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Diagnosis and Prognosis in Inflammatory Eye Diseases
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Diagnosis and Prognosis in Inflammatory Eye Diseases

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Ophthalmology".

Deadline for manuscript submissions: closed (1 October 2021) | Viewed by 17040

Special Issue Editor

Dr. Yoshihiko Usui

E-Mail Website
Guest Editor
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan
Interests: biomarker; inflammatory eye disease; uveitis; omics analysis; ocular tumors; metabolomics

Special Issue Information

Dear Colleagues,

Inflammation causes potential blindness that affects many intraocular diseases. This inflammation can be caused by ischemia, diabetes, autoimmunity, infections, tumors, or disease of unknown cause. The correct diagnosis of inflammatory eye diseases in daily practice remains complicated and challenging due to the lack of specific diagnostic biomarkers. Biomarkers provide useful information in guiding clinical decision making in patients with inflammatory eye diseases. There are a huge number of inflammatory eye-disease-related biomarkers in the literature, but only a few biomarkers have been validated for clinical use. Novel approaches to biomarker discovery and validation are required for further progress to be made. Omic analyses may be able to answer these clinical questions and will be featured as particularly promising examples, and are strongly supporting the identification of novel biomarkers in inflammatory eye diseases. Various methodologies can be used for this purpose. These investigations may involve tumor tissue, adjacent stromal tissue, ocular fluids, and blood samples. For this Special Issue, I am looking for original research articles and the state-of-the-art reviews on novel or established genomic, proteomic, transcriptomic, or metabolomic biomarkers, aiming to elucidate the pathophysiology of inflammatory eye diseases as well as to identify new diagnostic biomarker or therapeutic targets.

Dr. Yoshihiko Usui
Guest Editor

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Keywords

  • omics analysis
  • inflammatory eye disease
  • multi-omics
  • proteomics
  • metabolomics
  • genetics
  • biomarker
  • liquid biopsy pathophysiology
  • diagnostic, stratification, and prognosis therapeutic targets

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Published Papers (6 papers)

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Research

13 pages, 1876 KiB  
Article
Comprehensive Proteomic Profiling of Vitreous Humor in Ocular Sarcoidosis Compared with Other Vitreoretinal Diseases
by Hiroyuki Komatsu, Yoshihiko Usui, Kinya Tsubota, Risa Fujii, Takefumi Yamaguchi, Kazuichi Maruyama, Ryo Wakita, Masaki Asakage, Hiroyuki Shimizu, Naoyuki Yamakawa, Naoya Nezu, Koji Ueda and Hiroshi Goto
J. Clin. Med. 2022, 11(13), 3606; https://doi.org/10.3390/jcm11133606 - 22 Jun 2022
Cited by 4 | Viewed by 2068
Abstract
Ocular sarcoidosis is an inflammatory disease that manifests as uveitis, and is often difficult to distinguish from other forms of uveitis based on nonspecific findings alone. Comprehensive proteomic analyses of vitreous humor using LC-MS/MS were performed in each patient with ocular sarcoidosis, vitreoretinal [...] Read more.
Ocular sarcoidosis is an inflammatory disease that manifests as uveitis, and is often difficult to distinguish from other forms of uveitis based on nonspecific findings alone. Comprehensive proteomic analyses of vitreous humor using LC-MS/MS were performed in each patient with ocular sarcoidosis, vitreoretinal lymphoma (VRL), and controls with epiretinal membrane or macular hole. Differential expression proteins (DEPs) were identified by comparing with VRL and controls, and functional pathway analysis was performed. The candidate biomarker proteins for ocular sarcoidosis were validated using enzyme-linked immunosorbent assay. A total of 1590 proteins were identified in all samples. Of these, 290 and 174 DEPs were detected in vitreous of ocular sarcoidosis compared with controls and VRL, respectively. Enrichment pathway analysis revealed that pathways related to the immune system were most upregulated. Validation of two candidate biomarkers for ocular sarcoidosis, neutrophil gelatinase-associated lipocalin (NGAL) and junctional adhesion molecules B (JAMB), confirmed upregulated NGAL and JAMB protein expressions in ocular sarcoidosis compared to controls and VRL. The results of this study revealed that altered vitreous protein expression levels may discriminate ocular sarcoidosis from other uveitis diseases. Vitreous NGAL and JAMB are potential biomarkers and may serve as an auxiliary tool for the diagnosis of ocular sarcoidosis. Full article
(This article belongs to the Special Issue Diagnosis and Prognosis in Inflammatory Eye Diseases)
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19 pages, 2263 KiB  
Article
Identification of Markers Predicting Clinical Course in Patients with IgG4-Related Ophthalmic Disease by Unbiased Clustering Analysis
by Kinya Tsubota, Yoshihiko Usui, Rey Nemoto and Hiroshi Goto
J. Clin. Med. 2020, 9(12), 4084; https://doi.org/10.3390/jcm9124084 - 17 Dec 2020
Cited by 3 | Viewed by 1851
Abstract
Purpose: To describe the clinical features of patients with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD) grouped by unbiased cluster analysis using peripheral blood test data and to find novel biomarkers for predicting clinical features. Methods: One hundred and seven patients diagnosed with IgG4-ROD [...] Read more.
Purpose: To describe the clinical features of patients with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD) grouped by unbiased cluster analysis using peripheral blood test data and to find novel biomarkers for predicting clinical features. Methods: One hundred and seven patients diagnosed with IgG4-ROD were divided into four groups by unsupervised hierarchical cluster analysis using peripheral blood test data. The clinical features of the four groups were compared and novel markers for prediction of clinical course were explored. Results: Unbiased cluster analysis divided patients into four groups. Group B had a significantly higher frequency of extraocular muscle enlargement (p < 0.001). The frequency of patients with decreased best corrected visual acuity (BCVA) was significantly higher in group D (p = 0.002). Receiver operating characteristic (ROC) curves for the prediction of extraocular muscle enlargement and worsened BCVA using a panel consisting of important blood test data identified by machine learning yielded areas under the curve of 0.78 and 0.86, respectively. Clinical features were compared between patients divided into two groups by the cutoff serum IgE or IgG4 level obtained from ROC curves. Patients with serum IgE above 425 IU/mL had a higher frequency of extraocular muscle enlargement (25% versus 6%, p = 0.004). Patients with serum IgG4 above 712 mg/dL had a higher frequency of decreased BCVA (37% versus 5%, p ≤ 0.001). Conclusion: Unsupervised hierarchical clustering analysis using routine blood test data differentiates four distinct clinical phenotypes of IgG4-ROD, which suggest differences in pathophysiologic mechanisms. High serum IgG4 is a potential predictor of worsened BCVA, and high serum IgE is a potential predictor of extraocular muscle enlargement in IgG4-ROD patients. Full article
(This article belongs to the Special Issue Diagnosis and Prognosis in Inflammatory Eye Diseases)
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21 pages, 4113 KiB  
Article
Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing
by Masaki Asakage, Yoshihiko Usui, Naoya Nezu, Hiroyuki Shimizu, Kinya Tsubota, Kazuhiko Umazume, Naoyuki Yamakawa, Tomohiro Umezu, Hirotsugu Suwanai, Masahiko Kuroda and Hiroshi Goto
J. Clin. Med. 2020, 9(11), 3458; https://doi.org/10.3390/jcm9113458 - 27 Oct 2020
Cited by 9 | Viewed by 3149
Abstract
High-throughput RNA sequencing (RNA-seq) uses massive parallel sequencing technology, allowing the unbiased analysis of genome-wide transcription levels and tumor mutation status. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory disease characterized by the enlargement of the ocular adnexal tissues. We analyzed RNA expression [...] Read more.
High-throughput RNA sequencing (RNA-seq) uses massive parallel sequencing technology, allowing the unbiased analysis of genome-wide transcription levels and tumor mutation status. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory disease characterized by the enlargement of the ocular adnexal tissues. We analyzed RNA expression levels via RNA-seq in the biopsy specimens of three patients diagnosed with IgG4-ROD. Mucosa-associated lymphoid tissue (MALT) lymphoma, reactive lymphoid hyperplasia (RLH), normal lacrimal gland tissue, and adjacent adipose tissue were used as the controls (n = 3 each). RNA-seq was performed using the NextSeq 500 system, and genes with |fold change| ≥ 2 and p < 0.05 relative to the controls were defined as differentially expressed genes (DEGs) in IgG4-ROD. To validate the results of RNA-seq, real-time polymerase chain reaction (PCR) was performed in 30 IgG4-ROD and 30 orbital MALT lymphoma tissue samples. RNA-seq identified 35 up-regulated genes, including matrix metallopeptidase 12 (MMP12) and secreted phosphoprotein 1 (SPP1), in IgG4-ROD tissues when compared to all the controls. Many pathways related to the immune system were included when compared to all the controls. Expressions of MMP12 and SPP1 in IgG4-ROD tissues were confirmed by real-time PCR and immunohistochemistry. In conclusion, we identified novel DEGs, including those associated with extracellular matrix degradation, fibrosis, and inflammation, in IgG4-ROD biopsy specimens. These data provide new insights into molecular pathogenetic mechanisms and may contribute to the development of new biomarkers for diagnosis and molecular targeted drugs. Full article
(This article belongs to the Special Issue Diagnosis and Prognosis in Inflammatory Eye Diseases)
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13 pages, 804 KiB  
Article
Biologic Therapy in Refractory Non-Multiple Sclerosis Optic Neuritis Isolated or Associated to Immune-Mediated Inflammatory Diseases. A Multicenter Study
by Alba Herrero-Morant, Carmen Álvarez-Reguera, José L. Martín-Varillas, Vanesa Calvo-Río, Alfonso Casado, Diana Prieto-Peña, Belén Atienza-Mateo, Olga Maiz-Alonso, Ana Blanco, Esther Vicente, Íñigo Rúa-Figueroa, Laura Cáceres-Martin, José L. García-Serrano, José Luis Callejas-Rubio, Norberto Ortego-Centeno, Javier Narváez, Susana Romero-Yuste, Julio Sánchez, Paula Estrada, Rosalía Demetrio-Pablo, David Martínez-López, Santos Castañeda, José L. Hernández, Miguel Á. González-Gay and Ricardo Blancoadd Show full author list remove Hide full author list
J. Clin. Med. 2020, 9(8), 2608; https://doi.org/10.3390/jcm9082608 - 11 Aug 2020
Cited by 2 | Viewed by 3460
Abstract
We aimed to assess the efficacy of biologic therapy in refractory non-Multiple Sclerosis (MS) Optic Neuritis (ON), a condition more infrequent, chronic and severe than MS ON. This was an open-label multicenter study of patients with non-MS ON refractory to systemic corticosteroids and [...] Read more.
We aimed to assess the efficacy of biologic therapy in refractory non-Multiple Sclerosis (MS) Optic Neuritis (ON), a condition more infrequent, chronic and severe than MS ON. This was an open-label multicenter study of patients with non-MS ON refractory to systemic corticosteroids and at least one conventional immunosuppressive drug. The main outcomes were Best Corrected Visual Acuity (BCVA) and both Macular Thickness (MT) and Retinal Nerve Fiber Layer (RNFL) using Optical Coherence Tomography (OCT). These outcome variables were assessed at baseline, 1 week, and 1, 3, 6 and 12 months after biologic therapy initiation. Remission was defined as the absence of ON symptoms and signs that lasted longer than 24 h, with or without an associated new lesion on magnetic resonance imaging with gadolinium contrast agents for at least 3 months. We studied 19 patients (11 women/8 men; mean age, 34.8 ± 13.9 years). The underlying diseases were Bechet’s disease (n = 5), neuromyelitis optica (n = 3), systemic lupus erythematosus (n = 2), sarcoidosis (n = 1), relapsing polychondritis (n = 1) and anti-neutrophil cytoplasmic antibody -associated vasculitis (n = 1). It was idiopathic in 6 patients. The first biologic agent used in each patient was: adalimumab (n = 6), rituximab (n = 6), infliximab (n = 5) and tocilizumab (n = 2). A second immunosuppressive drug was simultaneously used in 11 patients: methotrexate (n = 11), azathioprine (n = 2), mycophenolate mofetil (n = 1) and hydroxychloroquine (n = 1). Improvement of the main outcomes was observed after 1 year of therapy when compared with baseline data: mean ± SD BCVA (0.8 ± 0.3 LogMAR vs. 0.6 ± 0.3 LogMAR; p = 0.03), mean ± SD RNFL (190.5 ± 175.4 μm vs. 183.4 ± 139.5 μm; p = 0.02), mean ± SD MT (270.7 ± 23.2 μm vs. 369.6 ± 137.4 μm; p = 0.03). Besides, the median (IQR) prednisone-dose was also reduced from 40 (10–61.5) mg/day at baseline to. 2.5 (0–5) mg/day after one year of follow-up; p = 0.001. After a mean ± SD follow-up of 35 months, 15 patients (78.9%) achieved ocular remission, and 2 (10.5%) experienced severe adverse events. Biologic therapy is effective in patients with refractory non-MS ON. Full article
(This article belongs to the Special Issue Diagnosis and Prognosis in Inflammatory Eye Diseases)
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18 pages, 3226 KiB  
Article
Distinctive Tissue and Serum MicroRNA Profile of IgG4-Related Ophthalmic Disease and MALT Lymphoma
by Naoya Nezu, Yoshihiko Usui, Masaki Asakage, Hiroyuki Shimizu, Kinya Tsubota, Akitomo Narimatsu, Kazuhiko Umazume, Naoyuki Yamakawa, Shin-ichiro Ohno, Masakatsu Takanashi, Masahiko Kuroda and Hiroshi Goto
J. Clin. Med. 2020, 9(8), 2530; https://doi.org/10.3390/jcm9082530 - 5 Aug 2020
Cited by 5 | Viewed by 3057
Abstract
The molecular pathogenesis of orbital lymphoproliferative disorders, such as immunoglobulin G4-related ophthalmic disease (IgG4-ROD) and orbital mucosa-associated lymphoid tissue (MALT) lymphoma, remains essentially unknown. Differentiation between the two disorders, which is important since the work-up and treatment can vary greatly, is often challenging [...] Read more.
The molecular pathogenesis of orbital lymphoproliferative disorders, such as immunoglobulin G4-related ophthalmic disease (IgG4-ROD) and orbital mucosa-associated lymphoid tissue (MALT) lymphoma, remains essentially unknown. Differentiation between the two disorders, which is important since the work-up and treatment can vary greatly, is often challenging due to the lack of specific biomarkers. Although miRNAs play an important role in the regulation of carcinogenesis and inflammation, the relationship between miRNA and orbital lymphoproliferative diseases remains unknown. We performed a comprehensive analysis of 2565 miRNAs from biopsy and serum specimens of 17 cases with IgG4-ROD, where 21 cases with orbital MALT lymphoma were performed. We identified specific miRNA signatures and their miRNA target pathways, as well as the network analysis for IgG4-ROD and orbital MALT lymphoma. Machine-learning analysis identified miR-202-3p and miR-7112-3p as the best discriminators of IgG4-ROD and orbital MALT lymphoma, respectively. Enrichment analyses of biological pathways showed that the longevity-regulating pathway in IgG4-ROD and the mitogen-activated protein kinase (MAPK) signaling pathway in orbital MALT lymphoma was most enriched by target genes of downregulated miRNAs. This is the first evidence of miRNA profiles of biopsy and serum specimens of patients with IgG4-ROD and orbital MALT lymphoma. These data will be useful for developing diagnostic and therapeutic interventions, as well as elucidating the pathogenesis of these disorders. Full article
(This article belongs to the Special Issue Diagnosis and Prognosis in Inflammatory Eye Diseases)
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12 pages, 807 KiB  
Article
Identification of Prognostic Markers in Patients with Primary Vitreoretinal Lymphoma by Clustering Analysis Using Clinical Data
by Kinya Tsubota, Yoshihiko Usui and Hiroshi Goto
J. Clin. Med. 2020, 9(7), 2298; https://doi.org/10.3390/jcm9072298 - 20 Jul 2020
Cited by 8 | Viewed by 2327
Abstract
(1) Purpose: Primary vitreoretinal lymphoma (PVRL) is associated with poor prognosis because most of the patients with PVRL develop central nerve system lymphoma. The prognostic biomarker of PVRL is largely unknown. Cluster analysis has been used to identify phenotypic groups within various diseases. [...] Read more.
(1) Purpose: Primary vitreoretinal lymphoma (PVRL) is associated with poor prognosis because most of the patients with PVRL develop central nerve system lymphoma. The prognostic biomarker of PVRL is largely unknown. Cluster analysis has been used to identify phenotypic groups within various diseases. In this study, we aimed to describe clinical features of patients with PVRL grouped by clustering analysis and to identify biomarkers for predicting survival prognosis in patients with PVRL. (2) Materials and Methods: Forty patients with PVRL were divided into two groups by clustering analysis using clinical data. Clinical features of the two groups were compared. (3) Result: Clustering analysis classified patients into groups A and B. The survival rate during the follow-up period was significantly lower in group B than in group A (p = 0.03). Serum IgG, serum IgA, vitreous IL-10 and vitreous IL-10 to IL-6 ratio were significantly different between groups A and B (p = 0.03, 0.005, 0.008 and 0.03, respectively). Receiver operating characteristic (ROC) curves generated for the four variables indicated that serum IgA was most suitable for the prediction of prognosis. Patients with serum IgA below 184 mg/dL obtained from the ROC curve had a lower three-year survival rate (p = 0.03) and more episodes of recurrence of lymphoma (3.2 times versus 1.8 times, p = 0.02) compared with patients with serum IgA above 184 mg/dL. (4) Conclusion: The survival rate was significantly different in PVRL patients classified into two groups by clustering analysis. Patients with lower serum IgA had more recurrences and poorer survival than patients with higher IgA. Full article
(This article belongs to the Special Issue Diagnosis and Prognosis in Inflammatory Eye Diseases)
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