Current trends of biologic therapies in uveitis and scleritis

Biologic Drugs for the Treatment of Noninfectious Uveitis.

Uveitis is an inflammatory condition involving the iris, ciliary body, and choroid, and it represents a significant cause of vision loss in both children and adults. The primary goals of uveitis management are to control inflammation, prevent recurrences, and minimize structural damage and subsequent visual impairment. Currently, corticosteroids remain the mainstay of therapy for noninfectious uveitis. In patients with sight-threatening disease, immunosuppressive or steroid-sparing agents are commonly employed. However, for individuals who are intolerant of or refractory to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as effective alternative treatments. Among these, anti-tumor necrosis factor alpha (TNF-α) agents have demonstrated efficacy in both uveitis and systemic autoimmune disorders. Adalimumab, an anti-TNF-α agent, was the first biologic approved by the U.S. Food and Drug Administration for the treatment of noninfectious uveitis. Prior to initiating biologic therapy, potential safety concerns, including the risk of infections and demyelinating diseases, must be carefully evaluated. Other biologic agents, such as interferons, interleukin inhibitors, and Janus kinase inhibitors, are emerging as promising therapeutic options for noninfectious uveitis. Further studies are required to better establish the long-term safety and efficacy of biologic therapies. This review highlights the role and effectiveness of biologic agents in the management of noninfectious uveitis.

ABSTRACTIntroduction: The treatment strategies for noninfectious uveitis (NIU) aim to achieve disease remission, prevention of recurrences, and preserving vision, while minimizing the side effects associated with the therapies used.Areas covered: The index review aims to provide a detailed overview of the adverse events and safety parameters associated with the systemic therapies for the management of the NIU.Expert opinion: Despite being the cornerstone of management of acute cases of NIU, long-term corticosteroid use is associated with multi-system side effects, requiring the use of steroid-sparing agents. Adalimumab was recently approved by the FDA for the management of NIU based on the results of VISUAL studies. Similarly, newer drugs targeting various aspects of the inflammatory cascade are being developed. However, until we completely understand the molecular pathways of the inflammatory diseases, the therapeutic profile of these newer agents needs to be broad enough to suppress inflammatory cascade and narrow enough to spare normal cellular processes. Another strategy that has shown some potential in decreasing the systemic side effects is to provide local drug delivery. Therefore, the future of management of NIU is very bright with many novel therapeutic agents and strategies of drug delivery on the horizon.

Purpose: This study assessed the comparative efficacy and safety of tumor necrosis factor alpha (TNF-α) inhibitors in treating noninfectious uveitis (NIU). Methods: A comprehensive search was performed in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang Database from January 2010 to March 2024. The outcomes measured included inflammation improvement, visual acuity (VA) improvement, corticosteroid (CS)-sparing effect, central macular thickness (CMT) reduction, and adverse event incidence. Meta-analyses were conducted using RevMan 5.4 and Stata 16 software. Results: A total of 40 studies were included, involving 3,250 patients. TNF-α inhibitors showed a 90.4% inflammation improvement rate [95% confidence interval (CI): 0.770-0.987], 35.2% VA improvement (95% CI: 0.152-0.553), 55.3% CS-sparing effect (95% CI: 0.297-0.796), and CMT reduction of 62.37 µm (95% CI: 45.41-79.32 µm). Adverse events occurred in 24.0% of patients (95% CI: 0.170-0.310). No significant differences were observed between adalimumab and infliximab in inflammation improvement (P = 0.60) or CMT reduction (P = 0.55), but infliximab had higher adverse event rates (P = 0.0001; relative risk = 1.71, 95% CI: 1.30-2.24). Conclusions: This meta-analysis demonstrates that TNF-α inhibitors significantly improve inflammation, VA, and reduce CMT and CS use in NIU. While adalimumab and infliximab exhibit comparable efficacy, infliximab is associated with a higher adverse event rate, highlighting the need for personalized treatment.

PurposeTo provide a comprehensive review of rituximab use for the treatment of non-infectious uveitis and scleritis.MethodsReview of literature through December 2020.ResultsIndividual data was available for 229 patients with refractory non-infectious uveitis (n = 108) or scleritis (n = 121) who received treatment with rituximab (RTX). Rituximab was generally utilized as third-line or later treatment (uveitis: 67/90, 74.4%; scleritis: 90/96, 93.8%) at a mean of 33.5 months following the diagnosis of uveitis (range = 0 to 168.0 months; median = 24.0 months) and 39.4 months after diagnosis of scleritis (range = 1.0 to 168.0 months; median = 21.0 months). Patients with non-infectious uveitis and scleritis either received prior treatment with corticosteroids only (uveitis: 18/90, 20%; scleritis: 4/94, 4.3%), or with one (uveitis: 19/90, 21.1%; scleritis: 30/94, 31.9%), two (uveitis: 11/90, 12.2%; scleritis 27/94, 28.7%), or three or more (uveitis: 37/90, 41.1%; scleritis: 31/94, 33.0%) corticosteroid-sparing immunosuppressive agents with or without corticosteroids before initiation of RTX treatment. The rheumatologic protocol (two infusions of 1 gram of RTX separated by 14 days) was utilized most frequently (uveitis: 45/87, 51.7%; scleritis: 87/114, 76.3%), followed by the Foster protocol (eight weekly infusions of 375 mg/m2 RTX; uveitis: 18/87, 20.7%; scleritis: 10/114, 8.8%), and the oncologic protocol (four weekly infusions of 375 mg/m2 RTX; uveitis: 5/87, 5.7%; scleritis: 6/114, 5.3%). Various other off-label regimens were used infrequently (uveitis: 19/87, 21.8%; scleritis 11/114, 9.6%). Rituximab treatments resulted in a positive therapeutic response for the majority of patients with non-infectious uveitis (81/97, 83.5%). Commonly treated uveitic diagnoses included non-paraneoplastic autoimmune retinopathy (30/107, 28.0%), juvenile idiopathic arthritis (21/107, 19.6%), Vogt-Koyanagi-Harada disease (12/107, 11.2%), and Behçet disease (11/107, 10.3%). Cases of non-infectious scleritis were most commonly attributed to granulomatosis with polyangiitis (75/121, 62.0%) and rheumatoid arthritis (15/121, 12.4%), and showed an even greater rate of positive therapeutic response (112/120, 93.3%) following RTX treatment. No side effects were reported in 76.3% (74/97) of uveitis and 85.5% (71/83) scleritis cases. Of those cases associated with RTX-induced adverse events, the most common were infusion reactions of various severity (11/35, 31.4%).ConclusionsOverall, RTX appeared to be both effective and well-tolerated as second or third-line therapy for patients with non-infectious uveitis and scleritis.

Voclosporin is a novel calcineurin inhibitor that functions by binding cyclophilin, consequently inhibiting calcineurin activity and preventing the transcription of many genes involved in lymphocyte proliferation and cytokine release. Voclosporin has been shown to be effective in a variety of autoimmune diseases, such as rheumatoid arthritis, psoriasis and renal transplant rejection. Noninfectious uveitis is also an immune-mediated disease which, if left untreated, can cause severe loss of vision. Presently, corticosteroids are the mainstay of therapy in noninfectious uveitis. However, there are several metabolic and ophthalmic adverse effects associated with the long-term use of corticosteroids. Voclosporin has recently been shown in the LX-211 Uveitis Multicenter Investigation of a New Approach to Treatment (LUMINATE) clinical trial program to be effective in the treatment of noninfectious uveitis. With an acceptable side-effects profile, voclosporin is an exciting addition to the therapeutic options available in the management of noninfectious uveitis.

Immunomodulatory therapy in non-infectious Uveitis: Current landscape, gaps, and future directions.

A retrospective review of all cases of noninfectious uveitis and scleritis presenting to our center from July 2019 to January 2021 and had been treated with biological therapy were included. We included 12 eyes of 10 patients. The mean age was 42.10±9.71 years. Anterior nongranulomatous uveitis comprised 70% of the cases and the most common etiology of anterior uveitis was spondyloarthritis (seven cases among which five cases were nonradiographic) axial spondyloarthritis (human leukocyte antigen B27 positive) followed by radiographic axial spondyloarthritis (two cases). The first line of treatment in all cases was conventional synthetic disease-modifying antirheumatic agents among which 50% (n=5) had received methotrexate (≥15mg/week). As a second line of treatment, one or more biologics was used. Majority of the patients received oral tofacitinib 50% (n=5) followed by Inj adalimumab 30% (n=3). One case of Behcet's disease required sequential biologics (Inj adalimumab followed by oral tofacitinib). All patients tolerated and responded well to the treatment and no recurrences were observed after discontinuation of biologics drugs during the follow-up period of 1 year. Biologics are a relatively safe and effective modality of treatment in refractory, recurrent noninfectious uveitis.

Clinical Efficacy of Biosimilar Switch of Adalimumab and Infliximab for Noninfectious Uveitis: Systematic Review and Meta-Analysis.

BackgroundUveitis consists of a spectrum of inflammatory disorders characterized by ocular inflammation. The underlying pathophysiology consists of a complex interplay of various inflammatory pathways. Interleukin 6 is an important mediator of inflammation in uveitis and constitutes focus of research toward development of newer biological therapies in the management of non-infectious uveitis.Main bodyPan-blockade of the inflammatory pathways with steroids is generally the first step in the management of acute non-infectious uveitis. However, long-term therapy with steroids is associated with systemic and ocular side effects, thereby necessitating the need for development of steroid sparing agents. IL-6 is a cytokine produced by various immune cells, in response to molecular patterns and affects multiple inflammatory cells. In particular, IL-6 is involved in differentiation of CD-4 cells into Th-17 cells that have been shown to play a significant role in various immune-mediated diseases such as uveitis. This broad-spectrum immunomodulatory activity makes IL-6 an excellent target for immunomodulatory therapy. Tocilizumab was the first IL-6 inhibitor to demonstrate efficacy in humans. It inhibits IL-6 from binding to both membrane-bound and soluble receptor and can be administered via intravenous (IV) and subcutaneous (SC) routes. It has been FDA approved for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Following the approval in systemic diseases, its efficacy was demonstrated in various uveitis studies including a phase 2 clinical trial (STOP-Uveitis). Overall, tocilizumab has shown a good safety profile with the risk of malignancy consistent with that expected in patients with rheumatoid arthritis. However, tocilizumab therapy has been shown to increase the risk for gastrointestinal perforation and dose-dependent neutropenia. Following the success of tocilizumab, several other agents targeting the IL-6 pathway are in the pipeline. These include sirukumab, siltuximab, olokizumab, clazakizumab, and EBI-031 which target IL-6; Sarilumab and ALX-0061 act on the IL-6 receptor.ConclusionStudies have shown that IL-6 inhibitors can be effective in the management of NIU. In addition, the levels of IL-6 are elevated in other ocular vascular diseases such as retinal vein occlusion and diabetic macular edema. The roles of IL-6 inhibition may be broadened in the future to include the management of retinal vascular diseases and non-uveitic macular edema.

Retrospective analysis of children with uveitis treated with infliximab

Glycosylation-enhanced biocompatibility of the supramolecular hydrogel of an anti-inflammatory drug for topical suppression of inflammation

Background:Janus kinase inhibitors (JAKi) are effective therapies for the management of rheumatoid arthritis (RA). However, concerns about their safety in certain “at-risk” populations have resulted in risk minimisation measures being...

Tamoxifen has been US Food and Drug Administration-approved for primary prevention of breast cancer since 1998 but has not been widely adopted, in part because of increased risk of serious side effects. Little is known about the risk-benefit profiles of women who use chemoprevention outside of a clinical trial. We examined characteristics associated with initiation and discontinuation of tamoxifen for primary prevention of breast cancer within a large cohort of women with a first-degree family history of breast cancer. This research was conducted within The Sister Study, a cohort of 50884 US and Puerto Rican women age 35 to 74 years enrolled from 2003 to 2009. Eligible women were breast cancer-free at enrollment and had a sister who had been diagnosed with breast cancer. Participants reported tamoxifen use, ages started and stopped taking tamoxifen, and total duration of use at enrollment. We identified 788 tamoxifen users and 3131 nonusers matched on age and year of enrollment who had no history of contraindicating factors (stroke, transient ischemic attack, cataract, endometrial or uterine cancer). Characteristics associated with tamoxifen initiation were evaluated with multivariable conditional logistic regression. All statistical tests were two-sided. Based on published risk-benefit indices, 20% of women who used tamoxifen had insufficient evidence that the benefits of tamoxifen outweigh the risk of serious side effects. After 4.5 years, 46% of women had discontinued tamoxifen. While the majority of women who used tamoxifen for primary prevention of breast cancer were likely to benefit, substantial discontinuation of tamoxifen before five years and use by women at risk of serious side effects may attenuate benefits for breast cancer prevention.

Ocular Adverse Events Following Coronavirus Disease 2019 Infection: A Self-controlled Case Series Study from the Entire Korean Population