Best Practice & Research Clinical Rheumatology: Sergio Schwartzman

Best Practice & Research Clinical Rheumatology xxx (2016) 1e12
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Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh
Advancements in the management of uveitis

Sergio Schwartzman
Weill Medical College of Cornell University Hospital for Special Surgery, New York Presbyterian Hospital, USA
a b s t r a c t
Keywords:
Autoimmune ophthalmic disease Uveitis may exist as a clinical manifestation of an underlying
Uveitis systemic disease or may represent an idiopathic entity, sometimes
Biologic therapy with a very characteristic pattern. Different forms of uveitis have
Ocular complications been defined on the basis of three important variables: chronicity,
anatomic location, and underlying etiology. The evolving under-
standing of the immune system has resulted in a more targeted
approach to manage patients with different forms of uveitis,
although clearly this approach is at a very early stage.
Altered patterns of cellular processing and different cytokine
expression, including TNF, IL-1, IL-2, IL-6, and IL17, have been
defined in uveitis, and this has laid the pathway for targeted
therapy. Furthermore, approved biologic therapies for some of
the more common autoimmune illnesses have now been tested
in uveitis. Adalimumab and infliximab have been the best studied
anti-TNF agents and indeed have now been recommended by an
expert panel as the first line of treatment for ocular manifesta-
tions of Behçet's disease and the second line of treatment for
other forms of uveitis. Adalimumab has been recently approved
for intermediate uveitis, posterior uveitis, and panuveitis. Other
biologic agents have been tested, including daclizumab, a
monoclonal antibody directed against IL-2, anti-IL1, and anti-IL-6
receptor agents and therapies that block antigen-presenting cell
and T-cell interaction, such as abatacept. In small case series,
other biologics such as interferon and rituximab have also been
evaluated.
Although these biologic therapies have provided a larger arma-
mentarium to treat uveitis, challenges remain. Uveitis is not a
disease, but a manifestation of many potential systemic diseases
that may have specific individual therapeutic targets. Identification
and characterization of these underlying diseases are not always
possible and, more importantly, the most effective therapies for
E-mail address: SchwartzmanS@HSS.edu.
http://dx.doi.org/10.1016/j.berh.2016.07.005
1521-6942/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best
Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005
2 S. Schwartzman / Best Practice & Research Clinical Rheumatology xxx (2016) 1e12
each entity have not been defined. In this study, an approach to

manage patients with uveitis is presented and current therapy is
reviewed.
© 2016 Published by Elsevier Ltd.
Introduction
Different forms of uveitis have been defined on the basis of three variables: chronicity, anatomic
location, and underlying etiology. Uveitis can exist as a primary, idiopathic ophthalmic entity or as a co-
manifestation of an established underlying disease. Further, uveitis may be the presenting manifes-
tation of a systemic illness that evolves over time. In approximately 50% of patients presenting with
uveitis, a recognized illness will be identified, although this is to some extent determined by the
healthcare professional or center where the patient is evaluated. There is a paucity of data defining the
incidence and prevalence of uveitis and, more importantly, the prognostic implications of this group of
diseases. In a northern California cross-sectional managed care study using a retrospective database
and medical record review of 731,895 participants, a uveitis incidence of 52.4/100,000 person-years
and a prevalence of 115.3/100,000 persons was noted [1]. Before the emergence of the concept of
aggressive immunosuppression for autoimmune diseases and use of biologic therapies, it was esti-
mated that in the United States, uveitis was responsible for an estimated 30,000 cases of blindness
annually [2]. In a more recent retrospective cohort study of uveitis patients managed at a tertiary care
center, outcome evaluated was best-corrected visual acuity at initial referral and after 1 year. In 133
patients, at 1-year follow-up, bilateral visual impairment was observed in only 4%, but at least one
ocular complication developed in 66% of patients. In 30% of patients, intraocular surgery was required
and 8% of patients required hospitalization [3]. Over the last two decades, the rates of ocular and
systemic morbidity have decreased.
Ideally, therapy for an identified systemic disease should be successful in controlling uveitis;
however, this is not always the case. The therapeutic approach to uveitis requires careful consideration
of etiology, anatomic site involved, chronicity, prior treatment failure, and potential ophthalmic and
systemic risks of proposed therapy. Patients with uveitis need to be carefully evaluated by both an
ophthalmologist and a physician trained in internal medicine (preferably a rheumatologist or immu-
nologist) to establish a diagnosis and assure that an infectious, primary neurologic, or malignant
process is not present, as therapy in these circumstances is very different from that for other forms of
autoimmune uveitis. In this study, we focus on the current use of different therapeutic modalities in
patients with uveitis.
Nonbiologic therapeutic approach to uveitis
The most frequent type of uveitis is acute and anterior uveitis, and the conditions responsible for
this type of uveitis generally respond well to topical corticosteroids and cycloplegic and/or mydriatic
agents. Patients with chronic disease, intermediate uveitis, posterior uveitis, or panuveitis, who have
the highest morbidity require aggressive therapy. High-dose systemic steroids are generally the first
therapeutic intervention. The recommended initial therapy is usually prednisone at doses of 40e80 mg
per day. In severe cases, parenteral steroids are used, and there are data for “pulse dose” steroids in
uveitis.
As was the case in rheumatology several decades ago, there is currently an ophthalmology-led
emphasis being placed on using second-line agents earlier in patients with poor prognosis. Metho-
trexate and mycophenolate are frequently the first agents used, although cyclosporine, tacrolimus, and
azathioprine are used as well.
Methotrexate has been used to treat noninfectious uveitis as an oral agent, parenterally and as an
intra-ocular injection. It is a folate antagonist that inhibits dihydrofolate reductase. This enzyme is
critical in the synthesis of nucleic acid, and therefore methotrexate inhibits rapid cell growth and
S. Schwartzman / Best Practice & Research Clinical Rheumatology xxx (2016) 1e12 3
proliferation [4]. Although studies on both high- and low-dose methotrexate in uveitis have been
published [5,6], generally doses between 15 and 25 mg per week orally or parenterally are effective.
There are no prospective, randomized, masked studies evaluating the efficacy of this agent, although it
is very frequently used. The data supporting its use are predominantly case series and reviews [7,8]. In
one large retrospective noncomparative interventional case series of 160 patients with different types
of uveitis, inflammation control was achieved in 76.2% of patients, steroid-sparing effect was achieved
in 56%, and visual acuity was maintained or improved in 90% of patients [6].
Mycophenolate mofetil is a prodrug of mycophenolic acid, which is an inhibitor of inosine-50 -
monophosphate dehydrogenase. This therapy depletes guanosine nucleotides preferentially in T and B
lymphocytes and inhibits proliferation, thereby suppressing cell-mediated immune responses and
antibody formation [9]. Mycophenolate dosing generally requires 2e3 g/day in divided doses [10,11]. In
a retrospective case series that evaluated 84 consecutive patients with inflammatory eye disease who
were treated with mycophenolate, of which 61% had uveitis, the median dose of prednisone at the start
of mycophenolate mofetil therapy was 40 mg per day. The majority of the patients (82%) were
considered treatment success cases, as judged by the ability to control inflammation and taper
prednisone to 10 mg daily [12].
Cyclosporine is a specific T-cell inhibitor that forms a complex with cyclophilin, which then inhibits
the phosphatase activity of calcineurin. This effect regulates nuclear translocation and subsequent
activation of transcription factors [13]. Dosing range in autoimmune ophthalmic diseases is generally
between 2.5 and 5 mg/kg, and it is administered twice daily, although in some studies, lower doses
have been used. Cyclosporine has been studied in a number of uncontrolled trials in various forms of
uveitis [14e16]. In a larger randomized and controlled study of 96 patients, it succeeded in decreasing
the frequency and severity of disease flares [17]. This medication has been used broadly across different
autoimmune ophthalmic disease and it does appear to be fairly effective.
Tacrolimus, a macrolide antibiotic, although structurally unrelated to cyclosporine A, has a similar
mode of action. It binds to immunophilin, an FK506 binding protein, which then inhibits calcineurin
phosphatase [18]. Its dose range is 0.03e0.08 mg/kg/day. In a randomized trial of patients with various
etiologies of posterior uveitis comparing cyclosporine to tacrolimus, both groups responded equally. A
total of 13 patients (68%) taking tacrolimus and 12 patients (67%) taking cyclosporine responded to
treatment [19]. Some long-term studies following patients treated with tacrolimus have been suc-
cessful [20].
Azathioprine is an imidazolyl derivative and a prodrug for mercaptopurine, which is incorporated
into replicating DNA, blocking the pathway of purine synthesis and therefore impeding T and B cell
replication [21]. In a study of 21 patients with corticosteroid-resistant noninfectious uveitis, who were
treated with azathioprine (2.5 mg/kg/day), visual acuity evaluated resulted in complete success
observed in 62.5%, partial response in 20.9%, and failure in 16.6% of patients. Inflammation as an
outcome measure after azathioprine treatment resulted in complete success in 70.8%, partial response
in 29.1%, and failure in 16.6%. Complete response of steroid sparing was observed in 85.7% of patients
and complete success of the three listed criteria was observed in 57.1% of patients [22].
Other nonbiologic therapies for uveitis include the use of chlorambucil and cyclophosphamide.
These medications are now very infrequently used because of their potential toxicity and the avail-
ability of more targeted therapy with biologic agents. Both are alkylating agents and function by
interfering with DNA replication and damaging DNA, which results in cell cycle arrest and cellular
apoptosis with an immunosuppressant effect on the function of both T cells and B cells [23].
In a retrospective case series of 28 patients who were refractory to other immunomodulatory
therapy and systemic steroids, 68% showed response to chlorambucil. The median duration of treat-
ment was 12 months and the median daily dose was 8 mg. The medication was discontinued in 25% of
patients because of side effects [24]. Cyclophosphamide can be administered either orally or by
intravenous infusion. Most studies published actually combine numerous autoimmune ophthalmic
illnesses, as this agent is infrequently used. In a retrospective cohort study of 215 patients with
noninfectious ocular inflammation, where only 20.4% had uveitis, 49.2% gained sustained control of
inflammation within 6 months and 76% within 12 months. Corticosteroid-sparing success was ach-
ieved in 30.0% at 6 months and 61.2% at 12 months. Cyclophosphamide was discontinued by 33.5% of
patients within 1 year because of side effects [25].
Comparator trials have recently been initiated, but as these require large numbers of patients with
the same types of uveitis, they are difficult to perform and interpret. In a multicenter, randomized,
observer-masked clinical trial, patients with noninfectious posterior uveitis, intermediate uveitis, or
panuveitis were randomized to receive 25 mg weekly oral methotrexate or 1000 mg twice daily oral
mycophenolate mofetil. There were 35 methotrexate- and 32 mycophenolate mofetil-treated patients.
A proportion of 69% of patients achieved treatment success with methotrexate and 47% with myco-
phenolate mofetil (p ¼ 0.09). There was no statistically significant difference in corticosteroid-sparing
capacity [26]. At present, a larger comparative effectiveness study entitled First-line Antimetabolites as
Steroid-sparing Treatment (FAST trial) (clinicaltrials.gov) is ongoing.
Biologic therapeutic approach to uveitis
Biologic agents are defined by the FDA as: “Virus, therapeutic serum, toxin, antitoxin, vaccine, blood,
blood component or derivative, allergenic product, protein (except any chemically synthesized poly-
peptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent
organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of
human beings” (FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:
Guidance for Industry, April 2015). From a practical perspective, these include agents such as anti-
bodies, bioengineered receptor complexes, Fab fragments, and agents such as interferons that affect the
expression of pro- and anti-inflammatory components of the immune system.
Biologic therapy for autoimmune rheumatic disease was first approved in 1998. For uveitis, the
published literature, with exceptions, has suffered from differences in study designs, incorrect power
calculations, differences in inclusion criteria, and a lack of consensus regarding outcome measures.
However, published literature exists for many different classes of biologic agents including anti-TNF,
anti-IL1, anti-IL6 receptor, anti-IL17, anti-IL2 receptor, co-stimulatory blockade, interferon, and CD-
20 B cell-directed therapy. Adalimumab is now approved for the management of non-infectious, in-
termediate, posterior and panuveitis.
Anti-TNF agents
The anti-TNF agents have been predominantly studied in a retrospective manner, although some
prospective studies have now been successfully completed. Recently, three studies have been con-
ducted with adalimumab, with subsequent FDA and EMA approval, for the management of nonin-
fectious intermediate uveitis, posterior uveitis, and panuveitis.
There are more publications on the use of anti-TNF therapy for the treatment of uveitis than any
other group of biologic therapies, and the majority of them focus on the use of infliximab. This may
reflect the fact that this therapy was approved in 1998. Currently, there are over 65 published articles
on the use of this medication in uveitis. Infliximab, a chimeric mouse/human monoclonal antibody, is
unique in the anti-TNF group of therapies in that it is approved for the treatment of many rheumatic
illnesses in a wide range of doses, thus providing dosing flexibility that can range from 3 mg/kg every 8
weeks to 10 mg/kg every 4 weeks. It is not formally approved for the management of uveitis, although
it is frequently used for this group of illnesses. Given the potential impediment of the blood ocular
barrier and the frequent need for high-dose medications to treat ophthalmic inflammatory disease, this
may be an important advantage.
Infliximab has been used to treat various forms of uveitis in many systemic illnesses, where uveitis
is a common manifestation, and in patients with idiopathic forms of uveitis. It has been used in juvenile
idiopathic arthritis (JIA) [27e34], spondyloarthritis [35e37], Crohn's disease [38,39], sarcoidosis
[32,40], and Behcet's disease. In Japan, infliximab is approved for the treatment of Behcet's disease-
associated uveoretinitis. Prospective data from eight tertiary uveitis centers were analyzed in 50 pa-
tients. At 1 year, uveoretinitis had improved in 69%, improved somewhat in 23%, was unchanged in 8%,
and had worsened in none [41]. One of the few prospective studies enrolled 23 patients with various
underlying etiologies of resistant uveitis. At 10 weeks, 78% of patients met criteria for clinical success as
judged by a composite clinical end point of visual acuity, control of intraocular inflammation, ability to
taper concomitant therapy, and improvement of fluorescein angiography and/or ocular coherence
tomography. Serious adverse events experienced by the cohort included pulmonary embolus,
congestive heart failure, lupus-like reaction in two patients, and vitreous hemorrhage in two patients.
Although infliximab was effective, the number of potential toxicities differed from other studies
published across all indications for this medication. In a 2-year followeup, a 60% retention rate was
noted [42]. In a large observational retrospective study of 88 patients from a single center with
recalcitrant uveitis treated with infliximab, 81.8% of the patients achieved clinical remission and only
58.3% required additional immunomodulatory medications. In this study, 36.4% of the patients expe-
rienced at least one side effect, but only 19.3% discontinued treatment. The most commonly reported
adverse effects were skin rash (9.1%) and fatigue (8%). Interestingly, in contrast to the Suhler study [43],
in this large study, potential serious adverse events included only one case of autoimmune hepatitis,
two chronic infections, and one case of drug-induced lupus [44].
In patients with JIA, infliximab has been frequently used to treat uveitis [27e34]. In an interesting
retrospective study focusing on the importance of aggressive therapy to control recalcitrant uveitis in
children, 17 children with chronic uveitis were administered high-dose infliximab (10e20 mg/kg/
dose). All 17 patients showed a dramatic, rapid response, with no observed inflammation in 13 patients
after the second infusion [27].
Adalimumab, a human monoclonal antibody against TNF approved for the therapy of many auto-
immune diseases, has also been used to treat recalcitrant uveitis [32,34,45e73] and has been recently
approved for the management of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.
In a prospective, multicenter, open-label trial to assess the effectiveness and safety of adalimumab in
treating refractory uveitis patients with multiple underlying systemic conditions, 68% of patients were
responders at 10 weeks and 39% showed durable response at 50 weeks. No patient experienced
treatment-limiting toxicity related to the study therapy [49]. Two studies, VISUAL I and VISUAL II, were
responsible for the approval of adalimumab for the treatment of uveitis. In the first study, VISUAL I, 233
adults with noninfectious intermediate uveitis, posterior uveitis, or panuveitis with active uveitis
despite 2 weeks of prednisone were randomized to receive placebo or adalimumab subcutaneously
80 mg at week 0, followed by 40 mg every other week. All patients received a prednisone burst fol-
lowed by taper to 0 mg by week 15. The primary end point was the time to treatment failure. Risk of
treatment failure was reduced by 44% in the adalimumab arm. Median time to treatment failure was 3
months for placebo and 4.8 months for adalimumab. In VISUAL II, 258 patients with inactive disease
dependent on 10e35 mg/day of prednisone to maintain inactivity were randomized and treated
similarly. Median time to treatment failure was 5.6 months for placebo but not estimable for adali-
mumab, as more than half of the patients did not show treatment failure by week 80 (reference [114]).
In an interesting study, comparing infliximab to adalimumab in anterior uveitis, a higher benefit for
adalimumab was demonstrated. A total of 48 patients were treated with infliximab and 43 with
adalimumab. Fifty-three percent achieved remission, 32.9% had recurrent anterior uveitis, and 11.8%
did not respond. A higher remission rate was observed with adalimumab 67.4% versus 42.8% with
infliximab (p ¼ 0.025). Caution needs to be exercised in interpretation of this study, given the trial
design and the fact that these were patients with only anterior uveitis [34].
Golimumab, a fully human anti-TNF monoclonal antibody, which is available as a subcutaneous and
intravenous preparation approved for the treatment of a number of autoimmune diseases, has been
used to treat uveitis. In a series of patients with JIA and HLA B-27 associated uveitis (13 patients with
JIA, 4 with HLA-B27) who showed a failed response to other biologics, 70.5% response was achieved
[74]. Studies on this agent are ongoing [75].
Etanercept is a fusion protein containing IgG1 Fc and TNF receptor 2. Although etanercept was first
thought to play a potential role in treating resistant uveitis [35,76e78], further studies have shown no
benefit from this therapy [79,80]. A controversial area that requires clarification and further study is the
potential paradoxical role of anti-TNF agents as a cause of uveitis. A pivotal study published in 2010
clarifies this topic by demonstrating that while the incidence of uveitis is higher in patients treated
with etanercept than infliximab and adalimumab, the overall incidence of new-onset uveitis with all
three agents is very low. Cases of uveitis in patients treated with anti-TNF agents reported to the World
Health Organization adverse drug events database or the National Registry of Drug-Induced Ocular
Side Effects (Casey Eye Institute) from 1 January 1998 to 1 January 2006 were reviewed. There were 43
cases of uveitis associated with etanercept, 14 associated with infliximab, and 2 associated with
adalimumab. After normalizing for the estimated number of patients treated with each medication,
etanercept was associated with a higher number of uveitis cases than those of infliximab (p < 0.001)
and adalimumab (p < 0.01), while no such association was found between adalimumab and infliximab
(p > 0.5). The authors conclude that if there was an association between etanercept and uveitis, the
incidence of uveitis should have been much higher [81].
A difficult question that remains is whether to use etanercept in patients with underlying diseases
that in and of themselves have a risk for the development of uveitis. Previous studies showed that in
ankylosing spondylitis trials in which etanercept was used, there was no higher incidence of uveitis
[82]; yet, it is well accepted that uveitis can occur in 20e40% of patients with any of the HLA B-27-
associated inflammatory conditions [83].
In a published paper, an expert panel has made recommendations for the use of anti-TNF agents in
ocular inflammatory diseases [84]. A subcommittee of the Executive Committee of the American
Uveitis Society, using PubMed, reviewed all published clinical studies on the use of anti-TNF agents to
treat ocular inflammatory disorders. A total of 400 articles were identified, and using the validated
Grading of Recommendations Assessment Development and Evaluation methodology [85], recom-
mendations were made. Although five anti-TNF agents have been approved for the treatment of various
autoimmune diseases, the Executive Committee chose to evaluate only the data for etanercept,
infliximab, and adalimumab. Of note, for one of the excluded medications, golimumab, which was
approved in 2009 for RA, published literature is available on its use in uveitis [74,75,86e89].
The committee reviewed the structure, pharmacokinetics, indications, and safety of these agents
besides addressing their use in autoimmune ophthalmic diseases. For the ocular manifestations of
Behcet's disease, based on SIGN level IIeIII data, there was a strong recommendation and high-quality
evidence for the use of infliximab and moderate quality evidence for the use of adalimumab to treat
the ocular manifestations of this disease as first- or second-line corticosteroid-sparing agents. There was
insufficient quality evidence for the use of etanercept and hence discretionary recommendations for its
use in Behcet's disease-associated uveitis. For the ophthalmic manifestations of JIA, based on SIGN level
IIeIII data and high-quality evidence, there was strong recommendation to use infliximab or adalimumab
as second-line agents after MTX to treat patients with JIA-associated uveitis. There was a strong
recommendation based on the high-quality evidence that etanercept should not be used in this condition.
Recommendations for the ocular diseases in spondyloarthritis are more complicated as these dis-
eases, although sharing a common genetic link, present with different phenotypes. Similarly, the ocular
inflammatory manifestations of these illnesses vary across the specific entities. Nonetheless, on the
basis of SIGN level IeIII data, there were strong recommendations for the use of infliximab or adali-
mumab as corticosteroid-sparing agents for chronic uveitis and discretionary recommendations for the
use of either one of these two agents as adjunctive therapy for sight-threatening uveitis. The recom-
mendations for the treatment of autoimmune ophthalmic disease associated with sarcoidosis were
based on SIGN level IeIII data. Discretionary recommendations were made for the use of infliximab or
adalimumab and against the use of etanercept. Data for other less common forms of uveitis were
addressed, including birdshot chorioretinitis, different forms of choroiditis, and panuveitis. In sum-
mary, across all indications, there seems to be concrete evidence and therefore recommendations
supporting the potential use of infliximab or adalimumab to treat uveitis.
Interleukin blockers
Daclizumab, a monoclonal antibody directed against the 55k subunit of the IL-2 receptor, has been
used to treat uveitis. Initial reports on the use of this agent in patients with uveitis were published in
1999 [90] with subsequent supporting efficacy data [91]. It has now been studied as both an intra-
venous and subcutaneous mode of administration [92,93].
In a study on the use of daclizumab that included 39 patients with a follow-up of 40 months, 29
patients underwent intravenous administration with the standard regimen, 5 patients received a high-
dose intravenous regimen, and 5 patients received subcutaneous administration. Visual acuity
improved by two lines or more in 7 patients and worsened by two lines or more in 6 patients. There
was no statistically significant association between baseline anterior chamber cells, vitreous haze, and
vitreous cells. During the treatment period, the mean number of immunosuppressant medications
decreased from 1.89 per patient at baseline to 1.17 medications at the end of the follow-up. The mean
number of flares was of 2.05 per patient with a rate of 0.62 per patient-year [94].
Therapy targeting IL-17A has thus far not been successful. Secukinumab, a fully human monoclonal
antibody that targets interleukin-17A and is approved for psoriasis, psoriatic arthritis, and ankylosing
spondylitis, has been studied in uveitis. This medication was studied in three independent studies to
evaluate efficacy and safety. A total of 118 patients with Behcet's uveitis (SHIELD study); 31 nonin-
fectious, active non-Behcet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious,
non-Behcet's uveitis (ENDURE study) have been studied. Reductions of uveitis recurrence or vitreous
haze score during withdrawal of concomitant immunosuppressive medication were the main out-
comes studied. The primary efficacy endpoints of the three studies were not met [95].
Interleukin-1 is found in the vitreous fluid of patients with active uveitis [96]. Anakinra, an anti-IL-1
receptor antagonist, has been studied in a small number of patients with uveitis [97,98]. Gevokizumab,
a monoclonal antibody that binds to interleukin-1 beta, had been granted Orphan Drug Designation for
the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis, or chronic
noninfectious anterior uveitis on the basis of a small exploratory study. Seven patients with acute
posterior or panuveitis, and/or retinal vasculitis, resistant to azathioprine and/or cyclosporine were
enrolled. Immunosuppressive agents were discontinued at the baseline and patients received a single
infusion of gevokizumab. All patients responded and no serious adverse events were reported [99].
Larger phase III multicenter studies that were subsequently conducted were not supportive of pursuing
an indication for this condition, and Xoma Corporation may halt efforts to seek approval in uveitis.
IL-6 has also been identified as one of the cytokines overexpressed in the vitreous fluid of patients
with uveitis [100]. Tocilizumab, a monoclonal IL-6 receptor antibody with approved indications in RA,
polyarticular JIA, and systemic onset JIA, has been reported as an effective therapy to treat uveitis in a
small number of patients. Patients with uveitis and various underlying illnesses who previously failed
second-line agents, anti-TNF therapies, and abatacept have been successfully treated with tocilizumab
[101,102]. In a series of patients with JIA, Adan reported on five patients with uveitis refractory to
conventional therapy, including at least one biologic agent [103]. The patients received tocilizumab
(8 mg/kg) every 4 weeks. At the mean follow-up of 8.4 months, 50% of the affected eyes studied showed
improvement in visual acuity and 25% remained stable. All patients sustained uveitis remission at 6
months [104]. A current multicenter, randomized study of tocilizumab in intermediate uveitis, pos-
terior uveitis, and panuveitis is currently underway. Sarilumab, a second anti-IL-6 receptor monoclonal
antibody that is not yet approved, has completed phase II studies for the treatment of posterior
segment noninfectious uveitis.
IFN-a has been studied in uveitis, and there are a number of small studies demonstrating efficacy,
particularly in multiple sclerosis-associated uveitis. In a retrospective study of Behcet's uveitis unre-
sponsive to conventional immunosuppressive therapy, among 44 patients who had been treated with
IFN-a, 36.4% remained relapse free during treatment, whereas 63.6% had recurrent attacks. There was a
significant improvement in visual acuity, and this was preserved throughout follow-up in 38 (95%) of
40 patients [105].
In a small prospective study of 12 patients with sight-threatening uveitis that failed to respond to
one or more immunosuppressive therapies, IFN-alpha-2b was administered subcutaneously daily.
After a mean observational period of 11 months, a favorable clinical response was observed in 83% of
patients [106].
Other targets
In a small case series, other biologic agents have been used as therapy for uveitis. Abatacept, an
agent that blocks the CD 28 co-stimulatory signaling that normally leads to T cell activation, has been
used to treat autoimmune uveitis. This agent is currently approved for the treatment of rheumatoid
arthritis as both an intravenous and subcutaneous medication. In a series of seven patients with JIA and
uveitis, abatacept was found to be efficacious in maintaining clinical remission in six of the seven
patients for a period of 9.2 months [107]. The patients were found to have decreased uveitis flares after
6 months of therapy. There have been other smaller series of reports using abatacept to treat uveitis,
and interestingly, this medication has been effective in a few patients who did not respond or were
intolerant to anti-TNF agents [108e110].
Although the role of B cells is unknown in uveitis, in a pathologic study of an enucleated eye of a
patient with JIA-associated uveitis, focal aggregates of CD20-positive cells with CD3 and CD8 positive
cells were noted [111]. Therefore, there may be rationale for using anti-B cell therapy in the man-
agement of uveitis. In one study of eight patients with JIA-associated uveitis, seven were responders
[112]. In another study, 10 patients with JIA and severe uveitis with sight-threatening complications
resistant to traditional therapy, including anti-TNF agents, responded after one cycle of rituximab [113].
Conclusion
Over the last two decades, an evolving understanding of immunology has led to the development of
therapies for autoimmune disease that specifically targets unique cytokines, receptors, and cell surface
molecules. The strategy of treating uveitis has also morphed into an approach where early and aggressive
intervention is viewed as the therapeutic goal. A recent expert panel has recommended the use of two anti-
TNF agents, infliximab and adalimumab, as first-line therapy for the treatment of ocular manifestations of
Behcet's disease [84]. Adalimumab is now approved to treat some form of uveitis. Other identified targeted
therapies including anti-IL1, anti-IL6 receptor, anti-IL17, anti-IL2 receptor, co-stimulatory blockade,
interferon, and anti CD-20 B cell are increasingly being evaluated in patients with autoimmune ophthalmic
diseases. However, the challenges remain. Clinical trials in uveitis are difficult to perform given the rarity
and heterogeneity of this group of illnesses and defining appropriate outcome measures. Uveitis is not a
disease, but a phenotypic expression of an abnormality in the immune system. The exact genetic, cellular,
and cytokine etiology of specific forms of uveitis need to be better defined, and once this is accomplished,
appropriate targets in individual patients with uveitis will be identified.
Conflict of interest statement
Potential conflict of interest: Abbvie, Genentech, Janssen, Novartis, UCB, Regeneron, Pfizer.
References
[1] Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California epidemiology of
uveitis study. Ophthalmology 2004 Mar;111(3):491e500. discussion PubMed PMID: 15019324.
*[2] Nussenblatt RB. The natural history of uveitis. Int Ophthalmol 1990 Oct;14(5e6):303e8. PubMed PMID: 2249907.
*[3] Groen F, Ramdas W, de Hoog J, et al. Visual outcomes and ocular morbidity of patients with uveitis referred to a
tertiary center during first year of follow-up. Eye 2016 Mar;30(3):473e80. PubMed PMID: 26742865. Pubmed Central
PMCID: 4791707.
[4] Cutolo M, Sulli A, Pizzorni C, et al. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann
Rheum Dis 2001 Aug;60(8):729e35. PubMed PMID: 11454634. Pubmed Central PMCID: 1753808.
[5] Durrani K, Zakka FR, Ahmed M, et al. Systemic therapy with conventional and novel immunomodulatory agents for
ocular inflammatory disease. Surv Ophthalmol 2011 Nov-Dec;56(6):474e510. PubMed PMID: 22117884.
*[6] Samson CM, Waheed N, Baltatzis S, et al. Methotrexate therapy for chronic noninfectious uveitis: analysis of a case
series of 160 patients. Ophthalmology 2001 Jun;108(6):1134e9. PubMed PMID: 11382642.
[7] Ali A, Rosenbaum JT. Use of methotrexate in patients with uveitis. Clin Exp Rheumatol 2010 Sep-Oct;28(5 Suppl. 61):
S145e50. PubMed PMID: 21044449.
[8] Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrexate for ocular inflammatory diseases. Ophthalmology 2009
Nov;116(11):2188e2198 e1. PubMed PMID: 19748676. Pubmed Central PMCID: 3785935.
[9] Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005;14(Suppl. 1):s2e8. PubMed PMID: 15803924.
[10] Deuter CM, Doycheva D, Stuebiger N, et al. Mycophenolate sodium for immunosuppressive treatment in uveitis. Ocul
Immunol Inflamm 2009 Nov-Dec;17(6):415e9. PubMed PMID: 20001262.
[11] Klisovic DD. Mycophenolate mofetil use in the treatment of noninfectious uveitis. Dev Ophthalmol 2012;51:57e62.
PubMed PMID: 22517204.
*[12] Thorne JE, Jabs DA, Qazi FA, et al. Mycophenolate mofetil therapy for inflammatory eye disease. Ophthalmology 2005
Aug;112(8):1472e7. PubMed PMID: 16061096.
[13] Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology 2000 May;47(2e3):119e25.
[14] Nussenblatt RB, Palestine AG, Chan CC. Cyclosporin A therapy in the treatment of intraocular inflammatory disease
resistant to systemic corticosteroids and cytotoxic agents. Am J Ophthalmol 1983 Sep;96(3):275e82. PubMed PMID:
6614105.
[15] Nussenblatt RB, Palestine AG, Rook AH, et al. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet
1983 Jul 30;2(8344):235e8. PubMed PMID: 6135075.
[16] Towler HM, Whiting PH, Forrester JV. Combination low dose cyclosporin A and steroid therapy in chronic intraocular
inflammation. Eye 1990;4(Pt 3):514e20. PubMed PMID: 2209919.
[17] Masuda K, Nakajima A, Urayama A, et al. Double-masked trial of cyclosporin versus colchicine and long-term open
study of cyclosporin in Behcet's disease. Lancet 1989 May 20;1(8647):1093e6. PubMed PMID: 2566048.
[18] Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther
Drug Monit 1995 Dec;17(6):584e91. PubMed PMID: 8588225.
[19] Murphy CC, Greiner K, Plskova J, et al. Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis. Arch
Ophthalmol 2005 May;123(5):634e41. PubMed PMID: 15883282.
[20] Figueroa MS, Ciancas E, Orte L. Long-term follow-up of tacrolimus treatment in immune posterior uveitis. Eur J
Ophthalmol 2007 Jan-Feb;17(1):69e74. PubMed PMID: 17294385.
[21] Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest 2003 Apr;111(8):1122e4. PubMed PMID:
12697731. Pubmed Central PMCID: 152947.
[22] Mili-Boussen I, Zitouni M, Ammous I, et al. Azathioprine for glucocorticoid resistant noninfectious uveitis. La Tunis
Med 2015 Mar;93(3):158e63. PubMed PMID: 26367404.
[23] Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of
haematological malignancies. Blood Rev 1992 Sep;6(3):163e73. PubMed PMID: 1422285.
[24] Miserocchi E, Baltatzis S, Ekong A, et al. Efficacy and safety of chlorambucil in intractable noninfectious uveitis: the
Massachusetts Eye and Ear Infirmary experience. Ophthalmology 2002 Jan;109(1):137e42. PubMed PMID: 11772593.
[25] Pujari SS, Kempen JH, Newcomb CW, et al. Cyclophosphamide for ocular inflammatory diseases. Ophthalmology 2010
Feb;117(2):356e65. PubMed PMID: 19969366. Pubmed Central PMCID: 2819575.
[26] Rathinam SR, Babu M, Thundikandy R, et al. A randomized clinical trial comparing methotrexate and mycophenolate
mofetil for noninfectious uveitis. Ophthalmology 2014 Oct;121(10):1863e70. PubMed PMID: 24917273. Pubmed
Central PMCID: 4177935.
[27] Kahn P, Weiss M, Imundo LF, et al. Favorable response to high-dose infliximab for refractory childhood uveitis.
Ophthalmology 2006 May;113(5):860e864 e2. PubMed PMID: 16545455.
[28] Mangge H, Heinzl B, Grubbauer HM, et al. Therapeutic experience with infliximab in a patient with polyarticular
juvenile idiopathic arthritis and uveitis. Rheumatol Int 2003 Sep;23(5):258e61. PubMed PMID: 12687288.
[29] Rajaraman RT, Kimura Y, Li S, et al. Retrospective case review of pediatric patients with uveitis treated with infliximab.
Ophthalmology 2006 Feb;113(2):308e14. PubMed PMID: 16406545.
[30] Richards JC, Tay-Kearney ML, Murray K, et al. Infliximab for juvenile idiopathic arthritis-associated uveitis. Clin Exp
Ophthalmol 2005 Oct;33(5):461e8. PubMed PMID: 16181269.
[31] Sharma SM, Ramanan AV, Riley P, et al. Use of infliximab in juvenile onset rheumatological disease-associated re-
fractory uveitis: efficacy in joint and ocular disease. Ann Rheum Dis 2007 Jun;66(6):840e1. PubMed PMID: 17170050.
Pubmed Central PMCID: 1954647.
[32] Simonini G, Taddio A, Cattalini M, et al. Prevention of flare recurrences in childhood-refractory chronic uveitis: an
open-label comparative study of adalimumab versus infliximab. Arthritis Care Res 2011 Apr;63(4):612e8. PubMed
PMID: 21452272.
[33] Tynjala P, Lindahl P, Honkanen V, et al. Infliximab and etanercept in the treatment of chronic uveitis associated with
refractory juvenile idiopathic arthritis. Ann Rheum Dis 2007 Apr;66(4):548e50. PubMed PMID: 17068061. Pubmed
[34] Zannin ME, Birolo C, Gerloni VM, et al. Safety and efficacy of infliximab and adalimumab for refractory uveitis in
juvenile idiopathic arthritis: 1-year followup data from the Italian Registry. J Rheumatol 2013 Jan;40(1):74e9. PubMed
PMID: 23118110.
[35] Braun J, Baraliakos X, Listing J, et al. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis
treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum 2005 Aug;52(8):
2447e51. PubMed PMID: 16052578.
[36] Matsuda J, Kaburaki T, Kobayashi S, et al. Treatment of recurrent anterior uveitis with infliximab in patient with
ankylosing spondylitis. Jpn J Ophthalmol 2013 Jan;57(1):104e7. PubMed PMID: 23108527.
[37] Papadia M, Herbort CP. Infliximab-induced demyelination causes visual disturbance mistaken for recurrence of HLA-
B27-related uveitis. Ocul Immunol Inflamm 2010 Dec;18(6):482e4. PubMed PMID: 20735341.
[38] Ally MR, Veerappan GR, Koff JM. Treatment of recurrent Crohn's uveitis with infliximab. Am J Gastroenterol 2008 Aug;
103(8):2150e1. PubMed PMID: 18796120.
[39] Fries W, Giofre MR, Catanoso M, et al. Treatment of acute uveitis associated with Crohn's disease and sacroileitis with
infliximab. Am J Gastroenterol 2002 Feb;97(2):499e500. PubMed PMID: 11866306.
[40] Benitez-del-Castillo JM, Martinez-de-la-Casa JM, Pato-Cour E, et al. Long-term treatment of refractory posterior uveitis
with anti-TNFalpha (infliximab). Eye (Lond) 2005 Aug;19(8):841e5. PubMed PMID: 15389273.
[41] Okada AA, Goto H, Ohno S, et al. Ocular Behcet's Disease Research Group of J. Multicenter study of infliximab for
refractory uveoretinitis in Behcet disease. Arch Ophthalmol 2012 May;130(5):592e8. PubMed PMID: 22652845.
*[42] Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial. Arch
Ophthalmol 2009 Jun;127(6):819e22. PubMed PMID: 19506209.
[43] Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary
safety and efficacy outcomes. Arch Ophthalmol 2005 Jul;123(7):903e12. PubMed PMID: 16009830.
[44] Kruh JN, Yang P, Suelves AM, et al. Infliximab for the treatment of refractory noninfectious Uveitis: a study of 88
patients with long-term follow-up. Ophthalmology 2014 Jan;121(1):358e64. PubMed PMID: 24011995.
[45] Vazquez-Cobian LB, Flynn T, Lehman TJ. Adalimumab therapy for childhood uveitis. J Pediatr 2006 Oct;149(4):572e5.
[46] Tynjala P, Kotaniemi K, Lindahl P, et al. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis.
Rheumatol Oxf 2008 Mar;47(3):339e44. PubMed PMID: 18238789.
[47] Turel Ermertcan A, Emre S, Ozturk F, et al. Psoriatic uveitis responding to adalimumab therapy. Int J Dermatol 2013 Jul
24. PubMed PMID: 23879868.
[48] Takase K, Ohno S, Ideguchi H, et al. Successful switching to adalimumab in an infliximab-allergic patient with severe
Behcet disease-related uveitis. Rheumatol Int 2011 Feb;31(2):243e5. PubMed PMID: 19816689.
[49] Suhler EB, Lowder CY, Goldstein DA, et al. Adalimumab therapy for refractory uveitis: results of a multicentre, open-
label, prospective trial. Br J Ophthalmol 2013 Apr;97(4):481e6. PubMed PMID: 23376607.
[50] Soheilian M, Jabbarpourbonyadi M, Soheilian R, et al. Bilateral uveitis after phakic intraocular lens implantation and
management with adalimumab. J Cataract Refract Surg 2012 Jun;38(6):1094e6. PubMed PMID: 22624910.
[51] Simonini G, Taddio A, Cattalini M, et al. Superior efficacy of Adalimumab in treating childhood refractory chronic
uveitis when used as first biologic modifier drug: adalimumab as starting anti-TNF-alpha therapy in childhood chronic
uveitis. Pediatr Rheumatol Online J 2013 Apr 15;11(1):16. PubMed PMID: 23587261. Pubmed Central PMCID: 3637103.
[52] Seve P, Varron L, Broussolle C, et al. Sarcoid-related uveitis occurring during adalimumab therapy. Ocul Immunol
Inflamm 2012 Feb;20(1):59e60. PubMed PMID: 22017197.
[53] Sen ES, Sharma S, Hinchcliffe A, et al. Use of adalimumab in refractory non-infectious childhood chronic uveitis:
efficacy in ocular diseaseea case cohort interventional study. Rheumatol Oxf 2012 Dec;51(12):2199e203. PubMed
PMID: 22923752.
[54] Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients
with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis 2009 May;68(5):
696e701. PubMed PMID: 18662932. Pubmed Central PMCID: 2663712.
[55] Ramanan AV, Dick AD, Benton D, et al. A randomised controlled trial of the clinical effectiveness, safety and cost-
effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis
associated uveitis (SYCAMORE Trial). Trials 2014;15:14. PubMed PMID: 24405833. Pubmed Central PMCID: 3892031.
[56] Mushtaq B, Saeed T, Situnayake RD, et al. Adalimumab for sight-threatening uveitis in Behcet's disease. Eye (Lond)
2007 Jun;21(6):824e5. PubMed PMID: 16601736.
[57] Martel JN, Esterberg E, Nagpal A, et al. Infliximab and adalimumab for uveitis. Ocul Immunol Inflamm 2012 Feb;20(1):
18e26. PubMed PMID: 22324897.
[58] Mansour AM. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 2007 Mar;91(3):274e6. PubMed
PMID: 17322463. Pubmed Central PMCID: 1857669.
[59] Magli A, Forte R, Navarro P, et al. Adalimumab for juvenile idiopathic arthritis-associated uveitis. Graefes Arch Clin Exp
Ophthalmol 2013 Jun;251(6):1601e6. PubMed PMID: 23446556.
[60] Li SY, Birnbaum AD, Goldstein DA. Optic neuritis associated with adalimumab in the treatment of uveitis. Ocul
Immunol Inflamm 2010 Dec;18(6):475e81. PubMed PMID: 20809867.
[61] Leccese P, Latanza L, D'Angelo S, et al. Efficacy of switching to adalimumab in a patient with refractory uveitis of
Behcet's disease to infliximab. Clin Exp Rheumatol 2011 Jul-Aug;29(4 Suppl. 67):S93. PubMed PMID: 21813069.
[62] Kotaniemi K, Saila H, Kautiainen H. Long-term efficacy of adalimumab in the treatment of uveitis associated with
juvenile idiopathic arthritis. Clin Ophthalmol 2011;5:1425e9. PubMed PMID: 22034564. Pubmed Central PMCID:
3198418.
[63] Garcia-De-Vicuna C, Diaz-Llopis M, Salom D, et al. Usefulness of adalimumab in the treatment of refractory uveitis
associated with juvenile idiopathic arthritis. Mediat Inflamm 2013;2013:560632. PubMed PMID: 24489444. Pubmed
[64] Erckens RJ, Mostard RL, Wijnen PA, et al. Adalimumab successful in sarcoidosis patients with refractory chronic non-
infectious uveitis. Graefes Arch Clin Exp Ophthalmol 2012 May;250(5):713e20. PubMed PMID: 22119879. Pubmed
[65] Dobner BC, Max R, Becker MD, et al. A three-centre experience with adalimumab for the treatment of non-infectious
uveitis. Br J Ophthalmol 2013 Feb;97(2):134e8. PubMed PMID: 23212204.
[66] Diaz-Llopis M, Salom D, Garcia-de-Vicuna C, et al. Treatment of refractory uveitis with adalimumab: a prospective
multicenter study of 131 patients. Ophthalmology 2012 Aug;119(8):1575e81. PubMed PMID: 22525047.
[67] Diaz-Llopis M, Garcia-Delpech S, Salom D, et al. Adalimumab therapy for refractory uveitis: a pilot study. J Ocul
Pharmacol Ther 2008 Jun;24(3):351e61. PubMed PMID: 18476805.
[68] Cordero-Coma M, Calleja S, Llorente M, et al. Serum cytokine profile in adalimumab-treated refractory uveitis pa-
tients: decreased IL-22 correlates with clinical responses. Ocul Immunol Inflamm 2013 Jun;21(3):212e9. PubMed
PMID: 23617852.
[69] Callejas-Rubio JL, Sanchez-Cano D, Serrano JL, et al. Adalimumab therapy for refractory uveitis: a pilot study. J Ocul
Pharmacol Ther 2008 Dec;24(6):613e4. author reply 4. PubMed PMID: 19049264.
[70] Calleja S, Cordero-Coma M, Rodriguez E, et al. Ruiz de Morales JG. Adalimumab specifically induces CD3(þ) CD4(þ)
CD25(high) Foxp3(þ) CD127(-) T-regulatory cells and decreases vascular endothelial growth factor plasma levels in
refractory immuno-mediated uveitis: a non-randomized pilot intervention study. Eye (Lond) 2012 Mar;26(3):468e77.
PubMed PMID: 22222264. Pubmed Central PMCID: 3298996.
[71] Bravo-Ljubetic L, Peralta-Calvo J, Noval S, et al. Adalimumab therapy for refractory childhood uveitis. J AAPOS 2013
Oct;17(5):456e9. PubMed PMID: 24160962.
[72] Biester S, Deuter C, Michels H, et al. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 2007 Mar;
91(3):319e24. PubMed PMID: 17035274. Pubmed Central PMCID: 1857691.
[73] Androudi S, Tsironi E, Kalogeropoulos C, et al. Intravitreal adalimumab for refractory uveitis-related macular edema.
Ophthalmology 2010 Aug;117(8):1612e6. PubMed PMID: 20378179.
[74] Miserocchi E, Modorati G, Pontikaki I, et al. Long-term treatment with golimumab for severe uveitis. Ocul Immunol
Inflamm 2013 Oct 21. PubMed PMID: 24143896.
[75] Miserocchi E, Modorati G, Pontikaki I, et al. Golimumab treatment for complicated uveitis. Clin Exp Rheumatol 2013
Mar-Apr;31(2):320e1. PubMed PMID: 23331715.
[76] Reiff A, Takei S, Sadeghi S, et al. Etanercept therapy in children with treatment-resistant uveitis. Arthritis Rheum 2001
Jun;44(6):1411e5. PubMed PMID: 11407702.
[77] Smith BJ, McMillan VM, Newton JS. Corticosteroid-sparing effect of etanercept in idiopathic panuveitis resistant to
immunosuppressive therapy. Journal of clinical rheumatology. Pract Rep Rheumatic Musculoskelet Dis 2001 Jun;7(3):
175e8. PubMed PMID: 17039124.
[78] Foster CS, Tufail F, Waheed NK, et al. Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate.
Arch Ophthalmol 2003 Apr;121(4):437e40. PubMed PMID: 12695239.
[79] Schmeling H, Horneff G. Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatol Oxf 2005 Aug;
44(8):1008e11. PubMed PMID: 15855187.
[80] Smith JA, Thompson DJ, Whitcup SM, et al. A randomized, placebo-controlled, double-masked clinical trial of eta-
nercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum 2005 Feb 15;53(1):
18e23. PubMed PMID: 15696578.
*[81] Lim LL, Fraunfelder FW, Rosenbaum JT. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study.
Arthritis Rheum 2007 Oct;56(10):3248e52. PubMed PMID: 17907169.
[82] Sieper J, Koenig A, Baumgartner S, et al. Analysis of uveitis rates across all etanercept ankylosing spondylitis clinical
trials. Ann Rheum Dis 2010 Jan;69(1):226e9. PubMed PMID: 19465402.
*[83] Zeboulon N, Dougados M, Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: a sys-
tematic literature review. Ann Rheum Dis 2008 Jul;67(7):955e9. PubMed PMID: 17962239.
*[84] Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for the use of anti-tumor necrosis factor
biologic agents in patients with ocular inflammatory disorders. Ophthalmology 2013 Dec 17. PubMed PMID:
24359625.
[85] Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol
2011 Apr;64(4):401e6. PubMed PMID: 21208779.
[86] Cordero-Coma M, Salom D, Diaz-Llopis M, et al. Golimumab for uveitis. Ophthalmology 2011 Sep;118(9):1892 e3-4.
[87] Faez S, Lobo AM, Sobrin L, et al. Treatment of seronegative spondyloarthropathy-associated uveitis with golimumab:
retrospective case series. Clin Exp Ophthalmol 2013 Sep 11. PubMed PMID: 24024585.
[88] Mesquida M, Victoria Hernandez M, Llorenc V, et al. Behcet disease-associated uveitis successfully treated with
golimumab. Ocul Immunol Inflamm 2013 Apr;21(2):160e2. PubMed PMID: 23252659.
[89] William M, Faez S, Papaliodis GN, et al. Golimumab for the treatment of refractory juvenile idiopathic arthritis-
associated uveitis. J Ophthalmic Inflamm Infect 2012 Dec;2(4):231e3. PubMed PMID: 22581347. Pubmed Central
PMCID: 3500989.
[90] Nussenblatt RB, Fortin E, Schiffman R, et al. Treatment of noninfectious intermediate and posterior uveitis with the
humanized anti-Tac mAb: a phase I/II clinical trial. Proc Natl Acad Sci U S A 1999 Jun 22;96(13):7462e6. PubMed
PMID: 10377437. Pubmed Central PMCID: 22108.
[91] Nussenblatt RB, Thompson DJ, Li Z, et al. Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term re-
sults in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous
administration. J Autoimmun 2003 Nov;21(3):283e93. PubMed PMID: 14599854.
[92] Yeh S, Wroblewski K, Buggage R, et al. High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the
treatment of active, non-infectious uveitis. J Autoimmun 2008 Sep;31(2):91e7. PubMed PMID: 18571896. Pubmed
[93] Nussenblatt RB, Peterson JS, Foster CS, et al. Initial evaluation of subcutaneous daclizumab treatments for noninfec-
tious uveitis: a multicenter noncomparative interventional case series. Ophthalmology 2005 May;112(5):764e70.
[94] Wroblewski K, Sen HN, Yeh S, et al. Long-term daclizumab therapy for the treatment of noninfectious ocular in-
flammatory disease. Can J Ophthalmol 2011 Aug;46(4):322e8. PubMed PMID: 21816251. Pubmed Central PMCID:
3174008.
[95] Dick AD, Tugal-Tutkun I, Foster S, et al. Secukinumab in the treatment of noninfectious uveitis: results of three
randomized, controlled clinical trials. Ophthalmology 2013 Apr;120(4):777e87. PubMed PMID: 23290985.
*[96] Ooi KG, Galatowicz G, Calder VL, et al. Cytokines and chemokines in uveitis: is there a correlation with clinical
phenotype? Clin Med Res 2006 Dec;4(4):294e309. PubMed PMID: 17210978. Pubmed Central PMCID: 1764804.
[97] Emmi G, Silvestri E, Cameli AM, et al. Anakinra for resistant Behcet uveitis: why not? Clin Exp Rheumatol 2013 May-
Jun;31(3 Suppl. 77):152e3. PubMed PMID: 24064028.
[98] Teoh SC, Sharma S, Hogan A, et al. Tailoring biological treatment: anakinra treatment of posterior uveitis associated
with the CINCA syndrome. Br J Ophthalmol 2007 Feb;91(2):263e4. PubMed PMID: 17244662. Pubmed Central PMCID:
1857629.
[99] Gul A, Tugal-Tutkun I, Dinarello CA, et al. Interleukin-1beta-regulating antibody XOMA 052 (gevokizumab) in the
treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study. Ann Rheum Dis
2012 Apr;71(4):563e6. PubMed PMID: 22084392.
[100] Petrinovic-Doresic J, Mazuran R, Henc-Petrinovic L, et al. Interleukin 6 and its soluble receptor are elevated in aqueous
humor of patients with uveitis. Ocul Immunol Inflamm 1999 Jun;7(2):75e84. PubMed PMID: 10420202.
[101] Muselier A, Bielefeld P, Bidot S, et al. Efficacy of tocilizumab in two patients with anti-TNF-alpha refractory uveitis.
Ocul Immunol Inflamm 2011 Oct;19(5):382e3. PubMed PMID: 21970668.
[102] Tappeiner C, Heinz C, Ganser G, et al. Is tocilizumab an effective option for treatment of refractory uveitis associated
with juvenile idiopathic arthritis? J Rheumatol 2012 Jun;39(6):1294e5. PubMed PMID: 22661419.
[103] Adan A, Mesquida M, Llorenc V, et al. Tocilizumab treatment for refractory uveitis-related cystoid macular edema.
Graefes Arch Clin Exp Ophthalmol Albrecht von Graefes Archiv fur klinische und Exp Ophthalmol 2013 Nov;251(11):
2627e32. PubMed PMID: 23893042.
[104] Tsang AC, Roth J, Gottlieb C. Tocilizumab for severe chronic anterior uveitis associated with juvenile idiopathic arthritis
in a pediatric patient. Ocul Immunol Inflamm 2013 Dec 30. PubMed PMID: 24377416.
[105] Tugal-Tutkun I, Guney-Tefekli E, Urgancioglu M. Results of interferon-alfa therapy in patients with Behcet uveitis.
Graefe's Archive Clin Exp Ophthalmol Albrecht von Graefes Archiv fur klinische und Exp Ophthalmol 2006 Dec;
244(12):1692e5. PubMed PMID: 16673135.
[106] Plskova J, Greiner K, Forrester JV. Interferon-alpha as an effective treatment for noninfectious posterior uveitis and
panuveitis. Am J Ophthalmol 2007 Jul;144(1):55e61. PubMed PMID: 17601428.
[107] Zulian F, Balzarin M, Falcini F, et al. Abatacept for severe anti-tumor necrosis factor alpha refractory juvenile idiopathic
arthritis-related uveitis. Arthritis Care Res Hob 2010 Jun;62(6):821e5. PubMed PMID: 20191477.
[108] Kenawy N, Cleary G, Mewar D, et al. Abatacept: a potential therapy in refractory cases of juvenile idiopathic arthritis-
associated uveitis. Graefes Arch Clin Exp Ophthalmol 2011 Feb;249(2):297e300. PubMed PMID: 20922440.
[109] Angeles-Han S, Flynn T, Lehman T. Abatacept for refractory juvenile idiopathic arthritis-associated uveitis- a case
report. J Rheumatol 2008 Sep;35(9):1897e8. PubMed PMID: 18785302.
[110] Elhai M, Deslandre CJ, Kahan A. Abatacept for refractory juvenile idiopathic arthritis-associated uveitis: two new cases.
Comment on the article by Zulian et al. Arthritis Care Res Hob 2011 Feb;63(2):307e8. author reply 8. PubMed PMID:
20890986.
[111] Parikh JG, Tawansy KA, Rao NA. Immunohistochemical study of chronic nongranulomatous anterior uveitis in juvenile
idiopathic arthritis. Ophthalmology 2008 Oct;115(10):1833e6. PubMed PMID: 18495247.
[112] Miserocchi E, Modorati G. Rituximab for noninfectious uveitis. Dev Ophthalmol 2012;51:98e109. PubMed PMID:
22517208.
[113] Heiligenhaus A, Miserocchi E, Heinz C, et al. Treatment of severe uveitis associated with juvenile idiopathic arthritis
with anti-CD20 monoclonal antibody (rituximab). Rheumatol Oxf 2011 Aug;50(8):1390e4. PubMed PMID: 21378109.
*[114] Landewe R, van der Horst-Brinsma I, Tari S, et al. Quiescence in active and inactive non-infectious, intermediate,
posterior, or panuveitis in patients treated with adalimumab: visual I and visual II trials. Ann Rheum Dis 2016;
75(Suppl. 2):403.

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Best Practice & Research Clinical Rheumatology xxx (2016) 1e12

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Best Practice & Research Clinical

Advancements in the management of uveitis

E-mail address: SchwartzmanS@HSS.edu.

each entity have not been deﬁned. In this study, an approach to

Nonbiologic therapeutic approach to uveitis

Biologic therapeutic approach to uveitis

Conﬂict of interest statement

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