s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.elsevier.com/locate/survophthal

Major review

The Ocular Immunology and Uveitis Foundation

preferred practice patterns of uveitis management

C. Stephen Foster, MD, FACS, FACRa,b,c,*,

Srishti Kothari, DNB, DOMS, MNAMSa,b,d, Stephen D. Anesi, MDa,b,
Albert T. Vitale, MDb,e, David Chu, MDb,f,g,
Jamie Lynne Metzinger, MS, MPHa,b, Olga Ceron, MDa,b
a
Massachusetts Eye Research and Surgery Institution (MERSI), Waltham, Massachusetts, USA
b
Ocular Immunology and Uveitis Foundation (OIUF), Waltham, Massachusetts, USA
c
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
d
Department of Ophthalmology, The Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania, USA
e
Vitreoretinal Division, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA
f
Associate Director of Cornea and Refractive Surgery, Institute of Ophthalmology and Visual Science, New Jersey
Medical School, Rutgers University, Newark, New Jersey, USA
g
Metropolitan Eye Research and Surgery Institute, Palisades Park, New Jersey, USA

article info abstract

Article history: Ocular inflammatory disease is a leading cause of vision loss worldwide. Uveitis encom-
Received 15 January 2015 passes a wide spectrum of pathology, both with respect to its etiology and the anatomic
Received in revised form 25 June location within the eye. Inflammation can be confined to the eye and may also be seen
2015 systemically. The cornerstone of management of ocular inflammatory disease historically
Accepted 2 July 2015 has been corticosteroids, which are invaluable in the immediate control of inflammation;
Available online 9 July 2015 however, corticosteroids are inappropriate for long-term use as they are associated with a
wide array of toxic side effects. As we continue to learn more about the various etiologies
Keywords: and elucidate the basic science pathways and mechanisms of action that cause intraocular
uveitis inflammation, new therapeutic approaches have evolved. They include employment of
inflammation immunomodulatory agents (corticosteroid-sparing therapies) that have expanded our
immunomodulatory therapy treatment options for these vision-threatening diseases. These pharmacologics provide
immunosuppression therapy for ocular and systemic inflammation in an individualized, patient-tailored,
corticosteroid stepladder approach with the ultimate goal of durable, corticosteroid-free remission. We
ocular inflammatory disease review the preferred practice patterns of a tertiary care center specializing in ocular in-
biologic flammatory disease.
2016 Elsevier Inc. All rights reserved.

The protocols presented in the above tables (Table 8, specifically) are specific to the practice of Dr. C. Stephen Foster and are not
intended to suggest that they represent protocols in common usage.
* Corresponding author: C. Stephen Foster, MD, FACS, FACR, c/o Massachusetts Eye Research and Surgery Institution (MERSI), Ocular
Immunology and Uveitis Foundation (OIUF), 1440 Main Street, Suite 201, Waltham, MA 02451, USA.
E-mail address: sfoster@mersi.com (C.S. Foster).
0039-6257/$ e see front matter 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.survophthal.2015.07.001
2 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7

1. Global impact on vision
Intraocular inflammatory disorders encompass a broad
spectrum of disease in which the eye or its various parts may
be attacked by the immune system, leading to severe visual
impairment. Uveitis is the third leading cause of worldwide
blindness and currently accounts for approximately 10% of
preventable vision loss in the US and up to 15% world-
wide.10,21,24,47,63 In the US alone, uveitis has an estimated
prevalence of about 38 cases per 100,000 and an incidence of
15 cases per 100,000.24 An estimated more than 2 million
people worldwide have uveitis. Uveitis may affect individuals
of any age, from infancy to adulthood. A large, US population-
based study, the Northern California Epidemiology of Uveitis
Study (NCEUS)24 reported a 3-fold increase in the incidence of
uveitis, as compared to previous estimates, in addition to an
increased incidence due to an overall aging of the population.
There is a higher incidence of uveitis in women than men, and
the largest differences were seen in older age groups.24
2. Uveitis etiology: Noninfectious and
infectious
Several uveitis classifications schemes exist. They vary based
on the anatomic location of inflammation, clinical course,
etiology, and histopathology. The Standardization of Uveitis
Nomenclature (SUN) Working Group developed an anatomic
classification system in 2005 that arguably serves as the most
widely used today.28 The following are types of uveitis based
on anatomic location (Table 1).
(1) Anterior uveitis
(2) Intermediate uveitis
(3) Posterior uveitis
(4) Panuveitis
Table 2 e SUN Working Group grading scheme for
anterior chamber cells6
Grade Cells in fielda
0 <1
0.5 1e5
1 6e15
2 16e25
3 26e50
4 >50
a Field size is a 1 mm by 1 mm slit beam.
addition, the SUN Working Group recommended consistent
terminology for grading uveitic activity, whereby anterior
chamber cell, and flare, as well as vitreous haze are graded
on an escalating 0 to 4 severity scale (Tables 2e7). Although a
consensus has not been reached on the inclusion of vitreous
cell or retinal vasculitis in the classification system or indi-
vidual grading schemes, most uveitis experts will describe
the degree to which these features are seen in the same
fashion.
In the posterior segment, uveitis, macular edema, retinal
vasculitis, retinal detachments, and optic neuropathy
contribute to loss of vision. Intermediate uveitis, posterior
uveitis, and panuveitis are responsible for most visual
disability in patients with ocular inflammatory disease. The
other sight threatening complications of uveitis include
phthisis bulbi, hypotony,8,48 band keratopathy, glaucoma, and
retinopathy. The etiologic distribution of uveitis varies around
the globe. In general, anterior uveitis is most often idiopathic,
whereas an infectious etiology is more common among pa-
tients with posterior uveitis. Generally, infectious entities of
uveitis carry a poorer overall prognosis than the noninfectious
posterior uveitides.54

3. Medical management of uveitis

Anterior uveitis has the highest prevalence, followed by
panuveitis, then posterior and intermediate uveitis. In
Therapy for uveitis may appropriately involve medical or
surgical intervention. The preferred practice pattern that we
advocate in the care of patients with uveitis is aimed at cure.
The first stage in the successful pursuit of cure is the induction
Table 1 e SUN Working Group anatomic classification of
uveitis6 of durable, corticosteroid-free remissiondand doing what-
ever it takes to accomplish that goaldwhereas at the same
Type Primary site Includes
time doing no harm, not producing quality of life-altering side
of inflammation
effects or complications from the strategies used in that quest
Anterior Anterior chamber Iritis for durable remission.
Iridocyclitis
Anterior cyclitis
Intermediate Vitreous Pars planitis
Posterior cyclitis
Hyalitis Table 3 e SUN Working Group grading scheme for
Posterior Retina or choroid Focal, multifocal, anterior chamber flare6
or diffuse choroiditis
Grade Description
Chorioretinitis
Retinochoroiditis 0 None
Retinitis 1 Faint
Neuroretinitis 2 Moderate (iris and lens details clear)
Panuveitis Anterior chamber, vitreous, 3 Marked (iris and lens details hazy)
and retina or choroid 4 Intense (fibrin or plastic aqueous)
 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7 3

Table 4 e SUN Working Group descriptors in uveitis6 Table 6 e Criteria for grading vitreous flare as adopted
from the SUN Working Group6,8
Category Descriptor Comment
Grade Descriptors
Onset Sudden
Insidious 0 No inflammation present
Duration Limited 3 months duration 0.5 Trace inflammation present (slight blurring of optic
Persistent 3 months duration nerve margins, normal striations, and reflex of nerve
Course Acute Episode of sudden onset and fiber layer cannot be visualized)
limited duration 1 Mild blurring of the optic nerve and retinal vessels
Recurrent Repeat episodes separated by periods 2 Optic nerve visible,
of inactivity without therapy 3 borders blurred markedly
months duration 3 Optic nerve head not visible
Chronic Persistent with relapse in <3 months 4
after discontinuing therapy

remission with eventual withdrawal of all immunomodula-

tory medication and no relapse of ocular inflammation for 5 or
4. The stepladder approach
more years. We believe that this occurs, as in some other
autoimmune diseases, as a consequence of a resetting or re-
In an effort to prevent irreversible structural damage and
education of the immune system, such that it is no longer
blindness, the guiding principle of management of patients
inclined to mount an immune response against tissue of self.
with uveitis is diagnostic and therapeutic vigor. This means
Our experience informs us that the essential elements to
early diagnosis, referral to a uveitis specialist, and therapeutic
reach this goal are achieving corticosteroid-free remission
aggressiveness using a stepladder algorithmic approach,
through the employment of 1 or more immunomodulatory
which is both corticosteroid-sparing and titrated to the
agents, holding the problem in remission without any attempt
severity of intraocular inflammation16 (Fig. 1).
to taper the drugs that have accomplished that goal of
The cornerstone of medical therapy should include topical,
corticosteroid-free remission for a minimum of 2 years (3 is
regional and systemic corticosteroids, as well as topical
probably even better), with subsequent slow tapering of the
cycloplegics and mydriatics when appropriate. To achieve
immunomodulatory agents. We emphasize the importance of
durable corticosteroid-free remission or cure of the disease, a
steroid-free remission in the belief that corticosteroids,
long-term stepladder approach is used, involving initiation of
topical, or otherwise, mask any residual propensity of the
the lowest appropriately aggressive therapy for the specific
immune system to attack (i.e., low-grade inflammation not
disease process and severity, and advancement up the ladder
apparent as a consequence of corticosteroid use), and thus
to other modalities as needed, because of subjective
mask the need for more aggressive IMT in the quest for
intolerance or failure to control inflammation. Nonsteroidal
complete quiescence off all corticosteroids. Only in this way
anti-inflammatory drugs (NSAIDs) and immunomodulatory
can the immune system be adequately treated such that
therapy (IMT), including classic immunomodulators, newer
retolerization is accomplished.58
biologics, and cytotoxic agents, are initiated in conjunction
with corticosteroids, depending on the indication, or presence
of acute inflammation (Table 8). It is critical to recognize early 4.1. Mydriatic and cycloplegic agents
failure of a particular regimen to control inflammation to
escalate treatment, switching the drug or building onto the Topical mydriatic and cycloplegic agents are beneficial for
recipe in the quest to control inflammation without the use of breaking or preventing the formation of posterior synechiae
any form of corticosteroids. and for relieving photophobia and pain secondary to ciliary
We emphasize here that many forms of uveitis are curable, spasm. Relaxation of anterior segment structures may also
that is, can be placed into corticosteroid-free durable accelerate quiescence of inflammatory activity. There is a
tremendous advantage to preventing posterior synechiae
with regard to short-term and long-term outcomes, both to

Table 5 e SUN Working Group activity of uveitis

terminology6
Term Definition
Table 7 e Criteria for grading vitreous cells as adopted
Inactive Grade 0 cells (in anterior chamber) from the SUN Working Group6
Worsening activity 2-step increase in level of inflammation Grade Number of vitreous cells
(i.e., anterior chamber cells, vitreous haze)
or increase from grade 3 to 4 0 No cells
Improved activity 2-step decrease in level of inflammation 0.5 1e10
(i.e., anterior chamber cells, vitreous haze) 1 11e20
or decrease to grade 0 2 21e30
Remisssion Inactive disease for 3 months after 3 31e100
discontinuing all therapy for eye disease 4 >101
4 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
Fig. 1 e The stepladder approach. PPV, pars plana
vitrectomy; NSAIDs, nonsteroidal anti-inflammatory drugs.
patient and physician. Patients are able to see better, the pupil
is better cosmetically, and the physician is able to perform a
thorough examination of the posterior segment. Additionally,
risk of complications such as elevated intraocular pressure
(IOP) and permanent structural damage associated with pos-
terior synechiae formation may be mitigated. Some experts
prefer agents such as homatropine that are strong enough to
provide a desired effect, yet still allow intermittent pupillary
movement (Table 9).
4.2. Corticosteroids
The use of corticosteroids by Gordon and McLean in 1950 was
a landmark event that revolutionized the treatment of ocular
inflammatory disorders.45 The intervening half century has
allowed investigators to more clearly identify the pathways
involved in the systemic immune response, as well as the
mechanisms of autoimmunity and immune deviation, unique
to the eye.15,32
Corticosteroids are the mainstay of uveitis therapy;
however, they should be used in the acute management of
active uveitis, not as a long-term therapy strategy.23 The side
effects of corticosteroids are numerous and involve most
major organ systems: ocular, endocrine, neuropsychiatric,
gastrointestinal, musculoskeletal, cardiovascular, metabolic,
dermatologic, and immunologic adverse events are all
possible. Additionally, these events can be seen with any
mode of delivery of corticosteroid therapy (topical, sub-Tenon,
transseptal, intravitreal, or systemic). The dose and duration
must be tailored to the patient. Start therapy with a high dose
of corticosteroids and taper according to the clinical response
as the inflammation subsides rather than starting at a lower
dose and escalating therapy. The potential for inadequate
control of inflammation with prolonged exposure to cortico-
steroids in the latter approach places the patient at greater
risk for both inflammatory and corticosteroid-associated
ocular and systemic side effects. If therapy is required for
more than 2 weeks, taper before discontinuation to avoid a
pseudorecurrence associated with abrupt discontinuation
and, in the case of systemic therapy, to avoid acute cortico-
steroid withdrawal.
4.2.1. Topical corticosteroid administration
Topical corticosteroid drops are effective primarily for ante-
rior uveitis, although they may have beneficial effects on vit-
ritis or macular edema in patients who are pseudophakic,
aphakic, or post vitrectomy (Table 10). Instillation interval of
drops varies from a one to a few times daily, up to hourly,
dependent on severity of inflammation.
4.2.2. Periocular corticosteroid administration
Periocular corticosteroids are generally given as depot in-
jections when a more posterior effect is needed or when a
patient is noncompliant or poorly responsive to topical or
systemic administration (Table 11). Periocular injections are
preferred in patients with intermediate or posterior uveitis, or
for those with cystoid macular edema (CME), because they
deliver a therapeutic dose of medication close to the site of
inflammation, and have few, if any, systemic side effects in
adults. Periocular instillation can be performed using either a
transseptal (orbital floor) route, using a short, 27 gauge, 1/2
inch needle; or a sub-Tenon approach using a 25 gauge, 5/8
inch needle directed into the superotemporal or inferotem-
poral quadrant. The approaches are comparable with respect
to both efficacy and risk of cataract development or IOP
elevation, the latter being important to monitor closely after
injections are given. Preference for either may stem from
potential complications of each; both risk periorbital hemor-
rhage and globe perforation; however, transseptal instillation
includes increased risk of orbital fat prolapse, and super-
otemporal sub-Tenon injection has an increased risk of ble-
pharoptosis. Note that periocular injections should not be
used in cases of infectious uveitis, most importantly toxo-
plasmosis, and should be avoided in patients with necrotizing
scleritis or who have known corticosteroid-responsive eleva-
tions in IOP.
4.2.3. Intravitreal corticosteroid administration
Intravitreal corticosteroid injections are used extensively in
the treatment of uveitis and CME, typically for acute
inflammation recalcitrant to periocular injections, or as a
bridge to corticosteroid-sparing systemic IMT. Their benefit is
of limited duration, though a single pars plana intravitreal
injection of 4 mg (0.1 cm3 of 40 mg/mL solution) of triam-
cinolone may produce sustained visual acuity improvements
for 3e6 months or more. Multiple injections greatly increase
the risk of development of cataract or secondary glaucoma.
Sterile endophthalmitis, or pseudoendophthalmitis from
crystallization, may occur in up to 1% of patients and re-
quires extensive anti-inflammatory therapy. This is most
likely to develop within a day or 2 postinjection, as opposed
to 5 to 7 days as expected with infectious endophthalmitis (If
there is any doubt, the case treat as the latter with vitreous
paracentesis and intravitreal injection of broad spectrum
antibiotics).59,64
(1) Kenalog (triamcinolone acetonide injectable suspension
40 mg/mL; available for use off label, typically drawn with
filtered needle before delivery)
(2) Triesence (triamcinolone acetonide injectable suspension
40 mg/mL; preservative free; FDA approved for intraocular
use)
Table 8 e Immunosuppressive therapy
Class Generic name Initial dose Maximum Mechanism Expected Major Representative Lab testd Lab testd Comments
(trade name) (route) dose (route) onset indications side effects baseline follow up

Alkylating Cyclophosphamide 1 mg/kg/day (PO) or 3 mg/kg/day (PO) DNA cross-linking 2 weeks GPA, PAN, PUK & Necrotizing Sterile hemorrhagic cystitis CBC & Diff, CBC & Diffd The dose for IV infusions is
agents (Cytoxan) 1 g/m2 (BSA) infusions ScleritisdRA/RP, Bilateral (acrolein induced), LFTs, BUN/ q2 wks, LFTs, titrated based on changes in
q1e2 weeks (IVdpulse) Moorens Ulcer, OCP, SO, myelosuppression, reversible Cr, UA BUN/Cr, the total WBC count (aim,
ABD, Bilateral Moorens Ulcer alopecia, infections, sterility, UAdqmnth 3500e4500 cells/mL). ANC
secondary malignancies, blurring >1500 cells/mL, Platelet
of vision, elevated IOP counts >75,000/mL.
Cascading trends of counts
looked for at every infusion
visit. Cryopreservation of
sperms and eggs before
induction PRN. Consumption
of 2 to 4 liters of water daily.
Malignancy associated with
76 g (cumulative dose) or
50 mg (daily dose) for more

s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
than 2 years. Filgrastim
(G-CSF [SC/IV]) for accelerating
neutrophil recovery.
Chlorambucil 0.15 mg/kg/day (PO) 18 mg/kg/ DNA cross-linking 2 weeks ABD, SO, JIA iridocyclitis, Reversible myelosuppression CBC & CBC & Diff Other indicationsdPars planitis,
(Leukeran) day (PO) serpiginious choroiditis (moderate, rapid, protracted), Diff, LFTs dq1e3 wks, idiopathic, Crohns disease
irreversible bone marrow aplasia, LFTsdq3e4 and HLA B27eassociated
gonadal dysfunction, sterility, mnths uveitis. Routine prophylaxis
infections, secondary of pneumocystis pneumonia
malignancies is advised in conjunction.
Antimetabolites Methotrexate 7.5e15 mg/week or 0.15 20 mg/week (PO), Inhibitor of dihydrofolate 3e6 weeks UveitisdJIA, reactive Ulcerative stomatitis, CBC & Diff, CBC & Diff Alcoholism and outdoor
(Folex, Mexate, mg/kg/week (Oral/SC) 50 mg/week (SC), reductase arthritis, AS, IBD, psoriatic myelosuppression (leukopenia, LFTs BUN/ dq1e4 wks, activity to be avoided.
Rheumatrex) 200 mg/week (IV) arthritis and sarcoidosis, thrombocytopenia), GI distress, Cr, UA LFTs, BUN/Cr, Authors prefer administering
scleritisdreactive hepatotoxicity (hepatitis, UAdq3e6 wks doses of above 20 mg/week
arthritis and RA, SO cirrhosis), pulmonary toxicity, by SC mode of administration.
cutaneous vasculitis, fetal loss IV rescue doses are used
sparingly. Administered
along with folinic acid
to shield normal cells from
toxicity. leucovorin rescue.
Azathioprine (Imuran) 1 mg/kg/day 3 mg/kg/day (PO) Alters purine metabolism 1e3 months ScleritisdRP, OCP, JIA Myelosuppression (leukopenia, CBC & Diff, CBC & Diff Active metabolitedthioinosine
(POdq.d./b.i.d.) iridocyclitis, ABD, GPA, thrombocytopenia), GI distress, LFTs, BUN/Cr, dq1e4 wks, 5 phosphate (converted from
SLE, SO, VKH, sarcoidosis, hepatitis, infections, pancreatitis, TPMT activity LFTs, BUN/ 6-MP). CI in RA previously
pars planitis, Reiters Cancer Crdq3e6 wks treated with alkylating agents.
syndromediridocyclitis
Mycophenolate 1 g (POddivided dose), 3 g (POddivided Inosine monophosphate 2 weekse3 Scleritis, methotrexate GI distress, neutropenia, infection CBC & Diff, CBC & Diff Active componentd
mofetil (Cellcept), Sodiumd360 mg dose) dehydrogenase inhibitor months nonresponsive LFTs, BUN/Cr dq1e4 wks, mycophenolic acid.
Mycophenolate Sodiumd760 (purine synthesis) noninfectious uveitis LFTs, BUN/ Possibly better tolerated
sodium (Myfortic) mg (PO) on an in adults and children, Crdq3e than azathioprine.
empty adjuvant to cyclosporine 6 wks
stomach in ABD and BSRC
Leflunomide (Arava) 100 mg q.d.  3 then 10 mg/kg/day or Inhibits dihydroorotate Sarcoidosis, methotrexate Diarrhea, neurological effects Active metabolited
20 mg q.d. 20 mg q.d. (PO) dehydrogenase nonresponsive A771126 (M1).
or 0.01 mg/kg (PO) (pyrimidine synthesis) noninfectious uveitis
Cytosine arabinoside 100 mg (SC/IV) 300 mg (SC/IV) Pyrimidine antagonist
(Cytarabine, Ara-C,
Cytosar-U)
Calcinernin and Cyclosporine 2.5e5 mg/kg/day 10 mg/kg/day (PO) Calcineurin inhibitor 2e4 weeks ABD, BSRC, sarcoidosis, Nephrotoxicity, HT, CBC & Diff, CBC & Diff, Neoral has a greater
IL-2 inhibitors (Sandimmune, (POddivided dose) pars planitis, VKH, MS, hyperuricemia, DM, BUN/Cr, Cr BUN/Cr, LFTs, bioavailability than
Neoral, SangCya) SO, idiopathic posterior hypercholesterolemia, clearance, trough level Sandimmune so its dose
uveitis, PUK and scleritis neurotoxicity, hirsutism, gum LFTs, Fasting monitoring, should be reduced by
with GPA, corneal hyperplasia lipid profile BPdq1e3 weeks. 20% when substituting
graft rejection and BP, Fasting lipid the drug. Drug and
Trough level profile, Cr food interactions.
monitoring

(continued on next page)

5
 6
Table 8 e (continued )
Class Generic name Initial dose Maximum Mechanism Expected Major Representative Lab testd Lab testd Comments
(trade name) (route) dose (route) onset indications side effects baseline follow up

clearance
dq3mnth
Tacrolimus (Prograf, 0.05 mg/kg/day (PO) 0.3 mg/kg/ Calcineurin inhibitor ABD, idiopathic Nephrotoxicity, HT, DM, Similar to Similar to Can be used in cyclosporine
FK 506) day (PO) posterior uveitis, BSRC neurotoxicity, Secondary cyclosporine cyclosporine resistant ocular inflammatory
malignancies disorders. Drug and
food interactions.
Sirolimus (Rapamune, Loadingd6 mg/day (PO), 6 mg/day (PO) mTOR pathway Inhibitor Unknown, adjunct to GI distress and dermatological Similar to Similar to
Rapamycin) Maintenanced2 mg/day cyclosporine (rapamycin) manifestations, unknown cyclosporine, tacrolimus,
quantitative periodic
urinary protein quantitative
excretion urinary protein
monitoring excretion
monitoring
Voclosporin (Voclera, 0.4 mg/kg (POd Calcineurin inhibitor Lymphopenia, nephrotoxicity, HT,
Luveniq) divided dose) hirsutism, gingival hyperplasia
Antibiotics Dapsone 50 mg (PO) 150 mg (PO) Anti-inflammatory d OCP, scleritis with RP Hemolytic anemia,
stabilizes lysozomal methemoglobinemia, GI distress,

s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
membranes mononucleosis-like syndrome,
blurred vision
Adjuvants Bromocriptine 1.25e7.5 mg/day 10 mg/day (PO) Prolactin inhibitor Adjunct to cyclosporine, Postural hypotension, GI distress
(Parlodel) (POddivided) iridocyclitis, thyroid
ophthalmopathy
Ketoconazole (Nizoral) 200 mg/day (POddivided) 400 mg/day Inhibition of sterol Adjunct to cyclosporine Hepatotoxicity, endocrine
(POddivided) metabolism abnormalities, GI distress
Colchicine 1 mg (POddivided) 1.8 mg/day Microtubule formation ABD GI distress, myelosuppression, CBC & Diff, CBC & Diff,
(POddivided) inhibitor neurotoxicity LFTs, BUN/ LFTs BUN/Cr,
Cr, UA UAdq3mnth
Adalimumab (Humira) 40 mg/every other 40 mg/week (SC) Fully humanized Ig1 1e2 weeks Adjuvant in ocular Sepsis, injection site reactions, CBC & Diff, CBC& Diff,
week (SC) monoclonal inflammatory disorders demyelinating disorder, LFTs, LFTsdqvisit,
anti-TNFa antibody secondary to RA, JIA, anaphylaxis, drug induced lupus, tuberculin tuberculin
AS, psoriatic arthritis secondary malignancies testing, testingdq1 yr,
and plaque psoriasis, hepatitis hepatitis B
VKH, BSRC, orbital B (if at risk) (if at risk)d
pseudotumor several months
after therapy
Infliximab (Remicade) 5e20 mg/kg/day (IV) 20 mg/kg (IV) Chimeric IgG1k anti-TNFa 1e2 weeks Refractory ABD, Tuberculosis reactivation, CBC & Diff, CBC & Diff, Produced by phage
Loading dose 0, monoclonal antibody with a uveitis and scleritis invasive fungal and opportunistic LFTs, ANA, LFTsdqprior display technology.
2, 4 weeks  human constant and mouse secondary to JIA, AS, infections, nonmelanoma skin Tuberculin each infusion,
6 months after variable region GPA, sarcoidosis, cancer, and secondary testing, ANAdq3mnth,
steroid-free remission Crohns disease, malignancies hepatitis tuberculin
has been achieved. CIST-resistant uveitis B (if at risk) testing, hepatitis
Then taper B (if at risk)d
off with 3 infusions q1 yr
at 6, 8, 10, 12 week
interval each, before
withdrawal
Abatacept (Orencia) 500e1000 mg Recombinant soluble Recalcitrant JIA uveitis Drug induced CBC & Diff, CBC& Diff, LFTs Remicade Reaction
(IVdWt based), fusion protein consists lupus, thromboembolism, LFTs, ANA, qprior each infusion, flushing, lower back pain,
125 mg (SC) of extracellular domain tuberculosis reactivation, Tuberculin ANAdq3mnth, chest tightness, tachycardia.
of human CTLA-4 linked hepatitis B testing, tuberculin testing, Concomitant administration
to modified Fc portion reactivation, hepatitis hepatitis B (if with methotrexate to
of human IgG1 demyelinating B (if at risk) at risk)dq1 yr decrease formation of human
disorders, lymphoma, anti-chimeric antibodies.
and solid Lymphoma when
tissue cancers combined with 6-MP.
Daclizumab (Zenapax) 1 mg/kg (IV) q2 wks  5 4 mg/kg (IV) Humanized IgG1 2e4 weeks ABD, refractory Anaphylaxis, infections, GI CBC & Diff, CBC & Diff,
(renal transplant dose) antieIL-2 receptor BSRC, JIA uveitis distress LFTs, LFTsdqvisit
(CD25) monoclonal tuberculin
antibody testing
Certolizumab 400 mg/week (IV) 1000 mg/ Recombinant human Infections, psoriatic form rashes CBC & CBC & Diff, LFTsd Withdrawn. Inhibits auto
(Cimzia, CDP 870) week (IV) anti-TNFa antibody Diff, LFTs qprior each infusion reactive T cells without
Fab fragment suppressing function of
the immune system.
 Anakinra (Kineret) 100 mg/day (SC) Humanized antieIL-1 Unknown Similar to other BRMs CBC & Diff, LFTs CBC & Diff,
receptor monoclonal LFTsdqvisit
IgG antibody
Rituximab (Rituxan) Loadingd375 mg/kg mg Genetically engineered 12 weeks RAdscleritis, GPA, IgE mediated hypersensitivity to CBC & Diff, CBC & Diff, OCPdDose is 375 mg/m2
(IV) qwk,  8. Maintenance chimeric IgG1k murine/ ABD, OCP, orbital murine proteins, sepsis, CD20cells CD20cellsdqprior once/week for 8 consecutive
d375 mg/kg mg human anti-CD20 inflammatory syndrome nephrotoxicity, cardiotoxicity each infusion weeks. Then once/month
(IV) monthly monoclonal antibody  4 months, for a total
of 6 months of treatment.
Refer IVIG.
Golimumab (Simponi, Human IgGk anti-TNFa 2e4 weeks Serious infections, invasive fungal CBC & Diff, CBC & Diff,
CNTO148) monoclonal antibody infections, hepatitis B LFTs, lipids LFTsdqvisit
reactivation, malignancies, heart
failure, demyelinating disease,
hypersensitivity reactions
Tocilizumab (INN, 4 mg/kg (IV) 480 mg or 8 mg/kg Recombinant humanized 4e8 weeks Unknown Serious infections, CBC & Diff, CBC & Diff, At initiation ANC >2000/mL,
atlizumab, every 4 weeks (IV) IgG1k antieIL-6 receptor gastrointestinal perforation, LFTs, fasting LFTsdqprior platelets >1,00,000/mL.
Actemra, RoActemra) monoclonal antibody leucopenia (neutropenia, lipid profile, each infusion, Discontinue when ANC
thrombocytopenia) tuberculin lipidsdq4e8 weeks <500/mL, platelets <50,000 mL.
testing
Gevokizumab (SC) Human IL-1b antagonist Infections including oral herpes,
(Xoma 052) oushingoid, oropharyngeal pain,
GI distress, hepatotoxicity
Secukinumab (AIN57) (SC/IV) Human antieIL-17A Anaphylaxis, dizziness, GI

s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
antibody distress, arthralgia, elevated IOP,
ocular pain, blurred vision
Alemtuzumab 10 mg/day  5 days (IV) 12 mg/day  Recombinant humanized Uveitis, PUK with GPA, ABD,
(Campath-1H, 5 days (IV) IgG1k anti-CD52 SO, retinal vasculitis
Lemtrada) monoclonal antibody
Natalizumab (Tysabri, Recombinant humanized
Antegren) IgG4k anti-a4 integrin
monoclonal antibody
Ustekinumab Recombinant human
(Stelara, CNTO 1275) IgG1k antieIL-12, IL-23
monoclonal antibody
Efalizumab (Raptiva) Recombinant humanized
IgG1k anti-CD11a
monoclonal antibody
Basiliximab (Simulect) Recombinant chimeric
IgG1k antieIL-2Ra (CD25)
murine/human
monoclonal antibody
Apremilast Cyclic AMP Inhibitor, GI distress, Unknown
TNFa nhibitor,
antieIL23 and
proeIL-10
Sarilumab (Sanofi) AntieIL-6
ESBA-105 TNFa Inhibitor Unknown
Canakinumab (Iliaris) (SC) (SC) Recombinant, human IgG1k Serious infections,
antieIL-1b monoclonal GI distress, unknown
antibody
IVIG 1e2 g/kg/cycle over 2.5 mg/kg split Intact IgG OCP, Graves Aseptic meningitis, Anti-IgA immunization
3 days (IV) over 3 days (IV) ophthalmopathy, thromboembolism, risk of may occur. Proposed
demyelinating optic transmission of blood borne mechanism of action -
neuropathy, infections, CHF multiple. OCPdIVIG 1 month
uveitis, scleritis before Rituximab, then
qmnth until B-cell levels
return to normal. Thereafter
IVIG is administered at 6, 8,
10, 12, 14, and 16 weeks.
IFNa 2a (Pegasys, 3 million units per day or 6 million units/ Immunomodulatory Refractory ABD Fatal neuropsychiatric, CBC & Diff, Discontinue if ANC
Peginterferon 3 times a week (SC/IM) day (SC/IM) cytokine autoimmune, ischemic, and LFTs, BUN/Cr <500/mL, platelets <25,000 mL.
a 2a, Pegintron) infectious disorders
IFNb 1a Immunomodulatory MSduveitis, SO, Hepatotoxicity, cardiotoxicity, CBC & Diff, CBC, LFTsdq4 wks,
cytokine and idiopathic autoimmune thyroiditis, flu-like LFTs, thyroid function
posterior uveitis symptoms, injection site reactions thyroid testsdq3mnth
function
tests
Others Type II Collagen Structural protein JIA uveitis GI distress, unknown Induces tolerance
Pentoxifylline Anti-TNFa Unknown Contraindicated in
history of bleeding

7
(continued on next page)
8 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7

4.2.4. Sustained release devices: Corticosteroid implants

pressure; IV, intravenous; IVIG, intravenous immunoglobulin; JIA, juvenile idiopathic arthritis; LFTs, liver function tests; MP, mercaptopurine; MS, multiple sclerosis; mTOR, mammalian target of
CHF, congestive heart failure; CI, confidence interval; GI, gastrointestinal; CIST, classic immunosuppressive therapy; DM, diabetes mellitus; GPA, granulomatosis with polyangiitis (Wegeners

before every infusion; qvisit, every visit; qwk, every week; qyr, every year; q.i.d., four times a day; RA, rheumatoid arthritis; RP, relapsing polychondritis; SC, subcutaneous; SLE, systemic lupus er-
response modifiers; BSA, body surface area; BSRC, birdshot retinochoriodopathy; BUN/Cr, blood urea nitrogen, serum creatinine; b.i.d., twice a day; CBC & Diff, complete and differential blood count;

rapamycin; OCP, ocular cicatricial pemphigoid; PAN, polyarteritis nodosa; PO, per oral; PRN, Pro re nata; PUK, peripheral ulcerative keratitis; q.d., once a day; qmnth, every month; qprior each infusion,
ABD, Adamantiades-Behcet disease; AMP, adenosine monophosphate; ANA, antinuclear antibody; ANC, absolute neutrophil count; AS, ankylosing spondylitis; BP, blood pressure; BRM, biologic

granulomatosis); G-CSF, granulocyte-colony stimulating factor; HLA, human leukocyte antigen; HT, hypertension; IBD, inflammatory bowel disease; IFN, interferon; IM, intramuscular; IOP, intraocular

ythematosus; SO, sympathetic ophthalmia; TNFa, tumor necrosis factor alpha; TPMT, thiopurine S-methyltransferase; t.i.d., three times a day; UA, urine analysis; VKH, Vogt-Koyanagi-Harada
Sustained release corticosteroid implants are available in
various forms, and can be given by intravitreal injection or by
Comments

surgical fixation to sclera through a pars plana approach,

often in conjunction with vitrectomy (Table 12). These devices
are indicated for use in patients with severe or recalcitrant
unilateral or bilateral noninfectious uveitis, or in patients who
have failed or are intolerant of systemic corticosteroids or
IMT. Use of these devices does not replace the need for IMT for
active or life-threatening systemic inflammatory disease.
Lab testd
follow up

Longer duration of intraocular corticosteroid delivery also

imposes greater risk of secondary complications that may also
require surgical attention (cataract and glaucoma).17,26 They
are not viewed as first-line therapy options, though their uti-
Lab testd
baseline

lization may be individualized per patient preference.

The sustained release biodegradable implant Ozurdex
contains dexamethasone 0.7 mg in the Novadur solid polymer
drug delivery system. The duration of action averages
3e6 months. This injection is an office procedure. Retisert is a
Representative
side effects

nonbiodegradable implant and contains the active ingredient

fluocinolone acetonide 0.59 mg. The implant boasts a duration
of 30 months and needs to be surgically implanted into the
Unknown

posterior segment of the affected eye through a pars plana

incision. Each procedure can be performed multiple times.
Retisert has a high rate of both cataract formation and
development of secondary glaucoma. Owning to this fact, the
latest generation from the developers of Retisert created a
indications
Major

product with a smaller amount of corticosteroid. Iluvien is

currently approved for use in diabetic macular edema but is
undergoing clinical trials in posterior uveitis. Improvements
from the Retisert design include longer drug duration
Expected

(36 months), fewer side effects due to a smaller drug quantity

onset

(0.19 mg), and an adaptation to the delivery mechanism,

allowing this implant to be placed in the office, not the oper-
ating room.
phosphodiesterase IV
Mechanism

(1) Ozurdex (dexamethasone 0.7 mg injectable intravitreal

Inhibition of

implant; FDA approved for posterior noninfectious uveitis)

(2) Retisert (fluocinolone acetonide 0.59 mg intravitreal
implant; FDA approved for posterior noninfectious uveitis;
surgically implanted through pars plana incision)
dose (route)
Maximum

(3) Iluvien (fluocinolone acetonide 0.19 mg injectable intra-

vitreal implant; currently in clinical trial for use in uveitis,
results pending)

4.2.5. Systemic administration

Initial dose

Oral systemic therapy may supplement or replace other

(route)

routes of administration (Table 13). Systemic corticosteroids

are used for vision-threatening chronic uveitis when topical
corticosteroids are insufficient or when the patients systemic
syndrome; WBC, white blood cell.

disease also requires therapy. Prednisone is most commonly

used. The current standard of care for oral corticosteroids is to
Generic name
(trade name)

start prednisone at 1 mg/kg/day and then taper in a gradual

Table 8 e (continued )

fashion as inflammation subsides, usually by 5e10 mg each

Rolipram

week. If surgical intervention is required, the dosage may be

increased to prevent postoperative exacerbation of uveitis and
to reduce the risk of postoperative CME. If corticosteroid
therapy is required for longer than 3 months or if a dose
Class

greater than 5 mg daily is required to control inflammation,

IMT is indicated, as is bone preservation therapy.
 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7 9

Table 9 e Mydriatics and cycloplegics

Generic name (trade name) Strength (%) Mydriasis Cycloplegia

Maximal (minutes) Recovery (days) Maximal (hours) Recovery (days)

Atropine sulfate (multiple) 1 30e40 7e10 1e3 7e12

Scopolamine hydrobromide (multiple) 0.5 20e30 3e7 0.5e1 5e7
Homatropine hydrobromide (multiple) 1 40e60 1e3 0.5e1 1e3
Cyclopentolate hydrochloride (multiple) 0.5e1 30e60 1 0.5e1 1
Tropicamide (multiple) 0.5e1 20e40 0.25e1 0.5 <0.25
Phenylephrine hydrochloride (multiple) 0.5e1 20e60 3e6 None None

In cases of severe, noninfectious posterior uveitis or corticosteroid therapy.67 Bone mineral density screening
panuveitis, intravenous, high-dose, pulsed methylpredniso- (dual-energy X-ray absorptiometry) is important for patients
lone (1 g/day infused over 1 hour) may be administered each receiving corticosteroids for greater than 3 months or in high
day for 3 days, followed by a gradual taper of oral prednisone doses (greater than or equal to 60 mg). Bisphosphonate or
starting at 1 mg/kg/day. Patients on high-dose oral cortico- supplemental parathyroid hormone therapy can also be
steroids should be placed on histamine-2 receptor blockers or considered in this group. A team approach with the patients
proton pump inhibitors to lower risk of gastric and peptic primary care physician is highly recommended.
ulcers. The risk of gastric ulcer is particularly high in patients
who are concomitantly taking systemic NSAIDs, and these 4.3. Nonsteroidal anti-inflammatory drugs
medications can be transiently stopped during times when
systemic corticosteroids are used. Patients maintained on NSAIDs work by inhibiting cyclooxygenase (isoforms 1 and 2
long-term corticosteroid regimens, especially the elderly, or 2 alone), and reduce the synthesis of prostaglandins that
postmenopausal women, or any patient on a course for longer mediate inflammation. Topical NSAIDs may be used in the
than 3 months, should supplement their diet with calcium treatment of postoperative inflammation and CME, including
and vitamin D to lessen the risk of osteoporosis and perform CME which persists after the uveitis is quiescent. Systemic
regular, weight-bearing exercise, as increased risk of patho- NSAIDs can be efficacious in the prevention of recurrent,
logic fractures and bone loss begins at 3 months of systemic acute, or chronic iridocyclitis, especially idiopathic or
human leukocyte antigen B27eassociated, recurrent non-
granulomatous anterior uveitis.14,57,65 Potential side effects
from prolonged systemic NSAID use include gastric ulcera-
Table 10 e Topical Drops tion, gastrointestinal bleeding, hypertension, nephrotoxicity,
and hepatoxicity. Gastrointestinal side effects may be avoided
Generic name (trade name) Formulation
by selective COX-2 inhibitors (Tables 14 and 15).
Dexamethasone alcohol 0.1% suspension
(Decadron Phosphate)
4.4. Immunomodulatory therapy
Dexamethasone sodium phosphate 0.1% solution
Dexamethasone sodium 0.05% ointment
phosphate ointment Immunomodulatory agents offer patients additional thera-
Prednisolone acetate 1.0% suspension peutic efficacy, that is, both anti-inflammatory and
(Pred Forte, Econopred corticosteroid-sparing by inhibiting one or more elements of
Plus, AK-Tate) the immune response. Appropriate utilization involves
Prednisolone acetate 0.12% suspension following a stepladder approach and balancing the risk:benefit
(Pred Mild, Econopred)
ratio, with the ultimate goal of achievement of durable
Prednisolone sodium phosphate 1% solution
(Inflamase Forte, AK-Pred)
remission.
Prednisolone sodium 0.5% solution With the results from the multicenter collaborative Sys-
phosphate (Metreton) temic Immunosuppressive Therapy for Eye diseases (SITE)
Prednisolone phosphate (Hydeltrasol) 0.5%, 0.25% ointment study sponsored by the National Institutes of Health, we now
Fluorometholone alcohol (FML) 0.1% or 0.25% suspension have evidence that addresses potential for increased mortality
Fluorometholone (FML SOP) 0.1% ointment
and the development of malignancy associated with these
Medrysone (HMS) 1% Suspension
agents.27 The study concluded that use of immunosuppres-
Rimexolone (Vexol) 1% suspension
Medroxyprogesterone 1% suspension sive chemotherapeutic agents for the care of patients with
acetate (Provera) chronic or recurrent uveitis under close monitoring can be
Rimexolone (Vexol) 1.0% suspension both effective and safe and did not, with the exception of
Loteprednol etabonate (Lotemax) 0.5% suspension tumor necrosis factor alpha (TNFa) inhibitors, place the pa-
Loteprednol etabonate (Alrex) 0.2% suspension tient at increased risk for mortality or malignancy.27
Loteprednol etabonate 0.12% solution
The addition of IMT may benefit patients with sight-
(Inflamase Mild)
threatening uveitis or patients who are resistant to or intol-
Difluprednate (Durezol) 0.05% emulsion
erant of corticosteroids. A therapeutic response may not occur
10 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7

Table 11 e Regional preparations (subconjunctival or subtenons)

Generic name (trade name) Dose (route)

Hydrocortisone-100e1000 mg powder (hydrocortisone sodium succinate) 50e125 mg (subconjunctival/subtenon)

Methylprednisolone sodium succinate-40 mg/mL, 125 mg/mL, 2 g/30 mL 40e125 mg (sunconjunctival/subtenon)
solution (Solu-Medrol)
Methylprednisolone acetate-20e80 mg/mL (depot) suspension (Depo-Medrol) 40e80 mg/0.5 mL (transseptal, retrobulbar)
Triamcinolone diacetate-25e40 mg/mL suspension (Aristocort) 40 mg (subconjunctival/subtenons)
Triamcinolone acetonide-10e40 mg/mL suspension (Kenalog) 40 mg (transseptal)
Triamcinolone acetonide-40 mg/mL (Triescense) 4 mg (intravitreal)
Dexamethasone acetate-6e16 mg/mL suspension (Decadron-LA) 4e8 mg (subconjunctival/subtenon/transseptal)
Dexamethasone sodium phosphate 4, 10, 24 mg/mL solution (Decadron Phosphate) 0.4 mg (retrobulbar, intravitreal)
Betamethasone acetate and sodium phosphate-3 mg/mL suspension (Celestone Soluspan) 1 mg (subconjunctival/tenon/transseptal)

for several weeks after initiation of IMT, varying greatly be-  Active retinal vasculitis
tween medication classes; therefore, patients with acute  Juvenile idiopathic arthritis (formerly juvenile rheuma-
inflammation may require corticosteroid therapy until IMT toid arthritis or juvenile chronic arthritis)
takes effect, at which time the corticosteroid dose may be
gradually tapered. Because of the potential side effects of IMT, Use of IMT for these conditions improves the long-term
patients on such medications require close monitoring. visual prognosis and reduces ocular complica-
Reviews of peer-reviewed literature on the quality and the tions.3,7,9,19,20,23,25,30,31,33,34,39,40,49,52,59 An adequate clinical
strength of evidence for IMT efficacy and safety in treating response should be observed within 3 months of treatment. In
uveitis have resulted in the following recommendations. cases of inadequate or no clinical response at the maximum
Diseases which warrant the early use of immunomodulatory tolerable dose of drug or drug toxicity, IMT is either replaced or
medications for treatment of intraocular inflammation recipe building is used. If a good clinical response is achieved,
include: there are no inflammatory breakthroughs, and the patient is
free of corticosteroids in all forms (systemic, topical, or local),
(1) Absolute indications the drug can be tapered after 24 months. If no recurrence is
 Adamantiades-Behcets disease with retinal seen during the taper, the drug can be discontinued. This is
involvement the only avenue for achieving a lasting, durable remission.
 Sympathetic ophthalmia Immunomodulatory medications (Table 8) used in the
 Vogt-Koyanagi-Harada syndrome treatment of uveitis can be subdivided into:
 Antineutrophil cytoplasmic antibodyeassociated
vasculitidities (1) Antimetabolites
B Granulomatosis with polyangiitis (or Wegeners) (2) Inhibitors of T-lymphocytes signaling
B Microscopic polyangiitis (3) Biologic response modifiers41
B Polyarteritis nodosa (4) Alkylating agents
 Necrotizing scleritis and peripheral ulcerative keratitis,
associated with: We provide here guidelines for employment of specific
B Rheumatoid arthritis drugs and combinations of drugs, in general and for specific
B Relapsing polychondritis indications. Once it has been determined that NSAIDs therapy
B Bilateral Moorens ulcer is either not appropriate or ineffective in treating refractory
 Ocular cicatricial pemphigoid uveitis, or they are not tolerated, the treating ophthalmologist
(2) Relative indications must now move to IMT, and this initially involves discussion
 Birdshot retinochoroidopathy of antimetabolite therapy but may also include other medi-
 Serpiginous choroiditis cations, such as biologic response modifiers or alkylating
 Sarcoid-associated uveitis agents. As these drugs are considered chemotherapy, a
 Severe refractory chronic iridocyclitis, intermediate thoughtful and planned discussion must ensue to introduce
uveitis, panuveitis the patient to this concept, and the differences between
 Multifocal choroiditis treating inflammatory disease and malignancy, as these vary

Table 12 e Intravitreal implants

Generic name (trade name) Dose (mg) OPD procedure Biodegradability Maximum effectiveness Life (months)
(months)

Dexamethasone (Ozurdex) 0.7 Yes Yes 1e3 6

Fluocinolone acetonide (Iluvien) 0.19 Yes No 18e36
Fluocinolone acetonide (Retisert) 0.59 No No 18e30

OPD, out patient department.

 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7 11

Table 13 e Systemic corticosteroid preparations

Generic name (trade name) Formulation Duration

Hydrocortisone (Cortef) 5e20 mg tablet (PO), 10 mg/5 mL suspension Short acting

(PO), 25 and 50 mg suspension (IM)
Hydrocortisone (Hydrocortone Phosphate) 50 mg/mL solution (IM/IV) Short acting
Hydrocortisone (Solu-Cortef) 100e1000 mg powder (IM/IV) Short acting
Prednisone (Deltasone, Meticorten, Drasone) 1e50 mg tablet (PO) Intermediate acting
Prednisone (Liquid Pred) 5 mg/mL solution (PO) Intermediate acting
Prednisolone (Delta-Cortef) 1e5 mg tablet (PO) Intermediate acting
Prednisolone (Prelone) 15 mg/mL syrup (PO) Intermediate acting
Prednisolone acetate (Predalone) 25e100 mg/mL suspension (IM) Intermediate acting
Prednisolone sodium phosphate (Hydeltrasol) 20 mg/mL solution (IM/IV) Intermediate acting
Methylprednisolone (Medrol) 2e32 mg tablet (PO) Intermediate acting
Methylprednisolone acetate (Depomedrol) 20e80 mg/mL suspension (IM) Intermediate acting
Methylprednisolone sodium succinate (Solumedrol) 40e1000 mg powder (IM/IV) Intermediate acting
Triamcinolone diacetate (Kenacort) 4 mg/5 mL (PO) Intermediate acting
Triamcinolone diacetate (Aristocort) 1e8 mg tablet (PO), 40 mg/mL suspension (IM) Intermediate acting
Triamcinolone acetonide (Kenalog) 10e40 mg/mL suspension (PO) Long acting
Dexamethasone sodium (Decadron) 0.25e6 mg tablet (PO), 0.5 mg/5 mL elixir (PO), 0.5 Long acting
mg/5 mL solution (PO)
Dexamethasone sodium phosphate (Decadron Phosphate) 4e24 mg/mL solution (IM/IV) Long acting
Dexamethasone acetate (Decadron-LA) 8 mg/mL suspension Long acting
Betamethasone (Celestone) 0.6 mg tablet (PO), 0.6 mg/5 mL syrup (PO) Long acting
Betamethasone sodium phosphate (Celestone phosphate) 3 mg/mL solution (IV) Long acting
Betamethasone acetate (Celestone acetate) 3e6 mg/mL suspension (IM) Long acting
Betamethasone acetate and sodium phosphate 3 mg/mL suspension each (IM) Long acting
(Celestone Soluspan)

IM, intramuscular; IV, intravenous; PO, per oral.

dramatically. Knowing this difference often greatly eases the
patient with respect to the label of cancer drugs and the
expected side effects of chemotherapy. This discussion
includes the necessity for more frequent clinical visits for
examination as to efficacy of medication and to monitor reg-
ular blood work for signs of toxicity to medication. Visits are
usually scheduled every 6 to 8 weeks depending on
medication. Full interval history with review of systems is
critical in picking up toxicity. This often mandates a hold or
even complete discontinuation of the offending medication
and the need for re-evaluation of the current treatment
regimen. Blood work typically consists of complete blood
count with differential, as well as renal and liver function
testing, plus any ancillary tests as needed. Ophthalmologists

Table 14 e Nonsteroidal anti-inflammatory drugsdsystemic

Class of drug Generic name (trade name) Dose

Salicylates Aspirin (multiple brands) 650 mg q4 hrs

Diflunisal (Dolobid) 200e500 mg b.i.d.
Fenamates Mefenamat (Ponstel) 250 mg q.i.d.
Meclofenamate (Meclofen) 50e100 mg q.i.d.
Indoles Indomethacin (Indocin) 25e50 mg t.i.d.eq.i.d., 75 mg b.i.d.
Sulindac (Clinoril) 150e200 mg b.i.d.
Tolmetin (Tolectin) 400 mg t.i.d.
Phenyl acetic acid Diclofenac (Voltaren) 50e75 mg b.i.d.
Phenyl alkanoic acids Fenoprofen (Nalfon) 300e600 mg t.i.d.
Ketoprofen (Oridus) 75 mg t.i.d.e50 mg q.i.d.
Piroxicam (Feldene) 10 mg b.i.d., 20 mg q.i.d.
Flurbiprofen (Ansaid) 100 mg t.i.d.
Ketorolac (Toradol) 10 mg q.i.d.
Naproxen (Naprosyn) 250e500 mg b.i.d.
Naproxen (Anaprox) 275e550 mg b.i.d.
Ibuprofen (Motrin, Brufen, Advil, Nuprin) 400e800 mg t.i.d.
Pyrazolons Phenylbutazone (Butazolidin, Azolid) 100 mg t.i.d.eq.i.d.
Oxyphenylbutazone (Tendearil, Osalid) 100 mg t.i.d.eq.i.d.
Para-aminophenols Acetaminophen (multiple) 650 mg q4 hrs
Cox-2 inhibitors Celecoxib (Celebrex) 100e200 mg b.i.d.

b.i.d., twice a day; qhr, every hour; q.i.d., four times a day; t.i.d., three times a day.
12 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
Table 15 e Nonsteroidal anti-inflammatory
drugsdtopical
Drug name formulation (trade name)
Flurbiprofen 0.03% solution (Ocufen)
Diclofenac 0.1% solution (Voltaren)
Ketorolac 0.4% (Acular LS) and 0.5% solution (Acular)
Indomethacin 0.5% and 1% suspension
Bromfenac 0.07% solution (Prolensa)
Bromfenac 0.09% solution (Bromday)
Bromfenac 0.09% solution (Xibrom)
Nepafenac 0.1% suspension (Nevanac)
b.i.d., twice a day; q.d., once a day; qhr, every hour; q.i.d., four times
a day; t.i.d., three times a day.
who are not comfortable or have not been trained in handling
such medications will find benefit in teaming up with a
rheumatologist or hematologist to help administer them.
Much of the information in the following paragraphs is
summarized in Table 8.
4.5. Antimetabolites
Antimetabolites most commonly used to treat noninfectious
uveitis include methotrexate, azathioprine, and mycopheno-
late mofetil. Each works via a mechanism involving inhibition
of proper nucleotide synthesis or processing. Each has its own
dosing patterns, as well as individual risks and potential side
effects. Medication is chosen based on patient or physician
preference, preexisting risk factors (e.g., one would not choose
methotrexate for a patient with chronic hepatitis), and known
track record of medication for specific disease entities being
treated, if known (e.g., methotrexate is often effective in
treatment of sarcoidosis). In addition, these medications can
also be used to supplement therapy in some disease with
infectious origin, but only as adjunct with appropriate anti-
infectious agent (e.g., antiviral with azathioprine for
treatment of stubborn or severe herpes simplex uveitis).
Methotrexate is an inhibitor of dihydrofolic acid reductase
and folic acid metabolism and hence prevents regular syn-
thesis of thymidine, required for DNA synthesis.55 It can be
given orally, via intramuscular injection, by intravenous
infusion, or even intravitreally. Commonly, oral methotrexate
is started at a dose of 7.5e15 mg once weekly, usually up to
20e25 mg oral (or may go to 50 mg weekly intramuscular),
along with supplement of folic acid 1 mg daily except on days
taking methotrexate. Intramuscular delivery shows better
bioavailability at 20 mg and above and is recommended for
higher doses or for those who have significant gastrointestinal
discomfort with oral dosing. Intravenous dosing (100e200 mg
weekly) and intravitreal dosing (400 mg/0.1 mL) are typically
reserved for more severe or refractory disease. Major risks
involve bone marrow suppression, infection, liver toxicity,
pulmonary fibrosis, and phototoxicity. Patients are asked to
abstain from heavy sun exposure, alcohol use, heavy use of
acetaminophen, and eating grapefruit and star fruit due their
effects on cytochrome inhibition in liver.
Azathioprine (AZA) and mycophenolate mofetil are
prodrugs for mercaptopurine and mycophenolic acid,
respectively. Both are inhibitors of purine synthesis, critical to
the maturation of B- and T-lymphocytes. AZA is oral and
started at 75 to 100 mg daily (1 mg/kg/day), up to a dose of
Dose
200e250 mg daily (3 mg/kg/day). Mycophenolate mofetil is
q.i.d. also oral and started at 1e2 g daily in twice daily divided dose,
q.i.d. up to a dose of 3 g total daily; this must be taken on an empty
t.i.d.
stomach with no significant food or drink 2 hours before and
q.i.d.
1 hour after dose. Major risks of each include bone marrow
b.i.d.
q.d. suppression and infection. AZA may also rarely cause
b.i.d. pancreatitis. Thiopurine methyltransferase activity or geno-
t.i.d. type must be determined before AZA use as low levels or poor
metabolizers of AZA may lead to dangerously high serum
levels.
4.6. Calcineurin inhibitors
Calcineurin inhibitors are mainly helpful as adjuncts to other
medications for the treatment of uveitis and are not usually
effective when given alone. They work by interrupting T-cell
activity and growth via inhibition of calcineurin, and thus
down regulation of interleukin-2 transcription. Cyclosporine
is by far the most commonly used in this class, given orally in
doses of 50e200 mg daily in single or split dose. Major risks
involve bone marrow suppression, renal and nephrotoxicity,
hypertension, hyperlipidemia, gingival hyperplasia or hem-
orrhage, hyperkalemia, and hirsutism.
4.7. Biologic response modifiers
When antimetabolite therapy is not effective or well tolerated,
or when disease is more advanced or severe, biologic response
modifiers (BRMs), also known as biologics, are the next
medication in the stepladder approach to medical therapy of
ocular inflammation. These are molecules, typically anti-
bodies, developed to alter certain areas or deactivate specific
cytokines within the immune response. They can be used in
replacement of or in conjunction with both antimetabolites
and calcineurin inhibitors, but multiple BRMs are not recom-
mended to be used at the same time. There are several such
molecules that are indicated for use in various forms of sys-
temic autoimmune disease, with a growing percentage of
these having been tried successfully in the treatment of
various forms of uveitis and other ocular inflammatory
disease.
The BRMs most widely used for treating uveitis are the
TNFa inhibitors, specifically infliximab and adalimumab.
TNFa is a cell-signaling protein important to the immune
response which is elevated and important in systemic in-
flammatory disease. These molecules work to suppress the
immune response by blocking the effects of TNFa, which
include regulation of various immune cells and cytokines, as
well as apoptosis. Infliximab is a chimeric (murine or human)
monoclonal antibody and is given intravenously, whereas
adalimumab is a fully humanized monoclonal antibody and is
given by subcutaneous injection. Both have been widely
shown to be extremely effective in the treatment of many
forms of ocular inflammation. Etanercept is another such
molecule, but although its effect on systemic inflammation
may be beneficial, it has a poor track record in the treatment of
ocular inflammation.
 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
For ocular inflammation, infliximab is preferentially star-
ted at a dose of 5 mg/kg every 4 weeks, with 2 loading doses
given 2 weeks apart. Dose is usually increased to 10 mg/kg if
needed, or higher in some cases, and once the disease is felt to
be in remission, the intervals of administration can be
extended by 1e2 weeks at every fourth dose or when deemed
appropriate. The dose is administered in 1 L normal saline over
2 hours or longer with a structured protocol and preinfusion of
corticosteroid and diphenhydramine as needed. Infliximab is
usually used less frequently when initiated for systemic
disease only, but when ocular inflammation is involved,
almost always requires this more frequent and aggressive
regimen. Adalimumab is usually started at 40 mg given every
2 weeks (consider using 20 mg dose for children or small body
mass), and this can be increased to weekly if needed.
Risks of these medications include activation of latent
infection such as tuberculosis or hepatitis, and routine
screening of these before administration is highly recom-
mended. Additional risks include hepatotoxicity, anaphylaxis,
demyelinating disease, drug-induced autoimmune disease
(i.e., lupus, hepatitis, psoriatic rash), and secondary malig-
nancies. Unlike antimetabolites, the SITE study found that
these medications were associated with slightly increased
overall and cancer mortality when compared to patients who
never took immunosuppressive medications,33,41 but they
remain a successful and widely used group of medications for
treating uveitis.
Other types of BRMs are also being used for treatment of
ocular inflammation, and many of these can be found
in Table 8. Tocilizumab, mainly used to treat rheumatoid
arthritis and juvenile idiopathic arthritis, is a humanized
monoclonal antibody which inhibits IL-6, an extremely
important cytokine involved throughout the systemic immune
response. Tocilizumab, given at a dose of 4e8 mg/kg every
4 weeks and has a similar risk profile to the TNFa inhibitors, is
usually reserved for cases poorly responsive to TNFa inhibition
or those who have suffered severe adverse reactions to these.
Rituximab, a chimeric monoclonal antibody directed
against CD20 protein primarily found on the surface of B
lymphocytes, is another molecule now more widely used in
treating ocular inflammation, including many forms of re-
fractory uveitis. It is commonly used to treat diseases such as
rheumatoid arthritis and various systemic vasculitides
(including antineutrophil cytoplasmic antibodyeassociated
vasculitis), ocular cicatricial pemphigoid, and intraocular
lymphoma and is administered intravenously in various
doses ranging from 2 doses of 1 g given 2 weeks apart every
6 months, to a more aggressive approach using 375 mg/m2
body surface area weekly for 8 weeks, and then monthly for
4 months for 12 total doses over 6 months. It can also be given
via intravitreal injection at a dose of 1 mg/0.1 mL via standard
technique. Risks involve reactivation of latent infection, the
most worrisome being progressive multifocal leukoence-
phalopathy caused by activation of JC virus. Risks also include
hypotension, anaphylaxis, tumor lysis syndrome, and sec-
ondary malignancies.
Additional BRMs have been trialed and many of these are
listed in Table 8. There are limited data on the efficacy of many
of these agents, and some of these are currently undergoing
investigative trials.
13
4.8. Alkylating agents
Occasionally, severe, stubborn, or refractory uveitis will
require use of more potent immunomodulatory medications.
Patients may not tolerate most other medications or have
contraindications to using them. In this case, the use of
alkylating agents may be considered, which include cyclo-
phosphamide and chlorambucil. These work via the alkylation
of nucleotide bases and interference with DNA replication.
The aim of therapy is to keep serum leukocyte counts in the
3000 to 4500 cell/hpf range, and complete blood count with
differential is taken weekly for chlorambucil and at least
biweekly for cyclophosphamide to monitor for dangerous
toxicity and bone marrow suppression.
Both are available orally. Daily dosage of chlorambucil
starts at 0.15 mg/kg/day and cyclophosphamide at 1 mg/kg/
day. Cyclophosphamide may also be administered via pulsed
intravenous therapy at a dose of 1 g/m2 body surface area
every 2 weeks as tolerated. A preinfusion regimen for cyclo-
phosphamide is recommended and may include 50 mg
diphenhydramine, 8 mg ondansetron, and 1 g methylpred-
nisolone given in 1 L normal saline over 1 hour, followed by
administration of medication in 1 L normal saline over 1 hour,
followed by a third administration of 1 L normal saline over 1
hour, 3 hours total infusion. Risks of both include sterility,
infection, severe bone marrow suppression, and secondary
malignancy. Specific risks of cyclophosphamide also include
sterile hemorrhagic cystitis due to accumulation of toxic
acrolein in the bladder, and bladder carcinoma. Patients on
this medication are encouraged to drink 8 or more large cups
of water daily to avoid acrolein build up in their bladder and
induced cystitis. Urinalyses are checked monthly for epithelial
sloughing, evidence of hemorrhage, or casts. If confirmed, any
of these are grounds for immediate urology referral for
cystoscopy.
4.9. Other medications
There are many other classes of medications that have been
or are currently being used in the treatment of uveitis and
ocular inflammation, including intravenous immunoglobulin
and interferon. Please refer to Table 8 for more on these
medications.
4.10. Combination therapy
Combinations of different types of IMT can also be used by
uveitis practitioners to gain inflammatory remission. If 2
different classes are used, inflammation is targeted via 2
different pathways. This affords higher efficacy than mono-
therapy, in some cases, and allows for a lower administered
dose, affording fewer side effects. Common combinations
include antimetabolite agents plus biologic response modi-
fiers, antimetabolites plus calcineurin inhibitors, and others,
including adding intravenous immunoglobulin to any other
well-tolerated therapy. It is usually ill-advised to combine 2
medications from the same class unless the disease is
extremely recalcitrant.
14 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
5. Surgical management
5.1. Diagnostic procedures
An aqueous sample may be obtained for diagnostic purposes.
A tuberculin or 3 mL syringe is attached to a sterile 30-gauge
needle that is then advanced into the anterior chamber
through the temporal limbus or clear cornea parallel to the iris
plane avoiding the iris and lens. 0.1e0.2 cm3 of aqueous is
aspirated. The needle is removed and topical antibiotic
instilled. The aqueous sample may be sent for microbiologic,
histological evaluation, or polymerase chain reaction evalua-
tion. Potential side effects of aqueous paracentesis include
anterior chamber hemorrhage, endophthalmitis, and damage
to the iris or lens.
A 3-port pars plana vitrectomy may be performed for both
diagnostic and therapeutic purposes. Therapeutic vitrectomy,
with or without endolaser, may be beneficial in cases of
recalcitrant visually significant vitritis or CME (or both) that
have not responded to medical therapy or, in some cases, as
primary therapy. In addition, implantation of a sustained
release delivery system (i.e., Retisert) containing a cortico-
steroid or other immunomodulatory agent may require
limited pars plana vitrectomy.53 For diagnostic purposes, both
undiluted (pure) and dilute vitreous samples are required for
testing. About 1 cm3 of undiluted vitreous sample is harvested
(before completion of a subtotal vitrectomy using standard
vitrectomy techniques) and sent for cytopathology, as well as
other studies to rule out infection or malignancy. Cultures can
be performed in suspected bacterial or fungal endoph-
thalmitis and polymerase chain reaction for evidence of viral
or other microorganisms.
When intraocular lymphoma is suspected, cytokine anal-
ysis is requested to assess the ratio of interleukin 6 (IL-6) and
interleukin 10 (IL-10) in vitreous, and polymerase chain reac-
tion is performed for immunoglobulin heavy chain rear-
rangement studies; IL-10 to IL-6 ratio greater than one and
monoclonal immunoglobulin heavy chain pattern are both
suggestive of lymphoma.4 Flow cytometry can also be per-
formed to assess for light chain restriction and monoclonality.
Complications of vitrectomy in uveitic patients can include
retinal detachment, suprachoroidal hemorrhage, vitreous
hemorrhage, development or progression of cataract, wors-
ening inflammation and retinal tears or detachment.
Retinochoroidal biopsy, used when there is progressive or
severe disease despite conventional treatment, especially
when infectious or neoplastic etiology is suspected, is per-
formed when all other less invasive options have been
considered or performed. This procedure carries higher side-
effect profile that includes retinal detachment, cataract, vit-
reous and suprachoroidal hemorrhage, and decreased vision
or loss of vision.
5.2. Secondary glaucoma procedures
Ocular hypertension or glaucoma may occur in conjunction
with uveitis or other ocular inflammatory disease and a
response to corticosteroid therapy. Ocular hypertension refers
to IOP 10 mm Hg or greater above baseline without evidence of
glaucomatous optic nerve damage. Glaucoma is defined as
elevated IOP resulting in progressive neuroretinal rim loss or
development of typical glaucomatous field defects.
When medical management fails, further intervention
with laser or surgery is indicated. Although argon laser tra-
beculoplasty is not advised in uveitic glaucoma patients,
recent data show selective laser trabeculoplasty can be used
safely and effectively. In quiet eyes, selective laser trabecu-
loplasty may not exacerbate inflammation or damage the
structural integrity of the trabecular meshwork. Some
consider selective laser trabeculoplasty is appropriate as for
primary therapy.64
Ideally, and for best results, surgery is performed when
uveitis is in remission, but occasionally urgent glaucoma
procedures are necessary to correct severely elevated IOP or
intractable pain. Aqueous drainage devices (i.e., Ahmed,
Molteno, Baerveldt) are considered the standard for uveitic
glaucoma when surgical intervention is required.44 The uni-
directional valve design of the Ahmed valve results in less
postoperative hypotony. Standard trabeculectomy has a
greater risk of failure in uveitis patients. Results can be
improved using mitomycin C and aggressive topical cortico-
steroids, as postoperative inflammation often leads to filtering
failure in these patients. Alternatives to these procedures
include nonpenetrating deep sclerectomy with or without
drainage implant and the Ex-PRESS glaucoma filtration device,
or minishunt. The most critical element for success is
remission of uveitis and prevention of postoperative inflam-
mation via IMT.
Cyclodestructive procedures have typically been avoided
in uveitic eyes, as they have the potential to worsen ocular
inflammation and lead to hypotony and phthisis bulbi. Diode
endoscopic cyclophotocoagulation, a cyclodestructive
procedure, maximizes the advantage of ablating the ciliary
body epithelium to decrease IOP. Endoscopic cyclo-
photocoagulation uses a laser endoscope containing 3 fiber
groupings: an image guide, a light source, and the semi-
conductor diode laser. This technology allows direct visuali-
zation of the ciliary epithelium, allowing the laser energy to be
precisely delivered to the ciliary processes, thus limiting
damage to the underlying ciliary body and surrounding tissue.
In our experience, endoscopic cyclophotocoagulation has at
times been an effective tool for the treatment of refractory
glaucoma but should be reserved for eyes in remission.
5.3. Cataract extraction, with or without intraocular
lens placement
Cataract surgery may be more challenging in uveitic eyes than
in noninflamed eyes, and intraocular inflammation should be
well controlled before surgery. It is imperative to eliminate
anterior chamber cells and to have the eye quiet for at least
3 months without the need for concurrent corticosteroid
therapy. When cataract surgery is performed in an eye with a
large amount of inflammatory scar tissue (i.e., posterior syn-
echiae, pupillary membrane), or deemed necessary despite
active inflammation, high dose oral corticosteroids
(0.5e1.0 mg/kg/day), and frequent topical corticosteroids may
be started 1 day before surgery and continued with taper 1
month postoperative, depending on response. If this is
 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 1 e1 7
intolerable, intravitreal or transseptal corticosteroid or topical
NSAID therapy is indicated. Phacoemulsification using a clear
corneal approach is preferred.8 Continuous curvilinear cap-
sulorrhexis reduces posterior synechiae formation and facil-
itates placement of the intraocular lens in the capsular bag. A
hydrophobic acrylic posterior chamber intraocular lens is
preferred over silicone, polymethyl methacrylate, or heparin-
surface-modified polymethyl acrylate models.1
5.4. Sectoral or pan-retinal photocoagulation
Retinal neovascularization may develop in any chronic pos-
terior uveitic condition, but is more common in pars planitis,
sarcoid panuveitis, and retinal vasculitis of various etiologies.
Retinal neovascularization may be due to chronic inflamma-
tion or capillary nonperfusion. Treatment is directed toward
the underlying etiology. Scatter laser photocoagulation to
nonperfused retina and associated watershed areas can be
performed in cases of ischemic retinal neovascularization
while that from chronic inflammation may resolve with anti-
inflammatory therapy alone. Both conventional and wide-
field fluorescein angiography are essential in distinguishing
the 2, thus avoiding the potentially destructive effects of un-
necessary photocoagulation.
5.5. Intravitreal therapy
Vascular endothelial growth factor inhibitor, such as bev-
acizumab (Avastin), can be used off-label via intravitreal
injection, in the office or concurrent with major pro-
cedures, for the treatment of sequelae of uveitis, including
macular edema, neovascularization of the iris, and retinal
and choroidal neovascularization.6,43 In addition, various
forms of IMT can also be administered via intravitreal in-
jection to treat recalcitrant inflammation and intraocular
lymphoma, including methotrexate and rituximab. Other
medications being investigated for treating ocular inflam-
mation include sirolimus and the antieC5 monoclonal
antibody LFG316.
6. Emerging therapies
Transscleral iontophoresis is an active method of drug de-
livery that uses a small electrical current to enhance diffusion
of drug molecules across an intact sclera. As a noninvasive
and well-tolerated method, iontophoresis has the potential to
replace systemic administration and repeated intravitreal
injections for posterior segment diseases. Eyegate (Optis
Group, Paris, France) and OcuPhor (IOMED, Salt Lake City,
USA) are the main ophthalmic iontophoresis systems under
investigation.
The Cortiject implant (NOVA63035, Novagali Pharma) is a
preservative- and solvent-free injectable emulsion based on
the EYEJECT technology platform that contains a tissue-
activated corticosteroid prodrug. The prodrug is converted
into the active agent by enzymes present in the target tissues,
that is, retina and choroid. These enzymes are not present in
the vitreous or aqueous humor. The specific distribution of
15
enzymes may avoid common corticosteroid-related side ef-
fects such as glaucoma and cataract.
7. Conclusion
The continuing advances in understanding the mechanism of
action of drugs, the underlying pathogenesis of uveitic
entities, and the uveitic cascade are the keys to better un-
derstanding this devastating eye disease with vision threat-
ening potential. The approach of delivering targeted therapy
to intervene at these crucial points to achieve corticosteroid-
free durable remission, providing individualized care to our
patients, and thus enhancing their quality of life is our goal.
The use of the stepladder approach has now provided us
and our patients multiple options to treat their disease and
improve their quality of life and vision. In the current era,
uveitis specialists have determined that disease quiescence
with a goal of remission is best accomplished with a thera-
peutic strategy combining corticosteroids with the early
introduction of corticosteroid-sparing IMT if the disease is
recurrent or chronic. Future developments could include
devices containing complementary drugs, responsive sus-
tained release delivery systems, and the use of nanotech-
nology or systemic immune retraining.
8. Addendum
Drug tables.2,3,5,11e13,16,18,22,26,27,29,33e38,41,42,46,50,51,55,56,60e62,66
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