A Review of the Landscape of Targeted Immunomodulatory Therapies for Non-Infectious Uveitis.
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ABSTRACT:
SUBMITTER: Sharma SM
PROVIDER: S-EPMC5997593 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Non-infectious uveitis (NIU) is a disorder with various etiologies and is characterized by eye inflammation, mainly affecting people of working age. An accurate diagnosis of NIU is crucial for appropriate therapy. The aim of therapy is to improve vision, relieve ocular inflammation, prevent relapse, and avoid treatment side effects. At present, corticosteroids are the mainstay of topical or systemic therapy. However, repeated injections are required for the treatment of chronic NIU. Recently, new drug delivery systems that may ensure intraocular delivery of therapeutic drug levels have been highlighted. Furthermore, with the development of immunosuppressants and biologics, specific therapies can be selected based on the needs of each patient. Immunosuppressants used in the treatment of NIU include calcineurin inhibitors and antimetabolites. However, systemic immunosuppressive therapy itself is associated with adverse effects due to the inhibition of immune function. In patients with refractory NIU or those who cannot tolerate corticosteroids and immunosuppressors, biologics have emerged as alternative treatments. Thus, to improve the prognosis of patients with NIU, NIU should be managed with different drugs according to the response to treatment and possible side effects.
| S-EPMC10390404 | biostudies-literature
Project description:Non-infectious uveitis (NIU) is an inflammatory eye disease initiated via CD4+ T-cell activation and transmigration, resulting in focal retinal tissue damage and visual acuity disturbance. Cell adhesion molecules (CAMs) are activated during the inflammatory process to facilitate the leukocyte recruitment cascade. Our review focused on CAM-targeted therapies in experimental autoimmune uveitis (EAU) and NIU. We concluded that CAM-based therapies have demonstrated benefits for controlling EAU severity with decreases in immune cell migration, especially via ICAM-1/LFA-1 and VCAM-1/VLA-4 (integrin) pathways. P-selectin and E-selectin are more involved specifically in uveitis related to vasculitis. These therapies have potential clinical applications for the development of a more personalized and specific treatment. Localized therapies are the future direction to avoid serious systemic side effects.
| S-EPMC8745221 | biostudies-literature
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| S-EPMC5038923 | biostudies-literature
Project description: Not available
| S-EPMC9841887 | biostudies-literature
Project description:Non-infectious uveitis-or intraocular inflammatory disease-causes substantial visual morbidity and reduced quality of life amongst affected individuals. To date, research of pathogenic mechanisms has largely been focused on processes involving T lymphocyte and/or myeloid leukocyte populations. Involvement of B lymphocytes has received relatively little attention. In contrast, B-cell pathobiology is a major field within general immunological research, and large clinical trials have showed that treatments targeting B cells are highly effective for multiple systemic inflammatory diseases. B cells, including the terminally differentiated plasma cell that produces antibody, are found in the human eye in different forms of non-infectious uveitis; in some cases, these cells outnumber other leukocyte subsets. Recent case reports and small case series suggest that B-cell blockade may be therapeutic for patients with non-infectious uveitis. As well as secretion of antibody, B cells may promote intraocular inflammation by presentation of antigen to T cells, production of multiple inflammatory cytokines and support of T-cell survival. B cells may also perform various immunomodulatory activities within the eye. This translational review summarizes the evidence for B-cell involvement in non-infectious uveitis, and considers the potential contributions of B cells to the development and control of the disease. Manipulations of B cells and/or their products are promising new approaches to the treatment of non-infectious uveitis.
| S-EPMC4771944 | biostudies-other
Project description:Background: Non-infectious uveitis (NIU) is a severe intra ocular inflammation, which frequently requires prompt systemic immunosuppressive therapy (IMT) to halt the development of vision-threatening complications. IMT is considered when NIU cannot be treated with corticosteroids alone, which is unpredictable in advance. Previous studies have linked blood cell subsets to glucocorticoid sensitivity, which suggests that the composition of blood leukocytes may early identify patients that will require IMT. Objective: To map the blood leukocyte composition of NIU and identify cell subsets that stratify patients that required IMT during follow-up. Methods: We performed controlled flow cytometry experiments measuring a total of 37 protein markers in the blood of 30 IMT free patients with active non-infectious anterior, intermediate, and posterior uveitis, and compared these to 15 age and sex matched healthy controls. Results from manual gating were validated by automatic unsupervised gating using FlowSOM. Results: Patients with uveitis displayed lower relative frequencies of Natural Killer cells and higher relative frequencies of memory T cells, in particular the CCR6+ lineages. These results were confirmed by automatic gating by unsupervised clustering using FlowSOM. We observed considerable heterogeneity in memory T cell subsets and abundance of CXCR3-CCR6+ (Th17) cells between the uveitis subtypes. Importantly, regardless of the uveitis subtype, patients that eventually required IMT in the course of the study follow-up exhibited increased CCR6+ T cell abundance before commencing therapy. Conclusion: High-dimensional immunoprofiling in NIU patients shows that clinically distinct forms of human NIU exhibit shared as well as unique immune cell perturbations in the peripheral blood and link CCR6+ T cell abundance to systemic immunomodulatory treatment.
| S-EPMC6220365 | biostudies-literature
Project description:PurposeIn uveitis, a prolonged implicit time of the cone b-wave is a characteristic electroretinogram (ERG) abnormality. We investigated whether this can improve or deteriorate over time and which clinical factors are associated with change.MethodsProspective cohort study. Patients with a non-infectious uveitis were included. An ERG was measured in the first year of uveitis onset and a follow-up ERG one year later. Changes in the implicit time of the cone b-wave were investigated in relation to clinical parameters including the following: demographics, uveitis characteristics, treatment, best-corrected visual acuity, optical coherence tomography parameters and fluorescein angiography scores.ResultsOf 98 eyes (63 patients), 40 showed a prolonged cone b-wave on the first ERG, which improved in 10 eyes. Eyes with an improved ERG more often had a panuveitis with initially a higher incidence of cells in the anterior chamber during the first ERG, which resolved at the time of their follow-up ERG. Five of the 58 eyes with a normal first ERG had a deteriorated follow-up ERG. These eyes had more frequently an active uveitis at the time of the follow-up ERG. Of the 78 eyes with a stable cone b-wave, 16 had a quiescent inflammation during follow-up. There were no differences in age or treatment.ConclusionIn most patients with non-infectious uveitis, ERG abnormalities appear to be irreversible, even when the inflammation becomes quiescent. However, some ERGs improved, which was associated with reduction in inflammation of the anterior chamber due to panuveitis. In contrast, a worsened ERG was associated with a persistence of inflammation.
| S-EPMC7496825 | biostudies-literature
Project description:BackgroundNon-infectious uveitis represents a sub-type of intraocular inflammation often associated with disorders of immune dysregulation. If untreated, the intraocular inflammation may progress to severe visual impairment and blindness. Current treatment is heavily reliant on systemic corticosteroid, often at doses associated with severe side effects. There is a need for efficacious corticosteroid-sparing immunomodulatory therapy for these patients. Current immunomodulators include various immunosuppressants and biologics but mammalian target of rapamycin (mTOR) inhibitors (such as sirolimus and everolimus) may also be contenders for this role. The systematic review proposed here will evaluate the evidence for the use of sirolimus and everolimus in the context of non-infectious uveitis.Method/designStandard systematic review methodology will be used to identify, select and extract data from any comparative or non-comparative study of mTOR inhibitors in patients with non-infectious uveitis excluding case reports. Searches of bibliographic databases (MEDLINE, EMBASE, The Cochrane Library and CINAHL) and clinical trials registers will be performed, with no restriction on language or date of publication. Translation of non-English language articles will be undertaken where necessary. The primary outcome of interest will be uveitis activity as measured by vitreous haze. Secondary outcomes will include other pre-specified measures of uveitis activity (such as anterior chamber cells or central macular thickness) best corrected visual acuity, heath-related quality of life, requirement for concurrent treatment and adverse events. Risk of bias assessment will be performed appropriate to each study design. Study selection, data extraction and risk of bias assessment will be undertaken by two reviewers independently. Data will be grouped, tabulated and narratively synthesised. Meta-analysis will be undertaken where appropriate clinical and methodological homogeneity exists. The review will be published according to PRISMA guidance.DiscussionStudies of various designs have investigated the clinical use of mTOR inhibitors for non-infectious uveitis, and a large international randomised controlled trail of sirolimus for non-infectious uveitis is due to report. The findings of this systematic review will help inform ophthalmologists and aid the improvement of treatment protocols for non-infectious uveitis with regard to the use of mTOR inhibitors.Systematic review registrationPROSPERO CRD42017056390.
| S-EPMC5994244 | biostudies-literature
Project description:BackgroundUveitis is a group of intraocular inflammatory diseases whose primary treatment involves immunosuppression. Although corticosteroids (CSs) remain the mainstay therapy, sirolimus is among the recently studied immunomodulatory drugs for treating noninfectious uveitis (NIU).ObjectiveThe aim of this review was to assess and summarize the updated evidence on the outcomes of treatment with sirolimus for NIU.Materials and methodsTwo reviewers conducted a systematic search on November 5, 2018, of electronic databases (EMBASE, MEDLINE, and The Cochrane Library) and clinical trial registers having no restrictions on language or publication date. The primary outcome was uveitis activity as measured by vitreous haze (VH), while the secondary outcomes included central macular thickness (CMT), best-corrected visual acuity (BCVA), CS-sparing effect, IOP elevation, and other adverse events. A meta-analysis was conducted on selected studies with appropriate clinical and methodological homogeneity.ResultsSeven studies were included and reviewed. Four randomized clinical trials were eligible for meta-analysis: SAVE 2013, One-year outcomes of the SAVE study, SAVE 2 2016, SAKURA 2016. The pooled proportions of inflammation control (VH improvement) were 38% (95% CI 16.19%-62.66%) during a 6-month follow-up and 49.97% (95% CI 16.19%-83.03%) during a 6- to 12-month follow-up with the latter showing a significantly higher response rate (p=0.0472). BCVA improvement was 62.2% (95% CI 33.17%-87.11%) during a 6-month follow-up and 56.86% (95% CI 20.91%-89.05%) during a 6- to 12-month follow-up with no significant difference between the two (p=0.3705). Increased IOP remained at 7.11% (95% CI 3.46%-12.68%) for both a 6-month follow-up and up to a 12-month follow-up duration. The CS-sparing effect of sirolimus was also well demonstrated. A reduction in CMT was observed, and only minor drug-related adverse events were reported in all the studies reviewed.ConclusionThis review provided evidence that sirolimus is a promising treatment option for controlling inflammatory activity, improving visual acuity, and sparing CS use with minor adverse events for NIU.
| S-EPMC6478489 | biostudies-literature
Project description:Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians' treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.
| S-EPMC10051556 | biostudies-literature