt-Koyanagi-Harada disease, primary central nervous system lymphoma, multiple sclerosis, and herpes virus infections. CONCLUSIONS: Neurological disease is common among patients attending a uveitis service. The distinctive characteristics of the uveal inflammation may be useful in diagnosing the neurological disease.

Changing patterns of intraocular inflammatory disease in Japan.

PURPOSE: We investigated the frequencies and clinical characteristics of Japanese patients with uveitis. METHODS: Records of 189 patients referred from April 1999 to March 2001 were retrospectively reviewed. RESULTS: Fifty-six patients (29.6%) had anterior uveitis, 13 (6.9%) intermediate uveitis, 59 (31.2%) posterior uveitis, 58 (30.7%) panuveitis, and three (1.6%) papillitis. The most common diagnoses were Vogt-Koyanagi-Harada (VKH) disease (10.1%), biopsy-proven or presumed sarcoidosis (9.5%), acute anterior uveitis (7.9%), tuberculosis (6.9%), and Behçet's disease (5.8%). Seventy-three patients (38.6%) were treated with local therapy alone, and 95 patients (50.3%) required systemic therapy. Ocular complications developed in 19.6% of patients, and systemic complications in 2.1%. CONCLUSIONS: These results confirm a continued high frequency of VKH disease and sarcoidosis, but suggest a decreased frequency of Behçet's disease and an increased frequency of tuberculosis. Roughly one-half of the patients required systemic treatment in addition to local therapy, and ocular and/or systemic complications developed in one-fifth of the patients.

Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada disease is a chronic, granulomatous systemic autoimmune disease with manifestations in the ocular, central nervous, auditory, and integumentary systems. The target of attack seems to be antigens associated with melanocytes. Patients are usually of Asian, Middle Eastern, Asian Indian, Native American, or Hispanic ethnicity, and complain of neurologic symptoms quickly followed by decreased vision caused by a choroiditis, frequently with exudative retinal detachments. Corticosteroids are the mainstay of therapy, but other immunosuppressive therapy may be required. Complications, including cataract, glaucoma, choroidal neovascular membrane formation, and subretinal fibrosis, may limit final visual acuity.

Analysis of 87 cases with Vogt-Koyanagi-Harada disease.

PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is known to have varied manifestations in different ethnic groups. In order to analyze the clinical profile of VKH cases in the Indian population, we studied 87 consecutive cases of VKH disease treated in an uveitis clinic in South India between 1985 and 1996. METHODS: Retrospective analysis and review of charts of consecutive new VKH cases diagnosed in a referral clinic. RESULTS: VKH disease comprised 2.2% of all uveitis referrals. Extraocular symptoms or signs were seen in 64% of cases at the time of presentation. Most common was meningism (95.9%). However, subsequently all patients developed extraocular manifestations. Panuveitis (92%) was the commonest presentation. Systemic corticosteroid was the usual form of therapy (50.3%) followed by immunosuppressive therapy (39%); surgical treatment was needed in 8% of the cases. Complicated cataract (33%) and glaucoma (24%) were major complications. Final vision was between 6/60 and 6/18 in 88% of the cases and 6/18 and better in 15.4%; there was no improvement in 11% of the cases. CONCLUSIONS: VKH disease occurs less frequently in India than in Japan and about as commonly as in the United States. Extraocular signs are far less common than in the Japanese population. Visual prognosis is good in patients presenting within 1 month of onset of symptoms. Immunosuppressive agents and vitreoretinal surgery are needed in advanced cases and in cases reported later. Jpn J Ophthalmol 2000;44:296-301

Síndrome de Vogt Koyanagi Harada / Vogt-Koyanagi-Hada syndrome

El síndrome de Vogt Koyanagi Harada es una uveitis difusa, bilateral, aguda, granulomatosa, asociada a manifestaciones dermatológicas, auditivas y del sistema nervioso central. Es la panuveitis bilateral más frecuentemente encontrada en la población mestiza e indígena mexicana. Una respuesta autoinmune, regulada por factores genéticos y aparentemente dirigada contra los melanocitos parece ser la causa del proceso inflamatorio. El diagnóstico básicamente es clínico, aunque la florangiografía de retina y el estudio ecográfico pueden ayudar a sustentar el diagnóstico básicamente es clínico, aunque la florangiografía de retina y el estudio ecográfico pueden ayudar a sustentar el diagnóstico en algunos casos. En el presente artículo revisamos los conocimientos que en relación a fisiopatogenia, diagnóstico, pronóstico, tratamiento médico y quirúrgico se tienen actualmente

Vogt-Koyanagi-Harada syndrome complicating allogeneic bone marrow transplantation.

Vogt-Koyanagi-Harada (VKH) syndrome is an uncommon acute ophthalmological disorder, characterised by bilateral serous retinal detachment with diffuse choroiditis, in association with specific extra-ocular manifestations. We describe a patient with unequivocal VKH syndrome arising 49 days after matched unrelated donor bone marrow transplantation (BMT) performed as treatment for severe aplastic anaemia. The visual symptoms and retinal changes responded well to corticosteroids. The haematological relevance of VKH syndrome is to distinguish it from retinitis due to cytomegalovirus, which requires different therapy and has a far worse visual prognosis.