Proteomic profiling of aqueous humor-derived exosomes in Vogt-Koyanagi-Harada disease and Behcet's uveitis.

Vogt-Koyanagi-Harada (VKH) disease and Behcet's uveitis (BU) are the two major vision-threatening uveitis entities. This study performed the first label-free quantitative proteomics on aqueous humor-derived exosomes from 84 patients with VKH or BU to determine their potential roles. Sixty-five differentially expressed proteins (DEPs) and 40 DEPs were detected in the VKH and BU groups, respectively. GO and KEGG analysis showed that DEPs were mainly enriched in the complement-related pathways. The complement C1q subcomponent subunit B (C1QB) was identified as a key exosomal protein, and its expression was significantly increased by western blotting in both diseases. Additionally, the integrated analysis based on the published scRNA-seq data showed that C1QB-containing exosomes were mainly produced by mononuclear macrophages in the anterior segment tissue. Overall, our proteomic profiling highlights that complement-related pathways may be actively involved in the pathogenesis of these two diseases. These pathways may also serve as treatment targets for both diseases.

Genetic association of PRKCD and CARD9 polymorphisms with Vogt-Koyanagi-Harada disease in the Chinese Han population.

BACKGROUND: Protein kinase C delta (PRKCD) and caspase recruitment domain family member 9 (CARD9) are genes involved in B and T cell activation, and cytokine production, which are vital mechanisms underlying autoimmune disease development. This study aimed to explore the association of the PRKCD and CARD9 genes with Vogt-Koyanagi-Harada disease (VKH) disease. The case-control study was performed to in 912 patients with VKH and 878 normal controls. MassARRAY system, SHEsis online platform, real-time PCR, and enzyme-linked immunosorbent assay were used to detect genotyping, haplotyping, mRNA expression, and cytokine levels, respectively. RESULTS: We found that rs74437127 C allele of PRKCD, rs3812555 CC genotype, and C allele of CARD9 were associated with increased susceptibility of VKH (Pc = 0.020, OR = 1.624; Pc = 2.04 × 10-5, OR = 1.810; Pc = 2.76 × 10-5, OR = 1.698, respectively). However, the rs74437127 T allele, and rs3812555 TC genotype and T allele were linked with decreased susceptibility to VKH (Pc = 0.020, OR = 0.616; Pc = 7.85 × 10-5, OR = 0.559; Pc = 2.76 × 10-5, OR = 0.589, respectively). PRKCD ATG and CARD9 GCTTA haplotypes decreased susceptibility to VKH (Pc = 3.11 × 10-3, OR = 0.594; Pc = 5.00 × 10-3, OR = 0.639, respectively). Functional studies on rs3812555 genotyped individuals revealed that CC carriers had significantly higher CARD9 mRNA expression and tumour necrosis factor-α production than TC/TT carriers (P = 1.00 × 10-4; P = 2.00 × 10-3, respectively). CONCLUSIONS: We found an association between PRKCD rs74437127 and CARD9 rs3812555 polymorphisms and VKH susceptibility and revealed that the increased susceptibility of rs3812555 for VKH may be mediated by regulating CARD9 gene expression and the production of pro-inflammatory cytokines, such as TNF-α.

Vogt-Koyanagi-Harada disease developed during chemotherapy for Hodgkin lymphoma: a case report.

BACKGROUND: Ocular manifestations are known for non-Hodgkin lymphoma, but are rare for Hodgkin lymphoma. We report a case of Vogt-Koyanagi-Harada (VKH) disease presenting as serous retinal detachment and uveitis in both eyes in a child undergoing chemotherapy for Hodgkin lymphoma. CASE PRESENTATION: The patient was a 7-year-old boy with stage IIB Hodgkin lymphoma (nodular lymphocyte predominant type) who was undergoing chemotherapy, including 2 cycles of the OEPA regimen and 1 cycle of the COPDAC regimen. Two days after the end of the COPDAC regimen, the patient complained of headache and of blurred and decreased vision in both eyes. On the basis of optic symptoms, such as uveitis and serous retinal detachment in both eyes, increased cell counts in cerebrospinal fluid, and positivity for human leukocyte antigen (HLA)-DR4 in peripheral blood cells, incomplete VKH disease was diagnosed. Intravenous treatment with high-dose prednisolone (60mg/m2/day) for 7 days improved both visual acuity and serous retinal detachment and enabled the remains of the COPDAC chemotherapy cycle to be administered. With prednisolone treatment, visual acuity improved from 20/500 to 20/20 in the right eye and from 20/63 to 20/25 in the left eye. Because multiple vitiligo lesions later appeared in the abdomen, complete VKH disease was finally diagnosed. CONCLUSION: The onset of VKH disease occurred during chemotherapy for Hodgkin lymphoma. The patient was HLA-DR4-positive and might have had a predisposition to develop autoimmune diseases, including VKH disease. However, the anticancer drugs administered to this patient have not been reported to cause uveitis. Whether Hodgkin lymphoma triggered the development of VKH remains unclear. Early diagnosis of VKH disease and prompt treatment with high-dose prednisone enabled the patient to maintain good visual function despite chemotherapy for Hodgkin lymphoma.

Predictive factors and adalimumab efficacy in managing chronic recurrence Vogt-Koyanagi-Harada disease.

BACKGROUND: This study explores prognostic factors influencing Vogt-Koyanagi-Harada (VKH) disease and observes the efficacy and safety of Adalimumab (ADA) in treating recurrence in Vogt-Koyanagi-Harada (VKH) patients. METHODS: A retrospective study was conducted on all patients diagnosed with VKH disease at Beijing Tongren Hospital between 2020 and 2023. Clinical data included initial and final visual acuity, age, gender, ocular complications, treatment modalities, disease duration, and recurrence frequency. RESULTS: A total of 62 VKH patients were included, comprising 34 in the acute-resolved group and 28 in the chronic-recurrent group. The mean age of patients in the acute-resolved group was 38.29 ± 15.46 years, while the mean age of chronic-recurrent group had a 49.00 ± 16.43 years. Initial best-corrected visual acuity (BCVA) examination at the first visit showed an average BCVA of 0.64 ± 0.29 logMAR in the acute-resolved group and 1.38 ± 0.54 logMAR in the chronic-recurrent group (p = 0.002). During follow-up, ocular complications were observed in 29.4% of the acute-resolved group patients and 41.7% of the chronic-recurrent group patients (P = 0.006). "Sunset glow fundus" was observed in 23.5% of the acute-resolved group and 64.3% of the chronic-recurrent group patients (P = 0.001). Poor initial BCVA (P = 0.046) and the occurrence of "sunset glow fundus" (P = 0.040) were significantly associated with progression to the chronic recurrent phase. Logistic regression analysis revealed that older age at onset (P = 0.042) and the occurrence of "sunset glow fundus" (P = 0.037) were significant predictors for progression to the chronic recurrent phase. ADA significantly reduced anterior chamber inflammatory cells (P = 0.000) and vitreous cavity inflammatory cells (P = 0.001) in the chronic-recurrent group, and markedly decreased the recurrence rate in VKH patients (P = 0.009). CONCLUSION: In comparison to acute-resolved patients, chronic-recurrent patients exhibited poorer initial BCVA and a significantly increased incidence of "sunset glow fundus." Older age at onset and the occurrence of "sunset glow fundus" at diagnosis are crucial predictive factors for VKH patients progressing to the chronic recurrent phase. ADA effectively alleviates refractory VKH disease and is generally well-tolerated.

A case report: co-occurrence of probable Vogt-Koyanagi-Harada disease and diabetic retinopathy.

BACKGROUND: Bilateral retinal detachment and choroidal detachment in a patient are rare occurrences. The presence of bilateral diabetic retinopathy (DR) in such a case is even rarer and complicates the condition. CASE PRESENTATION: In this study, we document a case of unconventional VKH. Manifestations in this patient included intense peripheral retinal detachment and choroidal detachment, along with vitreous opacities akin to cotton wool spots, concurrent with DR. The diagnosis was considered as probable VKH with DR. Treatment according to VKH protocols, including high-dose corticosteroids, yielded positive results. CONCLUSIONS: VKH can co-occurrence with DR. VKH manifestations vary, and early, aggressive, and long-term treatment is essential. The complexity of treatment increases with concurrent DR, necessitating the use of immunosuppressants.

Development of Vogt-Koyanagi-Harada disease-like uveitis during treatment by anti-programmed death-1 antibody: a case report.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.

Uveodermatological syndrome associated with alopecia areata in a one-year-old female spayed Cavalier King Charles Spaniel dog.

Uveodermatological syndrome and alopecia areata are autoimmune disorders causing ocular and dermatological inflammation and alopecia, respectively, in dogs. This is the first report to document concurrent development of the two diseases in a dog, as has been reported in human patients. Clinical presentation and histopathological diagnosis, treatment and clinical follow-up are described.

iPSC-based model of Vogt-Koyanagi-Harada disease for phenotype recapitulation and drug screening.

Vogt-Koyanagi-Harada (VKH) disease, a major blinding eye disease, is characterized by an autoimmune response against melanocytes in multiple organs throughout the body. Currently, the aetiology and pathogenesis of VKH disease are unclear, and the treatment strategy needs to be further optimized. The retinal pigment epithelium (RPE), a monolayer of pigmented cells of the fundus, is essential for maintaining normal visual function and is involved in both the acute and chronic stages of VKH disease. Therefore, the functions of the RPE may play a critical role in the aetiology and treatment of VKH disease. Herein, we established a human induced pluripotent stem cell (hiPSC) RPE model of VKH disease by reprogramming peripheral blood mononuclear cells (PBMCs) into iPSCs and then differentiating them into RPE cells. Patient-derived RPE cells exhibited barrier disruption, impaired phagocytosis, and depigmentation compared with those from normal controls, which was consistent with the features of VKH disease. Furthermore, a small molecular compound targeting EGR2 was found to rescue the barrier and phagocytic functions of the hiPSC-RPE cells through high-throughput virtual screening and functional studies, suggesting a promising strategy for the treatment of VKH disease.

Gut microbial signatures and their functions in Behcet's uveitis and Vogt-Koyanagi-Harada disease.

BACKGROUND: A number of public metagenomic studies reveal an association between the gut microbiome and various immune-mediated diseases including Behcet's uveitis (BU) and Vogt-Koyanagi-Harada disease (VKH). Integrated-analysis and subsequent validation of these results could be a potentially powerful way to understand the microbial signatures and their functions in these two uveitis entities. METHODS: We integrated the sequencing data of our previous metagenomic studies on two major uveitis entities, BU and VKH as well as four other publicly available immune-mediated diseases datasets, including Ankylosing Spondylitis (AS), Rheumatoid Arthritis (RA), Crohn's disease (CD) and Ulcerative Colitis (UC). Alpha-diversity and beta-diversity analysis were used to compare the gut microbiome signatures between both uveitis entities and other immune-mediated diseases and healthy controls. Amino acid homology between microbial proteins and a uveitogenic peptide of the interphotoreceptor retinoid-binding protein (IRBP)161-180 was investigated using a similarity search in the NCBI protein BLAST program (BLASTP). Enzyme-linked Immunosorbent Assay (ELISA) was performed to evaluate the cross-reactive responses of experimental autoimmune uveitis (EAU)-derived lymphocytes and BU patients-derived peripheral blood mononuclear cells (PBMCs) against homologous peptides. The area under the curve (AUC) analysis was used to test the sensitivity and specificity of gut microbial biomarkers. RESULTS: Depleted Dorea, Blautia, Coprococcus, Erysipelotrichaceae and Lachnospiraceae as well as enriched Bilophila and Stenotrophomonas were identified in BU patients. An enriched Alistipes along with a lower level of Dorea were observed in VKH patients. A peptide antigen (SteTDR) encoded by BU specifically enriched Stenotrophomonas was identified to share homology with IRBP161-180. In vitro experiments showed that lymphocytes from EAU or PBMCs from BU patients reacted to this peptide antigen as shown by the production of IFN-γ and IL-17. Addition of the SteTDR peptide to the classical IRBP immunization protocol exacerbated EAU severity. Gut microbial marker profiles consisted of 24 species and 32 species respectively differentiated BU and VKH from each other as well as from the other four immune-mediated diseases and healthy controls. Protein annotation identified 148 and 119 specific microbial proteins associated with BU and VKH, respectively. For metabolic function analysis, 108 and 178 metabolic pathways were shown to be associated with BU and VKH, respectively. CONCLUSIONS: Our study revealed specific gut microbial signatures and their potentially functional roles in BU and VKH pathogenesis that differ significantly from other immune-mediated diseases as well as healthy controls.

Polyautoimmunity manifest as inflammatory myopathy, uveitis, and progressive cutaneous depigmentation in a mixed breed dog: a case report.

BACKGROUND: Polyautoimmunity is the expression of more than one autoimmune disease in a single patient. This report documents polyautoimmunity in a mixed breed dog with concurrent uveitis, cutaneous depigmentation, and inflammatory myopathy. CASE PRESENTATION: A 1-year-old male neutered mixed breed dog was presented for progressive generalized leukotrichia and leukoderma, bilateral panuveitis, and masticatory muscle atrophy. The latter progressed to myositis of lingual, pharyngeal, and masticatory muscles confirmed by biopsy. Temporalis muscle was completely replaced by adipose and fibrous tissue, and necrotic myofibers with extensive infiltration of mononuclear cells indicated active myositis of lingual muscle. Skin biopsies showed severe melanin clumping in epidermis, hair follicles, and hair shafts, and perifollicular pigmentary incontinence. Uveitis, depigmentation, and myositis affecting the masticatory, pharyngeal, and tongue muscles were diagnosed based on clinical, histological, and laboratory findings. CONCLUSIONS: To the authors' knowledge, this is the first report of concurrent uveitis, progressive cutaneous depigmentation, and inflammatory myopathy in a dog.

Vogt-Koyanagi-Harada disease in pediatric, adult and elderly: clinical characteristics and visual outcomes.

PURPOSE: To depict a whole spectrum of clinical feartures and visual prognosis among pediatric, adult, and elderly Vogt-Koyanagi-Harada disease (VKH) patients. METHODS: Retrospective chart review was conducted in 2571 VKH patients diagnosed from April 2008 to January 2022. Based on age of disease onset, patients were divided into pediatric (age ≤ 16 years), adult (16 < age < 65 years), and elderly (age ≥ 65 years) VKH group. Ocular and extraocular manifestations were compared among these patients. Visual outcomes and complications were evaluated using logistic regression models and restricted cubic splines analysis. RESULTS: The median follow-up time was 48 (IQR, 12-60) months. Pediatric, adult and elderly VKH were found in 106 (4.1%), 2355 (91.6%), and 110 (4.3%) patients, respectively. All of the patients showed similar ocular manifestations in the context of disease phasing. The proportion of neurological and auditory manifestations in pediatric (42.3% and 7.5%) VKH patients was significantly lower than that in adults (66.5% and 47.9%) and elderly (68.2% and 50%) (both p < 0.0001). An increased risk of macular abnormalities was seen in adults (OR, 3.43; 95% CI, 1.62-7.29) compared with elderly VKH. An inverted-U-shaped pattern was observed between disease onset age and a poor visual outcome (visual acuity 6/18 or worse) according to OR value in VKH patients. The highest risk of BCVA ≤ 6/18 was observed in 32 years at disease onset (OR, 1.51; 95% CI, 1.18-1.94). A higher risk of visual loss was observed in adult VKH patients (OR, 9.06; 95% CI, 2.18-37.6) compared with elderly VKH patients. And stratified by macular abnormalities, the interaction test was not significant (P = 0.634). CONCLUSION: Our study identified, for the first time, a whole spectrum of clinical features of VKH based on a large cohort of Chinese patients. Adult VKH patients have an increased risk of poor visual outcomes, possibly due to increased frequency of macular abnormalities.

Acute phase clinical manifestations of patients with Vogt-Koyanagi-Harada disease in Southern China.

BACKGROUNDS: To characterize the acute phase clinical manifestations and visual outcomes of the patients with Vogt-Koyanagi Harada (VKH) disease in southern China. METHODS: In total, 186 patients with acute-onset VKH disease were recruited. The demographic data, clinical signs, ophthalmic examinations, and visual outcomes were analyzed. RESULTS: Among the 186 VKH patients, 3 were diagnosed as complete VKH, 125 as incomplete VKH, and 58 as probable VKH. All patients visited the hospital within 3 months of onset and complained of decreased vision. For the extraocular manifestations, 121 patients (65%) referred neurological symptoms. Anterior chamber activity was negative in most eyes within an onset of 7 days, which increased slightly with onset beyond 1 week. Exudative retinal detachment (366 eyes, 98%) and optic disc hyperaemia (314 eyes, 84%) were commonly observed at presentation. A typical ancillary examination helped with the diagnosis of VKH. Systemic corticosteroid therapy was prescribed. The logMAR best-corrected visual acuity improved significantly from 0.74 ± 0.54 at baseline to 0.12 ± 0.24 at the 1-year follow-up visit. The recurrence rate was 18% in the follow-up visits. Erythrocyte sedimentation rate and C-reactive protein were significantly correlated to VKH recurrences. CONCLUSION: Posterior uveitis, followed by mild anterior uveitis, is the typical initial manifestation in the acute phase of Chinese VKH patients. Visual outcome improvement is promising in most patients receiving systemic corticosteroid therapy in the acute phase. Detection of the clinical features at the initial onset of VKH could facilitate early treatment and better vision improvement.

Genetic landscape and autoimmunity of monocytes in developing Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder affecting multiple organs, including eyes, skin, and central nervous system. It is known that monocytes significantly contribute to the development of autoimmune disease. However, the subset heterogeneity with unique functions and signatures in human circulating monocytes and the identity of disease-specific monocytic populations remain largely unknown. Here, we employed an advanced single-cell RNA sequencing technology to systematically analyze 11,259 human circulating monocytes and genetically defined their subpopulations. We constructed a precise atlas of human blood monocytes, identified six subpopulations-including S100A12, HLA, CD16, proinflammatory, megakaryocyte-like, and NK-like monocyte subsets-and uncovered two previously unidentified subsets: HLA and megakaryocyte-like monocyte subsets. Relative to healthy individuals, cellular composition, gene expression signatures, and activation states were markedly alternated in VKH patients utilizing cell type-specific programs, especially the CD16 and proinflammatory monocyte subpopulations. Notably, we discovered a disease-relevant subgroup, proinflammatory monocytes, which showed a discriminative gene expression signature indicative of inflammation, antiviral activity, and pathologic activation, and converted into a pathologic activation state implicating the active inflammation during VKH disease. Additionally, we found the cell type-specific transcriptional signature of proinflammatory monocytes, ISG15, whose production might reflect the treatment response. Taken together, in this study, we present discoveries on accurate classification, molecular markers, and signaling pathways for VKH disease-associated monocytes. Therapeutically targeting this proinflammatory monocyte subpopulation would provide an attractive approach for treating VKH, as well as other autoimmune diseases.

Outcomes of initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease occurred during pregnancy.

PURPOSE: To investigate the outcomes of initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease that occurred during pregnancy. METHODS: This is a retrospective case series. RESULTS: During the period between January 2001 and December 2021, we identified 112 patients with initial-onset acute uveitis associated with VKH disease, 67 (59.8%) were females. Among the female patients, 10 (14.9%) patients (20 eyes) were pregnant. Of these patients, 5 patients presented in the first trimester, 3 in the second trimester and 2 in the third trimester. The follow-up period ranged from 8 to 108 months (mean 35.2 ± 28.3 months). At presentation, 8 (80%) patients had initial-onset acute VKH disease with anterior segment (AS) inflammation and 2 (20%) initial-onset acute VKH disease without AS inflammation. All patients were initially treated with systemic corticosteroids combined with cyclosporine. During follow-up period, none of the patients with initial-onset acute VKH disease without AS inflammation developed any complications. Complications including "sunset glow fundus" in 8 (40%) eyes, cataract in 2 (10%) eyes and subretinal fibrosis in 1 (5%) eye were recorded in patients with initial-onset acute VKH disease with AS inflammation. Four (40%) patients developed pregnancy-related complications, including abortion in 1 patient, systemic hypertension in 1 patient and premature rupture of membrane in 2 patients. There were no documented congenital anomalies in all born babies. Best-corrected visual acuity of ≥ 20/20 was achieved in 16 (80%) eyes at the final follow-up. CONCLUSION: Primary treatment with combined systemic corticosteroids and cyclosporine in initial-onset acute uveitis associated with VKH disease was safe and effective.

Incidence and pre/post-treatment risk factors of glaucoma in Vogt-Koyanagi-Harada disease.

PURPOSE: To investigate the incidence and pre/post-treatment risk factors of glaucoma in patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: Data regarding secondary glaucoma were collected from the medical records of patients with VKH disease who were followed up at the uveitis service at Hiroshima University for more than 6 months. We examined the incidence of glaucoma and pre/post-treatment risk factors for glaucoma in patients with VKH disease. RESULTS: Forty-nine patients with VKH disease were included in this study (31 women and 18 men). The mean age at onset was 50.4 ± 15.4 years and the mean length of follow-up was 40.7 ± 25.5 months. The most common initial treatment was pulse intravenous corticosteroid therapy (89.8%). Fifteen patients developed secondary glaucoma during follow-up. The median time of glaucoma onset from VKH development was 4.5 months (range 0-44 months). Disc swelling type as a pre-treatment factor (p = 0.089, hazard ratio = 7.268), worse final best corrected visual acuity (p = 0.099, odds ratio = 1.545), and cataract progression (p = 0.076, odds ratio = 7.886) as post-treatment factors showed trends for glaucoma development. The patients who progressed to the chronic recurrent stage had more complications including glaucoma. CONCLUSION: Secondary glaucoma occurred in more than 30% of patients with VKH disease. The factors that showed a trend toward glaucoma development may reflect an association with delayed treatment initiation and prolonged ocular inflammation.

Outcomes of patients with acute Vogt-Koyanagi-Harada disease treated with intravenous corticosteroid pulse followed by the slow tapering of oral corticosteroid therapy.

PURPOSE: To elucidate the intravenous corticosteroid pulse treatment outcomes of patients with acute Vogt-Koyanagi-Harada (VKH) disease and assess the differences between patients with no inflammation worsening and those with persistent or worsening inflammation. Potential factors responsible for eyes with low visual outcomes were also investigated. METHODS: We retrospectively reviewed the clinical records of patients with acute VKH disease who first visited us between 2009 and 2018 and were followed up for > 300 days. Clinical characteristics, treatments, and posttreatment conditions were assessed. Patients were classified into no inflammation worsening (acute-resolved [AR]) and inflammation worsening (chronic-recurrent [CR]) groups based on conditions after 6 months from disease onset. RESULTS: This study included 60 eyes from 30 patients (mean age: 52.7 years). Patients were treated with methylprednisolone pulse followed by the slow tapering of oral prednisolone; 73% of patients developed AR and 27% CR, and the best-corrected visual acuity (BCVA) was ≥ 1.0 in 83% of eyes at 6 months following the introduction of treatment. Although the total prednisolone dose was higher in patients with CR disease, no significant difference was noted in the final BCVA. Among the patients, five eyes had a final BCVA of ≤ 0.5 due to anisometropic amblyopia, diabetic maculopathy, pre-existing macular hole, epiretinal membrane, and ellipsoid zone loss. CONCLUSIONS: Patients with acute VKH disease treated with corticosteroid pulse appear to demonstrate good visual outcomes, including patients with CR; the majority of eyes with low visual outcomes have pre-existing conditions that explain the low vision.

Unusual neurologic manifestations of Vogt-Koyanagi-Harada disease: a systematic literature review.

BACKGROUND AND PURPOSE: The usual neurologic manifestations of Vogt-Koyanagi-Harada (VKH) disease include aseptic meningitis and headaches. We performed the present study to review all unusual neurologic manifestations reported in VKH disease to summarize them. METHODS: A literature search was performed in the English language on Scopus and Medline via PubMed from 1946 to July 31, 2021, by using the following terms: "Vogt Koyanagi Harada disease" OR "VKH disease" AND "Brain" OR "Spinal cord" OR "CNS" OR "Central nervous system" OR "Neurologic" OR "Peripheral nervous system" OR "Polyneuropathies. Our inclusion criteria were unusual neurologic manifestations of VKH disease. RESULTS: Our literature search yielded 417 total articles (PubMed = 334, Scopus = 83) from which 32 studies comprising 43 patients (22 men and 21 women, of which 62.8% were younger than 50 years) were included in this systematic literature review. Regarding the study design, all studies were case reports and published between 1981 and 2021. CNS involvement was the most reported (93%) in VKH disease. Peripheral nervous system involvement represents 7% of cases. The cerebral lesions were parenchymal inflammatory lesions in the white matter or posterior fossa with or no contrast enhancement (16.3%), leptomeningitis (9.3%), pachymeningitis (7%), meningoencephalitis (2.3%), ischemic stroke (4.6%), hemorrhagic stroke (2.3%), transient ischemic attack (2.3%), and hydrocephalus (2.3%). The optic nerve lesions were anterior ischemic optic neuropathy (20.9%) and optic neuritis (9.3%). Concerning spinal cord lesion, it was mainly myelitis (14%). CONCLUSION: This systematic literature review provides a summary of the different unusual neurologic manifestations reported in VKH disease.

Different MicroRNA profiles in Peripheral Blood mononuclear cells from patients with initial-onset and recurrent vogt-Koyanagi-Harada Disease.

BACKGROUND: Vogt-Koyanagi-Harada (VKH) disease is a common type of uveitis that leads to blindness. The clinical manifestations and treatment solutions are different between initial-onset and recurrent VKH. Therefore, identifying the microRNA (miRNA) profiles from initial-onset and recurrent VKH patients may shed light on the molecular mechanisms underlying the pathogenesis of VKH disease. METHODS AND RESULTS: RNAs isolated from peripheral blood mononuclear cells (PBMCs) from patients with initial-onset VKH, recurrent VKH, and healthy individuals were subjected to high-throughput miRNA sequencing. Pairwise analysis of miRNA sequencing data between groups was conducted to identify differentially expressed miRNAs (DEMs), which were verified using real-time quantitative polymerase chain reaction. After receiver operating characteristic analyses, we found that hsa-miR-4664-3p, hsa-miR-7704, hsa-miR-4504, and hsa-miR-206 may serve as biomarkers of different VKH stages. DEMs were classified into three groups based on their differential expression: DEMs in initial-onset stage, DEMs in recurrent stage, and DEMs common between both VKH stages (shared DEMs). Pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes identified the mitogen-activated protein kinase, tumor necrosis factor, and mechanistic target of rapamycin kinase pathways as significantly enriched among the target genes of recurrent stage and shared DEMs. Furthermore, we mapped a network of competing endogenous RNAs for hsa-miR-206, which we used to identify putative targets for VKH treatment. CONCLUSION: Hsa-miR-4664-3p, hsa-miR-7704, hsa-miR-4504, and hsa-miR-206 may serve as biomarkers for different stages of VKH. Additionally, our competing endogenous RNA network of hsa-miR-206 provides a new direction for VKH treatment.

Vogt-Koyanagi-Harada syndrome-like uveitis after nivolumab administration as a treatment for ovarian cancer.

PURPOSE: To report a case of Vogt-Koyanagi-Harada (VKH) syndrome-like posterior uveitis after nivolumab administration to treat an ovarian cancer with an electrophysiological finding. A 61-year-old woman with ovarian cancer (stage 3A) and salpingo-oophorectomy surgery history visited the clinic complaining of blurred vision in both eyes. She had been enrolled a clinical trial using nivolumab in patients with ovarian cancer. She received four cycles of nivolumab administration and experienced blurred vision one week before the initial visit. There was no remarkable finding in the anterior segment and the vitreous body. Multiple subretinal fluid accumulations and serous retinal detachment were identified on the posterior pole. Subretinal fluid with choroidal folding was noted in optical coherence tomography, and multiple leakage points were also observed in wide-field fundus fluorescein angiography. Therefore, intravenous high-dose steroid pulse therapy was applied under the diagnosis of VKH syndrome-like posterior uveitis induced by an immunotherapy agent. After steroid therapy, the subretinal fluid was absorbed completely, and the patient's visual acuity was recovered to the normal range. The amplitudes in the multifocal electroretinogram were also restored after the treatment. CONCLUSION: Nivolumab is a human IgG4 monoclonal antibody and an immune checkpoint inhibitor. It is associated with the upregulation of T-cell activity by interfering with the interaction between the programmed death-1 (PD-1) receptor and the PD-ligand. Targeted therapy using immunotherapy agents has been widely used for malignant melanoma, lung cancer, renal cell carcinoma, and other cancers. However, immunotherapy agents such as nivolumab can induce autoimmune-related adverse events including uveitis. This report suggests that VKH syndrome-like posterior uveitis could be induced by nivolumab administration for an ovarian cancer treatment, which was resolved by steroid pulse therapy.

Long-term changes of choroidal blood flow velocity in Vogt-Koyanagi-Harada disease.

PURPOSE: To evaluate changes in choroidal blood flow in patients with Vogt-Koyanagi-Harada (VKH) disease after initiation of corticosteroid treatment. METHODS: Fourteen patients (10 men and 4 women) with acute VKH disease followed for 2 years were retrospectively reviewed; only right eyes were included in the analysis. Mean blur rate (MBR) in the macula was measured by laser speckle flowgraphy (LSFG) and central choroidal thickness (CCT) was measured by optical coherence tomography (OCT), both prior to treatment and over 2 years after initiation of corticosteroid treatment. RESULTS: Of 14 patients included in this study, 13 received initial treatment consisting of intravenous corticosteroid pulse therapy and one patient was treated using bilateral sub-Tenon injections of triamcinolone acetonide. Mean percentage change in MBR was significantly increased after initiation of treatment compared to pretreatment values (P < 0.001). Mean CCTs were significantly decreased after initiation of treatment, compared to pretreatment thicknesses (P < 0.001). There was no significant change in either MBR change or CCT at 1 month after initiation of treatment through 2 years of follow-up. The mean MBR percentage change was significantly higher in eyes with sunset glow fundus (SGF) compared to eyes without SGF at 1 year. CONCLUSION: With initiation of corticosteroid treatment in VKH disease patients, choroidal blood flow improved and was maintained for 2 years. However, the presence of SGF should be taken into consideration when interpreting MBR results in VKH disease patients.