Active Noninfectious Uveitis Research Articles

Filgotinib in Active Noninfectious Uveitis

Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options. To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis. The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day). Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks. The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo. Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo -30.1%; 95% CI, -56.2% to -4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial. Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor. ClinicalTrials.gov Identifier: NCT03207815.

Interobserver Reliability and Sensitivity to Change of a Composite Ocular Inflammatory Activity Index: UVEDAI©.

This was a multicenter, prospective, longitudinal, observational study involving eight Spanish tertiary hospitals to determine the interobserver reliability of an uveitis disease activity index, (UVEDAI) and assess its sensitivity to change in patients with receiving pharmacologic treatment. Patients aged ≥ 18years diagnosed with active noninfectious uveitis were included. A complete baseline assessment was performed by two ophthalmologists who determined ocular inflammatory activity using the UVEDAI index independently of each other. The principal ophthalmologist made a new visit at 4weeks to determine the change in inflammatory activity. The interobserver reliability analysis was performed by calculating the intraclass correlation coefficient (ICC), with the values of the variables and the UVEDAI obtained by both ophthalmologists in the more active eye at the baseline visit. Sensitivity to change in the UVEDAI index was assessed at 4weeks from the start of pharmacologic treatment by determining the clinically relevant change, defined as a change in UVEDAI of ≥ 0.8 points over baseline. The mean change between both measures was compared using the repeated-measures t-test. A total of 111 patients were included. In the interobserver reliability analysis, the ICC for the UVEDAI value was 0.9, and, when compared with the mean UVEDAI values obtained by the ophthalmologists, no statistically significant differences were found (p value > 0.05). As for the sensitivity to change in UVEDAI, statistically significant differences (p value = 0.00) were found for the mean values of the index compared with baseline. In all cases, the index value decreased by > 1 point at the 4-week visit. The interobserver reliability of the UVEDAI was high in the total sample. Furthermore, the index was sensitive in determining the change in inflammatory activity after treatment. We believe that UVEDAI is a disease activity index that enables objective comparison of results in clinical practice and trials.

Infographic: Adalimumab in patients with active noninfectious uveitis (VISUAL I).

Infographic: Adalimumab in patients with active noninfectious uveitis (VISUAL I).

Association of Optic Disc Hyperfluorescence with Subclinical Macular and Optic Disc Edema in Uveitis Patients

Purpose: To investigate the frequency of optic disc hyperfluorescence (ODH) and their association with macular and optic nerve head thickness in patients with active uveitis.Methods: This retrospective cross-sectional study included 37 eyes of 30 patients with active noninfectious uveitis who underwent spectral domain-optical coherence tomography (OCT) and fluorescein angiography. OCT parameters were compared between baseline and post-treatment according to the ODH.Results: ODH was observed clearly in 22 eyes (64.7%) and equivocally in five eyes (14.7%) at baseline. In subgroup analysis without clinically significant optic disc edema, central subfield thickness, peripapillary retinal nerve fiber layer thickness, disc rim area, and disc area were 262.2 μm, 110.9 μm, 1.49 mm<sup>2</sup>, and 2.02 mm<sup>2</sup> at baseline and significantly decreased after treatment (249.5 μm, 102.1 μm, 1.34 mm<sup>2</sup>, and 1.95 mm<sup>2</sup>, respectively) in eyes with ODH (<i>p</i> = 0.044, <i>p</i> < 0.001, <i>p</i> = 0.001, <i>p</i> = 0.024, respectively). However, there was no significant changes in the eyes without ODH (all <i>p</i> > 0.05).Conclusions: There was a difference in the thickness reduction of the macula and optic nerve head according to the ODH. Baseline ODH should be regarded as a sign of ocular inflammation and carefully monitored.

Efficacy and safety of adalimumab for inflammatory flare prevention in paediatric non-infectious anterior uveitis with peripheral retinal vascular leakage: a study protocol for a single-centre, randomised controlled trial

IntroductionPaediatric patients with chronic anterior uveitis are more prone to suffer from the chronic course of intraocular inflammation and adverse effects of long-term immunomodulatory therapy, either topical glucocorticosteroids or systemic...

Association between Vaccination with the BNT162b2 mRNA Coronavirus Disease 2019 Vaccine and Noninfectious Uveitis: A Population-Based Study

PurposeTo assess the association between BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccine and the risk of active noninfectious uveitis (NIU).DesignRetrospective, population-based study.ParticipantsTwo million six hundred two thousand five hundred fifty-seven people who received the first vaccine dose between December 20, 2020, and April 30, 2021, and 2 441 719 people who received the second vaccine dose between January 10, 2021, and April 30, 2021.MethodsEvents of active NIU were included if they occurred within 21 days after either vaccine dose. Active NIU was defined as newly active or worsening ocular inflammation requiring initiation or increase in local or systemic corticosteroids. Observed cases were compared with the expected number, based on the experience of the population in 2019.Main Outcome MeasuresAge- and sex-adjusted standardized incidence ratios (SIRs) and attributable risks after BNT126b2 vaccination.ResultsOverall, 100 and 88 events of active NIU were recorded within 21 days after the first and second vaccine doses, respectively. Using the experience of the population in 2019 as a reference, after the first dose, the estimated age- and sex-adjusted SIR was 1.41 (95% confidence interval [CI], 1.15–1.71) along with a 21-day attributable risk of 1.12 cases per 100 000 vaccinees. After the second dose, the SIR was 1.31 (95% CI, 1.05–1.62), with an estimated attributable risk of 0.86 cases per 100 000 vaccinees. Anterior uveitis was the most common site of inflammation, occurring in 90.96% of eyes, and idiopathic uveitis was the most common cause (56.38%).ConclusionsThis study suggests that the BNT162b2 mRNA COVID-19 vaccine may be associated with an increased risk of active NIU. However, considering the small effect size and study limitations, this study does not provide proof for a cause-and-effect relationship. The small estimated attributable risks suggest that the impact on public health is relatively minor.

Adalimumab for the Treatment of Adults With Non-Infectious Uveitis


 Four systematic reviews (SRs) and 1 economic evaluation were identified regarding the clinical effectiveness (including safety) and cost-effectiveness of adalimumab in adults with non-infectious uveitis.
 In adults with active non-infectious uveitis (VISUAL I), adalimumab significantly lowered the risk of treatment failure and significantly improved changes in best-corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Additionally, the number and rate of adverse events and serious adverse events were greater in the adalimumab group compared to the placebo group. Clinical effectiveness and safety findings from the Japanese sub study (VISUAL I Japan) and data from a randomized controlled trial of a younger adult population (ADUR) demonstrated that adalimumab may have no treatment effect.
 In adults with inactive non-infectious uveitis (VISUAL II), adalimumab significantly lowered risk of treatment failure; however, adalimumab may have no treatment effect on changes in best-corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Additionally, the number and rate of adverse events and serious adverse events were variable in the adalimumab versus placebo groups (e.g., number of adverse events was greater in the adalimumab group but the rate of adverse events was higher in the placebo groups). Clinical effectiveness and safety findings from the Japanese substudy (VISUAL II Japan) demonstrated that adalimumab may have no treatment effect.
 Considering both active and inactive non-infectious uveitis (VISUAL I, VISUAL I [Japan], VISUAL II, VISUAL II [Japan], and ADUR), change in vitreous haze grade improved significantly more in the adalimumab group than the control group.
 In the perspective of the health care system in the UK, adalimumab (plus systemic corticosteroid and immunosuppressant therapy) is not more cost-effective than systemic corticosteroid and immunosuppressant use alone (modelled by placebo data) in adults with active and inactive non-infectious uveitis influencing the posterior segment (i.e., back of the eye).
 No evidence-based guidelines regarding the use of adalimumab for the treatment of adults with non-infectious uveitis were identified.

The Role of Plasma Calprotectin in Non-infectious Uveitis

ABSTRACT Purpose To investigate the role of plasma calprotectin in non-infectious uveitis. Methods This is an observational both cross-sectional and prospective study. Patients with active non-infectious uveitis were recruited as well as nonuveitic controls. Plasma calprotectin was determined and an ophthalmological examination was performed for both patients and controls. Independent variables possibly influencing levels of plasma calprotectin were recorded and analyzed. Categorical variables were compared by chi-square test (applying correction by continuity if necessary). T-test (or Kruskal-Wallis when appropriate) was used to compare averages. Multiple linear regression analysis was used to assess relationship between plasma calprotectin levels and independent variables. Spearman coefficient was calculated in order to establish correlation between plasma calprotectin and anterior chamber cell grading. Changes in plasma calprotectin levels between the flare beginning and its resolution were determined with mixed model for repeated measures. R software (version 3.6.0) was used to perform the statistical analysis. Results We included 74 patients and 40 controls in the cross-sectional study. Plasma calprotectin levels were higher in uveitis patients compared to those of controls (p = .003), being higher in younger patients and patients with posterior uveitis. No correlation between calprotectin and anterior chamber inflammation degree was found (p = .198). For the prospective study, we included 36 patients. We found no significant differences in calprotectin levels between active and inactive uveitis (p = .344). Conclusions Plasma calprotectin levels are elevated in uveitis patients and are influenced by age and anatomical location of uveitis. Further investigation is needed to assess the relationship between calprotectin and uveitis activity.

The Effect of Adalimumab in Korean Patients with Refractory Noninfectious Uveitis.

We sought to analyze the efficacy of adalimumab in active noninfectious uveitis, and evaluate its efficacy and safety for the management of refractory noninfectious uveitis in Korean patients. A retrospective observational study was conducted. A total of 23 eyes of 14 Korean patients with noninfectious uveitis refractory to conventional treatment, including corticosteroid and immunosuppressive agents, were treated with adalimumab between December 2017 and February 2020. The primary outcomes were vitreous haziness grades, anterior chamber cell grades, and central macular thickness measured prior to injection and at 1, 3, 6, and 12 months after the first adalimumab injection. Among the 23 eyes, 14 eyes (60.9%) were diagnosed with panuveitis and 9 eyes (39.1%) with posterior uveitis [mean follow-up period: 22.3 months (7–27)]. The most common etiologic diagnoses requiring adalimumab injection were Behçet's disease (9 eyes, 39.1%), followed by undifferentiated inflammation (6 eyes, 26.1%), Vogt-Koyanagi-Harada disease (3 eyes, 13.0%), psoriasis (2 eyes, 8.7%), serpiginous chorioretinopathy (2 eyes, 8.7%), and systemic lupus erythematosus (1 eye, 4.3%). At the 1-year follow-up after the first injection, anterior chamber cell grade decreased from 0.5±0.4 to 0.3±0.4, and vitreous haziness grade decreased from 1.1±1.1 to 0.3±0.5 (p<0.05). Central macular thickness improved from 347.2±98.1 µm to 264.3±61.1 µm (p<0.05). Adalimumab injection in patients with refractory noninfectious uveitis decreased the anterior chamber cell grade, vitreous haziness grade, and central macular thickness with no severe side effect. Overall, adalimumab injection may, therefore, be an effective and relatively safe treatment modality for noninfectious uveitis in Korean patients.

Impact of COVID-19 pandemic on uveitis patients receiving immunomodulatory and biological therapies (COPE STUDY)

PurposeTo evaluate the change in the ongoing immunomodulatory (IMT) and biological therapies among patients with non-infectious uveitis (NIU), and determine the number of uveitis relapses during the COVID-19 pandemic.MethodsIn this...

Regulatory T cells and IL-17A levels in noninfectious uveitis.

Regulatory T cells (Tregs) have been intensively studied in a myriad of autoimmune diseases. As for noninfectious uveitis (NIU), results have been contradictory, and studies have failed to demonstrate a consistent reduction in Treg cell frequency in patients with active disease. The present study aims to characterize T lymphocyte subsets, including naïve and memory Tregs as well as their respective CD39 expression, in the peripheral blood of NIU patients. Inflammatory as well as suppressive cytokine profiles were also evaluated. T cell subpopulations were evaluated by multiparametric flow cytometry using anti-CD3, anti-CD4, anti-CD45, anti-CD45RA, anti-CD197, anti-CD25, anti-CD127, and anti-CD39. Treg cells were defined as CD3 + CD4+CD25hiCD127low. A multiplex bead-based immunoassay was used to determine TNF-α, IFN-ɣ, IL-17A, IL-10, and TGF-β levels. Twenty-nine patients with active NIU were included as well as 15 sex- and age-matched controls. There were no significant differences in T lymphocyte subsets, including Tregs, between patients and controls. However, patients with a lower grade of anterior chamber or vitreous inflammatory cellular reaction showed higher memory Treg counts than controls, with no respective increase in CD39+ expression, and a tendency for higher IL-17A levels (p = 0.06). This IL-17A elevation was present in the total NIU group (p = 0.08) as well as a positive correlation between IL-17A levels and the absolute counts of memory Tregs (p = 0.013; R = 0.465). Patients with higher IL-17A levels also showed higher serum concentrations of memory (p = 0.001) and naïve (p = 0.003) Tregs as well as elevated TNF-α (p < 0.0001) and IFN-ɣ (p = 0.016) levels. Negative correlations were observed between IL-10 and TGF-β levels and the percentages of memory (p = 0.030; R = - 0.411) and total CD39+ Tregs (p = 0.051; R = - 0.373) in the peripheral blood of NIU patients. Our results showed that total Treg levels were not reduced in patients with NIU. Further characterization of Treg subsets, including memory Tregs and respective CD39 expression, may provide additional insight on the role of Treg cells in NIU. Consistent high levels of circulating IL-17A in NIU patients are in accordance with previous studies and reinforce this cytokine's vital role in uveitis pathogenesis and its possible use as a therapeutic target.

A 48 Week Study to Evaluate the Efficacy and Safety of Two (2) EYS606 Treatment Regimens in Subjects With Active Chronic Non-infectious Uveitis (CNIU)

A 48 Week Study to Evaluate the Efficacy and Safety of Two (2) EYS606 Treatment Regimens in Subjects With Active Chronic Non-infectious Uveitis (CNIU)

Iontophoretic Dexamethasone Phosphate Compared to Topical Prednisolone Acetate 1% for Noninfectious Anterior Segment Uveitis

To evaluate the safety and efficacy of dexamethasone phosphate ophthalmic solution (EGP-437) delivered by a transscleral iontophoresis delivery system (EyeGate II) compared to that of topical prednisolone acetate 1% (PA 1%) in subjects with noninfectious anterior uveitis. Prospective, randomized, double-masked, parallel group, noninferiority clinical trial. A total of 193 subjects with active noninfectious anterior uveitis (anterior chamber [AC] cell count ≥11 cells) were randomized to EGP-437 delivered by iontophoresis (days 0 and 7) or self-administered PA 1% daily (tapered schedule, days 0-28). Masking was maintained with placebo iontophoresis or eye drops. The primary efficacy endpoint was the proportion of subjects with an AC cell count of zero on day 14. Noninferiority of EGP-437 was defined if the lower limit of the confidence interval (CI) for the difference (EGP-437minus PA 1%) was less than-10%. At day 14, 32 of 96 EGP-437 subjects (33.3%) and 32 of 97 PA 1% subjects (33.0%) had an AC cell count of zero (difference, 0.34; 95% CI,-12.94 to 13.63; P= 0.064). Efficacy trended better with EGP-437 among patients with more severe baseline uveitis (AC cell count >25). Safety and tolerability were good with both treatments. EGP-437 subjects experienced fewer IOP elevations ≥6mm Hg versus PA 1% subjects (13 vs 24 incidents, respectively, through day28). Despite clinically similar response rates, statistical noninferiority of EGP-437 versus a tapered regimen of PA 1% was not achieved. Numerical trends suggesting fewer IOP elevations with EGP-437, similar efficacy overall, and possibly better efficacy in more severe disease warrant further study.

Long-Term Outcomes of Treatment with Biological Agents in Eyes with Refractory, Active, Noninfectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis

To examine a large cohort of patients treated with biologic agents for active noninfectious intermediate uveitis, posterior uveitis, or panuveitis (NIPPU) and to compare their efficacy and long-term effect. Retrospective, longitudinal study. Eighty-two patients (156 eyes) with active NIPPU after failure of treatment with corticosteroids and a second-line immunosuppression drug and treated with biologic agents who were treated at Moorfields Eye Hospital between 2001 and2016. Information was gathered from the clinical notes of all patients. Time to first disease flare, rate of treatment failure, best-corrected visual acuity, and risk factors for treatment failure. Patients were followed on average for 4.7±0.4 years (724 eye-years). All patients demonstrated active uveitis at baseline, and 34 patients (41.5%) demonstrated a coexisting active systemic disease. Control of ocular inflammation was achieved in 136 eyes (87.2%). The average oral prednisolone dose at baseline was 16.4±1.7 mg/day, and by 6 months reduced to 6.5±0.7 mg/day (P < 0.0001), remaining stable for up to 5 years follow-up. Best-corrected visual acuity at baseline was 0.5±0.1 logarithm of the minimum angle of resolution (logMAR), improved to 0.4±0.1 logMAR (P= 0.008) at 3 months, and remained stable during follow-up. After baseline, 42.3% of eyes experienced flares, and the average number of flares reduced from 1.8±0.1 flares/year to 0.6±0.1 flares/year (P < 0.0001). Median time to first flare was 5.4 years (95% confidence interval [CI], 2.2-5.4 years) with a 5-year survival rate of 58.7%. Treatment failed in 37 eyes (23.7%), with a 5-year survival rate of 68.0% and an estimated time to 75% survival of 2.9 years (95% CI, 2.1-4.4 years). The risk for treatment failure was lower when treatment used adalimumab (odds ratio, 0.4; 95% CI, 0.2-0.9; P= 0.03) but was greater when systemic disease also was active at baseline (odds ratio, 3.2; 95% CI, 1.5-7.1; P= 0.004). Overall, eyes treated with biologic agents after failure of treatment with corticosteroids and a second-line immunosuppression drug experienced satisfactory disease control (87.2%), reduced use of systemic immunosuppression, stable visual acuity, and a 23.7% risk of disease relapse. After multivariate adjustment, older age, treatment with adalimumab (versus infliximab), and inactive concomitant systemic disease were associated with a lower risk of treatment failure.

High-Dimensional Profiling Reveals Heterogeneity of the Th17 Subset and Its Association With Systemic Immunomodulatory Treatment in Non-infectious Uveitis.

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.

Single Dexamethasone Intravitreal Implant in the Treatment of Noninfectious Uveitis.

To investigate the effect of a single intravitreal dexamethasone implant (IVT-DI; Ozurdex; Allergan, Inc.) on visual acuity, macular thickness, and intraocular pressure (IOP) in active noninfectious uveitis. Medical records of patients with noninfectious active uveitis treated by IVT-DIs were retrospectively reviewed. Uveitis etiologies, treatment indications, best corrected visual acuity (BCVA), central retinal thickness measured by ocular coherence tomography, IOP, and systemic, local, and topical treatments were collected. Parameters were analyzed before the injection of the implant, after 1.5 ± 0.8 months and 4.4 ± 0.9 months for the BCVA, after 2 ± 1.3 months and 4.6 ± 1.3 months for the ocular coherence tomography, and after 1.3 ± 0.7 months and 4.4 ± 1 months for the IOP. We included 14 patients (20 eyes, 20 implant injections) with cystoid macular edema (78%), vasculitis (7%), choroiditis (7%), and vasculitis associated with choroiditis (7%). Before the injection, mean visual acuity was 0.4 ± 0.5 logMAR (logarithm of the minimum angle of resolution) that improved to 0.3 ± 0.5 logMAR (P = 0.0002) after 1.5 ± 0.8 months and to 0.3 ± 0.5 logMAR (P = 0.005) after 4.4 ± 0.9 months. A statistically significant decrease of macular thickness was observed both at 2 ± 1.3 months and at 4.6 ± 1.3 months after IVT-DI. Mean IOP was 16 ± 5 mmHg before injections, 18 ± 6 mmHg (P = 0.13) at 1.3 ± 0.7 months, and 15 ± 4 mmHg (P = 0.65) at 4.4 ± 1 months. By Kaplan-Meier analysis, we found that after 3.3 months, 17% of the eyes still present a BCVA amelioration ≥0.3 logMAR. In our patients with active noninfectious uveitis, injection of a first single dexamethasone implant was found to improve visual acuity and decrease macular thickness without significant increase of IOP, although the effect seems limited in time.

Adalimumab for Treatment of Noninfectious Uveitis: Immunogenicity and Clinical Relevance of Measuring Serum Drug Levels and Antidrug Antibodies

To evaluate the rate of immunogenicity induced by adalimumab and its relationship with drug serum levels and clinical responses in patients with noninfectious uveitis. Prospective observational study. Consecutive patients from 1 referral center who initiated treatment with adalimumab for active noninfectious uveitis resistant to conventional therapy. All patients received 40 mg adalimumab every other week. Patients were evaluated clinically and immunologically before and after 4, 8, and 24 weeks of treatment. Clinical evaluation included assessment of changes in visual acuity, degree of inflammation in the anterior chamber and vitreous cavity, central macular thickness, and retinal angiographic leakage. Immunologic evaluation included assessment of serum trough adalimumab and antibodies against adalimumab (AAA) levels and class II HLA typing. Twenty-five patients were enrolled. Overall, 18 of 25 patients (72%) showed a favorable clinical response to adalimumab therapy. Eleven patients (44%) achieved a complete response and 7 (28%) achieved a partial response. However, 7 of 25 patients (28%) were considered nonresponders. Median trough adalimumab serum levels were higher in responders than in nonresponders (P < 0.001). We observed AAA positivity (AAA+) at least 1 time point in 8 of 25 patients (32%), including 4 with transitory AAA and 4 with permanent AAA. In all patients with permanent AAA+, trough adalimumab levels became undetectable (P<0.001). However, in patients who demonstrated transitory AAA+, no correlation was observed between AAA titers and adalimumab trough levels (P= 0.2).Concomitant immunosuppression did not show any protective effect on adalimumab immunogenicity in our cohort. An association between the presence of AAA+ and a worse uveitis outcome was observed only in patients with permanent AAA+, which correlated with undetectable adalimumab trough levels (P= 0.014). Treatment of noninfectious uveitis with adalimumab is associated with high rates of favorable clinical response. Overall, adalimumab trough levels were higher in responder patients. Development of permanent AAA was associated with undetectable trough adalimumab levels and worse uveitis outcome. Immunogenicity was more common in patients in whom uveitis was associated with a systemic disease and was not influenced by concomitant immunosuppressors.

Intravitreal Sirolimus for Noninfectious Uveitis: A Phase III Sirolimus Study Assessing Double-masKed Uveitis TReAtment (SAKURA)

To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious uveitis (NIU) of the posterior segment (i.e., posterior, intermediate, or panuveitis). Phase III, randomized, double-masked, active-controlled, 6-month study with intravitreal sirolimus. Adults with active NIU of the posterior segment (intermediate, posterior, or panuveitis), defined as a vitreous haze (VH) score >1+. Subjects discontinued NIU medications before baseline, except for systemic corticosteroids, which were allowed only for those already receiving them at baseline and were rapidly tapered after baseline per protocol. Intravitreal sirolimus assigned 1:1:1 at doses of 44 (active control), 440, or 880 μg, administered on Days 1, 60, and120. The primary efficacy outcome was the percentage of subjects with VH 0 response at Month 5 (study eye) without use of rescue therapy. Secondary outcomes at Month 5 were VH 0 or 0.5+ response rate, corticosteroid tapering success rate (i.e., tapering to a prednisone-equivalent dosage of ≤5 mg/day), and changes in best-corrected visual acuity (BCVA). Adverse events during the double-masked treatment period are presented. A total of 347 subjects were randomized. Higher proportions of subjects in the intravitreal sirolimus 440 μg (22.8%; P= 0.025) and 880 μg (16.4%; P= 0.182) groups met the primary end point than in the 44 μg group (10.3%). Likewise, higher proportions of subjects in the 440 μg (52.6%; P= 0.008) and 880 μg (43.1%; P= 0.228) groups achieved a VH score of 0 or 0.5+ than in the 44 μg group (35.0%). Mean BCVA was maintained throughout the study in each dose group, and the majority of subjects receiving corticosteroids at baseline successfully tapered off corticosteroids (44 μg [63.6%], 440 μg [76.9%], and 880 μg [66.7%]). Adverse events in the treatment and active control groups were similar in incidence, and all doses were well tolerated. Intravitreal sirolimus 440 μg demonstrated a significant improvement in ocular inflammation with preservation of BCVA in subjects with active NIU of the posterior segment.

Adalimumab in Patients with Active Noninfectious Uveitis

BackgroundPatients with noninfectious uveitis are at risk for long-term complications of uncontrolled inflammation, as well as for the adverse effects of long-term glucocorticoid therapy. We conducted a trial to assess the efficacy and safety of adalimumab as a glucocorticoid-sparing agent for the treatment of noninfectious uveitis.MethodsThis multinational phase 3 trial involved adults who had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite having received prednisone treatment for 2 or more weeks. Investigators and patients were unaware of the study-group assignments. Patients were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. All patients received a mandatory prednisone burst followed by tapering of prednisone over the course of 15 weeks. The primary efficacy end point was the time to treatment failure occurring at or after week 6. Treatment failure was a multicomponent outcome that was based on assessment of new inflammatory lesions, best corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Nine ranked secondary efficacy end points were assessed, and adverse events were reported.ResultsThe median time to treatment failure was 24 weeks in the adalimumab group and 13 weeks in the placebo group. Among the 217 patients in the intention-to-treat population, those receiving adalimumab were less likely than those in the placebo group to have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70; P<0.001). Outcomes with regard to three secondary end points (change in anterior chamber cell grade, change in vitreous haze grade, and change in best corrected visual acuity) were significantly better in the adalimumab group than in the placebo group. Adverse events and serious adverse events were reported more frequently among patients who received adalimumab (1052.4 vs. 971.7 adverse events and 28.8 vs. 13.6 serious adverse events per 100 person-years).ConclusionsIn our trial, adalimumab was found to be associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than was placebo. (Funded by AbbVie; VISUAL I ClinicalTrials.gov number, NCT01138657.)

Long‐Term Safety of Intravitreal Sirolimus for the Treatment of Non‐infectious Uveitis (NIU) of the Posterior Segment: 12‐Month SAKURA Study 1 Results

PurposeIntravitreal sirolimus significantly reduced inflammation in subjects with NIU of the posterior segment and provided clinically relevant visual benefit, with an acceptable incidence of ocular adverse events (AEs), in the double‐masked period of SAKURA Study 1, the first of 2 phase 3 randomized trials. Here, we report the long‐term (12 month) safety findings from the combined double‐masked and open‐label treatment periods.MethodsSubjects with active NIU of the posterior segment (N = 347) were randomized to 44 μg (active control), 440 μg, or 880 μg injections of intravitreal sirolimus, administered every 2 months. At M6, all subjects transitioned to 880 µg injections every 2 months.Results287 subjects entered the open‐label treatment period and completed the M12 Vitreous Haze assessment. Of these, 211 received ≥1 intravitreal sirolimus injections. Through M12, the most common serious ocular AEs (study eye) occurring in ≥2% of subjects were ocular inflammation (2.9–5.8%), cataract (3.8%), and medication residue (transient drug depot in the visual axis; 2.3%). The mean change in intraocular pressure was &lt;2 mm Hg. The incidence of confirmed endophthalmitis was 0.06%/injection.ConclusionsThere was a low incidence of serious ocular AEs over 12 months with intravitreal sirolimus in this heterogeneous group of subjects with NIU of the posterior segment.