UVEITIS

Systematic Review on the Effectiveness of

Immunosuppressants and Biological Therapies
in the Treatment of Autoimmune Posterior Uveitis
Esperanza Pato, MD,* Santiago Muñoz-Fernández, MD, PhD,†
Félix Francisco, MD,‡ Miguel A. Abad, MD,§ Jesús Maese, MD,¶
Ana Ortiz, MD, PhD,储 and Loreto Carmona, MD, PhD,** On behalf of
Uveitis Working Group from Spanish Society of Rheumatology

Objectives: To analyze the effectiveness of immunosuppressants and biological therapies in autoimmune

posterior uveitis, chronic anterior uveitis associated with juvenile idiopathic arthritis, and macular edema.
Methods: Systematic review. We conducted a sensitive literature search in Medline (from 1961) and
EMBASE (from 1980) until October 2007. Selection criteria were as follows: (1) population: autoim-
mune posterior uveitis, chronic anterior uveitis in juvenile idiopathic arthritis, and macular edema; (2)
intervention: immunosuppressive and biologic therapies; (3) outcomes: visual acuity, Tyndall, vitreous
haze, macular edema, pars planitis, and retinal vasculitis. There were no limitations regarding study
design. The quality of each study was evaluated using the Jadad’s scale and Oxford Levels of Evidence.
Results: Two hundred sixty-five articles were selected for detailed review of the 4235 found in the initial
search: 128 records were on immunosuppressants, 105 on biological therapies, and 32 on macular
edema. Overall, both the immunosuppressive and the biologic therapies appeared effective in the
treatment of autoimmune posterior uveitis, except for daclizumab in uveitis related to Behçet’s disease,
and for etanercept in any uveitis. In the treatment of macular edema, the drugs tested were also effective.
Conclusions: Based on the evidence collated, immunosuppressants and biological therapies (ex-
cept for daclizumab in Behçet and etanercept) may be effective in autoimmune uveitis and macular
edema. No superiority may be inferred from this review.
© 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 40:314-323
Keywords: uveitis, cystoid macular edema, effectiveness, immunosuppressants, biological therapies

U veitis is defined as an inflammation of the uveal

*Rheumatology Department, Hospital Clínico San Carlos, Madrid, Spain.
†Rheumatology Department, Hospital Infanta Sofía, San Sebastián de los Reyes,
Madrid, Spain.
‡Rheumatology Department, Hospital Dr. Negrín, Las Palmas de Gran Canaria, Spain.
§Rheumatology Department, Hospital Virgen del Puerto, Plasencia, Spain.
¶Grupo SER de revisores, Madrid, Spain.
储Rheumatology Department, Hospital de la Princesa, Madrid, Spain.
**Research Unit, Sociedad Española de Reumatología, Madrid, Spain.
Sources of support: Schering Plough, S.A. donated to the Fundación Española de
Reumatología to facilitate the review. The Fundación Española de Reumatología
provided the personal resources and materials needed for the review.
The panel of experts of the Uveitis Working Group from the Spanish Society of
Rheumatology include the following: David Diaz Valle, MD, PhD; Ma Cruz Fernán-
dez Espartero, MD; Jose A. Fernández Sánchez, MD; Angel García Aparício, MD;
Estibaliz Loza Santamaría, MD; Roberto Miguelez Sánchez, MD; Carlos Montilla
Morales, MD; and Eduardo Úcar Ângulo, MD.
Address reprint requests to Dra. Esperanza Pato, Servicio de Reumatología, Hos-
pital Clínico San Carlos, Calle Martín Lagos, s/n, 28043 Madrid, Spain. E-mail:
epato.hcsc@salud.madrid.org.
314 0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.semarthrit.2010.05.008
tract (iris, ciliar body, and choroids). In clinical
practice, the term uveitis, as used currently, refers
to a great number of diseases characterized by intraocular
inflammation involving the uvea and other ocular struc-
tures (retina, orbit, sclera) (1). A high percentage of uveitis
has an autoimmune origin and good response to treat-
ment with corticosteroids and immunosuppressants
(ISS). Despite these treatments, uveitis may have a poor
visual prognosis, even lead to blindness (2).
Corticosteroids are the main treatment in autoimmune
uveitis (posterior uveitis, intermediate, and panuveitis),
but in some circumstances, they are not sufficient for
controlling the disease. ISS are indicated if the ocular
inflammation is not controlled with corticosteroids, if re-
currences occur despite using corticosteroids correctly,
and if corticosteroids cause side effects. ISS should be

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E. Pato et al.
maintained for long periods to stabilize symptoms and to
prevent relapses.
Cyclosporine A (CsA) is the only ISS approved in
Spain for the treatment of noninfectious uveitis. How-
ever, several ISS as methotrexate (MTX), azathioprine
(AZA), mycophenolate (MMF), or cyclophosphamide,
among others, are used routinely off-label in the treat-
ment of uveitis and other ocular inflammatory diseases.
Moreover, at present, biological therapies (anti-tumor ne-
crosis factor, IL-2 inhibitor, interferon) are commonly
used in refractory autoimmune uveitis, with promising
results documented in the literature.
Rheumatologists collaborate very often with ophthal-
mologists, as many rheumatic diseases involve the uveal
tract, such as ankylosing spondylitis, Behçet’s disease, or
juvenile idiopathic arthritis (JIA), as examples. Uveitis
clinics are attended by both types of specialists (3), as they
are also a sound place to screen for specific rheumatic
conditions and autoimmune ophthalmologic diseases. A
panel of experts of the Spanish Society of Rheumatology
together with ophthalmologists was confronted with the
task of making recommendations to guide these clinics.
Despite the fact that recommendations on the use of ISS
in inflammatory eye conditions have been issued (4),
these are not clearly evidence-based. Additionally, some
narrative reviews have been published on the topic
(1,5,6). However, conducting randomized trials or fol-
lowing large series of patients is very difficult in this topic,
as the number of patients with uveitis who need ISS is
small, and diagnoses associated with uveitis are varied.
Therefore, the assessment of efficacy is very difficult. The
objective of our work was to assess the efficacy and safety
of ISS or biological therapies in the treatment of autoim-
mune uveitis or of cystoid macular edema (CME) in light
of the best available evidence.
METHODS
We performed a systematic review on the effectiveness
and safety of ISS or biological therapies in the treatment
of autoimmune uveitis with posterior pole involvement,
chronic anterior uveitis associated with JIA, and CME.
Search Strategy
Three search strategies were designed to capture studies ISS,
biological therapies, and CME. PubMed, MEDLINE, and
EMBASE were searched from inception until October
2007 for the keywords “uveitis” OR “uveitis, intermedi-
ate” OR “uveitis, posterior” OR “endogenous uveitis”
OR “autoimmune uveitis” OR “panuveitis” in the 2 pure
uveitis searches and were crossed with MeSH and free-
text synonyms of all ISS and of all biologics, respectively.
Both strategies excluded records related to suppurative
uveitis. The third strategy included only terms to capture
studies on CME. The searches were initially run by 1
reviewer (L.C.) and then they were repeated by 2 review-
ers (E.P. and S.M.F.). Language was restricted to English
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315
and Spanish. All strategies are available in a supplemen-
tary file. The reference lists of all articles retrieved in full
were also searched. In addition, we consulted the expert
panel that had initially requested the systematic review.
Selection of Studies
The titles and abstracts of all articles retrieved by the
search strategy were reviewed by 2 independent reviewers
(E.P., S.M.F.). Subsequently, 4 independent reviewers
(F.F., M.A., J.M., A.O.) reviewed in detail the studies,
analyzed them in light of the selection criteria, and as-
sessed their quality. Selection criteria were as follows: (1)
trials of any methodological quality were included, with
an emphasis on randomized controlled trial (RCTs); (2)
patients with autoimmune noninfectious uveitis (inter-
mediate, posterior, or panuveitis), or uveitic CME; (3)
treatment should be any ISS, including CsA, tacrolimus,
sirolimus, methotrexate, azathioprine, mycophenolate
mofetil, cyclophosphamide, and chlorambucil, or biolog-
ical therapy (interferon, infliximab, adalimumab, etaner-
cept, daclizumab); (4) outcome measures that were exam-
ined to measure the effectiveness were visual acuity,
Tyndall (anterior chamber cells) (7,8), vitreous haze (9),
macular edema, pars planitis, and retinal vasculitis.
Data Collection and Analysis
All 4 reviewers used a standard form, based on our previ-
ous work, where the data were collected from the studies
included in the review. Each of the reviewers made the
selection and revision of 1 or more therapies and filled out
the forms. The information collected included descrip-
tion of study design, the sample studied, the number of
patients, and outcome variables. This information was
used to classify each study individually at a level of evi-
dence used to judge the quality of the study.
The level of evidence was the correspondent from the
Oxford Centre for Evidence-based Medicine Levels of
Evidence in the May 2001 adaptation (10), which grades
the studies on efficacy as follows: (1a) systematic reviews
of randomized controlled trials with homogeneity; (1b)
individual randomized controlled trials with narrow con-
fidence intervals; (1c) trials in which all patients are cured
or none are; (2a) systematic reviews of cohort studies with
homogeneity; (2b) individual cohort study, or low-qual-
ity randomized controlled trials; (2c) “outcomes” research
and ecological studies; (3a) systematic reviews of case-
control studies with homogeneity; (3b) individual case-
control study; (4) case-series and poor-quality cohort and
case-control studies; and (5) expert opinion without ex-
plicit critical appraisal, or based on physiology, bench
research, or “first principles.” The Jadad scale (11) was
additionally used to grade quality in case the study was a
RCT.
Evidence tables were produced with the included stud-
ies and a qualitative analysis was performed.
316 Immunosuppressants and biological therapies treating autoimmune posterior uveitis
Figure 1 Flow chart with the results from the 3 search strategies.
RESULTS
The complete literature search produced 4235 items in
both bibliographic databases reviewed (2674 in Medline
and 1561 in EMBASE). After removing the 506 items
that were duplicated, 3729 articles were revised and 167
finally included. Figure 1 shows the results of the selection
process for each of the 4 reviews.
The complete evidence table of the included studies is
available in a supplementary file. Most of the items found
were open prospective studies and case series; only 11
were RCT. The methodologic quality of most studies was
low. The ocular diseases were varied including the fol-
lowing: Behçet’s disease, ocular choroiditis (serpigi-
nous choroiditis, Birdshot, etc), sarcoidosis, Vogt-Koy-
anagi-Harada (VKH). The most frequently studied disease
was Behçet’s-associated uveitis. Outcome measures that
were used in studies to describe the results were ex-
tremely heterogeneous. Visual acuity (VA) was used in
most of the studies, but there was no uniformity in
terms of the scale used to measure it. Ocular inflam-
mation and number of relapses were also other vari-
ables frequently used to assess outcome, but each study
chose a different scale to measure inflammation. In
general, there was great diversity in terms of diseases
involved and of outcome variables used.
Immunosuppressants in Uveitis
The initial title and abstract selection left 128 articles on
ISS that were analyzed in detail. Of these, 90 studies were
finally included in the review. The results are presented by
type of ISS: T-cell inhibitors (CsA, tacrolimus, sirolimus);
antimetabolites (methotrexate, azathioprine, mycopheno-
late mofetil); and alkylating agents (cyclophosphamide, and
chlorambucil). Nine studies with different combinations of
treatments could not be analyzed.
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T-cell Inhibitors:
Cyclosporine A, Tacrolimus, and Sirolimus
There were 46 studies on CsA [8 RCT (12-19), 1 uncon-
trolled single masked trial (20), 16 prospective studies
(21-36), and 21 retrospective studies (37-57)]. They in-
clude over 800 patients with an average age between the
fourth and fifth decade (there is a study in children) (43).
Eye conditions treated were quite varied: Behçet’s-associ-
ated uveitis, ocular choroiditis, VKH, sympathetic oph-
thalmia, sarcoidosis, noninfectious uveitis posterior pole
of a different etiology, and JIA-associated uveitis. Signif-
icantly, the most frequent disease was Behçet-associated
uveitis. CsA dose varied from 3 to 10 mg/kg/d. The out-
come variables used were very varied, the most frequent
being VA and intraocular inflammation. The quality of
the studies was low except 4 RCT (12,14,16,17). In the
study by BenEzra and coworkers (12), 40 Behçet patients
were randomized to be treated with oral steroids/chloram-
bucil (n ⫽ 20) or CsA (n ⫽ 20). The analysis after 3 years
of follow-up showed that CsA was more effective in im-
proving ocular inflammation and in preserving the VA
than steroids/chlorambucil, although with more adverse
effects. De Vries and coworkers (14) included 27 patients
with severe chronic uveitis refractory to oral corticoste-
roids who were treated with CsA (n ⫽ 14) or placebo (n ⫽
13). Due to the small sample size, no significant differ-
ences in terms of improvement in VA or inflammatory
activity parameters between groups were detected. Nus-
senblatt and coworkers (17) described 56 patients with pos-
terior or intermediate uveitis treated with oral corticosteroids
(n ⫽ 28) or CsA (n ⫽ 28). The analysis of the improvement
of VA, inflammation in anterior chamber, and posterior seg-
ment did not detect differences between the groups. Adverse
effects were described in both groups, but hypertension and
increased creatinine were frequent in the CsA group.
Eight articles on tacrolimus were analyzed [1 RCT
(16), 2 open trials (58,59), 3 prospective studies (60-62),
E. Pato et al.
and 2 retrospective ones (63,64)]. All studies included
222 patients. The eye diseases treated were Behçet’s-asso-
ciated uveitis, choroiditis, and another noninfectious pos-
terior pole uveitis of different etiology. The tacrolimus
dose ranged from 0.05 to 0.2 mg/kg/d. The outcome
variables most frequently used were VA, intraocular in-
flammation, and the number of relapses. A RCT (16)
included 39 patients with posterior and intermediate uve-
itis to be treated with tracolimus (n ⫽ 19) or CsA (n ⫽
18). There were no differences between groups in terms of
improvement of VA and ocular inflammation, although
the CsA group had more adverse effects (hypertension
and elevated cholesterol levels).
Antimetabolites: Methotrexate,
Azathioprine, and Mycophenolate Mofetil
The review found 28 articles on methotrexate, of which
18 were excluded (see table of excluded studies in the
supplementary file). Ten articles were analyzed [1 pro-
spective study (65) and 9 retrospective ones (66-74)],
adding a total of 301 patients. The ocular diseases treated
were Behçet’s-associated uveitis, VKH, JIA-associated
uveitis, sarcoidosis, and noninfectious posterior pole uve-
itis of different etiology. The MTX dose ranged from 7.5
to 25 mg/wk. The outcome variables most frequently
used were VA, intraocular inflammation, and the number
of relapses.
On AZA we found 8 articles [2 RCT (75,76) and 6
retrospective studies (77-82)], adding 271 patients. Once
more, the ocular diseases more frequently treated were
Behçet’s-related uveitis, chronic iridocyclitis, uveitis, chil-
dren intraocular inflammatory pathology, and others.
AZA dose was 1 to 3 mg/kg/d. The outcome variables
most frequently used were VA, intraocular inflammation,
and the number of relapses. In the RCT by Mathews and
coworkers (75), 19 patients with chronic iridocyclitis
were randomized to AZA (n ⫽ 11) or placebo (n ⫽ 8).
There were no differences between groups in improve-
ment in VA and ocular inflammation. Yazici and cowork-
ers (76) included 73 patients with Behçet’s disease with or
without uveitis, and randomized them to AZA (n ⫽ 37)
or to placebo (n ⫽ 36). AZA patients had significantly
fewer episodes of ocular inflammation and lower inci-
dence of new onset of ocular involvement, and none dis-
continued due to severe ocular involvement.
Regarding MMF, 6 studies were included [2 prospec-
tive studies (83,84) and 4 retrospective ones (85-88)],
adding to a total of 241 patients with refractory chronic
uveitis, children-related uveitis, and other diagnoses. The
dose of MMF was 1 g/12 h. The outcome variables most
frequently used were the VA, the clinical activity of dis-
ease, and the number of relapses. In most patients there
was stability or improvement in VA, and improvement of
inflammatory parameters, as well as a decrease in the
number of relapses.
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317
Alkylating Agents: Cyclophosphamide and
Chlorambucil
We analyzed 12 articles of chlorambucil [3 prospective
studies (89-91) and 9 retrospective studies (77,78,92-98)]
that included over 200 patients. The ocular diseases
treated were Behçet’s-associated uveitis, sympathetic oph-
thalmia, serpiginous choroiditis, and other intraocular in-
flammatory etiologies. Chlorambucil dose ranged from
0.1 mg/kg/d to 15 mg/d, and the outcome variables most
frequently used were the VA and intraocular inflamma-
tion. In most patients, there was stability or improvement
in VA and improvement of inflammatory parameters.
Regarding cyclophosphamide, we analyzed 1 uncon-
trolled single-masked trial (20) and 2 retrospective studies
(92,99) that included a total of 70 patients with Behçet’s
uveitis, serpiginous choroiditis, and others. In 1 study
cyclophosphamide was given orally (92) and in 2 other
studies by intravenous bolus (20,99). The outcome vari-
ables most frequently used were VA and intraocular in-
flammation. Cyclophosphamide did not appear effica-
cious in Behçet’s uveitis (20), but it seemed efficacious in
stabilizing or improving VA and inflammatory parame-
ters in miscellaneous conditions.
Biological Therapies
Of the 629 articles found on treatment with biologic ther-
apies in both bibliographic databases, we excluded 524 by
reading the title and abstract (Fig. 1). The 105 remaining
articles on infliximab (IFX), etanercept (ETN), adalimumab
(ADA), daclizumab (DCZ), and interferon (IFN) were re-
viewed in detail.
Infliximab
We analyzed 31 items on IFX [1 open trial (100), 15
prospective studies (101-115), and 14 retrospective ones
(116-129)], adding up to over 300 patients with Behçet’s-
associated uveitis, JIA-associated uveitis, other children
uveitis, and different etiologies. The dose of IFX ranged
from 100 mg/dose to 10 mg/kg/dose, although the most
used dose was 5 mg/kg/dose. Infusion regimen was vari-
able. The outcome variables most frequently used were
VA, intraocular inflammation, and steroid-sparing effect.
There was great variability in the type of studies, patients,
pace, and doses of IFX, and in the outcomes measured.
Etanercept
Eight articles including 100 patients in total evaluated the
efficacy of ETN [2 RCT (130,131) 1 prospective study
(106), and 5 retrospective ones (117,124,126,128,132)].
The ocular conditions assessed were JIA-associated uve-
itis, children-related intraocular inflammatory diseases,
and different etiologies. ETN dose ranged from 0.4
mg/kg twice a week to 25 mg twice a week. The variables
most commonly used were VA, intraocular inflamma-
tion, and the number of relapses. There was great variabil-
318 Immunosuppressants and biological therapies treating autoimmune posterior uveitis
ity in the type of studies, patients, dosages, and the out-
comes measured. In the study by Foster and colleagues
(130), 20 patients with recurrent uveitis were randomized
to treatment with ETN (n ⫽ 10) or placebo (n ⫽ 10).
There were no differences between groups in the rate of
recurrences or in VA. Smith and coworkers (131) in-
cluded 12 patients with JIA-associated uveitis that were
treated with ETN (n ⫽ 7) or placebo (n ⫽ 5). There was
no therapeutic benefit of TNCs in uveitis associated with
JIA.
Adalimumab
Five retrospective studies on ADA with 43 patients in
total were included in the review (106,118,133-135).
Most patients had JIA-associated uveitis and the ADA
dose ranged from 0.4 mg/kg twice a week to 25 mg once
a week. Efficacy was measured through the VA and in-
traocular inflammation.
Daclizumab
The efficacy and safety of the IL-2 inhibitor was assessed
in 7 included studies [1 RCT (136), 2 open trials
(137,138), 1 prospective study (139), and 3 retrospective
ones (118,140,141)]. The studies included more than 70
patients in all. The ocular diseases treated were Behçet’s-
associated uveitis and others of various etiologies. The dose
varied around 1 to 2 mg/kg/IV. The outcome variables most
frequently used were VA, intraocular inflammation, and the
number of relapses. Buggage and colleagues (136) ran-
domized 17 patients with Behçet’s-associated uveitis to
DCZ (n ⫽ 9) or to placebo (n ⫽ 8) and found no differ-
ences between groups in the number of recurrences, or in
the corticosteroid-sparing effect of ISS.
Interferon
We analyzed 11 articles on IFN [5 prospective studies
(142-146), 5 retrospective studies (147-151), and 1 sys-
tematic review (152)] that included over 300 patients, the
most common uveitis being the 1 related to Behçet’s dis-
ease. The type of IFN used and the dose varied among stud-
ies, as well as the outcome variables, the most frequent being
VA and intraocular inflammation. The review (152) in-
cluded a RCT (153) where 50 patients with Behçet’s disease
were randomized to be treated with corticosteroids, INF-
␣2a (n ⫽ 23) or placebo (n ⫽ 21). The analysis after 9
months of follow-up showed that INF-␣2a was effective
in the treatment of Behçet’s disease.
Macular Edema
Of the 1833 articles found on the treatment of CME,
1801 were excluded by reading the title and abstract (Fig.
1), and 32 were reviewed in detail, 14 of which were ex-
cluded. We included 18 articles [5 RCT (17,18,154-156),
10 prospective studies (101,109,113,142,157-162), and 3
retrospective ones (140,163,164)]. Across studies more
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than 400 patients were included, with CME associated
with uveitis of different etiology. The drugs used were
quite varied (corticosteroids, acetazolamide, etc.), and the
outcome variables most frequently used were the VA and
the CME measured by angiography fluorescein angio-
gram (FAG). We found 5 RCT, 3 of which used acetazol-
amide, with improvement of the CME in all 3. In the
other 2 RCT, CsA was the drug used, also showing im-
provement in the CME.
Table 1 displays the summary of conclusions by treat-
ment and disease, with grade of recommendation and
level of evidence based on the results just presented above.
DISCUSSION
We have conducted a systematic review of the literature to
analyze the effectiveness of the ISS and biological thera-
pies in patients with autoimmune posterior uveitis,
chronic anterior uveitis associated with JIA, and CME.
This review was justified because uveitis may cause blind-
ness, and there are no clear recommendations for its man-
agement. The results of this review may help the clinician
to make better therapeutic decisions based on the avail-
able evidence. It may also serve as a reference for future
development of recommendations, consensus statements,
or clinical practice guidelines.
The results indicate that uveitis of various etiologies are
treated with the same drug, a finding that it is very de-
monstrative of daily clinical practice, although it is note-
worthy that the largest series of patients are those of Be-
hçet’s-associated uveitis. It should be noted that recently
there have been several large series from multicenter re-
search group on individual drugs (CsA, MTX, AZA,
MMF, and cyclophosphamide) (165-169).
We noted that, in general, both the ISS and the biolog-
ical therapies are effective in the treatment of autoim-
mune uveitis. However, it should be stressed that ETN
has not been shown effective in ocular inflammatory dis-
ease and that DCZ has not been proven effective also in
Behçet’s-associated uveitis.
Due to the special relevance of the CME as sign of severity
and as a complication of uveitis, we decided to undertake a
separate search and analysis thereof. The drugs tested in the
studies were effective in improving the CME in general,
without being able to make comparisons between drugs.
When interpreting these data, one must take into ac-
count the limitations of this systematic review. The first 1
is that the quality of the studies is generally low to mod-
erate. This does not mean that drugs are not effective, as
our clinical experience supports certain level of effective-
ness; it is simply a matter of poor design of the studies.
Although our preferences were given to RCT, in the ab-
sence of quality literature, we had to accept open studies,
and retrospective case series; otherwise, we would have
gathered no information.
Also related to quality, a major limitation to the review
is the heterogeneity in efficacy variables. Almost all studies
E. Pato et al. 319

Table 1 Summary of Conclusions from the Review of the Evidence

Treatment Conclusion Recommendation Evidence level
Cyclosporin Effective in noninfectious uveitis, especially in Behcet’s A 1b
Effective in CME B 2
Tracolimus Effective in noninfectious uveitis C 4
Azathriopine Effective in Behcet’s-associated uveitis A 1a
Effective in noninfectious uveitis C 4
Methotrexate Effective in noninfectious uveitis C 4
Effective in Behcet’s-associated uveitis B 2b
Mycophenolate mofetil Effective in noninfectious uveitis B 2b
Chlorambucil Effective in noninfectious uveitis C 4
Oral cyclophosphamide Effective in noninfectious uveitis C 4
Infliximab Effective in noninfectious uveitis C 4
Effective in CME C 4
Etanercept Not effective in autoimmune uveitis A 1b
Adalimumab Effective in autoimmune uveitis C 4
Daclizumab Not effective in Behcet’s-associated uveitis A 1b
Effective in other noninfectious uveitis C 4
Effective in CME C 4
INF-␣2a Effective in Behcet’s-associated uveitis A 1a
Effective in other noninfectious uveitis C 4
Effective in CME C 4
Acetazolamide Effective in CME B 2
Methylprednisolone Effective in CME C 4
For the quality grading we used a modification of the Oxford Centre for Evidence-based Medicine Levels of Evidence in its May 2001 update
(10), in which: (1a) systematic reviews of RCT with homogeneity; (1b) individual RCT with narrow confidence intervals; (1c) trials in which
all patients gets cured or none does; (2a) systematic reviews of cohort studies with homogeneity; (2b) individual cohort study, or low-quality
randomized controlled trials; (2c) “outcomes” research and ecological studies; (3a) systematic reviews of case-control studies with
homogeneity; (3b) individual case-control study; (4) case-series and poor-quality cohort and case-control studies; and (5) expert opinion
without explicit critical appraisal, or based on physiology, bench research, or “first principles.”
Recommendation (10):
A Consistent level 1 studies.
B Consistent level 2 or 3 studies or extrapolations from level 1 studies.
C Level 4 studies or extrapolations from level 2 or 3 studies.
D Level 5 evidence or troublingly inconsistent or inconclusive studies of any level.

use the VA, although there is a much larger variability
regarding other efficacy variables, such as posterior pole
inflammation, glucocorticosteroid-sparing effect, etc.
This severely limits the comparison between drugs. We
must add that there is no uniformity in relation to the
procedures or scales used to measure the efficacy variable.
For example, to measure the VA, some authors use the
Snellen chart, others the logMar scale, and even some
authors describe “improvement” without a quantity. In
addition, there are no performance criteria defined in the
various efficacy variables.
In conclusion, in general ISS have proven effective in
autoimmune uveitis and CME. Biological therapies (ex-
cept for ETN and DCZ in Behçet) have provided a ben-
efit in the treatment of autoimmune uveitis. No drug
seems superior to others. This review cannot recom-
mend a drug of choice for each type of uveitis. We
consider it very important to standardize the perfor-
mance criteria, which will evaluate the efficacy of drugs
in a more objective manner and, in turn, enable mean-
ingful comparisons between drugs. To achieve this,
multidisciplinary collaboration between ophthalmolo-
gists and specialists of patients with systemic inflam-
matory disease (rheumatologists, immunologists, in-
ternists, etc.) should be enhanced.
APPENDIX A. SUPPLEMENTARY DATA
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.semarthrit.2010.
05.008.
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