Treatment Of Noninfectious Uveitis Research Articles

Adalimumab for the Treatment of Non-Infectious Uveitis: A Real Life Experience

ABSTRACT Objective To describe the efficacy and safety of adalimumab for the treatment of non-infectious uveitis (NIU) in four Uveitis Units from tertiary Spanish hospitals. Methods Multicenter and retrospective clinical cohort study including all patients with NIU treated with adalimumab from January 2012 to October 2022 in four uveitis units was performed. Efficacy was measured with the number of relapses, ocular inflammation and reduction in immunosuppression and corticosteroid dosage before and after adalimumab use. We collected data regarding adverse effects and examined the immunogenicity of adalimumab. Results One hundred and twenty-two patients (59% females), with a mean age of 48.6 years (SD = 14.8) accounting for 217 eyes were included. The majority (92.6%) were Caucasian. Uveitis analyzed were predominantly panuveitis (34.7%), bilateral (77.9%), acute (41.5%), and non-granulomatous (90%). Most of them were immune mediated (42.6%), and the main reason to initiate adalimumab was refractory disease (96.7%). The analysis was statistically significant due to the reduction in the number of immunosuppressive drugs as well as the dose of oral corticosteroids and the number of relapses during follow-up (p < 0.001). The decrease in ocular inflammation parameters and the improvement in visual acuity (p < 0.05) were also significant. There were no deaths due to the drug and only one reported case of serious infection. In total, 10.9% of 73 patients tested developed anti-adalimumab antibodies and 4.1% lupus-like. Conclusions We consider adalimumab as a leading drug in the treatment of NIU with high safety and efficacy.

Efficacy of TNF-Alpha Inhibitors to Control Inflammation and Prevent Secondary Complications in Non-Infectious Uveitis: A Real-Life Experience from Switzerland

ABSTRACT Purpose To evaluate the efficacy of systemic tumor necrosis factor-alpha inhibitors (TNFi) in the treatment of non-infectious uveitis (NIU). Methods This Swiss multicenter retrospective cohort study included patients with NIU requiring TNFi during the period from 2001 to 2018. Risk factors for the occurrence of new complications were identified using Cox regression analysis and hazard ratios (HR). Results Seventy-one patients (126 eyes; mean age 40.6 ± 14.4 years, mean duration of uveitis 46.0 ± 61.8 months) were followed for 40.2 ± 17.3 months after addition of TNFi. Under TNFi, visual acuity improved from 0.2 ± 0.3 to 0.1 ± 0.3 logMAR (p < 0.001). The portion of patients under systemic corticosteroids decreased from 81.7% to 25.4% (p < 0.001), while that for conventional synthetic disease-modifying anti-rheumatic drugs insignificantly decreased from 63.4% to 50.7% (p > 0.05). In 80.2% of eyes, complications were present at baseline with epiretinal gliosis (39.7%), cataract (41.3%) and macular edema (ME; 27.8%) being the most common. New complications under TNFi were encountered in 49.2% of eyes, also including recurrence (5 eyes) or new onset of ME (14 eyes). The need for switching of TNFi was associated with further complications (HR 3.78, p = 0.012). Conclusion Although the efficacy and tolerability of TNFi in a real-life setting are favorable, treatment is often initiated late, i.e., after many eyes have already developed complications. Even with TNFi, new complications, particularly ME, cannot be completely avoided. Further research is needed to assess the impact of earlier initiation of TNFi therapy.

Indications and effects of biological agents in the treatment of noninfectious uveitis.

Noninfectious uveitis is a common blinding eye disease, and an autoimmune response is involved in its pathogenesis. Biological agents have gradually been introduced into the treatment of noninfectious uveitis. The authorsreviewed the clinical application and side effects of different biological agents on noninfectious uveitis. Biological agents that target TNF-α are widely used in the clinic. Other biological agents, such as IL-6- and IL-1-neutralizing antibodies, are used in patients who do not respond to TNF inhibitors. The efficacy of IL-17 neutralizing antibodies in noninfectious uveitis is controversial. Biological agents targeting T cells and signaling pathways provide new drug options for treatment of noninfectious uveitis. However, it cannot be ignored that these biological agents have side effects, such as increasing risk of infection.

Use of systemic corticosteroids in patients newly registered at a claims database with a diagnosis of non-infectious uveitis: results from a real-world claims database analysis.

To investigate the real-world dose of systemic corticosteroids in the treatment of non-infectious uveitis (NIU) in Japan. A retrospective, observational study. Patients newly registered at the Japan Medical Data Center health insurance claims database with a diagnosis of NIU who received systemic corticosteroids were identified, and their systemic corticosteroid dose (prednisolone equivalent) was assessed over 12 months of treatment (data extraction period: January 2008 to May 2017). The mean cumulative systemic corticosteroid dose in 12 months in 1641 new patients with NIU who received systemic corticosteroids was 593.7mg. The mean systemic corticosteroid dose was highest at month 1 (10.7, 218.1, 16.7, and 23.0mg/day in Behçet's disease [BD]-associated NIU [n = 19], Vogt-Koyanagi-Harada [VKH] disease-associated NIU [n = 49], sarcoidosis-associated NIU [n = 27], and "undifferentiated NIU" [NIU without specific primary disease information, n = 1545], respectively) and decreased over time. Systemic corticosteroids were prescribed at month 12 to 68.4%, 22.4%, 44.4%, and 5.6% of patients with BD-associated NIU, VKH disease-associated NIU, sarcoidosis-associated NIU, and undifferentiated NIU, respectively (mean dose, 6.0-14.3mg/day). Multivariate regression analysis identified female sex, middle age (30 to < 40 years), VKH disease, and immunosuppressive agent use as background factors associated with higher systemic corticosteroid dose. The systemic corticosteroid dose was highest at month 1 and decreased over time in all disease categories. This database research revealed that some patients with NIU continued being prescribed systemic corticosteroids for at least 1 year.

Current Knowledge of Biologics in Treatment of Noninfectious Uveitis.

The arena of uveitis deals with a number of entities, which can be infectious or immune mediated. Noninfectious uveitis (NIU) has been managed with corticosteroids and immunosuppressives. However, their prolonged use has side effects limiting clinical utility in the long run. Improved knowledge regarding pathogenesis of uveitis and associated systemic disease has led to a new epoch in the development of treatment strategies, of which biologics are the recent ones. Biologics revolutionized the management of NIU especially uveitis associated with spondyloarthropathy and refractory uveitis. They target inflammation at a molecular level with less side effects. The most widely used are tumor necrosis factor-alpha inhibitors (infliximab and adalimumab). Other drugs include anti-CD20 inhibitors (rituximab), interleukin-6R-inhibitor (tocilizumab), Interleukin-1R-inhibitor (anakinra), Iinterleukin-2-inhibitor (daclizumab), and the list is further increasing. New advances in biologics are the biosimilar molecules, which are biological products that are highly similar to the reference product, and they include Infimab (biosimilar of infliximab), Exemptia or Adfrar (biosimilar of adalimumab), and Intacept or Etacept (biosimilar of etanercept). Other group of biologics are Janus Associated Kinase inhibitors (JAK-inhibitors), which are long-term oral treatment options of rheumatoid arthritis. They inhibit JAKs, which cause activation of signal transducer and activator of transcription (STAT) proteins, and initiate transcription of inflammatory genes. Many inflammatory cytokines that are implicated in pathogenesis of ocular inflammation are known to utilize the JAK/STAT-signaling pathway, including interleukin-2 (IL-2) and IL-6. Thus, biologics are the future of uveitis treatment with promising results. This article aims to summarize the current knowledge on biologics and their clinical utility in the management of NIU.

Practice patterns regarding regional corticosteroid treatment in noninfectious Uveitis: a survey study

BackgroundRegional corticosteroid therapy for noninfectious uveitis is well-established but usage patterns have not been studied extensively. This study aims to assess practice patterns of retina and uveitis specialists regarding their preferences on the use of local corticosteroid therapy.MethodsA 13-question survey was developed regarding the practice patterns of regional corticosteroid use in specific situations and populations. The survey was distributed to both the American Uveitis Society and Macula Society.ResultsResponses from 87 ophthalmologists were analyzed. The two most commonly used drugs were the dexamethasone intravitreal implant (Ozurdex®) and posterior sub-tenon’s triamcinolone (also known as posterior sub-Tenon’s Kenalog, or PSTK). Regional corticosteroids were used more frequently as first-line treatment in more than half of posterior uveitis cases when compared to anterior uveitis (39.1–46.0% vs 10.3%, respectively). Respondents were more willing to use regional corticosteroids in more than half of unilateral uveitis cases than in bilateral cases (54.7% vs 18.6%, respectively). A majority of respondents (67.1%) stated that they would avoid using regional corticosteroids in patients under 8 years old.ConclusionsOur results demonstrate more frequent regional corticosteroid use in posterior segment uveitis, unilateral cases, and avoidance in younger pediatric patients. Overall, the variability in these responses highlights the need for guidelines regarding regional corticosteroid use.

Intravitreal dexamethasone implant for noninfectious uveitis in Chinese patients

To evaluate the effectiveness and safety of the dexamethasone intravitreal implant (DEX-I) in Non-Infectious Uveitis (NIU) in Chinese patients. Ninety-one eyes of 77 patients (56 men, 21 women) receiving 130 implant injections for NIU were included. Treatment indication, uveitis diagnosis, best-corrected visual acuity (BCVA), central retinal thickness (CRT), vitreous haze score, intraocular pressure, phakic status, number of injections, time to reinjection, and systemic treatments were collected at baseline, 1week, 1month, 3 and 6months after treatment. All patients were followed for at least 12weeks and had a mean follow-up period of 5.1months (range, 3-14months) after the first implant. The main treatment indications were macular edema (ME), retinal vasculitis, retinal vasculitis with ME. Sixty-one eyes (67.03%) received only one injection, while 31 eyes (32.97%) received two or more. In eyes that received 2 injections, the mean time to the second injection was 3.83months and in those that received 3 injections, the mean time to the third injection was 7.5months. BCVA and CRT significantly improved at 1week, 1month, 3months, and 6months after treatment. When compared to baseline, the mean prednisone (or equivalent) dosage significantly decreased at 3- and 6-month follow-up evaluations after DEX implantation.14.29% of eyes developed a transient increase in intraocular pressure, and a cataract was removed from 1 phakic eye. DEX implants, either alone or in combination with common adjunctive NIU treatments, is safe and effective in the treatment of NIU in Chinese patients.

Intravitreal lupeol: A new potential therapeutic strategy for noninfectious uveitis

Lupeol is a pentacyclic triterpene with known anti-inflammatory effects. However, its role in the treatment of noninfectious uveitis has not been explored. This work investigated anti-inflammatory activity of lupeol in ocular tissues with in vitro and in vivo models. First, we evaluated the effect of lupeol (100 µM) on inflammatory response induced by lipopolysaccharide (LPS) in retinal pigment epithelium cells (ARPE-19) by measuring levels of released interleukins (IL-6 and IL-8). Then, we investigated the anti-inflammatory action of intravitreal lupeol in a rodent model of panuveitis induced by Mycobacterium bovis Calmette-Guérin Bacillus (BCG). Rats were submitted to electroretinography and clinical analyses on days 3, 7, and 15 after uveitis induction. In addition, histopathological analysis, and indirect quantification of myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) in the posterior segment were performed. Treatment with lupeol (100 µM) significantly decreased IL-6 and IL-8 levels in comparison to untreated LPS-activated ARPE-19 cells. This reduction was similar to that detected in ARPE-19 cells treated with dexamethasone. The results of the in vivo assay demonstrated that intravitreal lupeol is able to modulate inflammation in the anterior and posterior segment of the rat eyes, indicating that it should be further investigated as a novel potential candidate for management of uveitis.

Efficacy of Tacrolimus in Uveitis, and the Usefulness of Serum Tacrolimus Levels in Predicting Disease Control. Results from a Single Large Center

ABSTRACT Aims: To evaluate the efficacy of tacrolimus in patients with noninfectious uveitis, as well as the usefulness of serum tacrolimus concentration measurements in predicting disease control. Methods: A retrospective review was carried out on 71 eligible patients from a single specialist uveitis center for minimum 1-year follow-up. Analysis was carried out on disease activity, visual acuity, and trough serum tacrolimus concentrations (STC). Results: At 1-year follow-up, disease control was achieved in 49 patients (69.0%), this was significantly more likely in patients with trough STC levels above 5 ng/mL (88% vs 53%, p = .002). There was a significant reduction in oral prednisolone (dose ≥7.5 mg, 86% vs 54%, p < .0001). Tacrolimus was discontinued in 12 patients (17%) due to side effects. Discussion: In this study cohort, oral tacrolimus was effective and well tolerated in the treatment of noninfectious uveitis. Trough STC between 5 ng/mL and 10 ng/ml was associated with better disease control at 1-year follow-up.

Intravitreal Fluocinolone 0.19mg Implant in the Management of Chronic Non-Infectious Uveitis: 12-Month Outcomes from a Single Tertiary Centre

ABSTRACT Aim To present efficacy and safety of 0.19 mg fluocinolone acetonide insert (FAi) to treat chronic noninfectious uveitis (NIU) in a single referral center. Methods A retrospective observational clinical study of 11 eyes with NIU complicated by chronic cystoid macular edema (CMO). Results The main indication for treatment was chronic CMO in all 11 eyes. The mean central retinal thickness (CRT) at baseline was 435 μm ± 176, improving to 296 μm ± 67 at 12 months. Raised intraocular pressure (IOP) was the commonest adverse event. An IOP >21 mmHg was observed in three eyes, and >30 mmHg in one eye, managed with topical therapy. The mean best corrected visual acuity (BCVA) was stable at 12 months. There were no observed recurrences of uveitis. Two eyes received adjunctive treatment for worsening CRT. Conclusions Our results suggest FAi is an effective maintenance treatment for NIU with favorable functional and anatomical outcomes.

Dexamethasone-peptide prodrug supramolecular hydrogel effectively alleviates experimental autoimmune uveitis (EAU)

Glucocorticoids (e.g., dexamethasone (Dex)) are the mainstay in the treatment of non-infectious uveitis, but optimal drug delivery system to maximally realize its potent bioactivity is still lacking. In the present study, we rationally designed and screened a dexamethasone-peptide amphiphile (Dex-GGD), which instantly formed a prodrug supramolecular hydrogel in phosphate-buffered saline (PBS, pH = 7.4) without external stimuli for the topical ocular drug delivery. The obtained Dex-GGD hydrogel was thoroughly characterized by rheology, circular dichroism (CD), and transmission electron microscopy (TEM). The results showed that Dex-GGD exhibited a potent in vitro anti-inflammatory capacity in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages with minimal cytotoxicity against L-929 fibroblasts, ARPE-19 cells, and RAW 264.7 macrophages. In a rat model of experimental autoimmune uveitis (EAU), the severity of uveitis was significantly alleviated after the treatment with Dex-GGD hydrogel owing to its potent ability to reduce the influx of inflammatory cells from peripheral blood and suppress the activation of macroglia and microglia in the retina. In contrast to the treatment with an equivalent dose of dexamethasone sodium phosphate (Dexp), the intravitreal injection of Dex-GGD hydrogel hardly induced the apparent ocular side-effects (e.g., elevated intraocular pressure or fundus blood vessel tortuosity). As a result, the proposed Dex-GGD prodrug supramolecular hydrogel may be an effective and safe therapeutic option for improving the clinical management of uveitis.

Comparative study of adalimumab versus conventional therapy in sight-threatening refractory Behçet’s uveitis with vasculitis

BackgroundAnti-tumor necrosis factor-alpha was regarded as an option in treatment of non-infectious uveitis. However, few studies in the far easter region have concentrated on this therapy and current studies have not emphasized the elimination of retinal vasculitis. To compare the effectiveness of adalimumab (ADA) plus conventional therapy (CT) versus CT alone in treating patients with retinal vasculitis (RV) due to refractory Behçet’s uveitis (BU). DesignRetrospective cohort study. MethodsClinical records of BU patients with previously treated but poorly controlled RV were analyzed. Patients were allocated into two groups depending on ADA use. Each group was treated for no less than 6 months between February 2015 and September 2020. The primary outcome parameter was the RV score. Best-corrected visual acuity (BCVA), number of relapses, macular thickness and ocular complications were considered concomitantly. ResultsForty-two patients (72 eyes) were included; 21 patients were in CT group, and 21 patients were in ADA group. Inflammatory parameters improved in both groups. The improvement in the fluorescein angiography (FA) score and anterior chamber inflammation were significantly better in ADA group than in CT group (P < 0.05). The relapse time was significantly lower in ADA group than in CT group (P = 0.01). Daily glucocorticoid dose tapers were more evident in ADA group than in CT group (P < 0.05). Adverse events were detected in 7 patients (5 had upper respiratory tract infection and 2 had gastrointestinal discomfort) in ADA group; in CT group, upper respiratory infection and recurrent gum swelling were observed in 1 patient each. ConclusionOur results indicate that ADA plus CT outperforms CT alone in patients with RV due to refractory BU. More agile ADA use in these patients should be considered to achieve optimal treatment.

Biotherapies in Uveitis.

Non-infectious uveitis (NIU) represents one of the leading causes of blindness in developed countries. The therapeutic strategy aims to rapidly control intra-ocular inflammation, prevent irremediable ocular damage, allow corticosteroid sparing and save the vision, and has evolved over the last few years. Anterior NIU is mostly managed with topical treatment in adults. However, for intermediate, posterior and pan-uveitis, notably when both eyes are involved, systemic treatment is usually warranted. Biotherapies are recommended in case of inefficacy or non-tolerance of conventional immunosuppressive drugs in non-anterior NIU. Anti-tumor necrosis factor alpha (anti-TNF-α) agents are by far the most widely used, especially adalimumab (ADA) and infliximab (IFX). In case of sight-threatening uveitis in Behçet’s disease or in case of risk of severe recurrences, respectively IFX and ADA may be recommended as first-line therapy. Many questions are left unanswered; how long to treat NIU, how to discontinue anti-TNF-α agents, what biologic to use in case of anti-TNF-α failure? The objective of this review is to present an updated overview of knowledge on the use of biological treatments in NIU.

Adalimumab in the treatment of non-infectious uveitis.

Non-infectious uveitis (NIU) is a serious sight-threatening condition whose pathogenesis is often autoimmune in nature. It may manifest in any age group, though adults aged 20-50 are the group most often affected. It causes 5-10% of visual impairment worldwide. The epidemiology of some specific uveitis diseases varies worldwide, because they are influenced by genetic, environmental and socioeconomic factors. It can occur only in the eye or as a symptom of a systemic condition. The most common cause of NIU is HLA-B-27-associated anterior uveitis (4-32%). The standard treatment for NIU is a local, topical and systemic steroid therapy in combination with immunomodulatory therapy. However, recently, a new drug - adalimumab, which is a tumor necrosis factor α (TNF-α) inhibitor - was approved by FDA in the treatment of NIU and is increasingly used to treat various conditions. Adalimumab has been proven in many studies to be safe and effective in the treatment of NIU associated with diverse systemic diseases.

Tuberculosis-Related Uveitis in Patients under Anti-TNF-alpha Therapy: A Case Series

ABSTRACT Tumor necrosis factor inhibitors (anti-TNF) have emerged as an effective treatment in noninfectious uveitis (NIU). Anti-TNF may increase the predisposition to infectious disease as tuberculosis (TB). TB-related uveitis in the context of an uveitogenic concurrent systemic immune-mediated disease under anti-TNF treatment remain a diagnostic challenge, deserving special focus on this rare context. Retrospective chart review of patients on anti-TNF drugs for systemic immune-mediated diseases that developed a multicentric microbiologically confirmed active TB with concurrent intraocular involvement. Three patients were recorded. Screening for TB before starting anti-TNF resulted negative in two patients. The other patient had received anti-tuberculous treatment in the past. All showed a microbiologically confirmed extraocular TB after unexpected atypical reactivation of the uveitis shifting to chronic granulomatous pattern. Specialists should be aware of TB reactivation, even with previous negative screening, when ocular uveitis signs and activity do not match with the expected pattern in a patient on anti-TNF drugs.

Update on noninfectious uveitis in children and its treatment.

To give an overview of recently published articles covering risk factors, novel biomarkers and treatment for noninfectious uveitis in children. In the last few years, several genetic markers, serum biomarkers, aqueous humor markers, tear biomarkers and clinical factors have been identified, which are associated with childhood noninfectious uveitis. We describe the most important reports in this field that may help to tailor the screening and monitoring of this population in the future and might become the target of novel therapies. The advances in the biologic therapy of paediatric uveitis, thanks to evidence provided by the SYCAMORE, ADJUVITE and APTITUDE trials, offer new possibilities for the treatment of patients who fail methotrexate with adalimumab and tocilizumab. We discuss the importance of comprehensive outcome measures as proposed by the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC). Paediatric noninfectious uveitis is a sight-threatening condition and the identification of risk factors and novel biomarkers is critical for tailored management. Biologic therapies are revolutionizing the outcomes of patients resistant to conventional therapy. Increasing our knowledge of disease pathogenesis is crucial to improve targeting of screening to those at highest risk and stratification of treatments.

Adalimumab in Elderly Patients with Non-Infectious Uveitis. Safety and Efficacy

ABSTRACT Purpose: To assess the efficacy and safety of adalimumab in elderly patients with noninfectious uveitis (NIU). Methods: An observational, retrospective, multicenter study was done. Changes in best-corrected visual acuity (BCVA), inflammatory activity parameters, central retinal thickness (CRT), and the occurrence of adverse events (AE) developed during follow-up were recorded. Results: A total of 82 eyes from 41 patients 60 years of age and older with noninfectious uveitis treated with adalimumab were included. A significant improvement in BCVA (71.5 to 75.4 letters, p = .001) and in CRT (311.1 μm to 265 μm, p = .001) was observed. Moreover, a significant decrease from baseline in the rate of patients with anterior chamber cell (ACC) >0+ (34.6% to 5.7%, p = <0.001) or vitreous haze>0+ (21.3% to 4.3%, p = .002) was determined. AEs were observed in 11 patients (26.8%). Conclusion: Adalimumab can be safe and efficacious for the treatment of NIU in patients 60 years of age and older.

Success of Weekly Adalimumab in Refractory Ocular Inflammatory Disease

Abstract Purpose Evaluate the efficacy of weekly adalimumab (ADA) in patients with non-infectious ocular inflammation who failed standard every other week (EOW) dosing. Design Single-center, retrospective, study. Subjects Patients with uncontrolled inflammation on ADA EOW who were escalated to weekly dosing. Methods Chart review conducted at Northwestern University, January 2012 to April 2019. Outcome: Number of treatment successes on weekly ADA at 6 and 12 months. Results Fourteen of 25 patients (56%) achieved disease control at 6 months; no additional failures occurred at 12 months. Conclusion Weekly ADA is a reasonable treatment option in patients with recalcitrant inflammation on standard dosing.

Suprachoroidal Injection of Triamcinolone- Review of a Novel Treatment for Macular Edema Caused by Noninfectious Uveitis.

Macular edema is the most frequent cause of visual deterioration in noninfectious uveitis. The treatment of noninfectious uveitis with associated macular edema commonly includes systemic or locally administered corticosteroids, with long-term use limited by significant side effects. The need for a treatment with an improved safety profile has driven the development of a novel ophthalmic therapy: a proprietary triamcinolone acetonide suspension (CLS-TA) administered in the suprachoroidal space (XIPERE™; Clearside Biomedical, Alpharetta, GA, USA). Suprachoroidal delivery of corticosteroids allows higher steroid concentration in the posterior segment and decreases the risk of other adverse ocular events. Recent results from the PEACHTREE trial (ClinicalTrials.gov Identifier: NCT02595398), a phase III trial with two suprachoroidal injections of CLS-TA at 0 and 12 weeks with follow up lasting 24 weeks, showed the significant improvement in visual acuity and reduction in central subfield thickness, all without increasing the risk of elevated intraocular pressure or accelerated cataract progression.

Orphan designation: Autologous collagen type II-specific regulatory T cells, Treatment of non-infectious uveitis

Orphan designation: Autologous collagen type II-specific regulatory T cells, Treatment of non-infectious uveitis