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.
Uveitis, or intraocular inflammation, is an important cause of visual loss in the developed world, reported as causing 10% of cases of blindness in the United States and as being the fifth, sixth, or seventh leading cause of blindness in various studies. Uveitis has a disproportionately high impact in terms of years of potential vision lost and economic effects because it often strikes at a younger age than common age-related eye disorders such as cataract, age-related macular degeneration, and glaucoma. The proportion of blindness caused by uveitis may be declining, presumably because of improving treatment. However, most patients managed in tertiary clinics experience visual loss at some point during their clinical course.
On the basis of clinical examination, uveitis can be classified into anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis—based on which portion of the eye is inflamed. The risk of vision loss is progressively higher along this spectrum. In developed countries, such as the United States, most intermediate uveitis and panuveitis cases and approximately one half of the posterior uveitis cases treated at uveitis practices, are presumed to be autoimmune, with no evidence of infection and a salutary response to corticosteroid and other anti-inflammatory therapies.
Noninfectious uveitides encompass a wide variety of specific syndromes, each with specific diagnostic features. However, for noninfectious cases, corticosteroids are the mainstay of treatment in most instances, regardless of the specific syndrome diagnosed. Use of systemic corticosteroids—with immunosuppressive drugs when indicated—historically has been the primary method advocated for control of severe cases of intermediate uveitis, posterior uveitis, and panuveitis. The fluocinolone acetonide implant (0.59 mg; Bausch & Lomb, Inc, Rochester, New York, USA), introduced in 2005, is designed to be effective in controlling uveitis for 2.5 to 3 years, and thus offers an alternative paradigm for the medium- or long-term management of these cases of uveitis. The relative efficacy and side-effect profiles of these alternatives have not been compared.
To provide evidence on the relative effectiveness and safety of systemic therapy with respect to fluocinolone acetonide implant therapy, we undertook a randomized, controlled clinical trial directly comparing these alternatives for the management of noninfectious intermediate uveitis, posterior uveitis, or panuveitis. This report describes the design of the trial and the baseline characteristics of the patients enrolled into the trial, providing new information about the demographic and clinical characteristics of intermediate uveitis, posterior uveitis, and panuveitis patients managed in tertiary uveitis practices.
Methods
The Multicenter Uveitis Steroid Treatment (MUST) trial is a randomized, partially masked, comparative multicenter clinical trial comparing the effectiveness and safety of local therapy with the fluocinolone acetonide implant (Bausch & Lomb, Inc) versus systemic therapy with oral corticosteroids and immunosuppressive drugs when indicated for patients with severe noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The specific aims of the trial are: (1) to compare visual outcomes between implant therapy and systemic therapy; (2) to compare effectiveness of these treatment strategies for controlling uveitis and avoiding the accumulation of complications thereof over time; (3) to compare rates of both ocular and systemic side effects; and (4) to compare quality of life between treatment strategies. Cost-effectiveness analysis also will be conducted. The overall goal is to ascertain the relative benefits and risks of the alternative therapies and the incremental cost-effectiveness of the 2 treatment approaches.
A detailed description of the study methods—including the rationale for the specific methodologies and treatment approaches selected—is provided as supplemental text (available online at www.AJO.com ). In brief, the MUST trial is designed to detect a difference between randomly assigned treatment groups of 7.5 letters (1.5 lines) in mean (eye-specific) change in logMAR visual acuity from baseline to follow-up at 2 years. Sample size calculations estimated that enrollment of 250 patients would provide 90% power to detect this difference, allowing for a type 1 error probability of 0.05, assuming 10% losses to follow-up. Eligible patients had active or recently active (within 60 days) intermediate uveitis, posterior uveitis, or panuveitis that was judged to require systemic corticosteroid therapy (eligibility criteria are given in Supplemental Table 1 ). These are the forms of uveitis for which the fluocinolone acetonide implant therapy is indicated and are forms of uveitis for which systemic therapy as studied in the trial is commonly indicated.
Because one of the alternative treatments is systemically administered, and the goal of the trial was to compare alternative treatment strategies at the level of the patient (including quality-of-life analysis), patients (rather than eyes) were randomized to the alternative treatments. Random treatment assignments to implant or systemic therapy (allocation ratio, 1:1) were stratified by clinical center. Within each clinical center, randomization also was stratified by the type of uveitis (intermediate uveitis vs posterior uveitis or panuveitis) because visual acuity outcomes likely differ between these disease categories (see Supplemental Figure 1 ).
Implant therapy (see Supplemental Figure 2 ) consisted of treatment with the commercially available fluocinolone acetonide 0.59-mg implant (Retisert; Bausch & Lomb, Inc) in each eye with uveitis of sufficient severity to justify treatment with systemic corticosteroids. After quieting of the anterior chamber to less than grade 1+ of anterior chamber cells, implantation was performed by a study-certified surgeon using a standard technique within 28 days of randomization. When applicable, the second eye was implanted within 28 days thereafter using the same approach. Eyes initially receiving systemic corticosteroid or immunosuppressive therapy were tapered off of such therapy after implant placement, generally within several weeks, but slowly enough to avoid complications related to adrenal suppression resulting from corticosteroid therapy. Eyes in which a reactivation of uveitis developed after implantation were reimplanted using the same approach; the choice to remove or leave in place a preexisting implant is left to the best medical judgment of the treating surgeon.
Systemic therapy consisted of oral corticosteroid therapy—supplemented when indicated by immunosuppression—in accordance with expert panel recommendations. Patients with active uveitis at baseline were started on prednisone 1 mg/kg per day up to a maximum adult oral dose of 60 mg/day (see Supplemental Figure 3 ), which was continued until the uveitis was controlled or until the patient had been receiving this dose of prednisone for 4 weeks. After suppression of uveitis was achieved, oral corticosteroids were tapered, according to specified guidelines. Patients whose uveitis already had been controlled within the 60 days before enrollment started at their current prednisone dose and tapered their prednisone dose in the same manner. When immunosuppressive therapy was indicated (see Supplemental Figure 3 and Supplemental Text ), the choice of which immunosuppressive drug to use was not dictated by the trial to permit selection of the agent with the best side-effect profile for an individual patient. However, the treatments selected were administered in accordance with expert panel guidelines, including laboratory monitoring for potential toxicities. Many additional treatment protocol details are given in the Supplemental Text (available at www.AJO.com ).
Because the primary goal of therapy for uveitis is to preserve vision, the primary outcome by which success is judged in the MUST trial is best-corrected visual acuity, as measured by standard logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts. Other outcomes evaluated pertain to control of intraocular inflammation, the occurrence of ocular complications of uveitis or of therapy, the occurrence of systemic complications of therapy, and self-reported quality of life. Imaging studies used and the representative features evaluated by them include: lens photography (cataract), fundus photography (macular edema, epiretinal membranes, optic nerve morphologic features, chorioretinal lesions, vascular occlusions), Stratus optical coherence tomography ([Carl Zeiss Meditec, Inc, Jena, Germany]; macular edema, vitreoretinal interface abnormalities including epiretinal membrane), and fluorescein angiography (macular edema, vascular leakage, perfusion abnormalities, choroidal neovascularization). Health-related quality-of-life data also are assessed, including health utility as measured by the EuroQol 5-dimension and Visual Analog Scale scores, general health-related quality of life as measured by the Short Form 36-item questionnaire, and vision-related quality of life as measured by the 25-item National Eye Institute Visual Function Questionnaire. Masking is applied to the determination of visual acuity (beginning 6 months after randomization, to avoid unmasking by visible postoperative changes), those outcomes based on photographic reading, and diagnosis of glaucoma by an outcomes committee. Because sham surgery is not performed, masking during ascertainment of the other outcomes is not feasible.
Statistical Methods for Baseline Analysis
Patient, ocular, and imaging characteristics at randomization were summarized for the population as a whole and were stratified by uveitis type at enrollment based on data collected as of October 1, 2009. For patient characteristics, differences between the strata were compared using the Wilcoxon rank-sum test for continuous variables and the chi-square test—or Fisher exact test if appropriate—for categorical variables. When the unit of analysis was the eye, linear, logistic, or multinomial regression models were used to compare strata after adjusting for the excess correlation between eyes from the same individual using generalized estimating equations-derived methods for continuous, binary, and multinomial outcomes, respectively.
Results
Between December 6, 2005, and December 9, 2008, 255 patients were enrolled at 23 clinical centers and were randomized to implant (129 patients) or systemic (126 patients) therapy. Ninety-seven patients (180 eyes with uveitis) were enrolled in the intermediate uveitis stratum, and 158 (301 eyes with uveitis) were enrolled in the posterior uveitis or panuveitis stratum (see Table 1 ). The age and sex distributions were similar between groups, but the race or ethnicity distribution differed significantly in that Hispanic persons were more likely to have posterior uveitis or panuveitis than intermediate uveitis. EuroQol visual analog scale health utility scores were similar between groups: the mean overall score (74.1; 95% CI, 71.6 to 76.6) was reduced with respect to normative population values (normative score, 80.0; standardized to the MUST population for age group and sex). Eighty-nine percent of patients had bilateral uveitis, with a similar proportion in both strata. In total, 21% of patients had a systemic inflammatory disease in association with uveitis, 15% in the intermediate uveitis group versus 25% in the posterior uveitis or panuveitis group ( P = .05). Patients with posterior uveitis or panuveitis were substantially more likely to have Behçet’s disease than patients with intermediate uveitis (5% vs 0%; P = .03). Osteoporosis, defined as a T score less than −2.5 on DEXA scanning of the spine (L2 to L4) and left femoral neck, was present among 8% of patients in both groups at baseline.
| Characteristics | Total | Disease Stratum | P Value a | |
|---|---|---|---|---|
| Intermediate | Posterior Uveitis or Panuveitis | |||
| Participants, n (%) | 255 | 97 (38%) | 158 (62%) | |
| Demographics | ||||
| Age at enrollment (yrs) | ||||
| Mean ± SD | 46.3 ± 15.0 | 45.4 ± 15.1 | 46.9 ± 15.0 | .46 |
| Median (25th to 75th percentile) | 47 (34 to 56) | 46 (33 to 55) | 47 (35 to 58) | |
| Male gender, n (%) | 64 (25%) | 28 (29%) | 36 (23%) | .28 |
| Race/ethnicity, n (%) | ||||
| White | 142 (56%) | 60 (62%) | 82 (52%) | <.01 |
| Hispanic or Latino (any race) | 33 (13%) | 5 (5%) | 28 (18%) | |
| Black | 66 (26%) | 29 (30%) | 37 (23%) | |
| Other | 14 (5%) | 3 (3%) | 11 (7%) | |
| Quality of life | ||||
| Health utility b (0 to 100) | ||||
| Mean ± SD | 74.1 ± 20.0 | 72.1 ± 21.0 | 75.3 ± 19.4 | .20 |
| Median (25th to 75th percentile) | 80 (67 to 90) | 75 (60 to 87) | 80 (70 to 90) | |
| Missing | 3 (1%) | 2 (2%) | 1 (1%) | |
| Clinical characteristics | ||||
| Uveitis, n (%) | ||||
| Bilateral | 226 (89%) | 83 (86%) | 143 (91%) | .23 |
| Unilateral | 29 (11%) | 14 (14%) | 15 (9%) | |
| Time since diagnosis (yrs) | ||||
| Mean ± SD | 6.1 ± 7.2 | 6.0 ± 5.0 | 6.2 ± 8.2 | .07 |
| Median (25th to 75th percentile) | 3.8 (1.2 to 8.0) | 5.0 (2.0 to 8.8) | 3.4 (0.9 to 7.9) | |
| Missing | 4 (2%) | 1 (1%) | 3 (2%) | |
| Systemic disease, n (%) | ||||
| None | 186 (73%) | 77 (79%) | 109 (69%) | .07 |
| Present | 69 (27%) | 20 (21%) | 49 (31%) | |
| Behçet’s disease | 8 (3%) | 0 (0%) | 8 (5%) | .03 c |
| Sarcoidosis | 26 (10%) | 7 (7%) | 19 (12%) | .29 c |
| Multiple sclerosis | 4 (2%) | 3 (3%) | 1 (1%) | .16 c |
| Juvenile idiopathic arthritis | 5 (2%) | 2 (2%) | 3 (2%) | >.99 c |
| Bone density, n (%) d | ||||
| Normal | 132 (53%) | 53 (56%) | 79 (51%) | .61 |
| Osteopenia | 96 (39%) | 33 (35%) | 63 (41%) | |
| Osteoporosis | 21 (8%) | 9 (9%) | 12 (8%) | |
| Missing | 6 (2%) | 2 (1%) | 4 (2%) | |
a Unless otherwise specified, P values compare the distribution of all primary categories except for the 2 missing strata.
b Health utility reflects the EuroQol visual analog scale score, where 0 reflects death and 100 reflects perfect health.
c P value indicates a comparison of a single category across strata.
d Osteopenia is defined as a T score between −1 and −2.49 inclusive at the spine or femoral neck (whichever is worse). Osteoporosis is defined as a T score of −2.5 or worse at the spine, femoral neck, or both.
Among 481 eyes with uveitis, 180 (37%) were in the intermediate uveitis stratum and 301 (63%) were in the posterior uveitis or panuveitis stratum (see Table 2 ). The distributions of severity of vitreous haze and vitreous inflammatory cells were similar at baseline between the 2 groups. Intraocular pressure also was similar in the 2 groups, with most patients having average intraocular pressure at baseline; patients with high intraocular pressures and uncontrolled glaucoma had been excluded from enrollment (see Supplemental Table 1 ). Approximately half of eyes with uveitis had low vision (best-corrected visual acuity worse than 20/40), and approximately 16% were legally blind (best-corrected visual acuity of 20/200 or worse), with a similar distribution across intermediate uveitis versus posterior uveitis or panuveitis cases. Considering the better eye of each patient, including eyes without uveitis, 31% had low vision and 5% were legally blind at baseline. As expected, visual field reductions were more extensive in the posterior uveitis or panuveitis group than the intermediate uveitis group (average Humphrey mean deviations, −8.7 vs −6.4 respectively; P < .01). Overall, 75% of patients had a mean deviation of −3.0 or worse.
| Characteristics | Total | Disease Stratum | P Value a | |
|---|---|---|---|---|
| Intermediate | Posterior Uveitis or Panuveitis | |||
| No. of participants | 255 | 97 | 158 | |
| Eyes with uveitis at enrollment, n (%) | 481 | 180 (37%) | 301 (63%) | |
| Vitreous haze, n (%) b | ||||
| 0 | 141 (31%) | 49 (29%) | 92 (32%) | .26 |
| 1+ | 205 (45%) | 71 (42%) | 134 (47%) | |
| 2+ | 77 (17%) | 36 (21%) | 41 (14%) | |
| 3+ | 20 (4%) | 9 (5%) | 11 (4%) | |
| 4+ | 4 (1%) | 0 (0%) | 4 (1%) | |
| Cannot assess | 8 (2%) | 6 (3%) | 2 (1%) | |
| Missing | 26 (5%) | 9 (5%) | 17 (6%) | |
| Anterior vitreous cells, n (%) c | ||||
| 0 | 75 (17%) | 29 (17%) | 46 (16%) | .82 |
| 0.5+ | 109 (24%) | 34 (20%) | 75 (27%) | |
| 1+ | 146 (32%) | 61 (36%) | 85 (30%) | |
| 2+ | 90 (20%) | 35 (21%) | 55 (19%) | |
| 3+ | 25 (6%) | 6 (4%) | 19 (7%) | |
| 4+ | 6 (1%) | 3 (2%) | 3 (1%) | |
| Cannot assess | 28 (6%) | 12 (7%) | 16 (5%) | |
| Missing | 2 (1%) | 0 (0%) | 2 (1%) | |
| IOP (mm Hg) | ||||
| Mean ± SD | 14.0 ± 4.7 | 13.7 ± 4.0 | 14.3 ± 5.0 | .14 |
| Median (25th to 75th percentile) | 14.0 (11.5 to 17.0) | 14.0 (11.5 to 16.0) | 14.5 (12.0 to 17.0) | |
| Missing | 4 (0%) | 0 (0%) | 4 (1%) | |
| Visual acuity | ||||
| Eyes with uveitis at enrollment | ||||
| Mean ± SD | 61.4 ± 26.4 | 61.8 ± 25.8 | 61.2 ± 26.9 | .92 |
| Median (25th to 75th percentile) | 70.1 (49.1 to 80.1) | 69.1 (49.1 to 81.1) | 70.1 (50.1 to 80.1) | |
| Worse than 20/40, n (%) | 237 (50%) | 94 (53%) | 143 (48%) | .34 d |
| Worse than 20/200, n (%) | 74 (15%) | 27 (15%) | 47 (16%) | .88 d |
| Missing | 6 (1%) | 1 (1%) | 5 (2%) | |
| Better eyes e | ||||
| Mean ± SD | 73.4 ± 18.0 | 73.5 ± 19.6 | 73.4 ± 16.9 | .48 |
| Median (25th to 75th percentile) | 78.1 (66.1 to 86.1) | 80.1 (64.1 to 87.1) | 77.1 (66.1 to 85.1) | |
| Worse than 20/40, n (%) | 79 (31%) | 32 (33%) | 47 (30%) | .68 d |
| Worse than 20/200, n (%) | 12 (5%) | 5 (5%) | 7 (4%) | .77 d |
| Missing | 1 (0.3%) | 0 (0%) | 1 (1%) | |
| Worse eyes e | ||||
| Mean ± SD | 50.5 ± 30.5 | 52.2 ± 29.2 | 49.5 ± 31.4 | .58 |
| Median (25th to 75th percentile) | 59.1 (30.1 to 75.1) | 61.1 (35.1 to 75.1) | 57.1 (29.1 to 75.1) | |
| Worse than 20/40, n (%) | 165 (65%) | 64 (66%) | 101 (64%) | .89 |
| Worse than 20/200, n (%) | 67 (26%) | 24 (25%) | 43 (27%) | .66 |
| Missing | 1 (0.3%) | 0 (0%) | 1 (1%) | |
| Visual field automated perimetry | ||||
| Mean deviation | ||||
| Mean ± SD | −7.8 ± 7.5 | −6.4 ± 6.5 | −8.7 ± 8.0 | <.01 |
| Median (25th to 75th percentile) | −5.2 (−9.5 to −3.0) | −4.0 (−7.6 to −2.8) | −5.8 (−11.2 to −3.2) | |
| Missing | 22 (5%) | 6 (3%) | 16 (5%) | |
a P values are calculated using linear, logistic, or multinomial regression adjusting for multiple measurements per individual with robust standard errors when appropriate. Unless otherwise indicated, the P value represents the comparison between strata across all categories except for missing or cannot assess.
b Vitreous haze measurements are based on the scale developed by Nussenblatt and associates and affirmed by the SUN Working Group.
c Anterior vitreous cell measurements are based on the following scale, based on cells present in a 1 × 0.5-mm beam: 0 = no cells; 0.5+ = 1 to 5 cells; 1+ = 6 to 10 cells; 2+ = 11 to 20 cells; 3+ = 21 to 50 cells; and 4+ = 51 cells or more.
d P value indicates a comparison of a single category across strata.
e Visual acuity for better and worse eyes are calculated based on all eyes, regardless of whether they have uveitis.
Regarding structural ocular abnormalities associated with inflammation, as ascertained by image grading, 41% of eyes were pseudophakic at baseline in each group, and 39% of the remainder were judged to have a lens opacity at baseline (see Table 3 ). The mean macular thickness tended to be greater in the intermediate uveitis group than in the posterior uveitis or panuveitis group (288 vs 256 μm; P = .09). Cystoid edema was present in the central macula in 38% of eyes, with a similar distribution across intermediate uveitis and posterior uveitis and panuveitis cases. Fluorescein angiographic grading demonstrated a similar degree of macular leakage in the 2 groups, with a mean of 3.5 ± 5.3 disc areas. By grading of color photographs, epiretinal membranes were significantly more common in the intermediate uveitis group than the posterior or panuveitis group (57% vs 42%; P = .01), although the difference arose from a greater frequency of subtle epiretinal membranes in the former group, whereas both groups had a similar proportion with definite epiretinal membrane (11% vs 13%; P = .63). Macular pigmentary disturbances were more common in posterior uveitis or panuveitis cases than intermediate uveitis cases (39% vs 16%; P < .01). Subretinal fibrosis (6% vs. 1%; P = .05) and disc swelling (6% vs 1%; P = .03) were infrequent, but were more common in the posterior uveitis and panuveitis group than in the intermediate uveitis group.
| Characteristics | Total | Disease Stratum | P Value a | |
|---|---|---|---|---|
| Intermediate | Posterior Uveitis or Panuveitis | |||
| No. of participants | 255 | 97 | 158 | |
| Eyes with uveitis at enrollment, n (%) | 481 | 180 | 301 | |
| Lens images, n | 464 | 180 | 284 | |
| Lens opacities, n (%) | ||||
| Absent | 134 (61%) | 56 (67%) | 78 (57%) | .21 b |
| Present | 87 (39%) | 27 (33%) | 60 (43%) | |
| Aphakic/pseudophakic | 191 (41%) | 75 (41%) | 116 (41%) | |
| Cannot grade c | 52 (11%) | 22 (12%) | 30 (10%) | |
| Optical coherence tomography, n | 454 | 171 | 283 | |
| Retinal thickness at center (μm) | ||||
| Mean ± SD | 268.0 ± 185.0 | 288.2 ± 188.8 | 256.0 ± 181.9 | .09 |
| Median (25th to 75th percentile) | 198.5 (162.0 to 296.5) | 211.0 (168.0 to 334.0) | 192.0 (158.0 to 270.0) | |
| ≤200 | 223 (51%) | 71 (44%) | 152 (56%) | .05 |
| 201 to 239 | 57 (12%) | 26 (15%) | 31 (11%) | |
| ≥240 | 156 (36%) | 66 (41%) | 90 (33%) | |
| Cannot grade c | 18 (4%) | 8 (4%) | 10 (3%) | |
| Cystoid spaces, n (%) | ||||
| Absent | 265 (62%) | 97 (61%) | 168 (62%) | .81 |
| Definite | 166 (38%) | 63 (39%) | 103 (38%) | |
| Not at center | 58 (13%) | 15 (9%) | 43 (16%) | |
| At center | 108 (25%) | 48 (30%) | 60 (22%) | |
| Cannot grade c | 23 (5%) | 11 (6%) | 12 (4%) | |
| Color fundus images, n | 436 | 165 | 271 | |
| Epiretinal membrane, n (%) | ||||
| Absent | 198 (52%) | 60 (42%) | 138 (57%) | .01 |
| Present | 185 (48%) | 82 (58%) | 103 (43%) | |
| Cellophane reflex/subtle | 139 (36%) | 66 (46%) | 73 (30%) | |
| Definite | 46 (12%) | 16 (11%) | 30 (13%) | |
| Cannot grade c | 53 (12%) | 23 (14%) | 30 (11%) | |
| Subretinal fibrosis, n (%) | ||||
| Absent | 367 (96%) | 141 (99%) | 226 (94%) | .05 |
| Definite | 17 (4%) | 2 (1%) | 15 (6%) | |
| Not at center | 14 (4%) | 2 (1%) | 12 (5%) | |
| At center | 3 (1%) | 0 (0%) | 3 (1%) | |
| Cannot grade c | 52 (12%) | 22 (13%) | 30 (11%) | |
| Cup-to-disc ratio (vertical) | ||||
| Mean ± SD | 0.31 ± 0.12 | 0.29 ± 0.13 | 0.33 ± 0.11 | .10 |
| Median (IQR) | 0.30 (0.21 to 0.39) | 0.27 (0.19 to 0.37) | 0.32 (0.24 to 0.40) | |
| Cannot grade c | 82 (18%) | 30 (18%) | 52 (19%) | |
| Papillary swelling | ||||
| Absent | 378 (96%) | 149 (99%) | 229 (94%) | .03 |
| Definite | 16 (4%) | 1 (1%) | 15 (6%) | |
| Cannot grade c | 42 (10%) | 15 (9%) | 27 (10%) | |
| Pigment disturbance within the macular area d | ||||
| Absent | 263 (69%) | 117 (84%) | 146 (61%) | <.01 |
| Definite | 116 (31%) | 23 (16%) | 93 (39%) | |
| Not at center | 70 (19%) | 15 (11%) | 55 (23%) | |
| At center point | 46 (12%) | 8 (6%) | 38 (16%) | |
| Cannot grade c | 57 (13%) | 25 (15%) | 32 (12%) | |
| Fluorescein angiography, n | 394 | 142 | 254 | |
| Cystoid changes in the macula | ||||
| Absent | 256 (70%) | 80 (60%) | 176 (76%) | <.01 |
| Present | 109 (30%) | 53 (40%) | 56 (24%) | |
| Cannot grade c | 31 (8%) | 9 (6%) | 22 (9%) | |
| Capillary loss within the macular area c | ||||
| Absent | 197 (95%) | 74 (96%) | 123 (94%) | .50 |
| Present | 11 (5%) | 3 (4%) | 8 (6%) | |
| Missing | 188 (47%) | 65 (46%) | 123 (48%) | |
| Leakage within the macular area d | ||||
| Mean ± SD | 3.5 ± 5.3 | 3.5 ± 5.0 | 3.6 ± 5.5 | .90 |
| Median (IQR) | 0.6 (0.0 to 4.9) | 1.1 (0.0 to 4.9) | 0.5 (0.0 to 4.6) | |
| Absent | 148 (40%) | 48 (36%) | 100 (43%) | .29 |
| Present | 218 (60%) | 85 (64%) | 133 (57%) | |
| Cannot grade c | 30 (8%) | 9 (6%) | 21 (8%) | |
a Unless otherwise specified, P values are calculated to compare primary categorizations excluding cannot grade, missing, or central point involvement.
b Comparing absent and present.
c Image quality insufficient to allow grading, usually because of ocular scarring preventing adequate imaging.
d The macular area refers to the 16-disc area–region centered on the fovea.
Results
Between December 6, 2005, and December 9, 2008, 255 patients were enrolled at 23 clinical centers and were randomized to implant (129 patients) or systemic (126 patients) therapy. Ninety-seven patients (180 eyes with uveitis) were enrolled in the intermediate uveitis stratum, and 158 (301 eyes with uveitis) were enrolled in the posterior uveitis or panuveitis stratum (see Table 1 ). The age and sex distributions were similar between groups, but the race or ethnicity distribution differed significantly in that Hispanic persons were more likely to have posterior uveitis or panuveitis than intermediate uveitis. EuroQol visual analog scale health utility scores were similar between groups: the mean overall score (74.1; 95% CI, 71.6 to 76.6) was reduced with respect to normative population values (normative score, 80.0; standardized to the MUST population for age group and sex). Eighty-nine percent of patients had bilateral uveitis, with a similar proportion in both strata. In total, 21% of patients had a systemic inflammatory disease in association with uveitis, 15% in the intermediate uveitis group versus 25% in the posterior uveitis or panuveitis group ( P = .05). Patients with posterior uveitis or panuveitis were substantially more likely to have Behçet’s disease than patients with intermediate uveitis (5% vs 0%; P = .03). Osteoporosis, defined as a T score less than −2.5 on DEXA scanning of the spine (L2 to L4) and left femoral neck, was present among 8% of patients in both groups at baseline.
| Characteristics | Total | Disease Stratum | P Value a | |
|---|---|---|---|---|
| Intermediate | Posterior Uveitis or Panuveitis | |||
| Participants, n (%) | 255 | 97 (38%) | 158 (62%) | |
| Demographics | ||||
| Age at enrollment (yrs) | ||||
| Mean ± SD | 46.3 ± 15.0 | 45.4 ± 15.1 | 46.9 ± 15.0 | .46 |
| Median (25th to 75th percentile) | 47 (34 to 56) | 46 (33 to 55) | 47 (35 to 58) | |
| Male gender, n (%) | 64 (25%) | 28 (29%) | 36 (23%) | .28 |
| Race/ethnicity, n (%) | ||||
| White | 142 (56%) | 60 (62%) | 82 (52%) | <.01 |
| Hispanic or Latino (any race) | 33 (13%) | 5 (5%) | 28 (18%) | |
| Black | 66 (26%) | 29 (30%) | 37 (23%) | |
| Other | 14 (5%) | 3 (3%) | 11 (7%) | |
| Quality of life | ||||
| Health utility b (0 to 100) | ||||
| Mean ± SD | 74.1 ± 20.0 | 72.1 ± 21.0 | 75.3 ± 19.4 | .20 |
| Median (25th to 75th percentile) | 80 (67 to 90) | 75 (60 to 87) | 80 (70 to 90) | |
| Missing | 3 (1%) | 2 (2%) | 1 (1%) | |
| Clinical characteristics | ||||
| Uveitis, n (%) | ||||
| Bilateral | 226 (89%) | 83 (86%) | 143 (91%) | .23 |
| Unilateral | 29 (11%) | 14 (14%) | 15 (9%) | |
| Time since diagnosis (yrs) | ||||
| Mean ± SD | 6.1 ± 7.2 | 6.0 ± 5.0 | 6.2 ± 8.2 | .07 |
| Median (25th to 75th percentile) | 3.8 (1.2 to 8.0) | 5.0 (2.0 to 8.8) | 3.4 (0.9 to 7.9) | |
| Missing | 4 (2%) | 1 (1%) | 3 (2%) | |
| Systemic disease, n (%) | ||||
| None | 186 (73%) | 77 (79%) | 109 (69%) | .07 |
| Present | 69 (27%) | 20 (21%) | 49 (31%) | |
| Behçet’s disease | 8 (3%) | 0 (0%) | 8 (5%) | .03 c |
| Sarcoidosis | 26 (10%) | 7 (7%) | 19 (12%) | .29 c |
| Multiple sclerosis | 4 (2%) | 3 (3%) | 1 (1%) | .16 c |
| Juvenile idiopathic arthritis | 5 (2%) | 2 (2%) | 3 (2%) | >.99 c |
| Bone density, n (%) d | ||||
| Normal | 132 (53%) | 53 (56%) | 79 (51%) | .61 |
| Osteopenia | 96 (39%) | 33 (35%) | 63 (41%) | |
| Osteoporosis | 21 (8%) | 9 (9%) | 12 (8%) | |
| Missing | 6 (2%) | 2 (1%) | 4 (2%) | |
a Unless otherwise specified, P values compare the distribution of all primary categories except for the 2 missing strata.
b Health utility reflects the EuroQol visual analog scale score, where 0 reflects death and 100 reflects perfect health.
c P value indicates a comparison of a single category across strata.
d Osteopenia is defined as a T score between −1 and −2.49 inclusive at the spine or femoral neck (whichever is worse). Osteoporosis is defined as a T score of −2.5 or worse at the spine, femoral neck, or both.
Among 481 eyes with uveitis, 180 (37%) were in the intermediate uveitis stratum and 301 (63%) were in the posterior uveitis or panuveitis stratum (see Table 2 ). The distributions of severity of vitreous haze and vitreous inflammatory cells were similar at baseline between the 2 groups. Intraocular pressure also was similar in the 2 groups, with most patients having average intraocular pressure at baseline; patients with high intraocular pressures and uncontrolled glaucoma had been excluded from enrollment (see Supplemental Table 1 ). Approximately half of eyes with uveitis had low vision (best-corrected visual acuity worse than 20/40), and approximately 16% were legally blind (best-corrected visual acuity of 20/200 or worse), with a similar distribution across intermediate uveitis versus posterior uveitis or panuveitis cases. Considering the better eye of each patient, including eyes without uveitis, 31% had low vision and 5% were legally blind at baseline. As expected, visual field reductions were more extensive in the posterior uveitis or panuveitis group than the intermediate uveitis group (average Humphrey mean deviations, −8.7 vs −6.4 respectively; P < .01). Overall, 75% of patients had a mean deviation of −3.0 or worse.
| Characteristics | Total | Disease Stratum | P Value a | |
|---|---|---|---|---|
| Intermediate | Posterior Uveitis or Panuveitis | |||
| No. of participants | 255 | 97 | 158 | |
| Eyes with uveitis at enrollment, n (%) | 481 | 180 (37%) | 301 (63%) | |
| Vitreous haze, n (%) b | ||||
| 0 | 141 (31%) | 49 (29%) | 92 (32%) | .26 |
| 1+ | 205 (45%) | 71 (42%) | 134 (47%) | |
| 2+ | 77 (17%) | 36 (21%) | 41 (14%) | |
| 3+ | 20 (4%) | 9 (5%) | 11 (4%) | |
| 4+ | 4 (1%) | 0 (0%) | 4 (1%) | |
| Cannot assess | 8 (2%) | 6 (3%) | 2 (1%) | |
| Missing | 26 (5%) | 9 (5%) | 17 (6%) | |
| Anterior vitreous cells, n (%) c | ||||
| 0 | 75 (17%) | 29 (17%) | 46 (16%) | .82 |
| 0.5+ | 109 (24%) | 34 (20%) | 75 (27%) | |
| 1+ | 146 (32%) | 61 (36%) | 85 (30%) | |
| 2+ | 90 (20%) | 35 (21%) | 55 (19%) | |
| 3+ | 25 (6%) | 6 (4%) | 19 (7%) | |
| 4+ | 6 (1%) | 3 (2%) | 3 (1%) | |
| Cannot assess | 28 (6%) | 12 (7%) | 16 (5%) | |
| Missing | 2 (1%) | 0 (0%) | 2 (1%) | |
| IOP (mm Hg) | ||||
| Mean ± SD | 14.0 ± 4.7 | 13.7 ± 4.0 | 14.3 ± 5.0 | .14 |
| Median (25th to 75th percentile) | 14.0 (11.5 to 17.0) | 14.0 (11.5 to 16.0) | 14.5 (12.0 to 17.0) | |
| Missing | 4 (0%) | 0 (0%) | 4 (1%) | |
| Visual acuity | ||||
| Eyes with uveitis at enrollment | ||||
| Mean ± SD | 61.4 ± 26.4 | 61.8 ± 25.8 | 61.2 ± 26.9 | .92 |
| Median (25th to 75th percentile) | 70.1 (49.1 to 80.1) | 69.1 (49.1 to 81.1) | 70.1 (50.1 to 80.1) | |
| Worse than 20/40, n (%) | 237 (50%) | 94 (53%) | 143 (48%) | .34 d |
| Worse than 20/200, n (%) | 74 (15%) | 27 (15%) | 47 (16%) | .88 d |
| Missing | 6 (1%) | 1 (1%) | 5 (2%) | |
| Better eyes e | ||||
| Mean ± SD | 73.4 ± 18.0 | 73.5 ± 19.6 | 73.4 ± 16.9 | .48 |
| Median (25th to 75th percentile) | 78.1 (66.1 to 86.1) | 80.1 (64.1 to 87.1) | 77.1 (66.1 to 85.1) | |
| Worse than 20/40, n (%) | 79 (31%) | 32 (33%) | 47 (30%) | .68 d |
| Worse than 20/200, n (%) | 12 (5%) | 5 (5%) | 7 (4%) | .77 d |
| Missing | 1 (0.3%) | 0 (0%) | 1 (1%) | |
| Worse eyes e | ||||
| Mean ± SD | 50.5 ± 30.5 | 52.2 ± 29.2 | 49.5 ± 31.4 | .58 |
| Median (25th to 75th percentile) | 59.1 (30.1 to 75.1) | 61.1 (35.1 to 75.1) | 57.1 (29.1 to 75.1) | |
| Worse than 20/40, n (%) | 165 (65%) | 64 (66%) | 101 (64%) | .89 |
| Worse than 20/200, n (%) | 67 (26%) | 24 (25%) | 43 (27%) | .66 |
| Missing | 1 (0.3%) | 0 (0%) | 1 (1%) | |
| Visual field automated perimetry | ||||
| Mean deviation | ||||
| Mean ± SD | −7.8 ± 7.5 | −6.4 ± 6.5 | −8.7 ± 8.0 | <.01 |
| Median (25th to 75th percentile) | −5.2 (−9.5 to −3.0) | −4.0 (−7.6 to −2.8) | −5.8 (−11.2 to −3.2) | |
| Missing | 22 (5%) | 6 (3%) | 16 (5%) | |
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