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The Multicenter Uveitis Steroid Treatment Trial:

Rationale, Design, and Baseline Characteristics


THE MULTICENTER UVEITIS STEROID TREATMENT TRIAL RESEARCH GROUP*
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
Supplemental Material available at AJO.com.
Accepted for publication Nov 13, 2009.
*Writing Committee: John H. Kempen, Michael M. Altaweel, Janet T.
Holbrook, Douglas A. Jabs, and Elizabeth A. Sugar.
From the Ocular Inflammation Service, Department of Ophthalmology/
Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania
(J.H.K.); the Center for Preventive Ophthalmology and Biostatistics,
Department of Ophthalmology/Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania (J.H.K.); the Center for Clinical
Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania (J.H.K.);
the Fundus Photograph Reading Center, Department of Ophthalmology,
University of Wisconsin, Madison, Wisconsin (M.M.A.); the Center for
Clinical Trials, The Johns Hopkins University Bloomberg School of
Public Health, Baltimore, Maryland (J.T.H., D.A.J., E.A.S.); the Department of Epidemiology, The Johns Hopkins University Bloomberg School
of Public Health, Baltimore, Maryland (J.T.H., D.A.J., E.A.S.); the
Department of Biostatistics, The Johns Hopkins University Bloomberg
School of Public Health, Baltimore, Maryland (E.A.S.); and the Departments of Ophthalmology and Medicine, The Mount Sinai School of
Medicine, New York, New York (D.A.J.).
Inquiries to John H. Kempen, Center for Preventive Ophthalmology
and Biostatistics, Department of Ophthalmology, University of Pennsylvania, 3535 Market Street, Suite 700, Philadelphia, PA 19104; e-mail:
john.kempen@uphs.upenn.edu; and Douglas A. Jabs, MUST Chairmans
Office, Department of Ophthalmology, Mount Sinai School of Medicine,
One Gustave L. Levy Place, Box 1183, New York, NY 10029-6574;
e-mail: douglas.jabs@mssm.edu

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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. (Am J
Ophthalmol 2010;149:550 561. 2010 by Elsevier Inc.
All rights reserved.)

VEITIS, OR INTRAOCULAR INFLAMMATION, IS AN

important cause of visual loss in the developed


world,13 reported as causing 10% of cases of
blindness in the United States2 and as being the fifth,
sixth, or seventh leading cause of blindness in various
studies.3,4 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.1 The proportion of
blindness caused by uveitis may be declining,3 presumably
because of improving treatment. However, most patients
managed in tertiary clinics experience visual loss at some
point during their clinical course.5
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.6,7 The risk of vision loss is progressively
higher along this spectrum.5,8 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.9 20
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.2123 Use of systemic
corticosteroidswith immunosuppressive drugs when indicated historically has been the primary method advocated for control of severe cases of intermediate uveitis,
posterior uveitis, and panuveitis.22 The fluocinolone ace-

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0002-9394/10/$36.00
doi:10.1016/j.ajo.2009.11.019

tonide implant (0.59 mg; Bausch & Lomb, Inc, Rochester,


New York, USA),24,25 introduced in 2005, is designed to
be effective in controlling uveitis for 2.5 to 3 years,26 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 indicated22 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 analysis27 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 methodsincluding
the rationale for the specific methodologies and treatment
approaches selectedis 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).
VOL. 149, NO. 4

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.22
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 categories8 (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,7 implantation was performed by a studycertified surgeon using a standard technique25 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 immunosuppressionin
accordance with expert panel recommendations.22 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

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551

TABLE 1. Characteristics of Patients with Uveitis at Randomization


Disease Stratum
Characteristics

Participants, n (%)
Demographics
Age at enrollment (yrs)
Mean SD
Median (25th to 75th percentile)
Male gender, n (%)
Race/ethnicity, n (%)
White
Hispanic or Latino (any race)
Black
Other
Quality of life
Health utilityb (0 to 100)
Mean SD
Median (25th to 75th percentile)
Missing
Clinical characteristics
Uveitis, n (%)
Bilateral
Unilateral
Time since diagnosis (yrs)
Mean SD
Median (25th to 75th percentile)
Missing
Systemic disease, n (%)
None
Present
Behets disease
Sarcoidosis
Multiple sclerosis
Juvenile idiopathic arthritis
Bone density, n (%)d
Normal
Osteopenia
Osteoporosis
Missing

Total

Intermediate

255

97 (38%)

46.3 15.0
47 (34 to 56)
64 (25%)
142 (56%)
33 (13%)
66 (26%)
14 (5%)

74.1 20.0
80 (67 to 90)
3 (1%)

Posterior Uveitis or Panuveitis

P Valuea

158 (62%)

45.4 15.1
46 (33 to 55)
28 (29%)

46.9 15.0
47 (35 to 58)
36 (23%)

60 (62%)
5 (5%)
29 (30%)
3 (3%)

82 (52%)
28 (18%)
37 (23%)
11 (7%)

72.1 21.0
75 (60 to 87)
2 (2%)

75.3 19.4
80 (70 to 90)
1 (1%)

.46
.28
.01

.20

226 (89%)
29 (11%)

83 (86%)
14 (14%)

143 (91%)
15 (9%)

.23

6.1 7.2
3.8 (1.2 to 8.0)
4 (2%)

6.0 5.0
5.0 (2.0 to 8.8)
1 (1%)

6.2 8.2
3.4 (0.9 to 7.9)
3 (2%)

.07

186 (73%)
69 (27%)
8 (3%)
26 (10%)
4 (2%)
5 (2%)

77 (79%)
20 (21%)
0 (0%)
7 (7%)
3 (3%)
2 (2%)

109 (69%)
49 (31%)
8 (5%)
19 (12%)
1 (1%)
3 (2%)

.07

132 (53%)
96 (39%)
21 (8%)
6 (2%)

53 (56%)
33 (35%)
9 (9%)
2 (1%)

79 (51%)
63 (41%)
12 (8%)
4 (2%)

.03c
.29c
.16c
.99c
.61

SD standard deviation; yrs years.


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,40 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.37
a

monitoring for potential toxicities.22 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.38 Other
outcomes evaluated pertain to control of intraocular inflammation, the occurrence of ocular complications of
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AMERICAN JOURNAL

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,
OF

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TABLE 2. Ocular Characteristics of Eyes with Uveitis at Baseline


Disease Stratum
Characteristics

No. of participants
Eyes with uveitis at enrollment, n (%)
Vitreous haze, n (%)b
0
1
2
3
4
Cannot assess
Missing
Anterior vitreous cells, n (%)c
0
0.5
1
2
3
4
Cannot assess
Missing
IOP (mm Hg)
Mean SD
Median (25th to 75th percentile)
Missing
Visual acuity
Eyes with uveitis at enrollment
Mean SD
Median (25th to 75th percentile)
Worse than 20/40, n (%)
Worse than 20/200, n (%)
Missing
Better eyese
Mean SD
Median (25th to 75th percentile)
Worse than 20/40, n (%)
Worse than 20/200, n (%)
Missing
Worse eyese
Mean SD
Median (25th to 75th percentile)
Worse than 20/40, n (%)
Worse than 20/200, n (%)
Missing
Visual field automated perimetry
Mean deviation
Mean SD
Median (25th to 75th percentile)
Missing

Total

Intermediate

255
481

Posterior Uveitis or Panuveitis

P Valuea

97
180 (37%)

158
301 (63%)

141 (31%)
205 (45%)
77 (17%)
20 (4%)
4 (1%)
8 (2%)
26 (5%)

49 (29%)
71 (42%)
36 (21%)
9 (5%)
0 (0%)
6 (3%)
9 (5%)

92 (32%)
134 (47%)
41 (14%)
11 (4%)
4 (1%)
2 (1%)
17 (6%)

.26

75 (17%)
109 (24%)
146 (32%)
90 (20%)
25 (6%)
6 (1%)
28 (6%)
2 (1%)

29 (17%)
34 (20%)
61 (36%)
35 (21%)
6 (4%)
3 (2%)
12 (7%)
0 (0%)

46 (16%)
75 (27%)
85 (30%)
55 (19%)
19 (7%)
3 (1%)
16 (5%)
2 (1%)

.82

14.0 4.7
14.0 (11.5 to 17.0)
4 (0%)

13.7 4.0
14.0 (11.5 to 16.0)
0 (0%)

14.3 5.0
14.5 (12.0 to 17.0)
4 (1%)

.14

61.4 26.4
70.1 (49.1 to 80.1)
237 (50%)
74 (15%)
6 (1%)

61.8 25.8
69.1 (49.1 to 81.1)
94 (53%)
27 (15%)
1 (1%)

61.2 26.9
70.1 (50.1 to 80.1)
143 (48%)
47 (16%)
5 (2%)

.92

73.4 18.0
78.1 (66.1 to 86.1)
79 (31%)
12 (5%)
1 (0.3%)

73.5 19.6
80.1 (64.1 to 87.1)
32 (33%)
5 (5%)
0 (0%)

73.4 16.9
77.1 (66.1 to 85.1)
47 (30%)
7 (4%)
1 (1%)

.48

50.5 30.5
59.1 (30.1 to 75.1)
165 (65%)
67 (26%)
1 (0.3%)

52.2 29.2
61.1 (35.1 to 75.1)
64 (66%)
24 (25%)
0 (0%)

49.5 31.4
57.1 (29.1 to 75.1)
101 (64%)
43 (27%)
1 (1%)

.58

7.8 7.5
5.2 (9.5 to 3.0)
22 (5%)

6.4 6.5
4.0 (7.6 to 2.8)
6 (3%)

8.7 8.0
5.8 (11.2 to 3.2)
16 (5%)

.34d
.88d

.68d
.77d

.89
.66

.01

IOP intraocular pressure; SD standard deviation.


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.

VOL. 149, NO. 4

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TABLE 3. Image Characteristics in Eyes with Uveitis at Enrollment


Disease Stratum
Characteristics

Total

No. of participants
Eyes with uveitis at enrollment, n (%)
Lens images, n
Lens opacities, n (%)
Absent
Present
Aphakic/pseudophakic
Cannot gradec
Optical coherence tomography, n
Retinal thickness at center (m)
Mean SD
Median (25th to 75th percentile)
200
201 to 239
240
Cannot gradec
Cystoid spaces, n (%)
Absent
Definite
Not at center
At center
Cannot gradec
Color fundus images, n
Epiretinal membrane, n (%)
Absent
Present
Cellophane reflex/subtle
Definite
Cannot gradec
Subretinal fibrosis, n (%)
Absent
Definite
Not at center
At center
Cannot gradec
Cup-to-disc ratio (vertical)
Mean SD
Median (IQR)
Cannot gradec
Papillary swelling
Absent
Definite
Cannot gradec
Pigment disturbance within the macular aread
Absent
Definite
Not at center
At center point
Cannot gradec
Fluorescein angiography, n
Cystoid changes in the macula
Absent
Present
Cannot gradec

Intermediate

Posterior Uveitis or Panuveitis

255
481
464

97
180
180

158
301
284

134 (61%)
87 (39%)
191 (41%)
52 (11%)
454

56 (67%)
27 (33%)
75 (41%)
22 (12%)
171

78 (57%)
60 (43%)
116 (41%)
30 (10%)
283

268.0 185.0
198.5 (162.0 to 296.5)
223 (51%)
57 (12%)
156 (36%)
18 (4%)

288.2 188.8
211.0 (168.0 to 334.0)
71 (44%)
26 (15%)
66 (41%)
8 (4%)

256.0 181.9
192.0 (158.0 to 270.0)
152 (56%)
31 (11%)
90 (33%)
10 (3%)

P Valuea

.21b

.09
.05

265 (62%)
166 (38%)
58 (13%)
108 (25%)
23 (5%)
436

97 (61%)
63 (39%)
15 (9%)
48 (30%)
11 (6%)
165

168 (62%)
103 (38%)
43 (16%)
60 (22%)
12 (4%)
271

.81

198 (52%)
185 (48%)
139 (36%)
46 (12%)
53 (12%)

60 (42%)
82 (58%)
66 (46%)
16 (11%)
23 (14%)

138 (57%)
103 (43%)
73 (30%)
30 (13%)
30 (11%)

.01

367 (96%)
17 (4%)
14 (4%)
3 (1%)
52 (12%)

141 (99%)
2 (1%)
2 (1%)
0 (0%)
22 (13%)

226 (94%)
15 (6%)
12 (5%)
3 (1%)
30 (11%)

.05

0.31 0.12
0.30 (0.21 to 0.39)
82 (18%)

0.29 0.13
0.27 (0.19 to 0.37)
30 (18%)

0.33 0.11
0.32 (0.24 to 0.40)
52 (19%)

.10

378 (96%)
16 (4%)
42 (10%)

149 (99%)
1 (1%)
15 (9%)

229 (94%)
15 (6%)
27 (10%)

.03

263 (69%)
116 (31%)
70 (19%)
46 (12%)
57 (13%)
394

117 (84%)
23 (16%)
15 (11%)
8 (6%)
25 (15%)
142

146 (61%)
93 (39%)
55 (23%)
38 (16%)
32 (12%)
254

.01

256 (70%)
109 (30%)
31 (8%)

80 (60%)
53 (40%)
9 (6%)

176 (76%)
56 (24%)
22 (9%)

.01

Continued on next page

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TABLE 3. Image Characteristics in Eyes with Uveitis at Enrollment (Continued)


Disease Stratum
Characteristics

Capillary loss within the macular areac


Absent
Present
Missing
Leakage within the macular aread
Mean SD
Median (IQR)
Absent
Present
Cannot gradec

Total

Intermediate

Posterior Uveitis or Panuveitis

P Valuea

197 (95%)
11 (5%)
188 (47%)

74 (96%)
3 (4%)
65 (46%)

123 (94%)
8 (6%)
123 (48%)

.50

3.5 5.3
0.6 (0.0 to 4.9)
148 (40%)
218 (60%)
30 (8%)

3.5 5.0
1.1 (0.0 to 4.9)
48 (36%)
85 (64%)
9 (6%)

3.6 5.5
0.5 (0.0 to 4.6)
100 (43%)
133 (57%)
21 (8%)

.90
.29

IQR interquartile range; SD standard deviation.


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 arearegion centered on the fovea.
a

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,39,40
general health-related quality of life as measured by the
Short Form 36-item questionnaire,41,42 and vision-related
quality of life as measured by the 25-item National Eye
Institute Visual Function Questionnaire.43 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
appropriatefor 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 equationsderived methods for continuous, binary, and multinomial
outcomes, respectively.35
VOL. 149, NO. 4

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 scale40 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 values59 (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 Behets 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,37 was present among 8%
of patients in both groups at baseline.
Among 481 eyes with uveitis, 180 (37%) were in the
intermediate uveitis stratum and 301 (63%) were in the

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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.
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
m; 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.

therapy is expected to be highly effective for control of


inflammation while the implant continues to deliver drug,
but is expected to result in a high incidence of cataract and
intraocular pressure elevation requiring treatment.24,25,28
Systemic therapy is likely to have more systemic side
effects22 and more relapses of inflammation because the
minimum suppressive prednisone dose is determined by
iterative tapering but is likely to result in a lower
incidence of local complications of corticosteroid therapy60,61 and may have systemic or ocular benefits by
addressing more comprehensively the autoimmunity that
likely underlies many of these cases. The MUST trial is
designed to provide guidance as to whether one of these
paradigms is superior.
Given that the proportion of eyes with bilateral uveitis
and the number of patients actually enrolled was higher
than expected (see Supplemental Text, available at www.
ajo.com), the trial will have greater statistical power than
originally estimated, and therefore is expected to answer
the questions of interest effectively. The trial is designed to
evaluate both the benefits and the side effects (local and
systemic) of the alternative treatments. Because local side
effects are expected to be more frequent in the implant
group24,25,28 and systemic side effects are expected to be
more frequent in the systemic therapy group,22 quality-oflife results may be highly informative regarding the merits
of the alternative treatments. Cost and cost-effectiveness
analyses27 will be performed to determine the relative costs
of each treatment approach and to determine the incremental cost of each incremental gain in benefit with the
superior treatment. Enrollment of the trial was completed
in December 2008, and the primary results at the 2-year
follow-up can be expected shortly after that follow-up
point is reached (early 2011).
In baseline observations from the MUST trial, intermediate uveitis was diagnosed in a lower proportion of Hispanic
persons than white or black persons; because clinical trial
patients are not necessarily sampled in a manner representative of the general population, it is unclear whether this
difference in the distribution of site of inflammation by
race/ethnicity is meaningful. The results also suggest that
systemic inflammatory disease is less commonly associated
with intermediate uveitis than with posterior uveitis or
panuveitis, confirming clinical impressions. Nearly 10% of
patients had osteoporosis at baseline, emphasizing the importance of following bone mineral density testing and providing
appropriate preventive and remedial treatment in patients for
whom systemic corticosteroid therapy will be used.22,37
At enrollment, patients and eyes had a high prevalence
of reduced visual acuity and of ocular complications of
uveitis, and patients reported a substantially reduced quality of life, emphasizing the significant adverse consequences of intermediate uveitis, posterior uveitis, and
panuveitis. Using a time tradeoff methodology, the losses
of health utility associated with a reduction of vision to the
20/60 to 20/100 range and to 20/200 or worse have been

DISCUSSION
THE 2005 INTRODUCTION OF THE FLUOCINOLONE IMPLANT,

which is effective for controlling severe posterior segment


ocular inflammation over long periods,24,25 raised questions
about the relative merits of local therapy with the fluocinolone acetonide implant versus systemic therapy for intermediate uveitis, posterior uveitis, and panuveitis. Implant
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estimated as being a 28% and a 39% reduction in the


quality of life, respectively.62 Our patients were observed to
have health utility similar to that associated with visual acuity
in the 20/60 to 20/100 range, although only 31% had low
vision in their better eye, suggesting that uveitis may have
additional health impact over and above its effect on vision,
perhaps via symptoms of inflammation unmeasured by visual
acuity, side effects of treatment, the impact of associated
systemic disease, or a combination thereof.
Among eyes with uveitis, visual acuity was similar in the
intermediate uveitis group and the posterior uveitis and
panuveitis group. Overall visual sensitivity as measured
by automated visual field testing was reduced in both
groupslikely reflecting the impact of macular edema and
other complications of uveitis but was significantly lower
in the posterior uveitis and panuveitis group, probably
reflecting the additional impact of chorioretinal lesions.
Lens opacities were common in both groups, with 80% either
pseudophakic or with lens opacity at enrollment, indicating
that there is a high risk of cataract in severe uveitis cases,
although likely in part reflecting a greater willingness to
consider randomization to implant treatment in pseudophakic or cataractous eyes, given that implant therapy is expected
to cause cataract in nearly all phakic eyes.25,63 Eyes with
intermediate uveitis tended to have a higher prevalence of
macular edema and epiretinal membrane, which may reflect a
practice pattern of using the occurrence of such events as an
indication for more aggressive anti-inflammatory therapy.
Other complications of posterior segment inflammation were
unusual in both groups.
In addition to addressing the clinical questions regarding
treatment approaches, the MUST trial will provide the first
large, prospective data set of long-term, longitudinal observations on the outcomes of patients with severe uveitis, potentially yielding information regarding the clinical
epidemiologic characteristics of complications of uveitis. The
large number of patients at baseline with reduced visual
acuity, and other uveitis-related problems such as macular
edema and epiretinal membrane, suggests that the study will
provide substantial power to evaluate several important open
questions for severe cases of these types of uveitis, including
the risk of both improvement in and loss of visual acuity, the
incidence of posterior segment complications of uveitis, and
the incidence of ocular surgery, among others.

Limitations of the study design arise primarily from


heterogeneity of the forms of uveitis involving the posterior segment. Posterior uveitis and panuveitis particularly
consist of a wide variety of inflammatory entities, which
potentially may be heterogeneous in their response to one
or both of the treatments. Results from the Bausch &
Lomb BLP 415 001 trial of the fluocinolone acetonide
implant suggest that implant therapy is highly effective
across a broad array of uveitis patients,24,25 suggesting that
heterogeneity is not likely to be relevant for the implant
arm. The benefits of systemic anti-inflammatory therapy
have been indicated in several specific disease states,61,64 66
also suggesting a broad usefulness of this therapeutic
approach. Because patients are being enrolled at tertiary
uveitis centers, where treatments of this nature often are
administered, it is likely that more severe cases were
enrolled than might have been enrolled at less specialized
centers. However, because qualitative treatment disease
severity interactions are unlikely, the relative risk of
change in vision likely also should be sufficiently generalizable to be useful in determining which treatment approach is best in a less specialized setting. Finally, because
patients enrolled in clinical trials usually are not typical
patients, the experience of MUST trial patients may differ
in some ways from that of future patients. However, the
strengths of the randomized clinical trial methodology
with respect to alternative designs outweigh this limitation, leaving the clinical trial approach as the most
favorable design available for evaluating the relative merits
of alternative treatments for specified disease diagnoses.
In summary, the MUST trial is a phase 4 effectiveness
trial that aims to evaluate whether fluocinolone acetonide
implant therapy or systemic corticosteroid therapy (supplemented when indicated by use of immunosuppressive
drugs) is superior for the management of noninfectious
intermediate uveitis, posterior uveitis, and panuveitis.
Enrollment was completed in December 2008, and the
primary 2-year follow-up results can be expected in early
2011. Observations from the baseline characteristics of the
MUST patients suggest that these patients have a high
prevalence of visual loss, cataract or pseudophakia, macular edema, and epiretinal membrane, and a reduced overall
quality of life greater in degree than would be expected
based on loss of visual acuity alone.

SUPPORTED BY COLLABORATIVE AGREEMENTS EYU10EY014655 (DR JABS), EYU10EY014660 (DR HOLBROOK), AND EY014656 (DR
Altaweel) from the National Eye Institute, Bethesda, Maryland. Additional support was provided by Research to Prevent Blindness, Inc, New York, New
York, and by the Paul and Evanina Mackall Foundation, New York, New York. Bausch & Lomb Inc., Rochester, New York, provided support to the
study in the form of donation of a limited number of fluocinolone implants for patients randomized to implant therapy who were uninsured or otherwise
unable to pay for implants. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. A representative of the
National Eye Institute participated in the conduct of the study, including the study design and the collection, management, analysis, and interpretation
of the data, as well as in the review and approval of this manuscript. Dr Kempen has served as a consultant to Alcon and Lux Biosciences; Dr Jabs has
served as a consultant to Abbott, Allergan, Applied Genetic Technologies, Genzyme, Glaxo Smith Kline, Novartis, and Roche. Involved in design and
conduct of study (MUST Research Group; J.H.K., M.M.A., J.T.H., D.A.J.); Collection, management, analysis, and interpretation of data (MUST
Research Group; J.H.K., M.M.A., J.T.H., D.A.J., E.A.S.); and preparation, review, or approval of the manuscript (MUST Research Group; J.H.K.,
M.M.A., J.T.H., D.A.J., E.A.S.). The study has been registered on clinicaltrials.gov (identifier NCT00132691) and was approved by the governing
institutional review boards of all participating institutions.

VOL. 149, NO. 4

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66.

MULTICENTER UVEITIS STEROID


TREATMENT TRIAL PARTICIPATING
CLINICAL CENTERS (ORDERED BY
NUMBER OF PATIENTS RECRUITED)

MUST TRIAL

United Kingdom Institute of Ophthalmology, London, United Kingdom: Susan L. Lightman (Director),
Lavnish Joshi, Patricio Pacheco, Timothy Stubbs, Simon
R. Taylor, Hamish M. A. Towler. Former Member: Kate
Edwards.
Johns Hopkins University, Baltimore, Maryland:
James P. Dunn (Director), Jeff Boring, Diane M. Brown,
Alison G. Livingston, Yavette Morton, Kisten Nolan,
Terry Reed, Priscilla Soto, Michelle Tarver-Carr, Yue
Wang. Former Members: Marie-Lynn Belair, Stephen G.
559

560

Bolton, Joseph B. Brodine, Lisa M. Brune, Anat Galor,


Meera Kapoor, Sanjay Kedhar, Stephen Kim, Henry A.
Leder, George B. Peters, Ricardo Stevenson.
Vitreoretinal Consultants, Houston, Texas: Rosa Y.
Kim (Director), Matthew S. Benz, David M. Brown,
Eric Chen, Richard H. Fish, Shayla Hay, Laura
Shawver, Tien P. Wong. Former Members: Rebecca
De La Garza, Karin Mutz.
University of Michigan, Ann Arbor, Michigan: Susan
G. Elner (Director), Melissa Bergeron, Rebecca Brown,
Linda Fournier, Julie R. Gothrup, Richard Hackel,
Robert Prusak, Stephen J. Saxe. Former Members: Rene
Blosser, Carrie Chrisman-McClure, Deanna Sizemore.
Washington University, St. Louis, Missouri: P. Kumar Rao (Director), Kevin J. Blinder, Rhonda Weeks.
Former Members: Rajendra S. Apte, Pam Light, Gaurav K. Shah, Russell VanGelder.
Massachusetts Eye Research and Surgery Institute,
Cambridge, Massachusetts: C. Stephen Foster (Director), Linda Bruner, Angelica Contrero, Kayleigh
Fitzpatrick, David M. Hinkle, Jyothir Johnson,
Danielle Marvell. Former Members: Sarah Acevedo,
Fahd Anzaar, Tom Cesca, Karina Q. Lebron, Chandra
Morgan, Nita Patel, Janet Sprague, Taygan Yilmaz.
University of Southern California, Los Angeles,
California: Narsing A. Rao (Director), Lawrence
Chong, Lupe Cisneros, Jackie Douglass, Dean Eliott,
Amani Fawzi, Margaret Padilla. Former Members:
Alexia Aguirre, Rahul Khurana, Jennifer Lim, Rachel
Mead, Julie H. Tsai.
Duke University, Durham, North Carolina: Glenn
J. Jaffe (Director), Brenda Branchaud, Joyce Bryant,
Michael Cusick, Justis P. Ehlers, Cindy Skalak. Former
Members: Claxton Allen Baer, Sai H. Chavala, Pouya
N. Dayani, Muge R. Kesen, Alex Melamud, Jawad A.
Qureshi, Adrienne Williams Scott, Robert Francis
See, Robert Keith Shuler.
Emory University, Atlanta, Georgia: Sunil Srivastava (Director), Alicides Fernandes, Deborah Gibbs.
Former Members: Daniel F. Martin.
Royal Victorian Eye & Ear Hospital, East Melbourne, Australia: Richard J. Stawell (Director), Lisa
Breayley, Carly DSylva, Julie Ewing, Lauren Hodgson, Ignatios Koukouras, Lyndell Lim, Cecilia Ling,
Rachel McIntosh, Andrew Newton, Richard Smallwood, Ehud Zamir. Former Members: Nicola Hunt,
Lisa Jones, Suzanne Williams.
University of California at San Diego, La Jolla,
California: William R. Freeman (Director), Denine
E. Cochran, Igor Kozak, Megan E. Loughran, Luzandra Magana, Vivian Nguyen, Stephen F. Oster, Debbie Powell. Former Members: Nichole Brumley, Tom
Clark, Joshua Hedaya, Tiara Kemper, Jacqueline M.
LeMoine, Francesca Mojana, Victoria Morrison.
University of Miami, Miami, Florida: Janet L. Davis
(Director), Thomas Albini, Jaclyn L. Kovach, ClauAMERICAN JOURNAL

OF

dia Teran. Former Members: Daniela Castao, Macy


Ho, Susan Pineda, Richard C.-S. Lin, Jackie K.-D.
Nguyen, Kimberly E. Stepien.
University of Pennsylvania, Philadelphia, Pennsylvania: John H. Kempen (Director), Jim Berger, Joan
DuPont, Sheri Grand, Dawn McCall, Albert M.
Maguire, Laurel Weeney, Wei Xu. Former Members:
Tim Hopkins, Monique McRay, Daniel Will.
University of Utah, Salt Lake City, Utah: Albert T.
Vitale (Director), Paul S. Bernstein, Bonnie Carlstrom, James Gilman, Sandra Hanseen, Paula Morris,
Diana Ramirez, Kimberley Wegner.
New York Eye & Ear Infirmary, New York, New
York: Paul A. Latkany (Director), Jenny Gallardo,
Monica Lorenzo-Latkany, Robert Masini, Susan Morell, Ann Nour, Meredith Sanchez, Kate Steinberg.
Former Members: Kenneth M. Boyd, Jacek Jarczynski,
Mirjana McGrosky.
University of California at San Francisco, San Francisco, California: Todd P. Margolis (Director), Nisha
Acharya, David Clay, Claire M. Khouri, Salena Lee,
Mary Lew, Jay Stewart, Ira G. Wong.
National Eye Institute, Bethesda, Maryland: H.
Nida Sen (Director), Denise Cunningham, Chloe
Gottlieb, Darryl Hayes, Dessie Koutsandreas, Richard
Mercer, Robert B. Nussenblatt, Dominic Obiyor,
Patty R. Sherry, Gregory L. Short. Former Members:
Allison Bamji, Hanna Coleman, Geetaniali Davuluri,
Lisa Faia, Guy V. Jirawuthiworavong, Julie C. Lew,
Cheryl H. Perry, Natalia Potapova, Eric Weichel,
Keith J. Wroblewski, Steven Yeh.
University of California at Los Angles, Los Angeles,
California: Gary N. Holland (Director), Robert D.
Almanzor, Jose T. Castellanos, Jean Pierre Hubschman,
Ann K. Johiro, Michael A. Kapamajian, Ralph D.
Levinson, Susan S. Ransome. Former Members: Christine R. Gonzales, Anurag Gupta, Peter J. Kappel.
Virginia Eye Consultants, Norfolk, Virginia: John
D. Sheppard (Director), Nancy Crawford, Stephen V.
Scoper, Jeanette Fernandez, Lisa Felix-Kent, Rebecca
Marx, Joseph Webb. Former Members: R. Denise
Cole, Gregory Schultz, Pamela Yeager, Jen Martin.
Rush University Medical Center, Chicago, Illinois:
Pauline T. Merrill (Director), Pam Hulvey, Elaine
Kernbauer, Scott Toennessen, Denise L. VoskuilMarre. Former Members: Bruce Gaines, Christina
Giannoulis, Heena S. Khan, Sarah J. Levine.
Texas Retina Associates, Dallas, Texas: Robert C.
Wang (Director), Hank Aguado, Sally Arceneaux,
Jean Arnwine, Kimberly Cummings, Gary E. Fish,
Susie Howden, Diana Jaramillo, Karin Mutz, Brenda
Sanchez. Former Members: David Callanan.
University of Illinois at Chicago, Chicago, Illinois:
Debra A. Goldstein (Director), Marcia Niec, Misel
Ramirez, Howard H. Tessler. Former Members: Catherine E. Crooke, Melody Huntley, Dimitry Pyatetsky.

OPHTHALMOLOGY

APRIL 2010

University of South Florida, Tampa, Florida: Peter


Reed Pavan (Director), JoAnn Leto, Lori Mayor,
Maria Ortiz, Scott E. Pautler, Wyatt Saxon, Judy
Soto. Former Members: Dee Dee Szalay.

MULTICENTER UVEITIS STEROID


TREATMENT TRIAL RESOURCE CENTERS

MULTICENTER UVEITIS STEROID


TREATMENT TRIAL COMMITTEES

Executive Committee: Douglas A. Jabs (Study Chairman), Michael A. Altaweel (Reading Center Director),
Janet T. Holbrook (Coordinating Center Director),
John H. Kempen (Study Vice-Chairman), Natalie
Kurinij (NEI Project Officer).
Steering Committee: Douglas A. Jabs (Chair), Robert
D. Almanzor, Michael M. Altaweel, Diane Brown,
James P. Dunn, James Gilman, Janet T. Holbrook,
Gary N. Holland, John H. Kempen, Rosa Y. Kim,
Natalie Kurinij, Nancy Prusakowski, Jennifer Thorne.
Former Members: Stephen G. Bolton, Lisa M. Brune,
Tom Clark, Larry D. Hubbard, Daniel F. Martin,
Robert B. Nussenblatt.
Data, Safety and Monitoring Committee: Janet Wittes (Chair), Michael M. Altaweel*, William E. Barlow, Marc Hochberg, Janet T. Holbrook*, Douglas A.
Jabs*, Natalie Kurinij, Alice T. Lyon, Alan G. Palestine, Lee S. Simon, Harmon Smith. Former Members:
James T. Rosenbaum. *Nonvoting members.
Surgical Quality Assurance Committee: John H.
Kempen (Chair), James P. Dunn, Glenn J. Jaffe.
Former Members: Daniel F. Martin.
Medical Therapy Quality Assurance Committee:
Jennifer E. Thorne (Chair), Nisha Acharya, Douglas
A. Jabs, John H. Kempen, Paul A. Latkany, Albert T.
Vitale. Former Members: Robert B. Nussenblatt, Russell Van Gelder.
Visual Function Quality Assurance Committee:
Robert D. Almanzor (Chair), Judith Alexander, Jeffrey A. Boring, Deborah Gibbs, Salena Lee, Jennifer
E. Thorne (Advisor). Former Members: Wai Ping Ng.
Glaucoma Committee: David S. Friedman (Chair),
Anna Adler, Alyce Burke, Janet T. Holbrook, Joanne
Katz, John H. Kempen, Nancy Prusakowski, Susan
Reed, Jennifer E. Thorne. Former Members: Nicholas
Cohen, Sanjukta Modak, Wai Ping Ng.
Statistical Analysis Committee: Elizabeth Sugar
(Chair), Lea Drye, Kevin Frick, Janet T. Holbrook,

VOL. 149, NO. 4

Joanne Katz, Thomas Louis, Mark L. Van Natta.


Former Members: Sanjukta Modak, David Shade.

MUST TRIAL

Chairmans Office, Mount Sinai School of Medicine,


New York, New York: Douglas A. Jabs (Chairman),
Melissa A. Nieves, Karen Pascual, Jill S. Slutsky.
Former Members: Yasmin Hilal. University of Pennsylvania, Philadelphia, Pennsylvania: John H. Kempen
(Vice-Chairman). Johns Hopkins University, Baltimore, Maryland: Former Members: Colby Glomp, Maria
Stevens.
Coordinating Center, Johns Hopkins University
Bloomberg School of Public Health, Baltimore,
Maryland: Janet Holbrook (Director), Anna Adler,
Judith Alexander, Jeff Boring, Alyce Burke, Paul
Chen, Karen Collins, John Dodge, Lea Drye, Cathleen Ewing, Kevin Frick, David Friedman, Rosetta
Jackson, Joanne Katz, Andrea Lears, Hope Livingston, Thomas Louis, Curtis Meinert, Jill Meinert,
Deborah Nowakowski, Nancy Prusakowski, Dave
Shade, Virginia Shen, Rochelle Smith, Elizabeth
Sugar, Jennifer Thorne, Ada Tieman, Mark Van
Natta, Richard Zheng. Former Members: Nicholas
Cohen, Sanjukta Modak, Wai Ping Ng, Charles
Shiflett.
Fundus Photograph Reading Center, University of
Wisconsin, Madison, Wisconsin: Michael A. Altaweel (Director), Wendy K. Benz, Geoffrey Chambers, Debra J. Christianson, Amitha Domalpally,
Jacquelyn Freund, Vonnie Gama, Sapna Gangaputra,
Anne Goulding, Kathleen E. Glander, Jeffrey M.
Joyce, Christina N. Kruse, Susan Reed, Amy Remm,
James L. Reimers, Lori La See, Ruth A. Susman,
Dennis Thayer, Erika Treichel, Kelly J. Warren,
Sheila M. Watson, James K. White, Tara Wilhelmson. Former Members: Margaret A. Fleischli, Dennis
Hafford, Susan E. Harris, Larry D. Hubbard, Kristine
A. Johnson, Dawn J. Myers, Lauren Nagle, Gwyn E.
Padden-Lechten, Alyson Pohlman, Peggy Sivesind,
Mary K. Webster, Tong Wu.
National Eye Institute, Bethesda, Maryland: Natalie
Kurinij.

561

SUPPLEMENTAL TEXT: DESIGN DETAILS


FOR THE MULTICENTER UVEITIS
STEROID TREATMENT TRIAL

SUPPLEMENTAL TABLE 1. Eligibility Criteria for the Multicenter


Uveitis Steroid Treatment (MUST) Trial
Inclusion criteria
1. Age 13 years or older
2. Diagnosis of noninfectious intermediate uveitis, posterior
uveitis, or panuveitis by a MUST-certified ophthalmologist
3. Active uveitis of a degree for which systemic
corticosteroid therapy is indicated in the judgment of a
MUST-certified ophthalmologist or such uveitis active within
the last 60 days as determined either by examination by a
MUST-certified ophthalmologist or by review of ophthalmic
medical records by a MUST-certified ophthalmologist
4. Uveitis with or without an associated systemic disease is
acceptable; however, the systemic disease must not be
sufficiently active that it dictates therapy with oral
corticosteroids or immunosuppressive agents at the time of
study entry
5. Best-corrected visual acuity of hand movements or better
in at least 1 eye with uveitis
6. Baseline intraocular pressure of 24 mm Hg or less in all
eyes with uveitis
7. Collection of required baseline data within 10 days before
randomization
8. Signed informed consent
Exclusion criteria
1. Use of a fluocinolone acetonide implant within the last 3
years
2. Diabetes mellitus that is inadequately controlled,
according to best medical judgment
3. A known allergy to a required study medication
4. Uncontrolled glaucoma
5. Advanced glaucomatous optic nerve injury meeting the
following criteria: (1) for patients able to undertake a
Humphrey visual field analysis, depression of 2 points or
more within 10 degrees of fixation by at least 10 dB, mean
deviation worse than 15 dB, or both; (2) for patients unable
to undertake a Humphrey visual field analysis, vertical cupto-disc ration 0.9
6. A history of scleritis (because of concerns regarding the
potential for scleral melting with local corticosteroid therapy)
7. Presence of an ocular toxoplasmosis scar
8. Pregnancy
9. Current breastfeeding
10. Known human immunodeficiency virus infection or other
immunodeficiency disease for which corticosteroid therapy
would be contraindicated according to best medical
judgment
11. Patients for whom participation in the trial would
constitute a risk exceeding the potential benefits of study
participation, in the judgment of the treating physician
12. Medical problems or drug or alcohol dependence
problems sufficient to prevent adherence to treatment and
study procedures

Eligibility: Eligibility criteria are given in Supplemental Table 1. Eligible patients had active or recently
active (within 60 days) intermediate uveitis, posterior
uveitis, or panuveitisthe forms of uveitis for which
the fluocinolone acetonide implant therapy is indicated. These are forms of uveitis for which systemic
therapy commonly is indicated.22 Because of safety
considerations, patients who were pregnant or breastfeeding, those younger than 13 years, those with
uncontrolled glaucoma or diabetes, those with allergies to required study medications, those with scleritis
or ocular toxoplasmosis, and those with known immunodeficiency syndromes were excluded. Because some
episodes of substantially elevated intraocular pressure
(IOP) were expected to occur in the implant arm,28
patients with advanced glaucoma who might experience irreversible damage from such an IOP spike also
were excluded. Patients with associated systemic inflammatory diseases likely to require systemic therapy
for a nonocular indication were excluded on the
grounds that systemic therapy would be preferable to
implant therapy. Patients were required to have a
visual acuity of hand movements or better in at least
1 eye with uveitis, because eyes with visual acuity
worse than this level may not benefit enough from
treatment to justify the potential risks of the alternative therapies.
Sample Size: The primary analysis for the MUST trial
is to compare the mean eye-specific change in logarithm of the minimum angle of resolution visual
acuity from baseline to follow-up at 2 years between
the randomly assigned treatment groups. Mean
change in visual acuity was chosen as the primary
outcome because of an increasing consensus among
the ophthalmology clinical trials community in favor
of designing clinical trials to detect a difference in the
mean visual acuity rather than the proportion achieving a given number of lines of visual acuity lost or
gained 29 Based on considerations that previous clinical trials demonstrating a difference of approximately
7.5 letters (equivalent to 1.5 lines on a logarithmic
visual acuity chart)30 in mean visual acuity between
treatment groups have resulted in the widespread
adoption of the new treatments,3134 the MUST trial
is designed to detect at least a 7.5-letter difference in
visual acuity between groups, with at least 90% power.
For the sample size calculation, the number of
independent observations needed (assuming only 1
eye from each patient) was adjusted to take into
account the percent of patients expected to have
bilateral disease at baseline (estimated as 67%) and
the expected between-eye correlation in acuity

561.e1

AMERICAN JOURNAL

changes for involved eyes (conservatively estimated


to be 0.4).35 We estimated the standard deviation of
change in visual acuity to be 16 letters (3.2 lines).
Based on these assumptions, and allowing for a crossover rate of 10%, a sample size of 250 (125 patients
OF

OPHTHALMOLOGY

APRIL 2010

SUPPLEMENTAL FIGURE 1. Randomization schema used for the Multicenter Uveitis Steroid Treatment Trial.

per group) was projected to have a power of 91% with


a 2-sided type 1 error rate of 5% to detect at least a
7.5-letter difference in visual acuity between groups.
Randomization: Uveitis may affect one or both eyes.
Implant therapy is given to one eye at a time, but
systemic treatment affects both eyes simultaneously.
Because one of the alternative treatments is systemically administered, and because 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 (allocation ratio, 1:1) were stratified by the
type of uveitis (intermediate uveitis vs posterior uveitis or panuveitis) because visual acuity outcomes
likely differ between these disease categories8 and also
by clinical center to balance any potential effects of
varying protocol implementation or population differences at the clinics across treatment arms (see Supplemental Figure 1). The Rallocate procedure36 in

VOL. 149, NO. 4

MUST TRIAL

Stata software version 9 (StataCorp, College Station,


Texas, USA) was used to generate permuted block
randomization tables with variable block sizes for each
stratum level. The treatment assignment procedure
was implemented using a web-based system that
returned treatment assignments in real time after
completion of eligibility checks. Randomization was
conducted after obtaining informed consent and entering required baseline data. Before randomization,
institutional review board approval was obtained by
each participating center. The MUST trial is registered at clinicaltrials.gov (identifier NCT00132691).
Implant Treatment Protocol: Implant therapy (see
Supplemental Figure 2) consisted of treatment with
the commercially available fluocinolone acetonide
0.59-mg implant (Retisert; Bausch & Lomb, Inc,
Rochester, New York, USA) in each eye with uveitis
of sufficient severity to justify treatment with systemic
corticosteroids. After quieting of the anterior chamber to a grade of less than 1 anterior chamber cells7
561.e2

SUPPLEMENTAL FIGURE 2. Fluocinolone acetonide implant treatment algorithm for the Multicenter Uveitis Steroid Treatment
Trial.

(using topical and/or periocular corticosteroids,


and/or systemic corticosteroid therapy when the first 2
approaches are judged insufficient), the protocol
called for surgical implantation of an implant by a
MUST-certified surgeon using a standard technique25
under conventional anesthesia within 28 days of
randomization in the first eye. When applicable, the
second eye was implanted within 28 days thereafter
using the same approach. For second eyes that initially did not meet criteria for implantation, but
subsequently worsened to the point where systemic
corticosteroid therapy would be justified, implantation was performed at the time the eye met such
criteria in the same manner. Eyes in which a reactivation of uveitis developed after implantation were
reimplanted (regardless of when the reactivation occurred with respect to the original surgery); eyes in
which a second reactivation developed within 18
months after reimplantation were managed according
to best medical judgment. Eyes also were managed
according to best medical judgment when any of the
following occurred: (1) the patient required systemic
prednisone or immunosuppressive therapy for systemic indications; (2) toxicity of implant therapy
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OF

occurred; or (3) inflammation was not controlled


initially after implantation.
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 from corticosteroid therapy. Eyes for which additional intraocular
surgerysuch as cataract surgerywas needed at
baseline (and so noted before randomization on an
enrollment form) were permitted under the protocol
to have the other intraocular surgery combined with
implant surgery. However, vitrectomy surgery to clear
vitreous opacities was not performed on the grounds
that implant therapy was expected to clear such
opacities.
Systemic Treatment Protocol: Systemic therapy consisted of oral corticosteroid therapysupplemented
when indicated by immunosuppressionin accordance with expert panel recommendations.22 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

OPHTHALMOLOGY

APRIL 2010

SUPPLEMENTAL FIGURE 3. Systemic treatment algorithm for the Multicenter Uveitis Steroid Treatment Trial.

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 the following guidelines: (1) 10 mg/day decrements each week
to 40 mg daily; (2) 5 mg/day decrements each week to
20 mg daily; (3) 2.5 mg/day decrements every week to
10 mg daily; (4) 2.5 mg/day decrements every 2 weeks
until off prednisone. Patients whose uveitis already
had been controlled within the 60 days before enrollment started tapering from their current prednisone
dose and tapered their prednisone dose in the same
manner.
Immunosuppressive therapy was used when: (1)
uveitis was not controlled on corticosteroids alone;
(2) maintenance of suppression of uveitis required a
prednisone dose of more than 10 mg/day or a dose
sufficient to cause intolerable side effects; (3) for
specific diseases known to respond poorly absent
initial immunosuppressive therapy, or (4) a combination thereof.22 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
VOL. 149, NO. 4

MUST TRIAL

for an individual patient. However, the immunosuppressive treatment(s) selected was administered in
accordance with expert panel guidelines, including
laboratory monitoring for potential toxicities.22 Because of the potential additive therapeutic effect of
antimetabolites and T-cell inhibitors, a second immunosuppressive drug of the alternative class was recommended for patients not meeting treatment goals with
1 immunosuppressive drug. Alkylating agents (cyclophosphamide and chlorambucil), although given in
conjunction with prednisone, were not to be combined with other immunosuppressive drugs because of
the potential for substantially increased toxicity with
such combinations.
When needed (i.e., for patients who had flare-ups
of uveitis while still taking oral corticosteroids), tapering of prednisone was repeated iteratively: the dose
of prednisone was raised to a level sufficient to control
the inflammation each time a flare-up of inflammation
occurred and then tapered until either uveitis was
controlled without prednisone or until a minimal
suppressive dose of prednisone (with or without concomitant immunosuppressive therapy) was identified
561.e4

that was effective for maintaining suppression of


inflammation and had an acceptable side-effect profile. If 2 iterations of tapering in the presence of an
immunosuppressive agent failed to achieve a tolerable
minimal suppressive prednisone dose, treatment was
to be directed by best medical judgment. Likewise, if
the suppressive dose proved to be too high to have a
favorable side-effect profile when an alkylating agent
was used as the initial immunosuppressive agent,
treatment thereafter was directed by best medical
judgment.
After 6 months of successful suppression of uveitis
using systemic therapy, an attempt was made to taper
the prednisone further with monthly decrements following the steps above. If such tapering resulted in
reactivation of uveitis, the prednisone dose was raised
sufficiently to control the uveitis, and then tapered
back to the suppressive dose, after which the patient
was to be maintained on suppressive systemic therapy
at the suppressive dose for 12 months before further
tapering attempts.
While receiving oral corticosteroids, patients
received calcium and vitamin D supplementation
to minimize the incidence of osteoporosis.37 Patients in whom osteoporosis developed were referred for treatment, according to guidelines of the
American College of Rheumatology.37 Patients in
whom hypertension or diabetes developed as a
result of systemically administered drugs also were
referred for appropriate management.
Ancillary Treatment: Patients in both treatment
arms were allowed topical corticosteroid therapy as
indicated by best medical judgment, given according
to study guidelines. Given the severe nature of the
uveitis of patients enrolled in this trial, and given the
limited penetration of topical corticosteroids past the
anterior chamber to the primary site of inflammation
in these patients,22 these drops are unlikely to have a
substantial effect on the major causes of visual loss.
The protocol also permitted the use of periocular
corticosteroid injections (triamcinolone acetonide, 40
mg) when indicated for the following circumstances:
(1) for patients randomized to implant therapy, periocular corticosteroids could be given before implantation to suppress intraocular inflammation rapidly
before surgery; or (2) for persistent or refractory
macular edema in either group. Periocular corticosteroids could be given either via the posterior subTenon route or via the orbital floor route. Ancillary
intravitreous corticosteroid therapy also could be
given for the same indications when periocular corticosteroid injections were likely to fail or had failed.
The protocol directed that periocular and intraocular
corticosteroid injections should not be given repetitively on a routine basis as a primary form of therapy.

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SUPPLEMENTAL TABLE 2. Data Collection Schedule for the


Multicenter Uveitis Steroid Treatment (MUST) Trial*
Target week
Visit ID

13 26 39 52

65

78

91

104

BL F1 F2 F3 F4 F5 F6a F7a F8a F9a

Visual acuity
x
Goldmann tonometry
x
Ophthalmic
examination
x
Gonioscopy
x
Color slit-lamp
lens photographs
x
Color fundus photographs
(disc, macula)
x
Fluorescein
angiography
x
Optical coherence
tomography
x
Humphrey 24-2
perimetry
x
Medical history
x
Blood pressure
x
Height
x
Weight
x
EuroQol
x
SF-36, NEI-VFQ
x
Complete blood count
x
Comprehensive
chemistry panel
x
Casual plasma glucose
Fasting plasma glucose
x
Fasting lipid analysis
x
Serum pregnancy test
xb
Bone densitometry
x

x x x x x
x x x x x

x
x

x
x

x
x

x
x

x x x x x

x
x

x
x

x
x x x x x
x x x x x
x
x x x x x
x x x x
x
x
x

x
x

x
x

x
x

x
x

x
x
x

x
x

x
x x x x

x
x
x
x
x
x
x
x
x

x
x

x
x

ID identification; NEI-VFQ National Eye Institute Visual


Function Questionnaire; SF Short Form 36-item questionnaire.
a
The F6, F7, F8, and F9 data collection schedules repeat every
12 months until the common study closeout.
b
For women who were able to become pregnant.

OF

Data Collection and Follow-up: Patients enrolled in


the MUST trial have visits for data collection at
baseline, at 1 and 3 months after randomization, and
then quarterly until the end of the trial (see Supplemental Table 2). Other than the visit 1 month after
randomization (which is excluded from the efficacy
analysis), study visits should not be conducted within
1 month of ocular surgery (e.g., implant surgery) to
avoid biasing visual acuity measurements downward
in recently operated eyes, which are expected to have
reduced visual acuity transiently in the early postoperative period. Patients generally receive more frequent visits for clinical care. Data regarding treatment
changes and events occurring between study visits are
collected at the subsequent study visit, except for
adverse events that meet requirements for expedited
reporting.

OPHTHALMOLOGY

APRIL 2010

Data and Safety Monitoring: The Data and Safety


Monitoring Committee (DSMC)an independent
board appointed by and advisory to the study
funding agency (the National Eye Institute)is
responsible for ongoing review of efficacy and safety
data, policy and ethical issues, and study performance. Members of the DSMC include 2 ophthalmologists, 2 rheumatologists, 2 biostatisticians, and
an ethicist. The DSMC meets twice yearly with the
option for ad hoc meetings if required. An OBrien
Fleming spending function was used to develop
guidelines for stopping the trial. The DSMC has
planned for 3 formal analyses of the efficacy data,
after 50%, 75%, and 100% of participants have
been followed up for 2 years. These guidelines call
for stopping the trial early only if large differences
between groups in the mean change in visual acuity
from baseline12.5 to 15 letters or moreare
observed at the interim analyses. One of the physician members of the DSMC reviews adverse event
data between DSMC meetings, which are reviewed
first by a Coordinating Center ophthalmologist and
safety officer.

Study Organization: The organizational structure


of the MUST Trial Research Group consists of 3
resource centersa Chairmans Office, Coordinating Center, and Reading Centerand 23 clinical
centers, funded via U10 cooperative agreements
with the National Eye Institute. Surgical treatment
in the MUST trial is administered by surgeons who
have been certified in the protocol procedures by a
Surgical Quality Assurance Committee, either by
live observation of surgery or by review of an
unedited video of surgery performed on a human or
animal eye. Adherence to the systemic therapy
protocol is assessed at approximately annual site
visits by expert clinicians serving on the Medical
Therapy Quality Assurance Committee. A Visual
Function Quality Assurance Committee oversees
the training, monitoring, and certification of all
visual function technicians in the trial, ensuring
the quality of visual acuity measurements made in
the trial. Other aspects of protocol enforcement
and clinic performance monitoring are conducted
by Coordinating Center staff through approximately annual site visits and remote surveillance of
study activities. Day-to-day study management is
conducted by an Executive Committee consisting
of the Study Chair and Vice-Chair, the Coordinating Center Director, the Reading Center Director,
and a representative of the National Eye Institute.
A Steering Committee consisting of the Executive
Committee and a majority of elected investigators
is charged with major policy decisions regarding
study implementation and management.

MUST TRIAL

561.e6

Outcomes: 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 bestcorrected visual acuity. 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 (QOL).
Masking is applied to the determination of visual
acuity, those outcomes based on photographic reading, and diagnosis of glaucoma by the Glaucoma
Outcomes Committee. Because sham surgery is not
performed, masking during ascertainment of the other
outcomes is not feasible.
The primary outcome best-corrected visual acuityis measured every 3 months at study visits under
standardized lighting conditions by certified study
examiners with best refractive correction in place,
using standard logarithmic (Early Treatment Diabetic
Retinopathy Study [ETDRS]) visual acuity charts.38
At the 6-month visit (by which time the impact of
implant surgery rarely would be visible in a darkened
room) and subsequently, these measurements are
made by examiners unaware of treatment assignment.
Eye-specific outcomes such as visual acuity are followed as by-eye variables, an approach that provides
more information than a by-patient analysis and
avoids the problem of having to select a study eye. In
the ETDRS system, 15 letters is equal to a change of
3 lines of visual acuity, for example, from 20/40 to
20/20 or vice versa, a halving or doubling of the visual
angle30; a change of 7.5 letters corresponds to a 25%
decrease or 50% increase in the visual angle.
Secondary outcomes for the MUST trial include
evaluation of inflammatory and morphologic characteristics of enrolled eyes, which are measured longitudinally throughout the course of the study (see
Appendix, below). Assessment is performed by unmasked ophthalmologist investigators and by masked
grading of imaging studies. The methods 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
(macular edema, vitreoretinal interface abnormalities
including epiretinal membrane), and fluorescein angiography (macular edema, vascular leakage, perfusion
abnormalities, choroidal neovascularization). Healthrelated quality-of-life data also are assessed, including
health utility as measured by the EuroQol 5-dimension and Visual Analog Scale scores,39,40 general
health-related QOL as measured by the Short Form
36-item questionnaire,41,42 and vision-related QOL as
measured by the 25-item National Eye Institute Visual Function Questionnaire.43

VOL. 149, NO. 4

APPENDIX: OUTCOME DEFINITIONS


AND PLANNED ANALYSES FOR THE
MULTICENTER UVEITIS STEROID
TREATMENT TRIAL

Visual Acuity: Best-corrected visual acuity score is


measured at every study visit under standardized
lighting conditions by certified study examiners
with best refractive correction in place, using logarithmic (ETDRS) visual acuity charts38 (as described above). The design outcome is based on
change by 2 years follow-up in visual acuity (number of letters read) from baseline in eyes meeting
trial inclusion criteria at baseline.
In addition to the primary analysis, visual acuity
data are to be analyzed in several different ways: (1)
calculating the proportion with low vision (worse
than 20/40) and legal blindness (20/200 or worse, or
visual field subtending an angle of 20 degrees or less)
over time and (2) assessment of gain or loss of vision
with respect to baseline ETDRS visual acuity on an
ordinal scale over time: loss of 30 letters or more, loss
of 15 to 29 letters, loss of 5 to 14 letters, within 4
letters of baseline visual acuity, gain of 5 to 14 letters,
gain of 15 to 29 letters, or gain of 30 letters or more.
These outcomes are evaluated both by patient (both
for the worse eye and for the better eye, only eyes with
uveitis) and by eye (only eyes with uveitis).
Intraocular Inflammation: Intraocular inflammation
is assessed at every visit by clinical examination.
Inflammatory status is based primarily on anterior
chamber cells and vitreous haze, each of which are
graded on ordinal scales.7
Uveitis is judged to be inactive when anterior
chamber cells are graded as 0 or 0.5 and vitreous
haze is graded as 0; gradings of 1 or higher on either
scale are interpreted as indicated that the uveitis is
active. The examining clinician also is asked to grade
the uveitis as active, mildly active, or inactive based
on her or his own judgment. For rare uveitic conditions, such as serpiginous choroidopathy, in which
inflammation may be limited to the choroid and
retina, clinical judgment of activity is substituted for
the composite score based on anterior chamber cells
and vitreous haze.
Clinical examination data regarding consequences
of intraocular inflammation also are noted at every
visit, including anterior chamber flare (graded over an
ordinal scale of 0, 1, 2, 3, 4),44 and the
presence or absence of posterior synechiae, preretinal
neovascularization, choroidal neovascularization,
epiretinal membrane or macular pucker, macular
edema, optic nerve swelling, pars plana exudation,
and retinal detachment. The presence of peripheral
anterior synechiae and angle closure are documented
by annual gonioscopy. If present, the extent (in

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degrees) of posterior synechiae and of peripheral


anterior synechiae or angle closure are recorded.
Cataract grading is performed by the Reading Center
from slit-lamp lens photographs and red reflex photographs of the lens plane (see below).
Retinal Morphologic Features: To document the
ocular abnormalities of uveitis and its complications,
MUST trial clinical centers obtain fundus photographs, fluorescein angiograms, optical coherence tomography (OCT) scans, and lens photographs using
standardized protocols generated by the Reading Center at the University of Wisconsin, Madison. Images
are graded at the Reading Center according to standardized protocols for status of and change in ocular
morphologic features. The resultant data are summarized into analysis variables and are transmitted to the
Coordinating Center.
Retinal morphologic features often are altered
pathologically as a result of intermediate uveitis,
posterior uveitis, or panuveitis. A common morphologic change, and the most common cause of vision
loss in uveitis, is the occurrence of macular edema.
Therefore, measurement of macular edema is a primary goal of ocular image analysis. The presence
versus absence of macular edema is determined by
fluorescein angiography (FA) and OCT. When edema
is present, severity of fluorescein leakage and of
cystoid spaces is assessed using a modification of the
ETDRS protocol. The area of retinal thickening and
of cystoid spaces found on concurrently graded FA
and color fundus photographs also is noted. The
extent of fluorescein leakage is noted in disc areas.
Central macular thickness is measured by OCT, as is
the volume within the ETDRS circle. Other OCT
features consistent with macular edema, such as cystoid spaces, are graded in terms of presence and
extent. These morphologic measures are expected to
correlate with visual acuity.
Additional retinal morphologic features (with the
image from which it is derived in parentheses) being
graded include vascular nonperfusion (FA), choroidal
neovascularization (FA), preretinal neovascularization (color fundus photographs, FA), retinal detachment (fundus photo, FA), optic disc edema (fundus
photo, FA), glaucomatous optic disc changes (enlarged cup-to-disc ratio, notching or thinning of the
disc rim, disc pallor, and disc hemorrhage; stereo
fundus photographs), vitreoretinal interface abnormalities (such as epiretinal membrane) and their
relationship to macular edema (OCT and fundus
photography), and chorioretinal lesions (fundus photography, FA with sweep fields). Morphologic features
in most cases are measured as dichotomous variables
(present or absent), and if present, their extent is
graded.

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APRIL 2010

Quality of Life: As an ocular disease, uveitis is


expected to affect QOL primarily through its impact
on vision. However, systemic therapy and associated
systemic disease may have effects on perceived general
health-related QOL and health utility. In addition,
because the effect of vision loss on general well-being
is profound, the effect of uveitis on general well-being
may be substantial despite localization of disease to
the eye.
The National Eye Institute Visual Function Questionnaire is an instrument designed to be responsive
to the effects of eye diseases on QOL, particularly
addressing vision-related QOL. It is based on aspects
of vision and ocular symptoms. The National Eye
Institute Visual Function Questionnaire has been
demonstrated to give valid and reliable results across
a variety of ocular conditions43,45 and is a widely used
instrument for measurement of vision-related QOL.
The Medical Outcomes Study Short Form Health
Survey is an instrument measuring general healthrelated QOL that has been demonstrated to fulfill
rigorous validity and reliability standards.41,42 It is the
instrument most commonly used to measure general
health-related QOL in clinical studies.46 The EuroQol is a generic health index widely used in clinical
research to calculate a health utility,39 the measurement of which has been recommended for all clinical
trials by the Panel on Cost Effectiveness in Health
and Medicine.27 A health utility score is useful as a
summary indicator of a patients self-perceived general
health status, which can be used to compare the
impact of uveitis (and its treatment) relative to the
impact of other diseases. Health utility also will
provide the primary effectiveness measure for costeffectiveness analysis. The MUST trial QOL battery
consists of these 3 instruments, all available in both
English and Spanish.
Potential Complications of Study Treatment: Both
randomized treatment approaches are expected to
result in side effects. The relative occurrence of such
events are key results of the study, which will play an
important part in interpretation of the overall results.
Specific complications to be evaluated prospectively
are described below. An adverse events reporting
system also is used to ascertain the occurrence of both
anticipated and unanticipated adverse events.
Ocular side effects of treatment anticipated to
occur with substantial frequency in the MUST trial
include cataract and glaucoma, which are common
side effects both of uveitis and of corticosteroid
therapy. Occurrence of complications of intraocular
surgerysuch as endophthalmitis, vitreous hemorrhage, and implant extrusionmost likely will be
uncommon, but are important. Because ocular adverse
events will be important for comparison of the alter-

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native treatments, detailed measurements are being


obtained.
Systemic therapy with corticosteroids or immunosuppressive (corticosteroid-sparing) agents can be associated with adverse systemic side effects. Because
the occurrence of systemic side effects with systemic
therapy is an important element of the rationale for
using the fluocinolone acetonide implant, detailed
data are collected on anticipated potential complications.
Elevated Intraocular Pressure and Glaucoma: IOP
elevation and glaucoma may be either a complication
of uveitis itself or may be corticosteroid induced. IOP
is measured using the protocol followed by the Collaborative Initial Glaucoma Treatment Study, before
gonioscopy or dilation.47 A certified technician operates a Goldmann applanation tonometer, while a second
observer records the findings. The second observer then
resets the tonometer, and the measurement is repeated.
If the 2 measures differ by 2 mm Hg or more, then a third
measurement is made to adjudicate the discrepancy.
Tono-Pen (Mentor Ophthalmics, Norwell, Massachusetts, USA) IOP measurement is acceptable when Goldmann tonometry cannot be performed. IOP measurements
of more than 21 mm Hg are considered to be elevated, and
measurements higher than 30 mm Hg are considered to
be highly elevated. Elevations of IOP and the outcomes
of these events are monitored.
Diagnosis of glaucoma is made through the integration of several inputs. Stereo optic nerve photographs
are graded by the Reading Center. Humphrey visual
field testing is used to screen for glaucomatous visual
field defects through use of the Glaucoma Hemifield
Test.48 Unreliable or abnormal results are evaluated
further by repeat testing. Eyes for which photographic,
visual field, or clinical evaluation, or a combination
thereof suggests glaucoma may be present undergo a
masked review by a Glaucoma Outcomes Committee
led by a glaucoma specialist or ophthalmic epidemiologist. Such eyes are followed up to make or exclude
the diagnosis of glaucomatous optic nerve damage,
applying the methodology used by the Baltimore Eye
Survey.49
Cataract: The occurrence and progression of cataract
is evaluated based on red reflex photographs and
slit-lamp photographs, graded using an adaptation of
the Age-Related Eye Diseases Study cataract grading
protocol.50 This system grades posterior subcapsular
and cortical cataracts based on the percentage of lens
involvement. Nuclear sclerotic cataracts are graded
on the basis of optical density, using a numerical scale
generated by the graders interpolation of the optical
density of the nuclear sclerosis between 4 anchor
standard photographs (1.0, 2.0, 3.0, and 4.0).
Pseudophakia and aphakia are noted based on
clinical examination or photographysuch eyes are
561.e8

excluded from cataract grading. The occurrence of


cataract surgery and of yttriumaluminum garnet laser capsulotomy or surgical capsulotomy during follow-up is noted. Whether sufficient posterior capsular
opacification exists to warrant yttriumaluminum
garnet capsulotomy, based on clinical examination
alone, is noted at each visit.
Other Ocular Complications: Other ocular complications that are expected to be uncommon, but are
important with respect to evaluation of the alternative treatments, include: retinal detachment, vitreous
hemorrhage, endophthalmitis, and implant extrusion.
Hyperglycemia and Diabetes Mellitus: Fasting plasma
glucose levels are measured at baseline, 3 months, 12
months, and annually thereafter. Casual plasma glucose levels are measured at all other visits. Results are
interpreted using the thresholds recommended by the
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (American Diabetes
Association) for hyperglycemia and diabetes.51 Treatment-induced diabetes mellitus is diagnosed when a
subject who is euglycemic at baseline: is observed to
have diabetic-level hyperglycemia during follow-up,
has medical records demonstrating that the subject
was diagnosed with diabetes mellitus (with or without
specification of treatment relationship) during followup, is started on therapy for diabetes mellitus, or a
combination thereof. The number of oral hypoglycemic medications and use of insulin at each visit are
applied to construct an ordinal scale evaluating the
degree of difficulty in controlling diabetes mellitus:
0 no hypoglycemic therapy; 1 one oral hypoglycemic agent; 2 2 or more oral hypoglycemic agents;
and 3 daily use of insulin. The baseline value on
this scale is subtracted from the maximum value of
this scale during follow-up to indicate the change in
glycemic status with therapy, allowing this outcome
to be evaluated both in subjects who at baseline were
nondiabetic and those who were diabetic but not
requiring insulin.
Osteoporosis: Subjects are screened for osteoporosis
using dual-emission radiograph absorptiometry scanning of the spine (L2 to L4) and of the left femoral
neck to measure bone mineral density at baseline and
annually thereafter. Bone mineral density, the single
best predictor of osteoporotic fracture risk,52 is worsened substantially by corticosteroid therapy.53 Generalizing the World Health Organization Study Group
postmenopausal osteoporosis guidelines54 to the setting of corticosteroid-induced bone lossfollowing
the adaptation of the American College of Rheumatology37the MUST trial defines osteopenia 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. Fracture events, likely to be

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OF

infrequent during the follow-up period of the trial,


also are noted when confirmed by medical records.
Hyperlipidemia: Fasting lipid panelsincluding total
cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and triglyceride levelsare obtained at baseline, the
3-month follow-up, the 12-month follow-up, and
annually thereafter. Because elevated LDL cholesterol
is a major cause of coronary heart disease and is the
primary target of cholesterol-lowering therapy,55
changes in LDL cholesterol from baseline are evaluated as the main indicator of treatment effects on
hyperlipidemia. Based on the categories of the National Cholesterol Education Program Expert Panel,55
LDL cholesterol levels are categorized ordinally as
follows: 100 mg/dL, 100 to 129 mg/dL, 130 to 159
mg/dL, 160 to 189 mg/dL, and 190 mg/dL or more.
The change in ordinal category from baseline is
evaluated as an indicator of the effect of alternative
treatments on LDL cholesterol levels. Comparisons of
change in ordinal National Cholesterol Education
Program category from baseline for the other lipid
parameters are measured. Quantitative change in
other lipid levels (e.g., high-density lipoprotein cholesterol, total cholesterol) from baseline also are
evaluated.
Hypertension: Blood pressure (BP) measurement is
obtained at all clinic visits. According to the method
used in the Framingham Heart Study, BP is measured
twice in the seated position after a patient has rested
at least 5 minutes. Measurements are obtained at least
2 minutes apart, on the left arm. The average of the 2
readings obtained is used for both systolic and diastolic BP.56 Blood pressure stages (an ordinal scale)
are evaluated in the same manner as that described for
hyperlipidemia above. Based on Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure recommendations,57 ordinal categories for systolic BP are: 130
mm Hg, 130 to 139 mm Hg, 140 to 159 mm Hg, 160
to 179 mm Hg, and 180 mm Hg or more. Ordinal
categories for diastolic BP are: 85 mm Hg, 85 to 89
mm Hg, 90 to 99 mm Hg, 100 to 109, and 110 mm Hg
or more. Quantitative changes in systolic BP, diastolic
BP, and mean arterial pressure from baseline also are
evaluated.
Weight Gain: Weight is measured using a balance
scale. Change in weight is evaluated directly and
according to the body mass index (in kg/m2). Change
from baseline and maximum values for these variables
are evaluated.
Other Potential Systemic Complications of Corticosteroid Therapy: Other less common potential complications of systemic corticosteroid therapy are
deemed to be present when medical records confirm
that a diagnosis has been made. Conditions specifi-

OPHTHALMOLOGY

APRIL 2010

cally monitored for include diagnosis of any of the


following conditions, when not present at baseline: a
systemic infection requiring anti-infectious therapy or
hospitalization, an axis I psychiatric disorder,58 pancreatitis, and ischemic necrosis of bone.
Potential Systemic Complications of Immunosuppressive Therapy: Each immunosuppressive agent
has a unique spectrum of potential systemic side
effects. Some of these agents can cause hypertension
and hyperlipidemia, which also can result from corticosteroid therapy, and are evaluated as described
above. Additional side effects associated with these
medications that are medically important and expected to occur with detectable frequency during the
trial are the following.
Bone marrow suppression. (1) Reversible neutropenia is evaluated over time as the proportion having a
total white blood cell count of 2500 cells/L or fewer,
which corresponds to an increased infectious risk and
is a common indication for interruption of therapy.
Change in white blood cell count from baseline and
use of granulocyte stimulatory factors also are noted.
(2) Reversible thrombocytopenia is evaluated over
time as the proportion having a platelet count 100
000/L or fewer, which is a common indication for
suspension of therapy. Change from baseline is noted.
Hemorrhagic events, requirement for platelet transfusion, or other treatments for thrombocytopenia also is
noted. (3) Reversible anemia is evaluated over time as
the proportion having a hemoglobin level of 10 g/dL
or less, a threshold often considered clinically significant. Change from baseline is noted. Use of transfusions and of erythropoietin also are noted.
Occurrence of myelodysplasia is noted when confirmed
in medical records. (1) Reversible hepatotoxicity is
evaluated over time as the proportion with any of the

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following, verified in laboratory reports: aspartate


aminotransferase or alanine aminotransferase levels
more than twice the upper range of normal confirmed
by repeat testing, or discontinuation of an immunosuppressive agent as a result of hepatotoxicity. Cases
of persistent elevation of aspartate aminotransferase,
alanine aminotransferase, or both after discontinuation of the offending agent are noted. (2) Reversible
nephrotoxicity is evaluated over time as the proportion with: serum creatinine elevated 30% above
baseline or to a level of 1.5 mg/dL or higher, or
discontinuation of an immunosuppressive drug for
renal toxicity. Persistent renal insufficiency is noted.
(3) Other potential systemic complications of immunosuppressive therapy are deemed to be present when
diagnosis is confirmed by medical records. Occurrence
of the following is noted (if not present at baseline):
liver cirrhosis, interstitial pneumonia, malignancy,
end-stage renal disease, and hemorrhagic cystitis.
Mortality: Mortality is not expected to occur at a
high rate in this study, because neither uveitis nor the
treatments being tested are thought to be associated
with substantially increased risk of death. However,
mortality is evaluated in the trial for safety analyses.
Death is considered to have occurred when one of the
following criteria are met: a death certificate for the
participant is obtained, the participant is listed as
deceased in the Social Security Death Index or the
National Death Index, notice of death appears in
print (e.g., an obituary), 2 or more relatives or
acquaintances testify that the participant has died and
provide the same date of death. Survival audits are
performed periodically, before publication of primary
MUST trial results, or both. Date of death is ascertained from the source reporting that death has
occurred.

561.e10