Vogt-Koyanagi-Harada Research Articles

Variants in IL23R-C1orf141 and ADO-ZNF365-EGR2 are associated with susceptibility to Vogt-Koyanagi-Harada disease in Japanese population.

Vogt-Koyanagi-Harada (VKH) disease is a systemic inflammatory disorder that affects pigment cell-containing organs such as the eye (e.g., chronic and/or recurrent granulomatous panuveitis). While the exact etiology and pathogenic mechanism of VKH disease are unclear, HLA-DR4 alleles have been documented to be strongly associated with VKH disease in various ethnic groups. Recently, a genome-wide association study (GWAS) found two new genetic risk factors (IL23R-C1orf141 and ADO-ZNF365-EGR2) in a non-HLA region from a Han Chinese population. In this study, we replicated these GWAS findings in a Japanese population. A total of 1,643 Japanese samples (380 cases with VKH disease and 1,263 healthy controls) were recruited. We assessed four single nucleotide polymorphisms (SNPs) shown in previous GWAS: rs78377598 and rs117633859 in IL23R-C1orf141, and rs442309 and rs224058 in ADO-ZNF365-EGR2. A significant allelic association with VKH disease was observed for all of the four SNPs (rs78377598: pc = 0.0057; rs117633859: pc = 0.0017; rs442309: pc = 0.021; rs224058: pc = 0.035). In genotypic association analysis, the minor alleles of IL23R-C1orf141 rs78377598 and rs117633859 had the strongest association with disease susceptibility under the additive model (pc = 0.0075 and pc = 0.0026, respectively). The minor alleles of ADO-ZNF365-EGR2 rs442309 and rs224058 were most strongly associated with disease susceptibility under the dominant model (pc = 0.00099 and pc = 0.0023, respectively). The meta-analysis of the current and previous studies found that all of the four SNPs exhibited a significantly strong association with VKH disease (meta-p < 0.00001: rs78377598, meta-odds ratio (OR) = 1.69; rs1176338, meta-OR = 1.82; rs442309, meta-OR = 1.34; rs224058, meta-OR = 1.33). In summary, our study replicated significant associations with VKH disease susceptibility reported in a previous GWAS. Thus, the IL23R-C1orf141 and ADO-ZNF365-EGR2 loci may play important roles in the development of VKH disease through genetic polymorphisms.

Increased Expression of Indoleamine 2,3-Dioxygenase (IDO) in Vogt-Koyanagi-Harada (VKH) Disease May Lead to a Shift of T Cell Responses Toward a Treg Population.

Previous studies have pointed out that indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme initiating tryptophan metabolism, plays a role in the regulation of the immune system. This project was designed to investigate the potential role of IDO in monocyte-derived dendritic cells (moDCs) obtained from active Vogt-Koyanagi-Harada (VKH) disease patients. In this study, we found that the IDO mRNA expression and enzyme activity were increased in active VKH patients as compared with healthy controls and patients in remission. To investigate the role of IDO in immune regulation, an effective inhibitor 1-methyl-L-tryptophan (1-MT) was used to suppress its activity in DCs. The results showed that inhibition of IDO with 1-MT significantly decreased the expression of DC marker CD86. IDO inhibition did not affect the cytokine production of IL-6, IL-1β, TNF-α, IL-10, and TGF-β in DCs. Downregulation of IDO in DCs also led to the reduction of regulatory T (Treg) cells and an increased CD4+ T cell proliferation. Treatment with 1-MT did not affect the phosphorylation of the MAPK pathway in DCs. In general, our study suggests that IDO may play an important role in the pathogenesis of VKH disease by regulating DC and CD4+ T cell function. Tryptophan deficiency and kynurenine accumulation may account for the complicated effects of IDO. Further research is needed to study the precise tryptophan metabolites that may limit immune responses in VKH disease.

Plasma metabolomics study of Vogt-Koyanagi-Harada disease identifies potential diagnostic biomarkers

Vogt-Koyanagi-Harada (VKH) disease is a common type of uveitis in China, but the diagnosis criteria of VKH disease is controversial. The aim of this study was to investigate potential diagnostic plasma biomarkers for VKH disease. A case-control study including 55 VKH patients (28 active patients and 27 inactive VKH patients) and 30 healthy controls in a tertiary referral center was performed. The metabolic phenotype of VKH patients showed a significant difference compared to healthy controls. Fifteen differentially expressed metabolites (DEMs) were identified between active VKH patients and healthy controls and nine DEMs were found between inactive VKH patients and healthy controls after controlling variable importance in the projection (VIP) value > 1 and false discovery rate (FDR) < 0.05. D-mannose, stearic acid and L-lysine were shown to be potential diagnostic biomarkers which can discriminate active VKH patients from healthy controls with a diagnostic performance with AUC = 0.965, 0.936 and 0.910 respectively in independent diagnosis and an AUC = 0.999 when combined. Sarcosine was recognized as an independent potential biomarker which could distinguish inactive VKH patients from healthy controls. This study reveals a significant difference of plasma metabolic phenotype and identifies diagnostic biomarkers for VKH disease. Changes in the metabolic profile may provide clues towards the pathophysiology of VKH disease.

Vogt-Koyanagi-Harada disease: recurrence rates after initial-onset disease differ according to treatment modality and geographic area.

Literature was reviewed for studies on the evolution of initial-onset VKH disease, looking at treatment modalities and proportion of cases with chronic evolution and/or sunset-glow fundus (SGF). PubMed search yielded 1249 references containing the term of Vogt-Koyanagi-Harada. Twenty references (15 from outside of Japan and 5 from Japan) contained information on the evolution of treated initial-onset disease. For the "international" group, percentage of chronic evolution after systemic corticosteroid monotherapy was 61%, and after combined steroidal and non-steroidal therapy it fell to 2% (0% in 3/4 studies). In the Japanese studies where all patients received systemic corticosteroids alone, chronic evolution was reported in 25%; however, SGF amounted to 61%. In the world at large, chronic evolution of initial-onset VKH disease treated with corticosteroids alone concerned two-thirds of patients. Japanese studies showed that chronic evolution was substantially less frequent, indicating possibly less severe disease in Japan. This proportion fell to almost zero when dual steroidal and non-steroidal immunosuppression was given at onset.

Retinal Microcirculation Defects on OCTA Correlate with Active Inflammation and Vision in Vogt–Koyanagi–Harada Disease

ABSTRACT Purpose: To analyze quantitative OCT-angiography (OCTA) measurements of Vogt-Koyanagi-Harada (VKH) disease at different disease stages. Methods: OCTA scans of 110 VKH patients in acute uveitic, convalescent and chronic recurrent stage were reviewed; posterior uveitis recurrent cases were excluded. Superficial and deep capillary plexus (SCP and DCP) vascular densities (VD) and subfoveal choroidal thickness (SFCT) were compared. Results: DCP VD was significantly lower and SFCT higher in VKH than normal controls (NC) in all 3 stages (all p < .001). Anterior uveitis recurrent patients had lower SCP and DCP VDs and thicker SFCT than convalescent patients (p = .001, p < .001, and p = .003, respectively). DCP VD was significantly correlated with visual acuity (p < .05). Patients with history of anterior recurrence had lower retinal VDs in the convalescent stage than those without (p < .001). Conclusion: Retinal microcirculation is impaired in VKH. DCP VD might be a sensitive indicator of inflammatory status and appeared to be well associated with visual outcome.

The Rs12569232 SNP Association with Vogt-Koyanagi-Harada Disease and Behcet’s Disease is Probably Mediated by Regulation of Linc00467 Expression

ABSTRACT Purpose: To investigate whether the rs12569232 SNP association with Vogt-Koyanagi-Harada disease and Behcet’s disease is mediated by regulation of Linc00467 expression. Methods: The expression of linc00467 was detected by real-time PCR. Adenovirus carrying the linc00467 was transduced into CD4+T cells and the effect on cell viability was measured by the CCK-8 test. Human proteome microarray and starBase 2.0 were used to identify the binding proteins of linc00467 and RNA Immunoprecipitation (RIP) was used to confirm the identity of bound proteins. Results: The rs12569232 was associated with the expression of linc00467. The expression of linc00467 was up-regulated in PBMCs and CD4+T cells from VKH disease and BD patients. Over-expression of linc00467 increased cell viability of CD4+T cells. HUR was the common binding protein identified by the two methods and confirmed by RIP. Conclusions: The rs12569232 association with VKH disease and BD may be mediated via regulating the expression of linc00467.

Assessment of macular capillary perfusion in patients with inactive Vogt-Koyanagi-Harada disease: an optical coherence tomography angiography study.

To assess macular capillary perfusion in patients with inactive Vogt-Koyanagi-Harada (VKH) disease by using optical coherence tomography angiography (OCTA). A total of 51 eyes of 51 patients with inactive VKH (group 1, n = 23) and healthy volunteers (group 2, n = 28) underwent detailed eye examination including OCTA (RTVue-XR Avanti) scanning. OCTA images (6 × 6mm) were assessed for central retinal thickness (CRT), subfoveal choroidal thickness (SFCT), vessel densities (VD) in superficial capillary plexus (SCP) and deep capillary plexus (DCP), choriocapillaris (CC) flow area and vessel flow density (VFD), foveal avascular zone (FAZ) area and acircularity index (AI). The mean ages of group 1 (13 female, 10 male) and group 2 (15 female, 13 male) were 39.9 ± 11.8 (range, 24-58) and 38.9 ± 8.5 (range, 29-51) years, respectively (p = 0.773). CRT and SFCT were 218.2 ± 39.4μm and 195.6 ± 28.6μm in group 1, while 243.5 ± 9.7μm and 316.7 ± 20.1μm in group 2, respectively (p < 0.05). VD in SCP and DCP were significantly lower in group 1 (50.6 ± 4.7% vs. 54.3 ± 3.4% and 53.9 ± 3.6% vs. 61.1 ± 2.7% respectively; p < 0.05). FAZ areas were 0.32 ± 0.11mm2 in group 1 and 0.25 ± 0.06mm2 in group 2 (p = 0.046). There was no statistically significant difference between groups regarding AI, CC flow area, and VFD (p > 0.05). There was weak negative correlation between BCVA (logMAR) and parafoveal and perifoveal VD in SCP and DCP of group 1 (p < 0.05). Macular capillary perfusion was significantly reduced both in SCP and DCP in patients with inactive VKH disease.

Identification of Ribosomal Protein S4, Y-Linked 1 as a cyclosporin A plus corticosteroid resistance gene

Combination of corticosteroids (CS) with cyclosporin A (CsA) is widely used in the treatment of autoimmune diseases, autoinflammatory diseases and transplantation rejection. However, some patients fail to respond or develop resistance to the combination regimen. In Vogt-Koyanagi-Harada (VKH) disease model, we performed RNA sequencing (RNA-seq) based transcriptomics, isobaric tags for relative and absolute quantification (iTRAQ) based proteomics and assays in vitro to screen and validate potential resistant molecules. We found that a total of 1697 differentially expressed genes (DEGs) and 21 differentially expressed proteins (DEPs) in CD4+ T cells between CsA & CS-resistant and -sensitive VKH patients. Ribosomal Protein S4, Y-Linked 1 (RPS4Y1) was verified to regulate the resistance of CD4+ T cells from male VKH patients to CsA & CS. Importantly, we showed that chlorambucil (CLB) could reverse the resistance by RPS4Y1 suppression. Taken together, we identify RPS4Y1 as an important CsA & CS resistance gene in VKH disease. Researchers should consider validating the resistant effect of RPS4Y1 in other autoimmune diseases or organ transplantation.

A Case Report: Recurrence of Vogt-Koyanagi-Harada Disease after Rapid Tapering of Corticosteroids

Background: Vogt-Koyanagi-Harada's disease (VKHD) is an autoimmune disorder that targets melanocyte-rich tissues in genetically susceptible individuals. It can affect the eyes, inner ears, skin, hair, and meninges. When VKHD affects the eye, it can cause bilateral granulomatous panuveitis with exudative bullous retinal detachment and is usually associated with meningismus. It may lead to permanent loss of visual acuity. While the pathogenesis remains unknown, viral infection has been implicated. The most accepted theory remains a T-cell mediated autoimmune reaction against one or more antigens associated with melanocytes, melanin, and retinal pigment epithelium (RPE). Case presentation: We report the case of a 17-year-old male patient presenting to our outpatient department for vision loss. The patient reported a 2-week history of hearing loss, tinnitus, and episodic headaches associated with vomiting. Physical examination showed white lashes (poliosis) and a bilateral decrease in visual acuity. Fluorescein angiography showed bullous exudative retinal detachments. The patient was diagnosed with VKHD. His symptoms resolved following a course of oral prednisolone that was initiated at 60 mg per day (1mg/Kg/day), then tapered down over 6 weeks. Six months later, the patient presented again with more pronounced symptoms. His Best Corrected Visual Acuity (BCVA) was lower than it was on his first presentation, and the retinal exam showed a sunset glow fundus and degenerative changes in the RPE. Combined therapy with prednisolone and methotrexate resulted in a complete resolution of symptoms, and his BCVA returned to more than 20/40. Conclusion: This case emphasizes the importance of avoiding the rapid tapering of corticosteroids in VKHD due to the high risk of disease recurrence.

Integrated omics analysis of sweat reveals an aberrant amino acid metabolism pathway in Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disease leading to visual impairment. Its pathogenic mechanisms remain poorly understood. Our purpose was to investigate the distinctive protein and metabolic profiles of sweat in patients with VKH disease. In the present study, proteomics and metabolomics analysis was performed on 60 sweat samples (30VKH patients and 30normal controls) using liquid chromatography tandem mass spectrometry. Parallel reaction monitoring (PRM) analysis was used to validate the results of our omics analysis. In total, we were able to detect 716proteins and 175metabolites. Among them, 116proteins (99decreased and 17increased) were observed to be significantly different in VKH patients when compared to controls. Twenty-one differentially expressed metabolites were identified in VKH patients, of which 18 included choline, L-tryptophan, betaine and L-serine were reduced, while the rest were increased. Our multi-omics strategy reveals an important role for the amino acid metabolic pathway in the pathogenesis of VKH disease. Significant differences in proteins and metabolites were identified in the sweat of VKH patients and, to some extent, an aberrant amino acid metabolism pathway may be a pathogenic factor in the pathogenesis of VKH disease.

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

PurposeDrug-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). MethodsRetrospective 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. Results1404 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. ConclusionsThe 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.

Pseudo-inflammatory manifestations of choroidal lymphoma resembling Vogt-Koyanagi-Harada disease: case report based on multimodal imaging

BackgroundHematologic malignancies occasionally cause serous retinal detachment (SRD); however, its pathogenesis remains unclear. Here we present the imaging characteristics of metastatic choroidal lymphoma masquerading as Vogt-Koyanagi-Harada (VKH) disease.Case presentationA 45-year-old Japanese woman was referred to our clinic because of bilateral SRD with blurred vision. Fluorescein angiography revealed multiple pinpoint leakage followed by pooling OU. Enhanced depth imaging optical coherence tomography showed marked choroidal thickening OU. Laser speckle flowgraphy detected choroidal circulation impairment OU. Although these results totally agreed with the inflammatory manifestations of acute VKH disease, indocyanine green angiography demonstrated various sizes of sharply marginated hypofluorescent lesions that seemed atypical for the finding of VKH disease, i.e., vaguely marginated hypofluorescent small dots. Cerebrospinal fluid pleocytosis was not detected. Blood tests revealed leukocytosis together with elevation of lactate dehydrogenase and soluble interleukin-2 receptor levels. Corticosteroid pulse therapy did not improve any ocular findings. Bone marrow biopsy was then performed, leading to a definite diagnosis of diffuse large B-cell lymphoma. After starting systemic chemotherapy, both SRD and choroidal thickening resolved rapidly with visual recovery. However, choroidal hypoperfusion persisted, which contrasted distinctly with the inflammatory pattern of VKH disease, i.e., the restoration of choroidal blood flow in parallel with normalization of choroidal thickness.ConclusionsOur detailed multimodal observations highlighted the differential imaging features of choroidal lymphoma despite close resemblance to VKH disease especially at the initial stage. Impaired circulation in the thickened choroid marked the pseudo-inflammatory pathogenesis of SRD due to choroidal involvement with neoplastic, but not inflammatory cells.

Clinical and therapeutic features of pediatric Vogt-Koyanagi-Harada disease

To analyze clinical, therapeutic and prognostic features of pediatric Vogt-Koyanagi-Harada (VKH) disease. This retrospective study included 16 eyes of 8 children diagnosed with VKH disease followed at a teaching hospital over a 10 year period. Diagnosis was based on the revised criteria of VKH disease. All data were analyzed using SPSS® software. There were 62.5% girls and 37.5% boys. The mean age (years) was 14.6±4.4. The mean follow-up (months) was 38.7±28.7. The mean initial visual acuity (VA) (LogMAR) was 1.4 with 68.8% of eyes presenting with severe visual loss at admission. The median time (days) required for resorption of the serous retinal detachment was 10 [8.25-25]. Extraocular signs were present in 62.5% of cases. The mean time until initiation of treatment was 25.6 days. 62.5% of patients received corticosteroids alone, and 37.5% of patients received a combination of corticosteroids and immunosuppressive therapy. Final VA was 0.4 [0.1-2.3]. In our study, the time until consultation, low initial VA and recurrences were statistically associated with severe visual loss (P≤0.05). Life expectancy in pediatric cases of VKH disease justifies the early initiation of immunosuppressive treatment or even biological therapy to achieve better steroid sparing and preserve visual function.

Chronological changes of the anterior chamber structure, axial length, and refraction in patients with Vogt–Koyanagi–Harada disease

To clarify the chronological changes in the anterior chamber structure and identify the spherical equivalent and axial length to assess the effects of steroid pulse treatment in patients with Vogt-Koyanagi-Harada disease with active uveitis. The anterior chamber condition, including anterior chamber volume, central anterior chamber depth, peripheral anterior chamber depth, anterior chamber angle, and pupil diameter, was measured using Pentacam, and axial length was measured using IOLMaster in patients with Vogt-Koyanagi-Harada disease between June 2015 and February 2018. Furthermore, the best-corrected visual acuity, spherical equivalent, and retinal foveola thickness were also analyzed. All patients were treated with steroid pulse. All these factors were compared before and at 1 and 6 months of treatment. Significant changes were observed in the anterior chamber volume, central anterior chamber depth, peripheral anterior chamber depth, anterior chamber angle, axial length, best-corrected visual acuity, spherical equivalent, and retinal foveal thickness before and at 1 and 6 months of steroid pulse treatment (P < 0.001, P < 0.001, P < 0.001, P = 0.0015, P = 0.027, P < 0.001, P = 0.0043, and P < 0.001, respectively). No significant difference was observed in the pupil diameter before and at 1 month and 6 months of steroid pulse treatment (P = 0.11). The anterior chamber structure, axial length, best-corrected visual acuity, spherical equivalent, and retinal foveal thickness were dramatically changed by steroid pulse treatment in patients with Vogt-Koyanagi-Harada disease who develop active uveitis. These changes were completed within 1 month.

The Doctor Patient Relationship: A Calculus of Two Languages? A Glimpse at VKH Disease Through the Doctor Patient Relationship

The Doctor Patient Relationship: A Calculus of Two Languages? A Glimpse at VKH Disease Through the Doctor Patient Relationship

The Doctor Patient Relationship: A Calculus of Two Languages? A Glimpse at VKH Disease Through the Doctor Patient Relationship

The Doctor Patient Relationship: A Calculus of Two Languages? A Glimpse at VKH Disease Through the Doctor Patient Relationship

Altered gut microbiome composition in patients with Vogt-Koyanagi-Harada disease

ABSTRACT Background Vogt-Koyanagi-Harada (VKH) disease is a multisystemic autoimmune disorder characterized by granulomatous panuveitis. Gut microbiome has been considered to play a role in the pathogenesis of this disease but whether the alternation of gut microbiome was involved is unclear. This study was set up to identify abnormalities of gut microbiome composition in VKH disease. Results Depleted butyrate-producing bacteria, lactate-producing bacteria and methanogens as well as enriched Gram-negative bacteria were identified in the active VKH patients, as well as in VKH patients of Mix enterotype and Bacteroides enterotype. Changes of gut microbiome in the VKH patients were partially restored after an immunosuppressive treatment. The disease susceptibility genotype HLA-DRA was associated with Bacteroides sp.2.1.33B, Paraprevotella clara, Alistipes finegoldii and Eubacterium eligens. A microbial marker profile including 40 disease-associated species was established to differentiate patients from controls. Another microbial marker profile including 37 species was found to be associated with the response to treatment. An animal experiment showed that transfer of gut microbiome from VKH patients could significantly exacerbate disease activity clinically and pathologically in the recipient mice. Conclusion Our results revealed a distinct gut microbiome signature in VKH patients and showed an exacerbating effect of this gut microbiome on experimental autoimmune uveitis (EAU). We also developed two microbial marker profiles in differentiating VKH patients from healthy controls as well as predicting the effectiveness of treatment.

Distinguishing Microvasculature Features of Vogt-Koyanagi-Harada in Patients in Acute and Convalescent Phases Using Optical Coherence Tomography Angiography

ABSTRACT Purpose: To evaluate retinal and choroidal microvascular features of VKH patients in acute and convalescent phases after treatment using OCTA. Methods: A prospective, observational study was conducted in patients with initial VKH at the acute stage (n = 15) and healthy participants (n = 15) served as controls. After 3-month systemic corticosteroid treatment, patients’ vascular parameters were recorded by OCTA before and after treatment and compared with results observed in healthy participants. Results: Our findings first uncovered that there are two types of abnormalities in the choriocapillary layer of patients with VKH in the acute stage: one is characterized as multiple dark spots of choriocapillary flow void and the other involves highly reflective areas surrounded by light spots with an increased flow area. During the convalescent stage, all eyes showed multifocal dark spots in the choriocapillary layer, leading to a reduced choroidal flow area. Conclusions: OCTA provides a better display of the microvascular appearance of the choroid to noninvasively evaluate choriocapillaris abnormalities in VKH disease.

Tofacitinib in Vogt-Koyanagi-Harada disease

Tofacitinib in Vogt-Koyanagi-Harada disease

Vogt-Koyanagi-Harada (VKH) syndrome: A new perspective for healthcare professionals.

Vogt–Koyanagi–Harada syndrome (VKH syndrome) is a rare granulomatous inflammatory disease that affects the melanin pigment producing melanocytes and mainly affects the pigmented structures such as eyes, ear, skin, meninges, and hair. VKT is an autoimmune disorder, which is mainly a T CD4+ Th1 lymphocyte–mediated aggression to melanocytes, in individuals with a genetic predisposition, in particular, the presence of HLA-DRB1 * 0405 allele. Melanin usually gives color to skin, hair, and eyes. Melanin is also found in the retina, where it plays a role in normal vision. This disease mainly leads to vision and hearing disturbances, followed by dermal problems. The most common symptoms include vitiligo, headaches, hair loss (alopecia), and hearing loss. This article describes the various signs and symptoms of VKH disease and its pathogenesis.