Dr. Altaweel is an Assistant Professor of Ophthalmology at the University of Wisconsin School of Medicine and Public Health and Co-Director of the University of Wisconsin Department of Ophthalmology Fundus Photograph Reading Center. His clinical specialties include diseases and surgery of the retina and vitreous, and fundus interpretation. His research interests include clinical trials of drug efficacy as well as the scientific grading of retinal photographs and fluorescein angiograms.
Periocular Triamcinolone vs. Intravitreal Triamcinolone vs. Intravitreal Dexamethasone Implant for the Treatment of Uveitic Macular Edema: The PeriOcular vs. INTravitreal corticosteroids for uveitic macular edema (POINT) Trial.
Ophthalmology. 2018 Sep 20;:
Authors: Multicenter Uveitis Steroid Treatment Trial Research Group, Writing Committee:, Thorne JE, Sugar EA, Holbrook JT, Burke AE, Altaweel MM, Vitale AT, Acharya NR, Kempen JH, Jabs DA
PURPOSE: To evaluate the comparative effectiveness of 3 regional corticosteroid injections for uveitic macular edema (ME): periocular triamcinolone acetonide (PTA), intravitreal triamcinolone acetonide (ITA), and the intravitreal dexamethasone implant (IDI).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: Patients with uveitic ME.
METHODS: Patients were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME were assigned the same treatment for both eyes.
MAIN OUTCOME MEASURES: The primary outcome was the proportion of baseline (PropBL) central subfield thickness (CST) at 8 weeks (CST at 8 weeks/CST at baseline) assessed with OCT by masked readers. Secondary outcomes included ≥20% improvement and resolution of ME, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) events over 24 weeks.
RESULTS: All treatment groups demonstrated improved CST during follow-up. At 8 weeks, each group had clinically meaningful reductions in CST relative to baseline (PropBL: 0.77, 0.61, and 0.54, respectively, which translates to reductions of 23%, 39%, and 46% for PTA, ITA, and IDI, respectively). Intravitreal triamcinolone acetonide (PropBL ITA/PropBL PTA, hazard ratio [HR], 0.79; 99.87% confidence interval [CI], 0.65-0.96) and IDI (PropBL IDI/PropBL PTA, HR, 0.69; 99.87% CI, 0.56-0.86) had larger reductions in CST than PTA (P < 0.0001). Intravitreal dexamethasone implant was noninferior to ITA at 8 weeks (PropBL IDI/PropBL ITA, HR, 0.88; 99.87% CI, 0.71-1.08). Both ITA and IDI treatments also were superior to PTA treatment in improving and resolving uveitic ME. All treatment groups demonstrated BCVA improvement throughout follow-up. Both ITA and IDI groups had improvements in BCVA that was 5 letters greater than in the PTA group at 8 weeks (P < 0.004). The risk of having IOP ≥24 mmHg was higher in the intravitreal treatment groups compared with the periocular group (HR, 1.83; 95% CI, 0.91-3.65 and HR, 2.52; 95% CI, 1.29-4.91 for ITA and IDI, respectively); however, there was no significant difference between the 2 intravitreal treatment groups.
CONCLUSIONS: Intravitreal triamcinolone acetonide and the IDI were superior to PTA for treating uveitic ME with modest increases in the risk of IOP elevation. This risk did not differ significantly between intravitreal treatments.
PMID: 30269924 [PubMed - as supplied by publisher]
Comparison of Monthly vs Treat-and-Extend Regimens for Individuals With Macular Edema Who Respond Well to Anti-Vascular Endothelial Growth Factor Medications: Secondary Outcomes From the SCORE2 Randomized Clinical Trial.
JAMA Ophthalmol. 2018 Feb 24;:
Authors: Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, Altaweel M, Berinstein DM, SCORE2 Investigator Group
Importance: Comparisons of monthly vs treat-and-extend anti-vascular endothelial growth factor (anti-VEGF) regimens for macular edema from central retinal vein occlusion or hemiretinal vein occlusion is needed.
Objective: To compare visual acuity letter score and central subfield thickness outcomes of participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial who then received either monthly injections or treat-and-extend (TAE) regimens of aflibercept or bevacizumab after a good response at month 6.
Design, Setting, and Participants: This randomized clinical trial enrolled participants from 66 private practice or academic centers in the United States. All participants had macular edema associated with central retinal vein occlusion or hemiretinal vein occlusion, had enrolled in the SCORE2 trial, and had a protocol-defined good response to monthly injections in the first 6 months of the trial. Participants initially assigned to receive monthly aflibercept were randomized to aflibercept on a monthly or TAE schedule, and participants initially assigned to receive monthly injections of bevacizumab were randomized to receive bevacizumab on a monthly or TAE schedule. The first participant was randomized in the SCORE2 trial on September 17, 2014, and the last month 12 visit occurred on October 24, 2016.
Main Outcomes and Measures: Change from month 6 to month 12 in best-corrected electronic visual acuity letter score (per the Early Treatment Diabetic Retinopathy Study).
Results: The 293 participants had a mean (SD) age of 68.9 (11.9) years; 127 (43.3%) were female. Of these, 79 were randomized to aflibercept on a monthly schedule, 80 to aflibercept on a TAE schedule, 67 to monthly bevacizumab, and 67 to bevacizumab on a TAE schedule. Mean treatment group difference (the change in visual acuity letter score in the monthly group minus the change in the TAE group) from month 6 to month 12 was 1.88 (97.5% CI, -1.07 to 4.83; P = .15) for aflibercept and 1.98 (97.5% CI, -1.08 to 5.03; P = .15) for bevacizumab. In the aflibercept arm, the mean number of injections between months 6 and 11 was 5.8 in the monthly injection group (95% CI, 5.6 to 5.9) and 3.8 in the TAE group (95% CI, 3.5 to 4.1; P < .001); in the bevacizumab arm, the mean number of injections was 5.8 (95% CI, 5.6 to 5.9) in the monthly group and 4.5 in the TAE group (95% CI, 4.2 to 4.8; P < .001).
Conclusions and Relevance: One to 2 fewer injections of aflibercept or bevacizumab were given to the TAE groups than the monthly groups in months 6 to 12 for macular edema associated with central retinal or hemiretinal vein occlusion. Because of wide confidence intervals on the differences between the groups, caution is warranted before concluding that the regimens are associated with similar vision outcomes.
Trial Registration: www.clinicaltrials.gov identifier: NCT01969708.
PMID: 29476687 [PubMed - as supplied by publisher]
VISCOELASTIC ASSISTED DRAINAGE OF SUPRACHOROIDAL HEMORRHAGE ASSOCIATED WITH SETON DEVICE IN GLAUCOMA FILTERING SURGERY.
Retina. 2017 Feb;37(2):396-399
Authors: Kurup SK, McClintic JI, Allen JC, Baartman BJ, Altaweel MM, Garg SJ, Quiroz-Mercado H
PURPOSE: The purpose of this article is to describe a novel surgical technique for the management of large suprachoroidal hemorrhages associated with the insertion of glaucoma seton devices.
METHODS: In this interventional case series, the authors describe six eyes of six patients who had management of suprachoroidal hemorrhage with pars plana choroidal drainage along with simultaneous insertion of viscoelastic into the posterior segment. All patients had a median of 8-month postoperative follow-up.
RESULTS: Five of the 6 patients had useful final vision ranging from 20/40 to 20/200. In all cases, the postoperative intraocular pressures did not increase beyond 28 mmHg and responded to aqueous humor suppressants.
CONCLUSION: As suprachoroidal hemorrhage can be a devastating complication of glaucoma surgery, the authors report a relatively straightforward surgical technique that can restore ambulatory vision in a high proportion of patients.
PMID: 28118286 [PubMed - in process]
Factors Predicting Visual Acuity Outcome in Intermediate, Posterior and Panuveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial.
Am J Ophthalmol. 2015 Sep 16;
Authors: Kempen JH, Van Natta ML, Altaweel MM, Dunn JP, Jabs DA, Lightman SL, Thorne JE, Holbrook JT, Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group
PURPOSE: To identify factors associated with best-corrected visual acuity (BCVA) presentation and two-year outcome in 479 intermediate, posterior, and panuveitic eyes.
DESIGN: Cohort study using randomized controlled trial data METHODS: Multicenter Uveitis Steroid Treatment (MUST) Trial masked BCVA measurements at baseline and 2 years' follow-up used gold standard methods. Twenty-three clinical centers documented characteristics per protocol, which were evaluated as potential predictive factors for baseline BCVA and two-year change in BCVA.
RESULTS: Baseline factors significantly associated with reduced BCVA included: age≥50 vs. <50 years; posterior vs. intermediate uveitis; uveitis duration>10 vs. <6 years; anterior chamber (AC) flare>grade 0; cataract; macular thickening; and exudative retinal detachment. Over two years, eyes better than 20/50 and 20/50 or worse at baseline improved, on average, by 1 letter (p=0.52) and 10 letters (p<0.001) respectively. Both treatment groups and all sites of uveitis improved similarly. Factors associated with improved BCVA included resolution of active AC cells, of macular thickening, and cataract surgery in an initially cataractous eye. Factors associated with worsening BCVA included longer duration of uveitis (6-10 or >10 vs. <6 years), incident AC flare, cataract at both baseline and follow-up, pseudophakia at baseline, persistence or incidence of vitreous haze, and incidence of macular thickening.
CONCLUSIONS: Intermediate, posterior and panuveitis have a similarly favorable prognosis with both systemic and fluocinolone acetonide implant treatment. Eyes with more prolonged/severe inflammatory damage and/or inflammatory findings initially or during follow-up have a worse visual acuity prognosis. The results indicate the value of implementing best practices in managing inflammation.
PMID: 26386159 [PubMed - as supplied by publisher]
Outcomes of eyes with lesions composed of >50% blood in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Ophthalmology. 2015 Feb;122(2):391-398.e5
Authors: Altaweel MM, Daniel E, Martin DF, Mittra RA, Grunwald JE, Lai MM, Melamud A, Morse LS, Huang J, Ferris FL, Fine SL, Maguire MG, Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Comparison of Age-related Macular Degeneration Treatments Trials CATT Research Group
OBJECTIVE: To compare baseline characteristics, treatment frequency, visual acuity (VA), and morphologic outcomes of eyes with >50% of the lesion composed of blood (B50 group) versus all other eyes (Other group) enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).
DESIGN: Prospective cohort study within a multicenter randomized clinical trial.
PARTICIPANTS: CATT patients with neovascular age-related macular degeneration (AMD).
METHODS: Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different dosing regimens over a 2-year period. Reading center graders evaluated baseline and follow-up morphology in color fundus photographs, fluorescein angiography (FA), and optical coherence tomography (OCT). Masked examiners tested VA.
MAIN OUTCOME MEASURES: Morphologic features and VA at 1 and 2 years.
RESULTS: The B50 group consisted of 84 of 1185 (7.1%) patients enrolled in CATT. Baseline lesion characteristics differed between groups. In the B50 group, choroidal neovascularization size was smaller (0.73 vs 1.83 disc areas [DA]; P < 0.001), total lesion size was greater (4.55 vs 2.31 DA; P <0.001), total retinal thickness was greater (524 vs 455 μm; P = 0.02), and mean VA was worse (56.0 vs 60.9 letters; P = 0.002). Increases in mean VA were similar in the B50 and Other groups at 1 year (+9.3 vs +7.2 letters; P = 0.22) and at 2 years (9.0 vs 6.1 letters; P = 0.17). Eyes treated PRN received a similar number of injections in the 2 groups (12.2 vs 13.4; P = 0.27). Mean lesion size in the B50 group decreased by 1.2 DA at both 1 and 2 years (primarily owing to resolution of hemorrhage) and increased in the Other group by 0.33 DA at 1 year and 0.91 DA at 2 years (P < 0.001). Leakage on FA and fluid on OCT were similar between groups at 1 and 2 years.
CONCLUSIONS: In CATT, the B50 group had a visual prognosis similar to the Other group. Lesion size decreased markedly through 2 years. Eyes like those enrolled in CATT with neovascular AMD lesions composed of >50% blood can be managed similarly to those with less or no blood.
PMID: 25307130 [PubMed - indexed for MEDLINE]
Shaggy photoreceptors with subfoveal fluid associated with a distant choroidal melanoma.
Case Rep Ophthalmol Med. 2015;2015:187542
Authors: Tran AQ, Eadie JA, Altaweel MM
Purpose. To describe the enhanced depth imaging optical coherence tomography (EDI-OCT) findings in a patient with an extra macula choroidal melanoma before and after treatment. Methods. Observational case report. Results. A 45 year-old Caucasian male patient was referred to retina clinic for management of choroidal melanoma. Examination revealed a nasal choroidal melanoma while EDI-OCT illustrated subfoveal fluid pocket with elongated shaggy photoreceptors distant and separate from the tumor. The patient was treated with plaque brachytherapy and intravitreal bevacizumab. One week after plaque removal, there was a dramatic reduction in the shaggy photoreceptors. Conclusion. Choroidal melanomas have effects that are not localized to the area of the tumor. This loculated pocket of subretinal fluid and coinciding changes to photoreceptor morphology may be related to global changes in choroidal function or release of tumor related cytokines.
PMID: 25713741 [PubMed]
Cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for noninfectious intermediate, posterior, and panuveitis.
Ophthalmology. 2014 Oct;121(10):1855-62
Authors: Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Sugar EA, Holbrook JT, Kempen JH, Burke AE, Drye LT, Thorne JE, Louis TA, Jabs DA, Altaweel MM, Frick KD
OBJECTIVE: To evaluate the 3-year incremental cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for the treatment of noninfectious intermediate, posterior, and panuveitis.
DESIGN: Randomized, controlled, clinical trial.
PARTICIPANTS: Patients with active or recently active intermediate, posterior, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment Trial.
METHODS: Data on cost and health utility during 3 years after randomization were evaluated at 6-month intervals. Analyses were stratified by disease laterality at randomization (31 unilateral vs 224 bilateral) because of the large upfront cost of the implant.
MAIN OUTCOME MEASURES: The primary outcome was the incremental cost-effectiveness ratio (ICER) over 3 years: the ratio of the difference in cost (in United States dollars) to the difference in quality-adjusted life-years (QALYs). Costs of medications, surgeries, hospitalizations, and regular procedures (e.g., laboratory monitoring for systemic therapy) were included. We computed QALYs as a weighted average of EQ-5D scores over 3 years of follow-up.
RESULTS: The ICER at 3 years was $297,800/QALY for bilateral disease, driven by the high cost of implant therapy (difference implant - systemic [Δ]: $16,900; P < 0.001) and the modest gains in QALYs (Δ = 0.057; P = 0.22). The probability of the ICER being cost-effective at thresholds of $50,000/QALY and $100,000/QALY was 0.003 and 0.04, respectively. The ICER for unilateral disease was more favorable, namely, $41,200/QALY at 3 years, because of a smaller difference in cost between the 2 therapies (Δ = $5300; P = 0.44) and a larger benefit in QALYs with the implant (Δ = 0.130; P = 0.12). The probability of the ICER being cost-effective at thresholds of $50,000/QALY and $100,000/QALY was 0.53 and 0.74, respectively.
CONCLUSIONS: Fluocinolone acetonide implant therapy was reasonably cost-effective compared with systemic therapy for individuals with unilateral intermediate, posterior, or panuveitis but not for those with bilateral disease. These results do not apply to the use of implant therapy when systemic therapy has failed or is contraindicated. Should the duration of implant effect prove to be substantially >3 years or should large changes in therapy pricing occur, the cost-effectiveness of implant versus systemic therapy would need to be reevaluated.
PMID: 24908205 [PubMed - indexed for MEDLINE]
Response to aflibercept in patients with persistent exudation despite prior treatment with bevacizumab or ranibizumab for age-related macular degeneration.
Ophthalmic Surg Lasers Imaging Retina. 2014 Sep-Oct;45(5):394-7
Authors: Eadie JA, Gottlieb JL, Ip MS, Blodi BA, Danis RP, Chandra SR, Nork TM, Altaweel MM, Stern-Hogan BS
BACKGROUND AND OBJECTIVE: This study examines the clinical response of patients transitioned to aflibercept, the newest anti-VEGF medication, due to persistent evidence of exudation on optical coherence tomography (OCT) despite regular treatment with bevacizumab and/or ranibizumab.
PATIENTS AND METHODS: Aflibercept was administered to 111 patients considered for study inclusion. Eyes were included if they were transitioned to aflibercept for treatment of persistent exudation on OCT despite regular treatment with at least three injections of ranibizumab or bevacizumab. Retrospective data were collected from medical records.
RESULTS: Complete resolution of exudation was seen in 34% of eyes at final follow-up. Clear improvement in exudation amount or severity without complete resolution was seen in 25%. No improvement was seen in 34%, and 6% demonstrated worsening of exudation. Snellen visual acuity at the time of transition versus final follow-up after aflibercept injection did not appreciably change (logMAR 0.494 to 0.505, Snellen equivalent 20/62 to 20/64; P = .84). The mean center point neurosensory retina thickness decreased from 228.6 to 176.9 µm (P = .001).
CONCLUSION: Aflibercept may decrease the amount of exudation in a significant number of patients. However, this reduction did not result in an improvement in Snellen visual acuity.
PMID: 25230402 [PubMed - in process]
Fluorescein angiography versus optical coherence tomography for diagnosis of uveitic macular edema.
Ophthalmology. 2013 Sep;120(9):1852-9
Authors: Kempen JH, Sugar EA, Jaffe GJ, Acharya NR, Dunn JP, Elner SG, Lightman SL, Thorne JE, Vitale AT, Altaweel MM, Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group
OBJECTIVE: To evaluate agreement between fluorescein angiography (FA) and optical coherence tomography (OCT) results for diagnosis of macular edema in patients with uveitis.
DESIGN: Multicenter cross-sectional study.
PARTICIPANTS: Four hundred seventy-nine eyes with uveitis from 255 patients.
METHODS: The macular status of dilated eyes with intermediate uveitis, posterior uveitis, or panuveitis was assessed via Stratus-3 OCT and FA. To evaluate agreement between the diagnostic approaches, κ statistics were used.
MAIN OUTCOME MEASURES: Macular thickening (MT; center point thickness, ≥ 240 μm per reading center grading of OCT images) and macular leakage (ML; central subfield fluorescein leakage, ≥ 0.44 disc areas per reading center grading of FA images), and agreement between these outcomes in diagnosing macular edema.
RESULTS: Optical coherence tomography (90.4%) more frequently returned usable information regarding macular edema than FA (77%) or biomicroscopy (76%). Agreement in diagnosis of MT and ML (κ = 0.44) was moderate. Macular leakage was present in 40% of cases free of MT, whereas MT was present in 34% of cases without ML. Biomicroscopic evaluation for macular edema failed to detect 40% and 45% of cases of MT and ML, respectively, and diagnosed 17% and 17% of cases with macular edema that did not have MT or ML, respectively; these results may underestimate biomicroscopic errors (ophthalmologists were not explicitly masked to OCT and FA results). Among eyes free of ML, phakic eyes without cataract rarely (4%) had MT. No factors were found that effectively ruled out ML when MT was absent.
CONCLUSIONS: Optical coherence tomography and FA offered only moderate agreement regarding macular edema status in uveitis cases, probably because what they measure (MT and ML) are related but nonidentical macular pathologic characteristics. Given its lower cost, greater safety, and greater likelihood of obtaining usable information, OCT may be the best initial test for evaluation of suspected macular edema. However, given that ML cannot be ruled out if MT is absent and vice versa, obtaining the second test after negative results on the first seems justified when detection of ML or MT would alter management. Given that biomicroscopic evaluation for macular edema erred frequently, ancillary testing for macular edema seems indicated when knowledge of ML or MT status would affect management.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
PMID: 23706700 [PubMed - indexed for MEDLINE]
Optical coherence tomography evaluation in the Multicenter Uveitis Steroid Treatment (MUST) trial.
Ocul Immunol Inflamm. 2012 Dec;20(6):443-7
Authors: Domalpally A, Altaweel MM, Kempen JH, Myers D, Davis JL, Foster CS, Latkany P, Srivastava SK, Stawell RJ, Holbrook JT, MUST Trial Research Group
PURPOSE: To describe the evaluation of optical coherence tomography (OCT) scans in the Muliticenter Uveitis Steroid Treatment (MUST) trial and report baseline OCT features of enrolled participants.
METHODS: Time-domain OCTs acquired by certified photographers using a standardized scan protocol were evaluated at a reading center. Accuracy of retinal thickness data was confirmed with quality evaluation, and caliper measurement of centerpoint thickness (CPT) was performed when retinal thickness data were unreliable. Morphological evaluation included cysts, subretinal fluid, epiretinal membranes (ERMs), and vitreomacular traction.
RESULTS: Of the 453 OCTs evaluated, automated retinal thickness was accurate in 69.5% of scans, caliper measurement was performed in 26%, and 4% were ungradable. Intraclass correlation was.98 for reproducibility of caliper measurement. Macular edema (centerpoint thickness ≥ 240 μm) was present in 36%. Cysts were present in 36.6% of scans and ERMs in 27.8%, predominantly central. Intergrader agreement ranged from 78 to 82% for morphological features.
CONCLUSION: Retinal thickness data can be retrieved in a majority of OCT scans in clinical trial submissions for uveitis studies. Small cysts and ERMs involving the center are common in intermediate and posterior/panuveitis requiring systemic corticosteroid therapy.
PMID: 23163490 [PubMed - indexed for MEDLINE]
Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.
Ophthalmology. 2012 Aug;119(8):1596-603
Authors: Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, Aaberg TM, Altaweel MM, Bardenstein DS, Finger PT, Gallie BL, Harocopos GJ, Hovland PG, McGowan HD, Milman T, Mruthyunjaya P, Simpson ER, Smith ME, Wilson DJ, Wirostko WJ, Harbour JW
PURPOSE: This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk).
DESIGN: Prospective, multicenter study.
PARTICIPANTS: A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers.
TESTING: Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status.
MAIN OUTCOME MEASURES: Patients were managed for their primary tumor and monitored for metastasis.
RESULTS: The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status.
CONCLUSIONS: The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.
PMID: 22521086 [PubMed - indexed for MEDLINE]
The impact of macular edema on visual function in intermediate, posterior, and panuveitis.
Ocul Immunol Inflamm. 2012 Jun;20(3):171-81
Authors: Taylor SR, Lightman SL, Sugar EA, Jaffe GJ, Freeman WR, Altaweel MM, Kozak I, Holbrook JT, Jabs DA, Kempen JH
PURPOSE: To evaluate the impact of macular edema on visual acuity and visual field sensitivity in uveitis.
DESIGN: This study utilized baseline data from the Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized, parallel treatment clinical trial comparing alternative treatments for intermediate, posterior and panuveitis.
PATIENTS & METHODS: 255 patients (481 eyes with uveitis) recruited at 23 subspecialty centers. Visual acuity, optical coherence tomography and Humphrey 24-2 visual field testing.
RESULTS: Macular edema was associated with impaired visual acuity (p < 0.01). Different phenotypes of macular edema were associated with different degrees of visual impairment: cystoid changes without retinal thickening were associated with moderately impaired visual acuity (-5 ETDRS letters), but visual acuity was worse in eyes with retinal thickening (-13 letters) and with both cysts and thickening (-19 letters). Uveitis sufficient to satisfy the study's inclusion criteria was associated with impaired visual field sensitivity, but eyes with macular edema had even worse visual field sensitivity (p < 0.01).
CONCLUSIONS: The observation that macular edema substantially reduces visual function suggests macular edema itself is an important endpoint to study in the treatment of uveitis. As uveitis and macular edema both impair visual field sensitivity as measured by Humphrey 24-2 perimetry, both should be considered when evaluating patients with uveitis and raised intraocular pressure for glaucoma.
PMID: 22530874 [PubMed - indexed for MEDLINE]
Challenges in the design and implementation of the Multicenter Uveitis Steroid Treatment (MUST) Trial--lessons for comparative effectiveness trials.
Clin Trials. 2011 Dec;8(6):736-43
Authors: Holbrook JT, Kempen JH, Prusakowski NA, Altaweel MM, Jabs DA, Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group
BACKGROUND: Randomized clinical trials (RCTs) are an important component of comparative effectiveness (CE) research because they are the optimal design for head-to-head comparisons of different treatment options.
PURPOSE: To describe decisions made in the design of the Multicenter Uveitis Steroid Treatment (MUST) Trial to ensure that the results would be widely generalizable.
METHODS: Review of design and implementation decisions and their rationale for the trial.
RESULTS: The MUST Trial is a multicenter randomized controlled CE trial evaluating a novel local therapy (intraocular fluocinolone acetonide implant) versus the systemic therapy standard of care for noninfectious uveitis. Decisions made in protocol design in order to broaden enrollment included allowing patients with very poor vision and media opacity to enroll and including clinical sites outside the United States. The treatment protocol was designed to follow standard care. The primary outcome, visual acuity, is important to patients and can be evaluated in all eyes with uveitis. Other outcomes include patient-reported visual function, quality of life, and disease and treatment related complications.
LIMITATIONS: The trial population is too small for subgroup analyses that are of interest and the trial is being conducted at tertiary medical centers.
CONCLUSION: CE trials require greater emphasis on generalizability than many RCTs but otherwise face similar challenges for design choices as any RCT. The increase in heterogeneity in patients and treatment required to ensure generalizability can be balanced with a rigorous approach to implementation, outcome assessment, and statistical design. This approach requires significant resources that may limit implementation in many RCTs, especially in clinical practice settings.
PMID: 21994128 [PubMed - indexed for MEDLINE]
Identifying a clinically meaningful threshold for change in uveitic macular edema evaluated by optical coherence tomography.
Am J Ophthalmol. 2011 Dec;152(6):1044-1052.e5
Authors: Sugar EA, Jabs DA, Altaweel MM, Lightman S, Acharya N, Vitale AT, Thorne JE, Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group
PURPOSE: To identify a clinically meaningful threshold for change in retinal thickness measured by optical coherence tomography for patients with uveitic macular edema using correlation with change in visual acuity.
DESIGN: Cross-sectional and longitudinal study.
METHODS: One hundred twenty-eight eyes (101 individuals) with macular edema enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. At enrollment and after 6 months of follow-up, retinal thickness was measured at the central subfield with time-domain optical coherence tomography and visual acuity was measured with logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts. Participants were classified as having macular edema if the retinal thickness was 260 μm or more.
RESULTS: A threshold for change in retinal center subfield thickness of 20% balanced the percentage of false positives and false negatives for predicting more than a 10-letter change in visual acuity with a sensitivity of 77% and a specificity of 75%. The results were similar for more than 5-letter changes and for 15-letter or more changes. Those with a 20% or more reduction in retinal thickness had a mean 11.0-letter improvement (95% confidence interval, 7.7 to 14.3) as compared with a -0.4-letter change (95% confidence interval, -4.1 to 3.3) in visual acuity for those without a 20% reduction (P < .01).
CONCLUSIONS: In addition to being above the level of measurement uncertainty, a 20% change in retinal thickness in patients with macular edema seems to be optimal for clinically important changes in visual acuity and may be considered as an outcome for clinical trials of treatments for uveitic macular edema.
PMID: 21861971 [PubMed - indexed for MEDLINE]
Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial.
Ophthalmology. 2011 Oct;118(10):1916-26
Authors: Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, Holbrook JT, Jabs DA, Louis TA, Sugar EA, Thorne JE
OBJECTIVE: To compare the relative effectiveness of systemic corticosteroids plus immunosuppression when indicated (systemic therapy) versus fluocinolone acetonide implant (implant therapy) for noninfectious intermediate, posterior, or panuveitis (uveitis).
DESIGN: Randomized controlled parallel superiority trial.
PARTICIPANTS: Patients with active or recently active uveitis.
METHODS: Participants were randomized (allocation ratio 1:1) to systemic or implant therapy at 23 centers (3 countries). Implant-assigned participants with bilateral uveitis were assigned to have each eye that warranted study treatment implanted. Treatment-outcome associations were analyzed by assigned treatment for all eyes with uveitis.
MAIN OUTCOME MEASURES: Masked examiners measured the primary outcome: change in best-corrected visual acuity from baseline. Secondary outcomes included patient-reported quality of life, ophthalmologist-graded uveitis activity, and local and systemic complications of uveitis or therapy. Reading Center graders and glaucoma specialists assessing ocular complications were masked. Participants, ophthalmologists, and coordinators were unmasked.
RESULTS: On evaluation of changes from baseline to 24 months among 255 patients randomized to implant and systemic therapy (479 eyes with uveitis), the implant and systemic therapy groups had an improvement in visual acuity of +6.0 and +3.2 letters (P = 0.16, 95% confidence interval on difference in improvement between groups, -1.2 to +6.7 letters, positive values favoring implant), an improvement in vision-related quality of life of +11.4 and +6.8 units (P = 0.043), a change in EuroQol-EQ5D health utility of +0.02 and -0.02 (P = 0.060), and residual active uveitis in 12% and 29% (P=0.001), respectively. Over the 24 month period, implant-assigned eyes had a higher risk of cataract surgery (80%, hazard ratio [HR] = 3.3, P < 0.0001), treatment for elevated intraocular pressure (61%, HR=4.2, P < 0.0001), and glaucoma (17%, HR=4.2, P = 0.0008). Patients assigned to systemic therapy had more prescription-requiring infections than patients assigned to implant therapy (0.60 vs 0.36/person-year, P=0.034), without notable long-term consequences; systemic adverse outcomes otherwise were unusual in both groups, with minimal differences between groups.
CONCLUSIONS: In each treatment group, mean visual acuity improved over 24 months, with neither approach superior to a degree detectable with the study's power. Therefore, the specific advantages and disadvantages identified should dictate selection between the alternative treatments in consideration of individual patients' particular circumstances. Systemic therapy with aggressive use of corticosteroid-sparing immunosuppression was well tolerated, suggesting that this approach is reasonably safe for local and systemic inflammatory disorders.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
PMID: 21840602 [PubMed - indexed for MEDLINE]
Morphologic assessment for glaucoma in the Multicenter Uveitis Steroid Treatment (MUST) trial.
Ocul Immunol Inflamm. 2011 Aug;19(4):267-74
Authors: Gangaputra SS, Altaweel MM, Peng Q, Friedman DS, Rao PK, Foster CS, Kim RY, Reed SB, Srivastava SK, Wong IG, Kempen JH, MUST Trial Research Group
PURPOSE: To compare Reading Center (RC) cup-to-disc ratio (CDR) assessment from stereoscopic photographs with clinician estimation in a uveitis clinical trial.
METHODS: Clinical estimation of CDR was performed by ophthalmologists via dilated biomicroscopy. Photographic evaluation was performed at an independent RC by masked, certified evaluators. Quality control was performed by repeat grading of 77 randomly selected images.
RESULTS: Among 479 eyes with uveitis, 353 eyes had clinical and photographic grades for CDR. Agreement between clinical and RC grading was fair, with exact agreement of 29%. Agreement within 0.1 and 0.2 CDR was 70 and 93%, respectively (weighted κ = .34). Intergrader reproducibility at the RC was better (weighted κ = .59, ICC 0.74).
CONCLUSION: Morphologic assessment of cup to disc ratio is an important outcome and safety measure for determining glaucomatous damage in clinical trials. Masked RC measurements are more likely to be accurate than biomicroscopic grading in identifying meaningful anatomical change associated with glaucoma.
PMID: 21770805 [PubMed - indexed for MEDLINE]
Validation of a photographic vitreous haze grading technique for clinical trials in uveitis.
Am J Ophthalmol. 2011 Aug;152(2):170-176.e1
Authors: Madow B, Galor A, Feuer WJ, Altaweel MM, Davis JL
PURPOSE: 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.
DESIGN: Retrospective study of clinical trials methodology.
SETTING: University-based department of ophthalmology.
STUDY POPULATION: Baseline fundus photographs of patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial.
OBSERVATIONAL PROCEDURE: Grading of vitreous haze using a previously described photographic scale. Regrading of a subset of photographs to assess intraobserver agreement.
MAIN OUTCOME MEASURES: 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.
RESULTS: 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).
CONCLUSIONS: 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.
PMID: 21652026 [PubMed - indexed for MEDLINE]
Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study system for evaluation of stereoscopic color fundus photographs and fluorescein angiograms: SCORE Study Report 9.
Arch Ophthalmol. 2010 Sep;128(9):1140-5
Authors: Blodi BA, Domalpally A, Scott IU, Ip MS, Oden NL, Elledge J, Warren K, Altaweel MM, Kim JE, Van Veldhuisen PC, SCORE Study Research Group
OBJECTIVE: To describe the procedures and reproducibility for grading stereoscopic color fundus photographs and fluorescein angiograms of participants in the SCORE Study.
METHODS: Standardized stereoscopic fundus photographs and fluorescein angiograms taken at 84 clinical centers were evaluated by graders at a central reading center. Type of retinal vein occlusion (RVO), area of retinal thickening, and area of retinal hemorrhage are evaluated from fundus photographs; area of fluorescein leakage and area of capillary nonperfusion are measured on fluorescein angiography. Temporal reproducibility consisted of annual regrading of a randomly selected dedicated subset of fundus photographs (60 subjects) and fluorescein angiograms (40 subjects) for 3 successive years. Contemporaneous reproducibility involved monthly regrading of a 5% random selection of recently evaluated fundus photographs (n = 73).
RESULTS: The intergrader agreement for RVO type and presence of retinal thickening was greater than 90% in the 3 annual regrades. The intraclass correlation (ICC) for area of retinal thickening in the 3 years ranged from 0.39 to 0.64 and for area of retinal hemorrhage, 0.87 to 0.96. The ICC for area of fluorescein leakage ranged from 0.66 to 0.75 and for capillary nonperfusion, 0.94 to 0.97. The contemporaneous reproducibility results were similar to those of temporal reproducibility for all variables except area of retinal thickening (ICC, 0.84).
CONCLUSIONS: The fundus photography and fluorescein angiography grading procedures for the SCORE Study are reproducible and can be used for multicenter longitudinal studies of RVO. A systematic temporal drift occurred in evaluating area of retinal thickening.
PMID: 20837797 [PubMed - indexed for MEDLINE]
The multicenter uveitis steroid treatment trial: rationale, design, and baseline characteristics.
Am J Ophthalmol. 2010 Apr;149(4):550-561.e10
Authors: Multicenter Uveitis Steroid Treatment Trial Research Group, Kempen JH, Altaweel MM, Holbrook JT, Jabs DA, Sugar EA
PURPOSE: To describe the design and methods of the Multicenter Uveitis Steroid Treatment (MUST) trial and the baseline characteristics of enrolled patients.
DESIGN: Baseline data from a 1:1 randomized, parallel treatment design clinical trial at 23 clinical centers comparing systemic corticosteroid therapy (and immunosuppression when indicated) with fluocinolone acetonide implant placement.
METHODS: Eligible patients had active or recently active noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The study design had 90% power (2-sided type I error rate, 0.05) to detect a 7.5-letter (1.5-line) difference between groups in the mean visual acuity change between baseline and 2 years. Secondary outcomes include ocular and systemic complications of therapy and quality of life. Baseline characteristics include demographic and clinical characteristics, quality of life, and reading center gradings of lens and fundus photographs, optical coherence tomography images, and fluorescein angiograms.
RESULTS: Over 3 years, 255 patients were enrolled (481 eyes with uveitis). At baseline, 50% of eyes with uveitis had best-corrected visual acuity worse than 20/40 (16% worse than 20/200). Lens opacities (39% of gradeable phakic eyes), macular edema (36%), and epiretinal membrane (48%) were common. Mean health utility was 74.1.
CONCLUSIONS: The MUST trial will compare fluocinolone acetonide implant versus systemic therapy for management of intermediate uveitis, posterior uveitis, and panuveitis. Patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the trial had a high burden of reduced visual acuity, cataract, macular edema, and epiretinal membrane; overall quality of life was lower than expected based on visual acuity.
PMID: 20097325 [PubMed - indexed for MEDLINE]
Association of fluorescein angiographic features with visual acuity and with optical coherence tomographic and stereoscopic color fundus photographic features of diabetic macular edema in a randomized clinical trial.
Retina. 2010 Nov-Dec;30(10):1627-37
Authors: Danis RP, Scott IU, Qin H, Altaweel MM, Bressler NM, Bressler SB, Browning DJ, Kollman C, Diabetic Retinopathy Clinical Research Network
BACKGROUND: Fluorescein angiography (FA) has been performed as part of the management of diabetic macular edema for many years. Its current role relative to the role of optical coherence tomography (OCT) is not well defined.
PURPOSE: To evaluate the associations of FA features with visual acuity (VA) and with OCT and fundus photographic characteristics in eyes with diabetic macular edema.
METHODS: In a clinical trial, conducted by the Diabetic Retinopathy Clinical Research Network to compare two methods of laser photocoagulation to treat diabetic macular edema, FA (film and digital), color photographs, OCT, and VA measurements were obtained at baseline and at 1 year. Grading of morphologic features was performed at a reading center. Reproducibility of FAs was assessed, and the correlations of FA features with VA, OCT, and color photograph features were computed.
RESULTS: From 79 clinical sites, data of 323 study eyes and 203 fellow nonstudy eyes were analyzed. Fluorescein leakage area at baseline was associated with reduced VA, increased OCT measures of retinal thickness and volume, and color photographic measurements of retinal thickening (r = 0.33-0.58). No important associations were found with changes from baseline to 12 months in these parameters or with any of the other variables analyzed.
CONCLUSION: Fluorescein leakage is associated with VA and some OCT and color photographic variables. We did not identify any unique FA variables that had a stronger association with VA than OCT measures of retinal thickness. These data may be useful to investigators planning future diabetic macular edema clinical trials.
PMID: 20706173 [PubMed - indexed for MEDLINE]