STATE OF THE ART REVIEW

Uveitis for the non-ophthalmologist

BMJ: first published as 10.1136/bmj.m4979 on 3 February 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Bryn M Burkholder,1 Douglas A Jabs1,2
A BST RAC T

1
The uveitides are a heterogeneous group of diseases characterized by inflammation
Wilmer Eye Institute,
Department of Ophthalmology, inside the eye. The uveitides are classified as infectious or non-infectious. The non-
the Johns Hopkins University
School of Medicine, Baltimore,
infectious uveitides, which are presumed to be immune mediated, can be further
MD, USA
2
divided into those that are associated with a known systemic disease and those that
Center for Clinical Trials and
Evidence Synthesis, the Johns are eye limited,—ie, not associated with a systemic disease. The ophthalmologist
Hopkins University Bloomberg
School of Public Health,
identifies the specific uveitic entity by medical history, clinical examination, and
Baltimore, MD, USA ocular imaging, as well as supplemental laboratory testing, if indicated. Treatment
Correspondence to:
BM Burkholder of the infectious uveitides is tailored to the particular infectious organism and may
bburkho1@jhmi.edu
include regional and/or systemic medication. First line treatment for non-infectious
Cite this as: BMJ 2021;372:m4979
http://dx.doi.org/10.1136/bmj.m4979 uveitides is corticosteroids that can be administered topically, as regional injections
Series explanation: State of the or surgical implants, or systemically. Systemic immunosuppressive therapy is used
Art Reviews are commissioned
on the basis of their relevance in patients with severe disease who cannot tolerate corticosteroids, require chronic
to academics and specialists
in the US and internationally. corticosteroids at >7.5 mg/day prednisone, or in whom the disease is known to
For this reason they are written
predominantly by US authors.
respond better to immunosuppression. Management of many of these diseases
is optimized by coordination between the ophthalmologist and rheumatologist or
internist.

Introduction
The uveitides are a collection of more than 30 diseases
characterized by inflammation inside the eye (table
1). They are distinct from and should not be confused
with diseases of the ocular surface and sclera, which
also may be affected by inflammation (eg, peripheral
ulcerative keratitis, scleritis, etc), although these latter
diseases may have an associated secondary intraocular
inflammation (eg, keratouveitis or sclerouveitis).
Although some of the uveitides are linked to a systemic
infection or a rheumatologic disease, many, if not
most, of the uveitides are eye limited, presumed to be
immune mediated, and without any known systemic
associations. The goal of the ophthalmologist is
to identify the specific uveitic entity by medical
history, clinical examination, ocular imaging, and
supplemental laboratory testing, as indicated.
For patients with associated systemic disease or
requiring systemic immunosuppression, management
is optimized by collaboration between the
ophthalmologist and rheumatologist and/or primary
care physician. In this review, we provide an overview
of the uveitides for the non-ophthalmologist clinician,
including the clinical findings and diagnosis of the
uveitides, and the treatment of the non-infectious
uveitides, particularly through use of systemic
therapy, including immunosuppressive drug therapy.
SOURCES AND SELECTION CRITERIA
We reviewed the literature from 1980 to the present,
using the search term “uveitis” in the PubMed
database, and identified relevant, peer reviewed
sources, with an emphasis on large, randomized
controlled trials and systematic reviews. We primarily
included articles published in the last 20 years but
included older sources if they contained data of
significance. We included smaller trials or retrospective
studies when better evidence was not available. We
also included consensus guidelines from expert panels
of uveitis specialists.
developed countries3 4 and collectively are the fifth or
sixth leading cause   of blindness worldwide.5 6 The
prevalence of uveitis in the United States is estimated
as 115-133 per 100 000.7-10 Unlike the other common
causes of visual impairment, such as cataract, age
related macular degeneration, and glaucoma, the
uveitides affect all age groups, including children,
have the potential to result in visual impairment over
a longer portion of the patient’s lifetime, and have
a much greater impact on years of potential vision
lost.11 Early diagnosis and proper treatment can
prevent blindness and long term disability.12 13

Epidemiology Clinical features

Worldwide the uveitides are a major cause of visual The uveitides have multiple distinct presentations.
impairment. They account for 10-15% of blindness in Uveitis can be classified across several dimensions,

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 STATE OF THE ART REVIEW
Table 1 | Anatomic classification of uveitis and associated diseases
Anatomic class of
uveitis Primary site of inflammation Systemic disease
Anterior uveitides Anterior chamber Spondyloarthritis/HLA B27 associated
anterior uveitis, juvenile idiopathic
arthritis associated chronic anterior
uveitis, sarcoidosis, Behçet disease
Intermediate Vitreous Multiple sclerosis associated
uveitides intermediate uveitis, sarcoidosis,
tubulointerstitial nephritis
Posterior uveitides Retina and/or choroid Sarcoidosis
Panuveitides Anterior chamber, vitreous, Sarcoidosis, Behçet disease, Vogt-
and retina or choroid (with no Koyanagi-Harada disease (separated
one site predominant) into early stage and late stage)
Anatomic classification of uveitis by primary site of inflammation, with examples of associated systemic diseases and infections for each type of uveitis.
*Classified as “posterior uveitis” because primary site of inflammation is the choroid, with minimal anterior/vitreous inflammation.
Adapted from the Standardization of Uveitis Nomenclature Working Group1 and Jabs and Busingye.2
including disease course, laterality, primary
anatomic location of inflammation, morphologic
features, and the host, including the presence or
absence of an associated systemic disease.2
In 2005, the Standardization of Uveitis
Nomenclature (SUN) Working Group developed a
classification scheme that structures the way clinicians
and researchers describe uveitis and grade its severity
(table 1).1 Anatomically, uveitis is classified by the
primary site of inflammation.14 Anterior uveitis, also
termed iritis or iridocyclitis, is inflammation primarily
in the anterior chamber of the eye. Intermediate
uveitis describes inflammation primarily in the
vitreous cavity. Posterior uveitis is inflammation
in the retina, choroid, or retinal blood vessels. Of
note, retinal edema and optic nerve edema may be
structural complications of inflammation elsewhere in
the eye and do not, in isolation, constitute “posterior
uveitis.” Panuveitis describes inflammation involving
anterior chamber, vitreous, and retina or choroid
without a predominance of any one anatomic class.
In general, eyes with posterior or panuveitis have a
worse prognosis, given that inflammation may cause
irreversible damage to structures critical to vision,
including the macula and optic nerve.4 5
Symptoms may vary greatly, even for patients
with the same anatomic type of inflammation.
For example, anterior chamber inflammation may
cause a red, painful eye, spondyloarthritis/HLA B27
associated uveitis being a classic example. Other
anterior uveitides may have no associated pain or
conjunctival injection, such as juvenile idiopathic
arthritis (JIA) associated chronic anterior uveitis.15 16
Similarly, the presence of symptoms does not
necessarily indicate active disease. A patient with
inactive disease may still have decreased vision from
complications of their disease (eg, band keratopathy
or chorioretinal scarring) and/or side effects of their
treatment (eg, cataracts or glaucoma). In many cases,
clinical examination, ocular imaging, or both are
necessary to determine disease activity.
2
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Infection No systemic disease
Herpes simplex virus anterior uveitis, Fuchs heterochromic iridocyclitis (Fuchs
varicella zoster virus anterior uveitis, uveitis syndrome)
cytomegalovirus anterior uveitis,
syphilis
Syphilis, Lyme disease Pars planitis, undifferentiated intermediate
uveitis (intermediate uveitis, non-pars
planitis type)
Toxoplasmic retinitis, syphilis, Acute posterior multifocal placoid
tuberculosis, cytomegalovirus pigment epitheliopathy, birdshot
retinitis, acute retinal necrosis chorioretinopathy, multiple evanescent
(herpes simplex virus or varicella white dot syndrome, punctate inner
zoster virus retinitis), Bartonella, choroiditis, relentless placoid choroiditis,
Lyme disease serpiginous choroiditis, multifocal
choroiditis and panuveitis*
Syphilis, Lyme disease Sympathetic ophthalmia
Examination
On ophthalmic examination with a slit lamp, it is
possible to see and quantify or grade leukocytes in
the anterior chamber and anterior vitreous. Other
signs of anterior chamber inflammation include
perilimbal injection, collections of inflammatory
cells on the corneal endothelium (known as “keratic
precipitates,” fig 1a), and iris nodules (fig 1b). Iris
atrophy (fig 1c) is common in unilateral anterior
chamber inflammation associated with the herpes
simplex (HSV) and varicella zoster (VZV) viruses.17
On fundus examination, optic disc edema may be
present (fig 2a) as a primary manifestation of optic
nerve inflammation, or as a secondary structural
complication of inflammation elsewhere in the eye.
Macular edema, the most common cause of vision
loss in uveitis, is caused by fluid leakage into the
macula and is detected by either clinical examination
or imaging (discussed below).18
Inflammation of retinal blood vessels may appear
as vascular sheathing (fig 2b) or as occlusive retinal
vasculitis with associated retinal hemorrhages,
cotton wool spots, and non-perfusion of the retina
(fig 2c). Retinitis is almost always due to infection,
such as with viruses—eg, cytomegalovirus (CMV)
(fig 3a), HSV, or VZV (fig 3b), or parasites—eg,
toxoplasmosis (fig 3c), although Behçet disease may
also present this way.2
Ocular nodules caused by granulomatous disease
may be seen on the iris or in the choroid and may
be the result of infections, such as tuberculosis, or
non-infectious granulomatous disease, such as
sarcoidosis (fig 4).
Disease course and severity
Disease course, anatomic class, and laterality
(unilateral, bilateral, or unilateral alternating [one
eye at a time, but either eye may be affected]) are
important considerations in both diagnosis and
treatment. Uveitides may be acute (characterized
by sudden onset and duration <3 months) and
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 STATE OF THE ART REVIEW

D monophasic; acute and recurrent; or chronic.

As with the diagnosis of the arthritides, course,

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laterality, and anatomic class are helpful in
narrowing the differential diagnosis. For example,
patients with an acute, unilateral alternating,
anterior uveitis have an ~80% chance of carrying
the HLA-B27 allele, and if HLA-B27 positive,
a ~60-80% chance of having an associated
spondyloarthritis.19-22
The ophthalmologist determines whether uveitis
is active or inactive based on clinical examination,
supplemented with ocular imaging. Fluorescein
angiography can show retinal vascular leakage
and/or non-perfusion (fig 5a); indocyanine green
angiography can show choroidal lesions (fig 5b);
and fundus autofluorescence often can distinguish
between active choroidal lesions and inactive scars
(figs 5c, 5d). Similarly, the presence of structural
complications of uveitis, shown on examination and/
E
or imaging, may help to determine disease activity
and severity and to guide treatment decisions. In
this regard, optical coherence tomography (OCT)
has proven to be highly useful in managing uveitic
macular edema (fig 5e).

Diagnostic evaluation for associated systemic disease

Uveitides are either infectious (ie, caused by
organisms in the eye) or non-infectious. The non-
infectious uveitides, which are presumed to be
immune mediated, can then be divided into those
with and without associated systemic disease; those
without an associated systemic disease may either be
diagnosable as a specific uveitic entity (eg, birdshot
chorioretinitis) or be “undifferentiated.”
A selected laboratory evaluation should be
conducted based on the clinical features of uveitis,
the patient’s medical history, and a focused review
of systems. The goals of a laboratory evaluation
are to diagnose an infection (where antimicrobial
F
or antiviral therapy is indicated) or to diagnose
an associated systemic disease that can affect the
patient’s systemic health.2 Identifying an infectious
cause of uveitis is important, because treating
infectious uveitides require antimicrobials or
antivirals, while non-infectious uveitides require
corticosteroids and immunosuppressive therapy.
Identifying an associated systemic disease is
important because it may prevent future morbidity
and influence choice of therapy that would treat both
systemic and ocular disease.

Identifying infectious causes of uveitis

Fig 1 | Anterior segment findings in uveitis. (a) Granulomatous keratic precipitates on
the inferior corneal endothelium. (b) Iris nodules (arrows). (c) Sectoral iris atrophy in
herpetic anterior uveitis
Although the laboratory evaluation should be
individualized, a syphilis test should be performed
for all adolescents and adults with uveitis because
syphilis is a treatable cause of uveitis that can present
as any class of disease (fig 2a, 5d). Non-treponemal
tests (eg, rapid plasma reagin) have an estimated
30% false negative rate, therefore a treponemal test
should be first performed in all cases, utilizing the
reverse screening algorithm from the Centers for
Disease Control and Prevention.23 24

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STATE OF THE ART REVIEW
D Lyme disease is an uncommon cause of uveitis.
E patients with possible exposure to tuberculosis who
F with uveitis
Fig 2 | Posterior segment findings in uveitis. (a) Optic disc swelling and hemorrhage in
syphilitic uveitis (photograph courtesy of Matthew Star, MD). (b) Perivenular sheathing
in sarcoidosis associated retinal vasculitis. (c) Fluorescein angiogram showing
peripheral retinal non-perfusion in sarcoidosis associated retinal vasculitis
4
Serologic Lyme disease testing is appropriate in
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Lyme endemic regions for intermediate uveitis and
for patients exposed to Lyme disease. However,
in non-endemic regions positive test results are
more likely to be false, and routine testing is not
recommended.25 26
Tuberculosis is a more common cause of uveitis
globally, but regional variation is great, and
tubercular uveitis is very uncommon in the US,
accounting for only 0.2-0.5% of uveitis cases.27
The positive predictive value of routine tuberculosis
testing for patients with uveitis in the US is low (in the
range 1 to ~10%).28 Routine tuberculosis testing is
therefore not recommended for patients with uveitis,
except those who have lived or travelled in endemic
regions and those with clinical presentations
highly suggestive of tubercular uveitis (figs 6a, 6b).
Additionally, tuberculosis testing is recommended in
are starting immunosuppression for non-infectious
uveitis, and in all patients, regardless of risk factors,
who are starting treatment with a tumor necrosis
factor-α (TNF-α) inhibitor.
Testing for selected infections using polymerase
chain reaction (PCR) technology has proven to
be useful. Either the aqueous or vitreous can be
sampled. Diseases in which such sampling often is
performed include herpetic anterior uveitis, herpetic
retinitis, and toxoplasmic retinitis.29-36 Because of the
low yield in routine testing, PCR for these infections
should be used selectively based on clinical findings,
where there is a limited differential.37-39 Of note, the
ability to perform PCR testing on ocular fluid requires
a laboratory capable of handling small volumes (eg,
0.1 mL) and may not be available in all locations.
Identifying non-infectious systemic disease associated
As with testing for infectious causes of uveitis,
laboratory testing for systemic disease associated
with non-infectious uveitis should be based on the
specific uveitic features.
HLA-B27 associated disease
HLA-B27 associated spondyloarthritis is the most
common systemic disease associated with adult
anterior uveitis. It was reported in 18-32% of patients
with anterior uveitis in Western countries, and in
6-13% of patients with anterior uveitis in Asia.40
When used in the appropriate clinical setting,
HLA-B27 provides prognostic information; patients
with spondyloarthritis/HLA-B27 associated anterior
uveitis typically have recurrent acute, unilateral, or
unilateral alternating episodes of anterior uveitis
that often respond well to topical corticosteroid
therapy.40 41
The average duration of an attack is around six
weeks, and the average frequency of attacks is
around one per year, although the interval between
recurrences can be highly variable, even within the
same patient.5 20 Because of the symptomatic nature
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D of attacks, short duration, and limited frequency,
E with acute anterior uveitis may have undiagnosed
F
Fig 3 Infectious retinitis. (a) Cytomegalovirus retinitis in a patient with acquired
immunodeficiency syndrome. (b) Acute retinal necrosis associated with varicella zoster
virus. (c) Focal retinitis associated with toxoplasma gondii infection
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STATE OF THE ART REVIEW
chronic, suppressive therapy typically is not needed.
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However, ~40% of patients will have at least one
attack that requires more than topical corticosteroids
(eg, a short course of oral prednisone), and ~5-10%
of patients will develop a crescendo pattern resulting
in chronic uveitis that requires chronic therapy.
HLA-B27 testing is also helpful in identifying
patients who may have undiagnosed
spondyloarthritis. In a large multicenter prospective
study of patients with anterior uveitis, those who
were HLA-B27 positive were more frequently
diagnosed with axial (69.8% v 27.3%) and
peripheral spondyloarthritis (21.9% v 11.1%)
than those who were HLA-B27 negative.42 Several
studies also have suggested that among patients
with HLA-B27 associated anterior uveitis who
have a spondyloarthritis, in approximately half,
the spondyloarthritis will have been undiagnosed
or misdiagnosed before the uveitis consultation.20
These results indicate that 30-50% of patients
spondyloarthritis.43 Early diagnosis may facilitate
appropriate treatment of the spondyloarthritis and
prevent future morbidity.44
Patients with inflammatory bowel disease may have
either of two distinct presentations of anterior uveitis;
those who are HLA-B27 positive and have an axial
spondyloarthritis typically have a recurrent acute
anterior uveitis, whereas those who are HLA-B27
negative and have either no arthritis or the peripheral
joint enteropathic arthritis may have a chronic
unilateral or bilateral anterior uveitis.45 Although
patients with psoriatic spondylitis may have an
HLA-B27 associated recurrent acute anterior uveitis,
some case series suggest that they are more likely
to develop chronic anterior uveitis than are patients
with ankylosing spondylitis or reactive arthritis.45 46
With the exceptions of HLA-B27 testing, and
HLA-A29 in patients with suspected birdshot
chorioretinitis (an eye limited disease), the utility of
HLA testing as part of a uveitis diagnostic evaluation
is limited.41
Antinuclear antibody associated disease
Antinuclear antibody (ANA) testing has poor utility
when used routinely in patients with uveitis.
Systemic lupus erythematosus (SLE) is uncommonly
associated with uveitis.27 47 In a meta-analysis
including 53 315 adult patients with uveitis, the
prevalence of SLE was estimated to be 0.47%, and
the positive predictive value of routine ANA testing in
patients with uveitis was estimated to be 2.9%.47 An
earlier analysis, using a prevalence of 0.1% for lupus
in patients with uveitis, calculated an even lower
positive predictive value of 0.6%.27 ANA testing
in adult patients has value only for those in whom
there is a high pretest probability of SLE, either in
patients with clinical features suggestive of lupus or
in patients with an occlusive retinal vasculopathy
suggesting anti-phospholipid antibody syndrome in
the context of SLE.
5
STATE OF THE ART REVIEW
Fig 4 | Choroidal granuloma in a patient with sarcoidosis
Juvenile idiopathic arthritis
Conversely, ANA testing is useful in children with
chronic anterior uveitis, because JIA is the most
common systemic disease associated with chronic
anterior uveitis in childhood, and comprises 75%
of all pediatric anterior uveitis cases.15 48 49 For
children with JIA without uveitis, ANA testing is
routinely performed as it identifies those at high risk
for the development of an insidious onset, typically
asymptomatic, and potentially blinding uveitis.
Chronic anterior uveitis occurs in 30% of children
with JIA who are ANA positive, and the risk is
similar for children with oligoarticular persistent,
oligoarticular extended, and rheumatoid factor
negative polyarthritis subsets.50 Because JIA
associated uveitis is often asymptomatic until vision
threatening complications occur, routine screening
eye examinations are important, particularly for
those at high risk,51-53 and screening algorithms have
been developed based on the type of arthritis, ANA
test results, age of the patient, and arthritis duration.
Early diagnosis and treatment, including
immunosuppressive drug therapy as needed,
markedly reduce the risk of vision loss in this
patient population.54 Children with the enthesitis
related arthritis subset of JIA, which is an HLA-B27
associated disease, develop a symptomatic recurrent
acute anterior uveitis.
Sarcoidosis
Sarcoidosis associated uveitis accounts for 5-10%
of cases in large case series and may present with
an acute or chronic anterior uveitis, intermediate
uveitis, focal posterior uveitis (fig 4), retinal vascular
sheathing (figs 2b,c), or a panuveitis.55 Therefore,
nearly all patients with uveitis should be screened
for sarcoidosis with radiographic imaging of the
chest.56 57
Ophthalmic manifestations of sarcoidosis occur in
30-60% of patients with systemic sarcoidosis, with
uveitis as the most common ocular manifestation.58
6
Definitive diagnosis is made by histologic
confirmation on biopsy of an affected tissue.
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Conjunctival nodules, if present, may demonstrate
granulomatous inflammation; frequently, however,
there is no ocular pathology that is amenable to
biopsy,
Previous studies have suggested that in patients
with bilateral hilar adenopathy and uveitis,
lung biopsy results nearly always confirm the
diagnosis of sarcoidosis58; however, in patients
with asymptomatic bilateral hilar adenopathy with
normal pulmonary function tests, a lung biopsy is
often not performed, because a definitive diagnosis
is unlikely to change management.
Debate surrounds the best approach to chest
imaging—chest radiograph or chest computed
tomography (CT). Chest CT is more sensitive than
chest radiography, but most cases are detected by
chest radiograph. Many uveitis experts use the chest
radiograph as a screening tool and reserve the chest
CT scan for cases in which the chest radiograph
is equivocal or atypical, or in which the suspicion
for sarcoidosis is high.59 60 The serum angiotensin
converting enzyme levels and lysozyme tests have
very poor positive predictive values (in the ~10-20%
range) and have limited utility as screening tests for
sarcoidosis.2
“Eye limited” uveitis
One common misconception is that uveitis must be a
manifestation of a specific underlying cause. In fact,
many of the uveitides are presumed to be immune
mediated and without a known association to any
systemic disease.
Uveitis in patients with no associated infection or
rheumatologic disease is classed as “eye limited.”
Among these cases, some have clinical features
that establish a specific diagnosis (eg, Fuchs
heterochromic iridocyclitis or acute posterior
multifocal placoid pigment epitheliopathy (fig 5c)).
Identifying these morphologically distinct diseases
provides information about management and
prognosis.
If no identifiable infection, associated systemic
disease, or specific ocular uveitic entity is present,
we describe these cases as “undifferentiated”
and add descriptors of course, laterality, and
anatomic location (for example, “chronic, bilateral,
panuveitis”).2
In the past, these cases were often described as
idiopathic, a practice that leads to the following
illogical conclusion: cases of chronic anterior uveitis
in a child without JIA are “idiopathic,” whereas those
with juvenile idiopathic arthritis are not idiopathic,
when in reality both are idiopathic (ie, of unknown
cause). Hence, we recommend using the term
undifferentiated instead of idiopathic.
Treatment of non-infectious uveitides
The treatment of non-infectious uveitis can be
conceptualized as local therapy (including topical
corticosteroids and regional injections or implants),
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 STATE OF THE ART REVIEW

D E

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F H

Fig 5 | Imaging in uveitis. (a) Fluorescein angiogram showing retinal vascular leakage in an eye with intermediate uveitis. (b) Indocyanine green
angiogram showing the classic choroidal lesions seen in birdshot chorioretinitis. (c) Fundus autofluorescence showing chorioretinal lesions in acute
posterior multifocal placoid pigment epitheliopathy. (d) Syphilitic posterior placoid chorioretinitis seen on fundus autofluorescence. (e) Fovea-
involving macular edema, seen on optical coherence tomography, pre- and post-treatment

systemic therapy (including oral corticosteroids,
immunosuppressive drug therapy, and biologics),
or a combination of the two approaches. In general,
the primary anatomic site of the inflammation
determines the initial approach to therapy.
Patients with anterior uveitides typically are
treated with topical corticosteroids, patients with
posterior uveitides with systemic medications, and
patients with panuveitis with topical corticosteroids
and systemic medications. Some patients with
intermediate uveitis can receive infrequent regional
corticosteroid injections, but about one quarter
will need systemic therapy.61 The predicted disease
course determines the chronicity of therapy; patients

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STATE OF THE ART REVIEW
D whereas those with chronic disease need chronic
E structures of the eye and are thus poorly suited to
Fig 6 | Clinical presentations of tubercular uveitis. (a) Active serpiginous chorioretinitis.
(b) Retinal vasculitis
with acute or recurrent acute disease (eg, spondylitis/
HLA-B27 associated anterior uveitis) are treated with
a short course of treatment during an acute attack,
8
suppressive therapy.
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Specific uveitic diseases may be more or less likely
to require systemic therapy. For example, in patients
with JIA associated chronic anterior uveitis, the use
of immunosuppression reduces the risk of vision
loss by ~40%, as shown in retrospective cohort
studies.16  54 Similarly, specific medications are also
more effective for certain type of uveitis; patients with
Behçet disease and an occlusive retinal vasculitis
appear to respond well to antiTNF monoclonal
antibody therapy.62-64 Studies have shown that
the presence of even low levels of inflammation
in patients with uveitis increase the risk of visual
impairment and blindness by twofold to threefold;
therefore the goal of therapy is complete suppression
of inflammation, while minimizing systemic and
ocular side effects.54 65-67
Corticosteroid treatment
Topical corticosteroids
Corticosteroids in their various forms typically
are first line treatment for non-infectious uveitis.
Even in those diseases where immunosuppression
is indicated, corticosteroids are part of the initial
regimen. Anterior chamber inflammation is amenable
to treatment with corticosteroid eye drops; however,
they have poor penetration to the more posterior
treat intermediate and posterior uveitis. Topical
corticosteroid potency for treating anterior uveitis
is dependent on the corticosteroid, the preparation
(salt), and the concentration, all of which influence
the penetrance into the anterior chamber.
Of the older topical corticosteroid preparations,
prednisolone acetate 1% had the best potency for
anterior uveitis and remains a standard therapy.68
Loteprednol is slightly less effective for uveitis, but is
less likely to raise the intraocular pressure, and often
is used when there is an intraocular pressure rise
with topical corticosteroids. Difluprednate is twice
as potent as prednisolone acetate 1%, allowing less
frequent use and improved adherence to treatment69
but has been associated with marked and sometimes
unpredictable elevations in intraocular pressure,
particularly in children.70 71
Adverse effects
As with corticosteroids in any form, the main risks
associated with topical corticosteroid use are cataract
and elevated intraocular pressure, which can lead to
glaucoma. Cataract in children carries the additional
risk of amblyopia, or permanent vision impairment
from lack of stimuli to the visual pathways in the
developing brain.
Untreated inflammation itself can cause cataract
and glaucoma, as well as additional irreversible
complications. In studies of JIA associated chronic
anterior uveitis, active uveitis was a stronger risk
factor for cataract than topical corticosteroid use,
and in a long term study of a large uveitis cohort,
active uveitis was a strong risk factor for subsequent
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intraocular pressure elevation.16 54 72 73 The use of
topical prednisolone acetate 1% three times a day has
a minimal risk of cataract formation, and prednisone
at a dose of ≤7.5 mg/day does not increase the risks
of cataract formation and intraocular pressure
elevation, according to a retrospective cohort study.72
Thus, prioritizing treating inflammation
using the necessary quantity of corticosteroids,
minimizing long term corticosteroid use with
immunosuppression, and managing any ocular
complications of corticosteroid use is now the
preferred treatment paradigm.
Corticosteroid injections and implants
Corticosteroids can be given into or around the eye
with an injection. A periocular depot of triamcinolone
acetonide (Kenalog40), injected into the orbital floor
or adjacent to the posterior globe, under the Tenon’s
layer, is a safe and effective treatment for uveitis and
uveitic macular edema.74-79 A single injection may be
sufficient to control inflammation for three months or
more, and one or two repeated injections, spaced >4
weeks apart, may have additional value.78
Corticosteroids can be delivered to the vitreous
cavity, in the form of injection or implant. Intravitreal
triamcinolone acetonide (Triescence) is used to
treat non-infectious intermediate, posterior, and
panuveitis, as well as uveitic macular edema.80-82
Corticosteroid implants, available in both short acting
and long acting forms, are injected into the vitreous
cavity and provide sustained release of corticosteroid
over time. The dexamethasone implant (Ozurdex) is a
biodegradable implant that releases dexamethasone
for up to six months (table 2).92-94 A randomized
controlled trial of the dexamethasone implant in
eyes with uveitis showed reduced inflammation and
visual acuity.94
A large, multicenter randomized clinical trial
studied the comparative effectiveness of the three
modalities of regional corticosteroid injections for
uveitic macular edema—periocular triamcinolone
acetonide, intravitreal triamcinolone acetonide,
and the intravitreal dexamethasone implant (table
2).85 All three treatment approaches were effective;
however, intravitreal corticosteroids were superior to
periocular triamcinolone. Intravitreal triamcinolone
and intravitreal dexamethasone implant had similar
effectiveness and duration of effect, and all three
approaches had similar and low rates of elevation of
intraocular pressure.
Injection of triamcinolone into the suprachoroidal
space has emerged as an alternative technique that
may offer more targeted delivery of corticosteroid
to the macula and posterior segment, potentially
reducing corticosteroid induced cataract and
elevation of intraocular pressure. A randomized
controlled trial of patients with uveitic macular
edema showed a clinically significant improvement
in vision in eyes treated with suprachoroidal
triamcinolone compared with sham injection (table
2).86 The relative merits of this approach and its role
in the management of patients with uveitis needs to
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STATE OF THE ART REVIEW
be defined, preferably by comparative effectiveness
trials.
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Longer acting corticosteroid implants have
also been available since the advent of the non-
erodible fluocinolone acetonide 0.59 mg implant
(Retisert), which was approved by the Food and
Drug Administration (FDA) for the treatment of non-
infectious intermediate, posterior, and panuveitides
in 2005.95 96 The implant is sutured to the sclera,
inside the vitreous cavity, and releases corticosteroid
for up to three years with minimal systemic
absorption. The implant may be replaced, if needed,
to create space for additional implants. Consistent
with the dose and duration of corticosteroid released
by the fluocinolone acetonide implant, high rates
of cataract and elevated intraocular pressure were
recorded; nearly all eyes that had not had cataract
surgery before placement of the implant developed
a cataract and needed cataract surgery within three
years of placement.96 Seventy eight per cent required
intraocular pressure lowering medications, and 40%
required glaucoma surgery to control eye pressure.
The Multicenter Uveitis Steroid Treatment (MUST)
trial was a multicenter randomized clinical trial that
compared systemic therapy with oral corticosteroids
and immunosuppression to the fluocinolone
acetonide implant for the treatment of non-infectious
intermediate, posterior, and panuveitides.97 Patients
in the MUST trial were followed for >7 years.11  91  98
Patients in the implant group underwent re-
implantation of second and even third implants
when the uveitis relapsed. Although both treatment
approaches improved vision similarly, and
successfully controlled inflammation for the first
five years, eyes with implants had slightly better
control of the inflammation; however, this effect
disappeared after five years, and at seven years, eyes
in the systemic treatment group had significantly
better visual acuity than those in the implant group,
with a near doubling of the risk of blindness in the
implant group (table 2).91
Ocular adverse effects were more common in the
implant group. Specifically, the risk of glaucoma
was around threefold higher in the implant group.91
99
Systemic therapy was well tolerated, with no
significant differences between the MUST trial
implant and systemic groups in terms of systemic
adverse events, with the exception of a greater use
of antibiotics in the systemic treatment group,
which reflects good medical care in patients on
immunosuppression. These results highlight the
relative safety of systemic corticosteroids and
immunosuppression when used correctly and
suggest a potential role for the fluocinolone acetonide
implant when systemic therapy cannot control the
inflammation or be tolerated.
More recently, long acting, injectable fluocinolone
acetonide 0.18 mg and 0.19 mg inserts (FAi) (Yutiq
and Iluvien, respectively) have been developed. Yutiq
was FDA approved for the treatment of non-infectious
intermediate, posterior, and panuveitides in 2018;
Iluvien had been approved for the same indication by
9
STATE OF THE ART REVIEW

Table 2 | Selected clinical trials in uveitis

Trial Year Participants No Treatment groups Follow-up Primary results

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Regional therapy trials
HURON83 2011 NIIPPU 229 Intravitreal dexamethasone 26 weeks IDI effective for uveitis.
implant (IDI) 0.7 mg v Grade 0 vitreous haze in 47% v 36% v 12% (0.7 mg IDI v
IDI 0.35 mg v sham injection 0.35 mg IDI v sham); P<0.001
Fluocinolone acetonide 2019 NIIPPU 129 Intravitreal FAi 0.18 mg v sham 12 months FAi effective for uveitis.
insert (FAi)84 injection Uveitis relapse in 38% v 98% at 1 year (FAi v sham); P<0.001
POINT85 2019 Uveitic macular 192 Periocular triamcinolone 24 weeks Periocular TA inferior to intravitreal TA and IDI for improvement
edema acetonide (TA) 40 mg v macular edema and visual acuity. Mean reduction in macular
intravitreal TA 4 mg v IDI 0.7 mg thickness on OCT 23% with periocular TA v 39% with
intravitreal TA (P<0.001) v 46% with IDI (P<0.001). Intravitreal
TA and IDI not different (ratio of reductions 0.88; 99% CI 0.71
to 1.08).
PEACHTREE86 2020 Uveitic macular 160 Suprachoroidal triamcinolone 24 weeks Suprachoroidal TA effective for uveitic macular edema. ≥15
edema acetonide 4 mg v sham injection letter improvement in best corrected visual acuity in 47% v
16% with sham; P<0.001
Systemic therapy trials
VISUAL I87 2016 Active NIIPPU 217 Adalimumab 40 mg q2 weeks 85 weeks Adalimumab effective for uveitis. HR for relapse uveitis=0.50;
v placebo 95% CI 0.36 to 0.70; P<0.001
VISUAL II88 2016 Inactive NIIPPU 226 Adalimumab 40 mg q2 weeks 20 months Adalimumab effective for uveitis. HR for relapse uveitis=0.57;
v placebo 95% CI 0.39 to 0.84; P=0.004.
SYCAMORE89 2017 JIA associated 90 Adalimumab v placebo 2 years Adalimumab effective 2nd drug for JIA associated uveitis. HR
uveitis on for relapse uveitis=0.25, 95% CI 0.12 to 0.49; P<0.001
methotrexate
FAST90 2019 NIIPPU 194 Methotrexate 25 mg/week v 12 months Methotrexate non-inferior to mycophenolate for corticosteroid
mycophenolate 3 g/day sparing. OR for treatment success (methotrexate v
mycophenolate)=1.5; 95% CI 0.81 to 2.81; P=0.20
Regional versus systemic therapy trials
MUST91 2017 NIIPPU 255 Intravitreal fluocinolone 7 years Systemic therapy superior for visual acuity at 7 years;
acetonide implant (FAI) 0.59 difference in mean improvement in visual acuity (systemic
mg v systemic therapy with therapy v FAI) 7 letters; 95% CI 2 to 12; P<0.001. OR for
oral corticosteroids and blindness (FAI v systemic therapy)=1.81; P=0.04. Greater
immunosuppression use antibiotics with systemic therapy (72% v 57%; P=0.015),
but no other significant differences in systemic side effects
between FAI and systemic therapy
No=number of participants. NIIPPU=non-infectious intermediate, posterior, or panuveitis. OCT=optical coherence tomography. OR=odds ratio. HR=hazard ratio. CI=confidence interval.

the European Medicines Agency two years earlier.100
Similar to the dexamethasone implant described
previously, the FAi inserts are injected into the
vitreous cavity; however, unlike the dexamethasone
implant, they are smaller, non-erodible, and release
corticosteroid for around three years.
Results from a randomized controlled study of FAi
compared with sham injection showed that the FAi
controls inflammation, reduces the need for adjuvant
therapy, and is reasonably safe to administer in a
clinic setting (table 2).84 101 However, the FAi appears
to be less effective than the fluocinolone acetonide
implant; the FAi relapse rate at one year was 38%,
whereas the fluocinolone acetonide implant rate
was 4%.84 96 For both implants, cataract surgery
was nearly universal, but the FAi may have a lower
risk of elevated intraocular pressure. To date, there
are no randomized trials comparing injectable FAi
with surgically implanted fluocinolone acetonide
implants.
Systemic corticosteroids
Systemic corticosteroids are used to treat severe
inflammation and/or inflammation in the more
posterior parts of the eye (eg, intermediate,
posterior, and panuveitis). As with the treatment of
rheumatologic diseases, our initial approach is to
give prednisone 1 mg/kg/day, up to a maximum 60
mg/day.102 103 If an adequate response is achieved,
we typically begin to taper the prednisone after
2-4 weeks. The goal of therapy is to achieve total
suppression of inflammation at a prednisone dose of
≤7.5 mg/day, which has been shown to be relatively
well tolerated over years with a low risk of systemic
side effects.104 105
For particularly severe, vision threatening
disease, high dose intravenous corticosteroids are
effective and safe for short term treatment of ocular
inflammation.106 107
Although the MUST trial showed the superior
efficacy of systemic therapy to relapse driven regional
therapy, patients on systemic therapy with uveitic
macular edema may benefit from a limited number
of adjunctive regional corticosteroid injections. The
MUST trial reported that, among patients with uveitic
macular edema treated with systemic therapy,
62% needed at least one short acting regional
corticosteroid injection, but that the median number
over a two year period was 1.108
Systemic corticosteroid sparing therapy
For patients requiring unacceptably high doses
of corticosteroids to control their uveitis or for
those in whom the disease is known to require
immunosuppression for control, corticosteroid
sparing therapy with immunosuppressive medication
is indicated.65 103 109 Several medications—including
antimetabolites, calcineurin inhibitors, alkylating
agents, and biologics—have been used successfully
to treat non-infectious uveitides (table 3).

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The Systemic Immunosuppressive Therapy
for Eye Diseases (SITE) cohort study, a large
retrospective study of 9250 patients with ocular
inflammation, provides information on the long
term outcomes of systemic therapy of eye diseases,
including corticosteroids, alkylating agents, and
non-alkylating agents.110-114 The study showed that
treatment with non-alkylating agents was associated
with control of inflammation in 52-73% of patients,
depending on the drug. Successful corticosteroid
sparing effect (prednisone <10 mg/day) was achieved
in 36-58%; however, sustained, drug free remission
was uncommon (<0.10 /person year) with non-
alkylating agent therapy. In contrast, treatment with
alkylating agents was associated with remission in
64-91% of patients, but current use of alkylating
agents is limited by the risk of serious side effects and
the availability of alternatives.114-117
Corticosteroid sparing medication
The antimetabolites methotrexate and
mycophenolate mofetil are the two most widely used
immunosuppressive medications for the treatment of
uveitis.65 111 112 118 Our standard treatment approach
is to start methotrexate at 15 mg/week and escalate
to 25 mg/week in a single step, if 15 mg/week is
insufficiently effective. This approach has been
used as most patients who respond to methotrexate
respond to 15 mg/week. Mycophenolate is initiated
at 2 g/day and escalated to 3 g/day as needed.
A retrospective analysis of the SITE cohort
suggested that mycophenolate and methotrexate
are similarly effective for long term (9 months and
beyond) use, but that mycophenolate achieves
corticosteroid sparing success faster than
methotrexate.90 However, methotrexate was given
in a dose escalation as needed approach in this
cohort.119 The First-Line Antimetabolites for Steroid-
Sparing Treatment (FAST) trial randomized patients
with intermediate, posterior, and panuveitides to
an initial lower dose of either mycophenolate or
methotrexate for two weeks and then, if tolerated,
increased to the maximum dose (table 2).120 The
study found that methotrexate was non-inferior to
mycophenolate (ie, mycophenolate was not superior
to methotrexate), suggesting that, at maximum
doses, both drugs are similarly effective.
Azathioprine, a less commonly used (in the US)
antimetabolite for uveitis, appears to be similarly
Table 3 | Immunosuppressive medications for the uveitides
Class Generic name
Antimetabolite Azathioprine, methotrexate,
mycophenolate
Calcineurin inhibitor Ciclosporin, tacrolimus
Alkylating agent Cyclophosphamide, chlorambucil
Biologic Adalimumab, infliximab
BID=twice per day.
*After loading dose.
Adapted from Jabs65
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STATE OF THE ART REVIEW
successful in achieving corticosteroid sparing
success to mycophenolate in retrospective studies.110
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However, azathioprine had a higher rate of treatment
related side effects, compared with other anti-
metabolites,121 and a greater proportion of patients
(24% in one study) discontinued the medication
because of them.110 Nevertheless, azathioprine is
less expensive than mycophenolate, and is more
widely used outside the US.
Although single agent antimetabolite therapy
often is effective, ~20% to 25% of cases will need
a second agent to control inflammation122; an
antimetabolite and a calcineurin inhibitor are
frequently paired together in this setting.65 Of the
calcineurin inhibitors, ciclosporin and tacrolimus
are most widely used in the treatment of uveitis.
Both medications appear to be similarly effective,
but tacrolimus is better tolerated.123 Ciclosporin
in particular is less well tolerated with increasing
age.113 124 The dose of ciclosporin is 2 mg/kg twice a
day; tacrolimus is initiated at 1 mg twice a day, and
the dose escalated every two to four weeks until a
therapeutic blood level is attained (maximum dose
3 mg twice a day).65
Alkylating agents cyclophosphamide and
chlorambucil are effective in the treatment of uveitis
but used less frequently because of their potential
toxicity.65 103 115 Unlike the non-alkylating agents,
they are substantially more likely to induce drug-
free remissions. In the SITE cohort, patients treated
with cyclophosphamide had a 64% remission rate
at two years. Two year remission rates were even
higher (91%) in a study of patients being treated with
cyclophosphamide for ocular mucous membrane
pemphigoid, which is also an immune mediated
ocular inflammatory disease.117 The relapse rate
is considerably lower than that of non-alkylating
agents.114 With the advent of newer alternatives for
the management of uveitides, use of alkylating agent
therapy has declined, and it is now used rarely.
Emerging treatments
Biologics
The advent of biologic medications has provided
new therapeutic avenues for treating non-infectious
uveitis. The tumor necrosis factor-α (TNF-α)
α inhibitors—in particular, adalimumab and
infliximab—are the most commonly used biologic
agents in these patients.
Trade name Suggested initial dose Typical maximum dose
Imuran, Rheumatrex, etc 2 mg/kg/day 3 mg/kg/day
Cellcept 15 mg/week 25 mg/week
1 g BID 1.5 g BID
Neoral, etc 2 mg/kg BID 2 mg/kg BID
Prograf 1 mg BID 3 mg BID
Cytoxan, Leukeran 2 mg/kg/day 250 mg/day
0.1 mg/kg/day 0.2 mg/kg/day
Humira, Remicade, etc 40 mg/2 week* 40 mg/week
5 mg/kg/4 week* 10 mg/kg/4 week
11
STATE OF THE ART REVIEW
Adalimumab is FDA approved for the treatment
of non-infectious uveitides. The results of two
randomized placebo controlled trials, VISUAL I87
and VISUAL II,88 showed the safety and efficacy of
adalimumab in patients with active and suppressed
non-infectious intermediate, posterior, and pan-
uveitides, respectively (table 2). In both studies,
treatment with adalimumab was associated with
reduced inflammation and lower risk of uveitis
relapse and vision loss through 52 weeks. The open
label extension study, VISUAL-III, showed similar
results through 78 weeks, and suggested a high rate
of corticosteroid sparing success.125
Adalimumab was effective in a randomized
placebo controlled study of patients with JIA
associated chronic anterior uveitis on a stable dose
of methotrexate (table 2).89 126 127 Adalimumab has
been reported to reduce attacks of recurrent uveitis
in patients being treated with adalimumab for
spondylitis.128 The efficacy of adalimumab versus
conventional immunosuppressive therapy currently
is unknown. For adult uveitis patients, adalimumab
is typically given as a loading dose of 80 mg,
followed one week later by a maintenance dose of 40
mg, which is then repeated every two weeks.129 For
patients on the standard dose of adalimumab who
have improved but have persistent inflammation,
an increase to weekly dosing has been tried by some
investigators with some apparent success, but has
not been proven successful in a clinical trial.130 131
Compared with adalimumab, infliximab appeared
to have similar efficacy in a retrospective study of
uveitis patients.132 Infliximab is well tolerated and
effective, with uncontrolled case series suggesting
corticosteroid sparing success in ~80%.129 133
Although infliximab is approved with a wide dose
range (3-10 mg/kg every four to eight weeks),
retrospective data suggest that doses ≥5 mg/kg every
four weeks are needed to control uveitis.103 129 133
Anti-TNF therapy appears to be particularly
effective for Behçet disease uveitis, and as a second
line agent in JIA associated chronic anterior
uveitis.62  64 109 129 134 135 Recommendations from an
expert panel of uveitis specialists suggested anti-
TNF monoclonal antibody therapy (eg, infliximab or
adalimumab) as first line therapy for Behçet disease
uveitis and as second line therapy for JIA associated
uveitis.129
Some experts recommend concurrent use of a
conventional immunosuppressive agent, such as
methotrexate or mycophenolate, with infliximab to
reduce the risk of anti-infliximab antibodies. This
practice has been shown to reduce the formation
of antibodies, prolong efficacy of treatment, and
prevent infusion reactions in patients receiving
infliximab for Crohn’s disease.136
Other TNF-α inhibitors have been used with varying
success in the treatment of uveitis in retrospective
case series. Data suggest that etanercept has
substantially lower efficacy in treating uveitis than
adalimumab or infliximab, and its use for uveitis
generally is not recommended.129 137-141 Golimumab
12
appears to reduce risk of uveitis in patients with
ankylosing spondylitis but has not been widely
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studied.142
As of 2020, the data on other biologics for
uveitis are fewer; however, preliminary case series
of tocilizumab, an interleukin (IL)-6 receptor
antagonist, have suggested that it may be effective
in treating uveitis, including uveitic macular
edema.143-145 Abatacept, a co-stimulation inhibitor,
has not shown particular promise in early studies
for JIA associated uveitis. One small study showed
a sustained treatment response in less than 15% of
patients with JIA associated uveitis,146 and a slightly
larger study reported 49% success over a year.147
The combined results of three clinical trials for
secukinumab, an IL-17A antagonist, did not show
benefit in treating uveitis, despite secukinumab
being very effective for psoriasis, psoriatic arthritis,
and ankylosing spondylitis.148
Long term safety of systemic therapy
Seven year data from the MUST trial show that, with
appropriate management, systemic therapy with
corticosteroids and immunosuppressive medication
is well tolerated.91 97 98 149 The question of long term
safety was also addressed by the SITE study, which
found no increased risk of mortality or cancer related
mortality with corticosteroids, antimetabolites, or
calcineurin inhibitors in this patient population.
Although alkylating agent therapy carried no
increased risk of mortality, there was a borderline
significant suggestion of an increased risk of cancer
related mortality.150-152
An Australian study published in 2015 reported
an increased risk of non-melanotic skin cancer
among patients with ocular inflammation treated
with immunosuppression; however, the study
included both alkylating and non-alkylating agents
together.153 Moreover, given the relatively higher
incidence of non-melanotic skin cancer in Australia,
this study’s results may not be representative of skin
cancer risk in the general population. Nevertheless,
it would seem prudent to recommend the use of
sunscreen and routine skin examinations in patients
with uveitis on immunosuppressive drug therapy.
The long term risks associated with biologic agents
in patients with uveitis are less clear, owing to the
more limited amount of data available. The data
from the SITE cohort were too few and the models
too unstable to conclusively evaluate the risks or
mortality and cancer related mortality in patients
with eye disease treated with anti-TNF therapy.150
Large registries of patients with rheumatoid
arthritis suggest only an increased risk of non-
melanoma skin cancer.154 155 The risk of infection
is increased, including with tuberculosis, with anti-
TNF therapy156; hence, screening for tuberculosis, as
well as hepatitis, before beginning anti-TNF therapy
is recommended. Additionally, because anti-TNF
therapy worsens multiple sclerosis, patients with
intermediate uveitis, which is associated with a
higher risk of multiple sclerosis, should be screened
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with magnetic resonance imaging of the brain before
initiating therapy with an anti-TNF agent.61 129 157
Treatment duration
The decision to discontinue therapy may be based
on several different factors, including disease course
and severity, risks associated with recurrence, and
the patient’s tolerance for the current therapy. When
a patient with uveitis also has associated systemic
disease, their ophthalmologist and rheumatologist
or internist should be involved in the decision about
if and when to discontinue therapy.
As previously discussed, achieving a sustained,
drug-free remission in patients with uveitis treated
with non-alkylating agents is uncommon. Data from
a cohort of patients with JIA associated chronic
anterior uveitis indicate that median time to a
sustained, drug-free remission was about 10 years in
patients with mild disease, and that less than 25%
of patients with severe disease achieved remission
even after 20 years.52 However, another study of
patients with JIA associated chronic anterior uveitis
showed that the risk of relapse is lower in patients
treated with methotrexate for more than three years
and in those who had inactive disease for more than
two years.158 This paradigm has been adopted for the
use of immunosuppression in the uveitides and, for a
patient who is tolerating therapy well, it is our practice
to treat with non-alkylating immunosuppressive
therapy for at least two years after corticosteroids
have been discontinued before considering tapering
immunosuppression. Given concerns for toxicity and
malignancy risk associated with alkylating agents,
if used at all, the target duration is one year after
achieving disease quiescence and discontinuing
prednisone, with a goal of limiting total duration of
therapy to fewer than 18-24 months.103 159
Guidelines
Three sets of published guidelines are available,
written by expert panels of uveitis specialists, for
the use of systemic medications in patients with
non-infectious uveitis.103 109 129 The first set of
guidelines was published before widespread use of
biologics in the treatment of uveitis103; the second
set focused specifically on the use of biologics.129
The most recent set of guidelines answered 10
specific questions, including those about the timing
of treatment escalation and discontinuation.109 All
of the guidelines advocate for early and aggressive
use of corticosteroid sparing therapy in patients
with severe, non-infectious uveitis. Additionally, as
discussed above, they recommend the use of anti-
TNF therapy early in the course of Behçet associated
uveitis and as second line therapy for chronic JIA
associated uveitis.
Conclusion
The uveitides are a collection of more than 30 distinct
diseases, and the goal of the uveitis evaluation
is the identification of the specific disease. Some
uveitides are associated with infection or systemic
the bmj | BMJ 2021;372:m4979 | doi: 10.1136/bmj.m4979
STATE OF THE ART REVIEW
QUESTIONS FOR FUTURE RESEARCH
BMJ: first published as 10.1136/bmj.m4979 on 3 February 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
• What is the role of molecular techniques such
as metagenomic deep sequencing in pathogen
discovery in patients with undifferentiated uveitides?
• What is the comparative effectiveness of adalimumab
versus conventional immunosuppressive agents as
corticosteroid sparing treatments for non-infectious
uveitides?
• What is the comparative effectiveness of long acting
injectable (eg, Yutiq) versus implanted (Retisert)
corticosteroid for the treatment of non-infectious
uveitides?
• What is the comparative efficacy of intravitreal versus
suprachoroidal corticosteroid, and what are the
relative risks of cataract and glaucoma?
disease; others are presumed to be immune
mediated and limited to the eyes. The diagnosis of
uveitis involves the intersection of clinical findings
(both ocular and systemic) and focused laboratory
testing. Treatment of the non-infectious uveitides
involves both corticosteroids and, when indicated,
immunosuppressive drug therapy. For patients with
uveitis and associated systemic disease, collaboration
of the ophthalmologist and rheumatologist facilitates
treatment of both ocular and systemic disease and
may prevent vision loss and other morbidity.
Grant support: Supported in part by grant R01 EY026593 from the
National Eye Institute, the National Institutes of Health, Bethesda, MD,
US.
Contributorship statement: Both DAJ and BMB performed the
literature search, wrote the article, and participated in its revisions.
DAJ is the guarantor.
Patient involvement: No patients were involved were directly
involved in the creation of this article.
Competing interests The BMJ has judged that there are no
disqualifying financial ties to commercial companies. The
authors declare the following other interests: none.
Further details of The BMJ policy on financial interests are here:
https://www.bmj.com/about-bmj/resources-authors/forms-policies-
and-checklists/declaration-competing-interests
Provenance and peer review: commissioned; externally peer
reviewed.
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