Vitreous Haze Grade Research Articles

Tuberculosis

SummaryThe diagnosis of intraocular tuberculosis (TB) is often presumptive, made on the basis of suggestive ocular features, evidence of latent or manifest TB, exclusion of other causes of uveitis, and positive response to antitubercular treatment (ATT). The most typical features include serpiginous‐like choroiditis and occlusive retinal vasculitis. When the posterior segment is involved, treatment relies on ATT, usually in association with systemic or periocular corticosteroids. Patients should be monitored for response of inflammation to treatment, recurrences, adherence to ATT and treatment side‐effects. Clinical assessment of ocular TB at presentation and during follow‐up includes grading of vitreous haze, characterization of choroidal involvement, retinal vascular involvement and optic disc changes, and evaluation of anterior chamber cells and flare. Laser flare photometry may be used to monitor anterior chamber inflammation. Ocular imaging tests including fundus autofluorescence, fluorescein angiography, indocyanine green angiography, SD and EDI optical coherence tomography (OCT), and OCT angiography may be very useful in analyzing and quantifying specific TB retinal and choroidal changes.

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.)

Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial

Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10-35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov number NCT01124838. Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77-357) in the placebo group and 245 days (119-564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39-0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. AbbVie.

Safety and Outcome of Microincision Vitreous Surgery in Uveitis

ABSTRACTPurpose: To report the outcome of microincision vitreous surgery (MIVS) in uveitis.Methods: In total, 103 patients (106 eyes) underwent diagnostic MIVS between March 2012 and April 2015. Postoperative evaluation included vitreous haze grading from clinical/electronic records, best-corrected visual acuity (BCVA), and complications.Results: Mean age was 36.8 ± 13.9 years (range: 8–80 years). Mean follow-up after MIVS was 12.2 ± 7.2 months (median 12 months). Mean vitreous haze grading was 2.39 ± 0.98 (preoperatively), 0.36 ± 0.73 postoperatively (1 week), and 0.02 ± 0.2 at 1 month (p < 0.001). Mean BCVA was 1.5 ± 1.0 logMAR preoperatively and 0.72 ± 0.68 logMAR at 1 month (p = 0.000). Postoperative complications included cataract (14.6%), rise in intraocular pressure (13.2%), vitreous hemorrhage (4.7%), hypotony (3.2%), retinal detachment (2.8%), epiretinal membrane (2.8%), and worsening of inflammation (0.9%).Conclusions: MIVS is safe and may have a therapeutic role in uveitis.

The effect of intravitreal adalimumab on the treatment of active noninfectious ocular inflammation: A pilot study

AbstractPurpose To evaluate the short term efficacy of intravitreal adalimumab (IVA) for the treatment of eyes with active noninfectious uveitis.Methods In a prospective noncomparative interventional case series, consecutive eyes with active noninfectious uveitis were injected with IVA at 0, 2 then every 4 weeks for total of 6 months. Change in VA, grade of inflammation (cells, haze, leakage on FA adopted from the angiography scoring for uveitis working group), and central retinal thickness (CRT) were recorded. No systemic or ocular therapies were added to the IVA treatment during the study period.Results Six out of seven patients (12 of 13 eyes) completed 26 weeks of treatment. One patient (1 eye) failed treatment. Median logMar VA at baseline was 0.243 and improved to 0.049 at 26 weeks. Seven out of twelve eyes had improvement of ≥2 ETDRS lines. All three eyes with anterior chamber cells grade ≥1 at baseline had zero cells at 26 weeks. Also, all nine eyes with vitreous haze grade ≥1 at baseline had zero haze on last follow up. Median CRT at baseline was 317 microns and decreased to 277 microns. Five out of eight eyes with macular edema had complete resolution. Median FA score at baseline was 14 and improved to 4. Using Wilcoxon Signed Rank test, the decrease in logMar, CRT and FA score at 26 weeks compared to baseline was significant (n=12 eyes; p=0.003, 0.021, 0.002 respectively). No local or systemic side effects were detected. Stratifying the data to include one eye per patient revealed similar results.Conclusion IVA was safe in this pilot study; was effective in improving the VA in 7/12 eyes, resolving macular edema in 5/8 eyes &amp; decreasing AC cells, vit haze and FA score in 12 eyes while 1 patient (1 eye) failed treatment.

Interobserver Agreement in Clinical Grading of Vitreous Haze Using Alternative Grading Scales

To evaluate the reliability of clinical grading of vitreous haze using a new 9-step ordinal scale versus the existing 6-step ordinal scale. Evaluation of diagnostic test (interobserver agreement study). A total of 119 consecutive patients (204 uveitic eyes) presenting for uveitis subspecialty care on the study day at 1 of 3 large uveitis centers. Five pairs of uveitis specialists clinically graded vitreous haze in the same eyes, one after the other using the same equipment, using the 6- and 9-step scales. Agreement in vitreous haze grade between each pair of specialists was evaluated by the κ statistic (exact agreement and agreement within 1 or 2 grades). The scales correlated well (Spearman's ρ = 0.84). Exact agreement was modest using both the 6-step and 9-step scales: average κ = 0.46 (range, 0.28-0.81) and κ = 0.40 (range, 0.15-0.63), respectively. Within 1-grade agreement was slightly more favorable for the scale with fewer steps, but values were excellent for both scales: κ = 0.75 (range, 0.66-0.96) and κ = 0.62 (range, 0.38-0.87), respectively. Within 2-grade agreement for the 9-step scale also was excellent (κ = 0.85; range, 0.79-0.92). Two-fold more cases were potentially clinical trial eligible on the basis of the 9-step than the 6-step scale (P<0.001). Both scales are sufficiently reproducible using clinical grading for clinical and research use with the appropriate threshold (≥ 2- and ≥ 3-step differences for the 6- and 9-step scales, respectively). The results suggest that more eyes are likely to meet eligibility criteria for trials using the 9-step scale. The 9-step scale appears to have higher reproducibility with Reading Center grading than clinical grading, suggesting that Reading Center grading may be preferable for clinical trials.

Risk factors associated with the relapse of uveitis in patients with juvenile idiopathic arthritis: a preliminary report

To identify risk factors associated with relapse of uveitis in patients with recurrent uveitis associated with juvenile idiopathic arthritis (JIA) after treatment with immunomodulatory therapy (IMT) and durable remission of 1 year. The medical records of 30 patients with JIA-associated uveitis who were successfully treated with IMT to a state of corticosteroid-free remission and subsequently remained in remission after discontinuation of IMT for a period of at least 1 year were retrospectively reviewed. In subsequent follow-up, some patients had relapse of uveitis, whereas others continued to be in remission. Remission was defined as <1 + cells in the anterior chamber and <1 + vitreous haze grading; relapse was defined as ≥ 1 + cell in the anterior chamber or ≥ 1 + vitreous haze grading. A total of 30 patients were included. Of these, 17 (56.7%) patients remained in uveitic remission, whereas 13 (43.3%) relapsed. The patients in remission received IMT earlier in the course of disease compared with patients who relapsed (median, 12 months vs 72 months; P = 0.002 [Mann-Whitney test]). Patients in remission had received treatment with IMT at a younger age compared with the relapse group (median age, 7 years vs 13 years; P = 0.02 [Mann-Whitney test]). None of the other factors studied revealed a statistically significant association. Patients with JIA-associated uveitis who were treated with IMT earlier in the course of disease and at a younger age were associated with a lower rate of relapse of uveitis after durable remission and 1 year of quiescence, compared with similar patients who relapsed.

Validation of a Photographic Vitreous Haze Grading Technique for Clinical Trials in Uveitis

To validate a photographic vitreous haze grading technique using a 9-step logarithmic scale in patients enrolled in a randomized, controlled clinical trial in uveitis. Retrospective study of clinical trials methodology. University-based department of ophthalmology. Baseline fundus photographs of patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. Grading of vitreous haze using a previously described photographic scale. Regrading of a subset of photographs to assess intraobserver agreement. Interobserver and intraobserver intraclass correlation for photographic haze grading, and correlation between photographic and clinical vitreous haze scores, assessment of the clinical findings that significantly affect the photographic haze score. Vitreous haze was graded in 271 eyes (142 patients) by 3 postgraduate ophthalmologists. The interobserver and intraobserver intraclass correlations were excellent, with correlation coefficients between 0.84 and 0.93. There was moderately strong correlation between the photographic and clinical vitreous haze scores (r=0.51; P<.001), with significant differences among the mean and median photographic haze scores for the 3 lowest clinical grades of haze, 0, 1+, and 2+. Other parameters that correlated with photographic vitreous haze score included visual acuity of 20/50 or worse (P=.003), degrees of posterior synechiae (P<.001), lens abnormality (P=.023) or posterior capsule obscuration (P=.001), and amount of anterior vitreous cell (P=.002). Photographic grading of vitreous haze with a 9-step logarithmic scale is a highly reproducible methodology that may be adaptable to use in future clinical trials.

Scale for Photographic Grading of Vitreous Haze in Uveitis

To validate a scale for grading vitreous haze in uveitis using digitized photographs and standardized scoring. Evaluation of clinical research methodology. Calibrated Bangerter diffusion filters inducing incremental decrements of spatial contrast were placed in front of the camera lens while photographing a normal eye to simulate vitreous haze. The photographs were digitized and an ordinal scale was created from 0 (none) to 8 (highest level of opacification at which fundus details could be seen). The scale steps correspond approximately to decimal Snellen visual acuities of 1.0, 0.8, 0.4, 0.2, 0.1, 0.04, 0.02, 0.01, and 0.002, with approximately 0.3 log step between each step. For validation, digitized fundus photographs of uveitis patients were displayed on a computer monitor for comparison with the standard photos. Three observers graded the test set twice under standard conditions. Interobserver and intraobserver variability and κ values for agreement greater than chance were calculated. Variance component analysis determined that 87.7% of the variance in grades was attributable to the test item rather than to grader or session. The intraclass correlation between graders and grading sessions varied from 0.84 to 0.91. Simple agreement within 1 grade between graders and sessions occurred in 90 ± 5.5% of gradings. κ values averaged 0.91, which is considered near perfect. A 9-step photographic scale was designed to standardize the grading of vitreous haze in uveitis patients using fundus photographs. The scale is potentially adaptable to clinical trials in uveitis.

Interobserver Agreement in Grading Activity and Site of Inflammation in Eyes of Patients with Uveitis

To evaluate the reproducibility of new criteria for grading the site and activity of intraocular inflammation. Cross-sectional agreement study. Grading of 202 eyes of 101 patients with uveitis was conducted by pairs of uveitis subspecialists at three uveitis subspecialty clinics. Agreement in grading location of inflammation, anterior chamber (AC) cells, AC flare, vitreous cells (present or absent), and vitreous haze was calculated. Proposed criteria for grading the location of intraocular inflammation had moderate reproducibility (kappa range, 0.49 to 0.61). Reproducibility improved (kappa range, 0.61 to 0.73) when the newly proposed category of anterior and intermediate uveitis was excluded. The ranges of kappa statistics for exact agreement on gradings of AC cells (range, 0.34 to 0.43) demonstrated low to moderate levels of agreement, and gradings of AC flare (range, 0.50 to 0.64), vitreous cells (range, 0.48 to 0.51), and vitreous haze (0.53) were in the moderate agreement range. However, agreement within 1 grade was outstanding for AC cells (kappa range, 0.81 to 1.00) and vitreous haze (kappa, 0.75). For AC flare, a distribution skewed toward low grades within 1 grade made kappa statistics unstable. Proposed methods for grading inflammatory activity have moderate reproducibility for exact agreement in most instances. However, agreement within 1 grade is excellent for grading of AC cells and vitreous haze. The method for grading the site of intraocular inflammation also produces moderate levels of agreement, and in our hands was improved by excluding both anterior and intermediate uveitis. Improved methods for grading AC flare and vitreous cells are needed.

High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, non-infectious uveitis

Purpose This study was designed to provide preliminary data regarding the safety and efficacy of high-dose humanized anti-IL-2 receptor (daclizumab) therapy for the treatment of active intermediate, posterior or panuveitis. Methods Five patients were recruited into this non-randomized, prospective pilot study of high-dose intravenous induction daclizumab therapy given at doses of 8 mg/kg at day 0 and 4 mg/kg at day 14. Patients who did not meet a safety endpoint at the 3-week follow-up evaluation were given the option of continuing therapy with subcutaneous daclizumab at 2 mg/kg every 4 weeks for 52 weeks. The primary outcome assessed was a two-step decrease in vitreous haze at day 21. Secondary outcomes evaluated included best-corrected visual acuity, retinal thickness as measured by optical coherence tomography, retinal vascular leakage assessed by fluorescein angiography, anterior chamber and vitreous cellular inflammation. Results Four male patients and one female patient were enrolled. Diagnoses included birdshot retinochoroidopathy (two patients), Vogt–Koyanagi–Harada's disease, bilateral idiopathic panuveitis and bilateral idiopathic intermediate uveitis. By the 4th week, four of five patients demonstrated a two-step decrease in vitreous haze. The other participant did not meet this criterion until week 20, but all five patients maintained stability in vitreous haze grade throughout their follow-up periods. At enrollment, mean visual acuity (10 eyes in 5 patients) was 69.2 ETDRS letters and following treatment was 78.2 letters ( p < 0.12). Anterior chamber cell, vitreous cell, and vitreous haze also improved in the majority of eyes. Adverse events were generally mild except for one episode of left-lower lobe pneumonia requiring hospitalization and treatment. Conclusion This is the first demonstration that high-dose daclizumab can reduce inflammation in active uveitis. Daclizumab was well tolerated but there may be a potential increased risk of infection associated with immunosuppression. All five patients demonstrated a decrease in vitreous haze and measures of intraocular inflammation at final follow-up. The results of this small, non-randomized pilot study support the consideration of high-dose daclizumab therapy in cases of active posterior uveitis.