Evaluating tocilizumab safety and immunomodulatory effects under ocular HTLV-1 infection in vitro.

There is growing interest in evaluating the safety and therapeutic potential of existing treatments such as tocilizumab (TCZ), an IL-6 receptor antagonist used to treat inflammatory diseases. However, there have been reports of increased inflammation in patients with HTLV-1 uveitis after TCZ treatment, and its ocular safety in the HTLV-1 infected state remains unknown. This study focused on assessing the impact of TCZ on HTLV-1-infected ocular cells using an in vitro model in which retinal pigment epithelial cells were cocultured with irradiated HTLV-1-infected T-cell lines. TCZ did not significantly affect cellular viability, inflammatory markers, or HTLV-1 proviral loads at various concentrations (25/50/100 µg/ml), indicating no increased risk of HTLV-1 viral infection and no exacerbation of the inflammatory aspects of HTLV-1 infection in the ocular cells. These promising results support the potential of TCZ as a safe treatment option for HTLV-1-infected patients, particularly those with eye infections.

Ripasudil as a Potential Therapeutic Agent in Treating Secondary Glaucoma in HTLV-1-Uveitis: An In Vitro Analysis.

Human T-cell leukemia virus type 1 (HTLV-1), a virus that affects 5-10 million people globally, causes several diseases, including adult T-cell leukemia-lymphoma and HTLV-1-associated uveitis (HU). HU is prevalent in Japan and often leads to secondary glaucoma, which is a serious complication. We investigated the efficacy of ripasudil, a Rho-associated coiled coil-forming protein kinase inhibitor, in alleviating changes in human trabecular meshwork cells (hTM cells) infected with HTLV-1. HTLV-1-infected hTM cells were modeled in vitro using MT-2 cells, followed by treatment with varying concentrations of ripasudil. We assessed changes in cell morphology, viability, and inflammatory cytokine levels, as well as NF-κB activation. The results showed that ripasudil treatment changed the cell morphology, reduced the distribution of F-actin and fibronectin, and decreased the levels of certain inflammatory cytokines, such as interleukin (IL)-6, IL-8, and IL-12. However, ripasudil did not significantly affect NF-κB activation or overall cell viability. These findings suggest that ripasudil has the potential to treat secondary glaucoma in patients with HU by modulating cytoskeletal organization and alleviating inflammation in HTLV-1-infected hTM cells. This study lays the foundation for further clinical studies exploring the effectiveness of ripasudil for the treatment of secondary glaucoma associated with HU.

Possible association between vaccination against SARS-CoV-2 and recurrence of macular edema due to branch retinal vein occlusion: a case report.

We herein describe a patient who developed recurrence of macular edema (ME) due to branch retinal vein occlusion (BRVO) 3 days after administration of the BNT162b2 vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A man in his early 50s visited our hospital because of vision loss in his right eye. His logarithmic best-corrected visual acuity (BCVA) was -0.79 in both eyes. ME due to superior temporal BRVO was observed in his right eye, and the central foveal thickness (CFT) was 486 µm. The patient was treated with an intravitreal aflibercept injection with logarithmic BCVA of -0.79, leading to resolution of the ME with a CFT of 299 µm. Three months after the initial visit, he received a fourth dose of an mRNA vaccine. Three days later, he developed vision loss in his right eye. Although the logarithmic BCVA was maintained at -0.79, ME recurred with a CFT of 507 µm. The patient was treated with an additional dose of intravitreal aflibercept injection. The ME resolved and the logarithmic BCVA in the right eye was maintained at -0.79. This case indicates a possible association between vaccination against SARS-CoV-2 and recurrence of ME due to BRVO.

Ocular Inflammation Post-Vaccination.

The association between vaccines and ocular disorders has attracted significant attention in scientific research. Numerous mainstream vaccines are associated with a range of uveitis types, including anterior, intermediate, and posterior uveitis. Additionally, they are associated with distinct ocular diseases such as multifocal choroiditis, Vogt-Koyanagi-Harada (VKH) disease, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and multiple evanescent white dot syndrome (MEWDS). These ocular conditions are often transient, with a vast majority of patients experiencing improvement after steroid intervention. To date, numerous cases of vaccine-induced uveitis have been reported. This study analyzed the correlation between antiviral vaccines, including the hepatitis B virus (HBV), human papillomavirus (HPV), measles-mumps-rubella (MMR), varicella zoster virus (VZV), and influenza vaccines, and different manifestations of uveitis. This is the first comprehensive study to offer a detailed analysis of uveitis types induced by antiviral vaccines. Through an extensive database search, we found a particularly strong link between influenza vaccines, followed by VZV and HPV vaccines. While anterior uveitis is common, conditions such as APMPPE, MEWDS, and VKH are particularly notable and merit careful consideration in clinical practice. Corticosteroid treatment was effective; however, half of the observed patients did not achieve full recovery, indicating potentially prolonged effects of the vaccine.

Granulomatosis with Polyangiitis Complicated by Severe Exudative Retinal Detachment and Orbital Granuloma Successfully Controlled with Rituximab: A Case Report.

We report a rare case of severe exudative retinal detachment with orbital granuloma associated with granulomatosis with polyangiitis (GPA). A 42-year-old man developed bilateral conjunctival hyperemia and eye pain 15 months before presenting to us. Because vitreous cells and retinal detachment were detected in his left eye, he was referred to us for further evaluation. The left eye showed scleral edema, cells in the anterior chamber and anterior vitreous, exudative retinal detachment, and elevated white subretinal lesions from the nasal to the inferior parts of the eye fundus. Orbital contrast-enhanced magnetic resonance imaging revealed a granulomatous lesion, retinal detachment, and fluid retention in the left eyeball. Comprehensive rheumatological evaluation revealed proteinase 3 anti-neutrophil cytoplasmic antibody positivity and a history of otitis media, leading to a GPA diagnosis. Methylprednisolone 1,000 mg/day was administered intravenously for 3 days, followed by oral prednisolone and intravenous cyclophosphamide. Although the retinal detachment decreased, scleritis and choroidal detachment relapse were observed in the left eye after the fifth cyclophosphamide administration. After switching from cyclophosphamide to rituximab, the scleritis and choroidal detachment resolved. Remission was successfully maintained with biannual rituximab administration. In this case, we conclude that rituximab was important to re-induce and maintain remission after recurrence. Collaboration with a rheumatologist is essential for proper treatment in related cases. This is the first report of ultra-widefield and multimodal imaging for retinal detachment associated with GPA.

Viral Conjunctivitis.

Viruses account for 80% of all cases of acute conjunctivitis and adenovirus; enterovirus and herpes virus are the common causative agents. In general, viral conjunctivitis spreads easily. Therefore, to control the spread, it is crucial to quickly diagnose illnesses, strictly implement hand washing laws, and sanitize surfaces. Swelling of the lid margin and ciliary injection are subjective symptoms, and eye discharge is frequently serofibrinous. Preauricular lymph node swelling can occasionally occur. Approximately 80% of cases of viral conjunctivitis are caused by adenoviruses. Adenoviral conjunctivitis may become a big global concern and may cause a pandemic. Diagnosis of herpes simplex viral conjunctivitis is crucial for using corticosteroid eye solution as a treatment for adenovirus conjunctivitis. Although specific treatments are not always accessible, early diagnosis of viral conjunctivitis may help to alleviate short-term symptoms and avoid long-term consequences.

Human Immunodeficiency Virus and Uveitis.

Uveitis is one of the most common ocular complications in people living with the Human immunodeficiency virus (HIV) and can be classified into HIV-induced uveitis, co-infection related uveitis, immune recovery uveitis, and drug-induced uveitis. The introduction of antiretroviral therapy has considerably changed the incidence, diagnosis, and treatment of different types of HIV-related uveitis. Furthermore, the specific immune condition of patients infected with HIV makes diagnosing HIV-related uveitis difficult. Recent studies have focused on the growing prevalence of syphilis/tuberculosis co-infection in uveitis. Simultaneously, more studies have demonstrated that HIV can directly contribute to the incidence of uveitis. However, the detailed mechanism has not been studied. Immune recovery uveitis is diagnosed by exclusion, and recent studies have addressed the role of biomarkers in its diagnosis. This review highlights recent updates on HIV-related uveitis. Furthermore, it aims to draw the attention of infectious disease physicians and ophthalmologists to the ocular health of patients infected with HIV.

Cytomegalovirus Anterior Uveitis: Clinical Manifestations, Diagnosis, Treatment, and Immunological Mechanisms.

Little is known regarding anterior uveitis (AU), the most common ocular disease associated with cytomegalovirus (CMV) infection in immunocompetent populations. CMV AU is highly prevalent in Asia, with a higher incidence in men. Clinically, it manifests mainly as anterior chamber inflammation and elevated intraocular pressure (IOP). Acute CMV AU may resemble Posner-Schlossman syndrome with its recurrent hypertensive iritis, while chronic CMV AU may resemble Fuchs uveitis because of its elevated IOP. Without prompt treatment, it may progress to glaucoma; therefore, early diagnosis is critical to prognosis. Knowledge regarding clinical features and aqueous humor analyses can facilitate accurate diagnoses; so, we compared and summarized these aspects. Early antiviral treatment reduces the risk of a glaucoma surgery requirement, and therapeutic effects vary based on drug delivery. Both oral valganciclovir and topical ganciclovir can produce positive clinical outcomes, and higher concentration and frequency are beneficial in chronic CMV retinitis. An extended antiviral course could prevent relapses, but should be limited to 6 months to prevent drug resistance and side effects. In this review, we have systematically summarized the pathogenesis, clinical features, diagnostic and therapeutic aspects, and immunological mechanisms of CMV AU with the goal of providing a theoretical foundation for early clinical diagnosis and treatment.

Factors associated with low prevalence of Fuchs' uveitis syndrome in Japan.

Aim: To investigate the causes of low prevalence of Fuchs' uveitis syndrome (FUS) in Japan. Methods: Medical records of 160 patients diagnosed with FUS at 14 uveitis specialty facilities in Japan were reviewed retrospectively. Results: In 160 FUS patients, mean follow-up period before referral to our uveitis facilities was 31.6 ± 50.9 months. The most common reason for referral was idiopathic uveitis (61.9%), followed by cataract (25.0%), high intraocular pressure (IOP) including glaucoma (16.3%), and FUS (14.4%). Unilateral involvement was 96.9%. The most frequent ocular finding of FUS was anterior inflammation (91.9%), followed by stellate-shaped keratic precipitates (88.1%), cataract/pseudophakia (88.1%), diffuse iris atrophy (84.4%), vitreous opacity (62.5%), heterochromia (53.1%) and high IOP including glaucoma (36.3%). As treatments of these ocular findings, cataract surgery was performed in 52.5%, glaucoma surgery in 10.6%, and vitrectomy in 13.8%. Mean logMAR VA was 0.28 ± 0.59 at the initial visit, and decreased significantly to 0.04 ± 0.32 at the last visit. Proportions of FUS patients with BCVA <0.1 and 0.1 to <0.5 decreased, while that of ≥0.5 increased at the last visit compared with the initial visit. Conclusions: Ocular findings of FUS in Japanese FUS patients were consistent with the characteristic features. The low prevalence of FUS in Japan may be a result of being overlooked and misdiagnosed as mild idiopathic uveitis, cataract, and/or glaucoma.

Mechanism of Secondary Glaucoma Development in HTLV-1 Uveitis.

Human T-cell lymphotropic virus type 1 (HTLV-1) was the first retrovirus identified as the causative agent of human diseases, such as adult T-cell leukemia, HTLV-1-associated myelopathy, and HTLV-1 uveitis (HU). HU is one of the most frequent ocular inflammatory diseases in endemic areas, which has raised considerable public health concerns. Approximately 30% of HU patients develop secondary glaucoma, which is higher than the general uveitis incidence. We therefore investigated the mechanism underlying the high incidence of glaucoma secondary to HU in vitro. After contact with HTLV-1-producing T cells (MT-2), human trabecular meshwork cells (HTMCs) were infected. The infected cells increased in number, and nuclear factor (NF)-κB expression was activated. Contact between MT-2 cells and HTMCs resulted in significantly upregulated production of inflammatory cytokines, such as IL-6, and chemokines, such as CXCL10, CCL2, and CXCL-8. These findings indicate that the mechanism underlying secondary glaucoma in HU may involve proliferation of trabecular meshwork tissue after contact with HTLV-1-infected cells, resulting in decreased aqueous humor outflow. Upregulated production of inflammatory cytokines and chemokines simultaneously disrupts the normal trabecular meshwork function. This mechanism presumably leads to increased intraocular pressure, eventually resulting in secondary glaucoma.

Updates on HTLV-1 Uveitis.

HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Recent studies have addressed several long-standing uncertainties about HU. HTLV-1-related diseases are known to be caused mainly through vertical transmission (mother-to-child transmission), but emerging HTLV-1 infection by horizontal transmission (such as sexual transmission) has become a major problem in metropolitan areas, such as Tokyo, Japan. Investigation in Tokyo showed that horizontal transmission of HTLV-1 was responsible for HU with severe and persistent ocular inflammation. The development of ATL and HAM is known to be related to a high provirus load and hence involves a long latency period. On the other hand, factors contributing to the development of HU are poorly understood. Recent investigations revealed that severe HU occurs against a background of Graves' disease despite a low provirus load and short latency period. This review highlights the recent knowledge on HU and provides an update on the topic of HU in consideration of a recent nationwide survey.

Long-term incidence of posterior capsular opacification in patients with non-infectious uveitis.

Little is known about the long-term incidence of posterior capsule opacification (PCO) after cataract surgery in patients with uveitis. This retrospective study included 211 eyes of 146 patients with non-infectious uveitis who underwent cataract surgery and implantation of an Acrysof SN60WF (Surface: plasma-treated, Optic and Haptic: hydrophobic acrylic), iSert XY-1 (Surface: UV-ozone-treated, Optic and Haptic: hydrophobic acrylic), or iSert 251/255 (Surface: UV-ozone-treated, Optics: hydrophobic acrylic, Haptic: polymethyl methacrylate). The cumulative incidences of PCO and subsequent yttrium-aluminum-garnet (Nd:YAG) capsulotomy over the 5-year follow-up were analyzed, and patients who were implanted with different intraocular lenses (IOLs) were compared. Mixed-effects Cox proportional hazard models showed that, compared with the Acrysof group, the iSert XY-1 group had higher risks of PCO (adjusted HR, 7.26; 95% CI, 1.82-28.8) and Nd:YAG capsulotomy (adjusted HR, 6.50; 95% CI, 1.55-27.2). Similar results were obtained when the Acrysof group was compared with the iSert 251/255 group for PCO (adjusted HR, 8.22; 95% CI, 2.35-28.7) and Nd:YAG capsulotomy (adjusted HR, 8.26; 1.90-36.0). These data suggest that a plasma-treated surface, hydrophobic acrylic optic and hydrophobic acrylic haptic, of the IOL could enhance biocompatibility even under inflammatory conditions, thus suppressing PCO development.

Dilated choroidal veins and their role in recurrences of myopic macular neovascularisations.

AIM: To determine whether there is a correlation between the presence of macular dilated choroidal vein (DCV) and the recurrence of myopic macular neovascularisation (MNV) after antivascular endothelial growth factor (VEGF) treatment. METHODS: Medical records of 168 eyes of 163 patients with myopic MNV were reviewed for the presence of macular DCV and episodes of recurrences. A macular DCV was defined as a choroidal vein whose diameter was 2× larger than the adjacent veins coursing in the macular area of 5.5 mm diameter. RESULTS: Macular DCV existed in 47 (28%) of the eyes with myopic MNV. 70 eyes (41.7%) had recurrence during a mean follow-up period of 52.5±23.0 months. Recurrence was found in 28 of the 47 eyes (59.6%) with DCV, which was significantly more frequent than the 42 of the 121 eyes (34.7%) without DCV (p=0.003). Cox model analysis showed that macular DCV was an independent risk factor (HR: 2.0, 95% CI 1.1 to 3.5) for recurrence. The recurrence rate was significantly higher in eyes with DCV within the first 2 years after the onset than in eyes without DCV. CONCLUSIONS: Macular DCVs may be indicators of a more aggressive phenotype of eyes with myopic MNV. These eyes need careful monitoring after anti-VEGF therapies.

Safety of intraocular anti-VEGF antibody treatment under in vitro HTLV-1 infection.

Introduction: HTLV-1 (human T-cell lymphotropic virus type 1) is a retrovirus that infects approximately 20 million people worldwide. Many diseases are caused by this virus, including HTLV-1-associated myelopathy, adult T-cell leukemia, and HTLV-1 uveitis. Intraocular anti-vascular endothelial growth factor (VEGF) antibody injection has been widely used in ophthalmology, and it is reportedly effective against age-related macular degeneration, complications of diabetic retinopathy, and retinal vein occlusions. HTLV-1 mimics VEGF165, the predominant isoform of VEGF, to recruit neuropilin-1 and heparan sulfate proteoglycans. VEGF165 is also a selective competitor of HTLV-1 entry. Here, we investigated the effects of an anti-VEGF antibody on ocular status under conditions of HTLV-1 infection in vitro. Methods: We used MT2 and TL-Om1 cells as HTLV-1-infected cells and Jurkat cells as controls. Primary human retinal pigment epithelial cells (HRPEpiCs) and ARPE19 HRPEpiCs were used as ocular cells; MT2/TL-Om1/Jurkat cells and HRPEpiCs/ARPE19 cells were co-cultured to simulate the intraocular environment of HTLV-1-infected patients. Aflibercept was administered as an anti-VEGF antibody. To avoid possible T-cell adhesion, we lethally irradiated MT2/TL-Om1/Jurkat cells prior to the experiments. Results: Anti-VEGF antibody treatment had no effect on activated NF-κB production, inflammatory cytokines, chemokines, HTLV-1 proviral load (PVL), or cell counts in the retinal pigment epithelium (RPE) under MT2 co-culture conditions. Under TL-Om1 co-culture conditions, anti-VEGF antibody treatment did not affect the production of activated NF-κB, chemokines, PVL, or cell counts, but production of the inflammatory cytokine IL-6 was increased. In addition, anti-VEGF treatment did not affect PVL in HTLV-1-infected T cells. Conclusion: This preliminary in vitro assessment indicates that intraocular anti-VEGF antibody treatment for HTLV-1 infection does not exacerbate HTLV-1-related inflammation and thus may be safe for use.

Treatment With FoxP3+ Antigen-Experienced T Regulatory Cells Arrests Progressive Retinal Damage in a Spontaneous Model of Uveitis.

We specify the clinical features of a spontaneous experimental autoimmune uveitis (EAU) model, in which foreign hen-egg lysozyme (HEL) is expressed in the retina, controlled by the promoter for interphotoreceptor retinol binding protein (IRBP). We previously reported 100% P21 (post-partum day) IRBP:HEL single transgenic (sTg) mice, when crossed to transgenic T cell receptor mice (3A9) generating the double transgenic (dTg) genotype, develop EAU despite profound lymphopenia (thymic HEL-specific T cell deletion). In this work, we characterized the immune component of this model and found conventional dTg CD4+ T cells were less anergic than those from 3A9 controls. Furthermore, prior in vitro HEL-activation of 3A9 anergic T cells (Tan) rendered them uveitogenic upon adoptive transfer (Tx) to sTg mice, while antigen-experienced (AgX, dTg), but not naïve (3A9) T cells halted disease in P21 dTg mice. Flow cytometric analysis of the AgX cells elucidated the underlying pathology: FoxP3+CD25hiCD4+ T regulatory cells (Treg) comprised ∼18%, while FR4+CD73+FoxP3-CD25lo/-CD4+ Tan comprised ∼1.2% of total cells. Further Treg-enrichment (∼80%) of the AgX population indicated FoxP3+CD25hiCD4+ Treg played a key role in EAU-suppression while FoxP3-CD25lo/-CD4+ T cells did not. Here we present the novel concept of dual immunological tolerance where spontaneous EAU is due to escape from anergy with consequent failure of Treg induction and subsequent imbalance in the [Treg:Teffector] cell ratio. The reduced numbers of Tan, normally sustaining Treg to prevent autoimmunity, are the trigger for disease, while immune homeostasis can be restored by supplementation with AgX, but not naïve, antigen-specific Treg.

HTLV-1 in Ophthalmology.

Human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus described as a causative agent for human disease. In the field of ophthalmology, a close relationship between HTLV-1 infection and uveitis was identified through a series of clinical and laboratory studies in the late 1980s-1990s. Since then, HTLV-1-related ocular manifestations such as keratoconjunctivitis sicca, interstitial keratitis, optic neuritis and adult T-cell leukemia/lymphoma (ATL)-related ocular manifestations have continuously been reported. During the three decades since the association between HTLV-1 and ocular pathologies was discovered, ophthalmic practice and research have advanced with the incorporation of new technologies into the field of ophthalmology. Accordingly, new findings from recent research have provided many insights into HTLV-1-associated ocular diseases. Advanced molecular technologies such as multiplex polymerase chain reaction (PCR)/broad-range PCR using ocular samples have enabled rapid and accurate diagnosis. Advanced ophthalmic technologies such as widefield fundus camera and optical coherence tomography (OCT) have clarified various features of HTLV-1-associated ocular manifestations, and identified characteristics such as the "knob-like ATL cell multiple ocular infiltration" (KAMOI) sign. Advanced drug delivery methods such as intravitreal injection and sub-Tenon injection have led to progress in preventing disease progression. This article describes global topics and the latest research findings for HTLV-1-associated ocular diseases, with reference to a large-scale nationwide survey of ophthalmologists. Current approaches and unmet needs for HTLV-1 infection in ophthalmology are also discussed.

Tackling HTLV-1 infection in ophthalmology: a nationwide survey of ophthalmic care in an endemic country, Japan.

INTRODUCTION: Japan is the most endemic of the developed nations in terms of human T-lymphotropic virus type 1 (HTLV-1) infection. Japan has been tackling HTLV-1 infection and has made remarkable progress. In ophthalmology, awareness of the association between HTLV-1 infection and uveitis has been increasing since the 1990s, when the relationship was first established. Here, we describe a nationwide survey and analysis of the current state of medical care for HTLV-1-associated uveitis (HAU) at ophthalmic facilities in Japan. METHODS: A questionnaire survey covered all university hospitals in Japan that were members of the Japanese Ophthalmological Society and all regional core facilities that were members of the Japanese Ocular Inflammation Society. Survey data were collected, and nationwide data on the state of medical care for HAU were tallied and analysed. RESULTS: Of the 115 facilities, 69 (60.0%) responded. HAU was most commonly diagnosed 'based on blood tests and characteristic ophthalmic findings'. Overall, 86.8% of facilities perform testing for HTLV-1 antibodies during medical care for diagnosing uveitis, with 58.3% routinely performing testing. Facilities with experience in providing medical care for HAU accounted for 67.6%. The survey also revealed that 85.5% of facilities had seen no decrease in the number of patients with HAU. CONCLUSIONS: In the two decades since the establishment of HAU as a pathological entity, the majority of facilities in Japan have started performing testing for HTLV-1 antibodies when considering differential diagnoses for uveitis. Our data suggest that providing information on HTLV-1 infection to ophthalmologists in Japan has been successfully implemented.