A review and update on orphan drugs for the treatment of noninfectious uveitis
A review and update on orphan drugs for the treatment of noninfectious uveitis
Caiyun You 2
Haitham F Sahawneh 1 2
Lina Ma 1 2
Buraa Kubaisi 1 2
Alexander Schmidt 1 2
C Stephen Foster 1 2 3
0 Department of Ophthalmology, Tianjin Medical University General Hospital , Tianjin , People's Republic of China
1 Ocular immunology and Uveitis Foundation , w eston, MA , USA
2 Massachusetts eye Research and Surgery institution (MeRSi) , w altham , USA
3 Harvard Medical School , Boston, MA , USA
8 1 0 2 - l u J - 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s rse l.y ep on PowerdbyTCPDF(ww.tcpdf.org) Introduction: Uveitis, a leading cause of preventable blindness around the world, is a critically underserved disease in regard to the medications approved for use. Multiple immunomodulatory therapy (IMT) drugs are appropriate for uveitis therapy but are still off-label. These IMT agents, including antimetabolites, calcineurin inhibitors, alkylating agents, and biologic agents, have been designated as “orphan drugs” and are widely used for systemic autoimmune diseases or organ transplantation. Area covered: The purpose of this paper is to comprehensively review and summarize the approved orphan drugs and biologics that are being used to treat systemic diseases and to discuss drugs that have not yet received approval as an “orphan drug for treating uveitis” by the US Food and Drug Administration (FDA). Our perspective: IMT, as a steroid-sparing agent for uveitis patients, has shown promising clinical results. Refractory and recurrent uveitis requires combination IMT agents. IMT is continued for a period of 2 years while the patient is in remission before considering tapering medication. Our current goals include developing further assessments regarding the efficacy, optimal dose, and safety in efforts to achieve FDA approval for “on-label” use of current IMT agents and biologics more quickly and to facilitate insurance coverage and expand access to the products for this orphan disease.
immunomodulatory; orphan drug; steroid sparing; uveitis
open access to scientific and medical research
Uveitis is a major cause of severe visual impairment. It can occur either alone or as
part of a systemic syndrome (systemic disease-associated autoimmune uveitis), such
as one of the spondyloarthritides (including those complicating inflammatory bowel
disorders and juvenile idiopathic arthritis [JIA]), Adamantiades–Behcet’s disease
(ABD), Vogt–Koyanagi–Harada (VKH) syndrome, systemic lupus erythematosus,
sarcoidosis, autoimmune hepatitis, and multiple sclerosis, in which the eye is one
of several organs involved.1 Autoimmune-mediated uveitis treatment is divided into
acute phase and maintenance therapy. The acute stage can be controlled with
mend the use of corticosteroids as first-line therapy for patients with active uveitis.2
However, long-term corticosteroid treatment can cause serious systemic and ocular side
effects, such as hypertension, diabetes, cataract, and glaucoma. Alternatively,
immunomodulatory therapy (IMT) drugs are given as steroid-sparing agents and have shown
good clinical results for both systemic diseases and ocular inflammatory diseases.3,4
Given the side effects of chronic corticosteroid therapy and better understanding of
the mechanisms of autoimmune-mediated uveitis, the aim of the treatment for patients
Clinical Ophthalmology 2017:11 257–265 257
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with noninfectious uveitis is steroid-free remission with IMT.
A stepladder approach is a common practice in
immunemediated uveitis: nonsteroidal anti-inflammatory drugs and
conventional immunomudulatory agents are usually used
before proceeding with biologic response modifiers.
IMT agents include the antimetabolites methotrexate,
azathioprine, and mycophenolate mofetil; the calcineurin
inhibitors that include cyclosporine, tacrolimus, and
18 sirolimus; alkylating agents that include cyclophosphamide
l-u02 and chlorambucil; biologic response modifiers that include
-J13 the tumor necrosis factor (TNF)-α inhibitors infliximab,
adalno imumab, etanercept, golimumab, and certolizumab;
lympho.027 cyte inhibitors that include daclizumab, rituximab, abatacept,
.964 and basiliximab; specific receptor antagonists that include
.y37b5 taunzaukminarba,, ecfaanlaizkuinmuamb,abse,cguekvionkuimzuamb,aabn,
dtoucsitleizkuinmuamba,ba;leamnd/om interferon (INF) treatments. Refractory and recurrent uveitis
.rscseep l.yon rperqoutoirceosl itmomcounntormolotdhuelaintoflraymmmoantoiothne.rCapoynotirnauicnogmebviindaetniocne
.vdoww lsunae shows that second-line agents, including antimetabolites,
T-cell inhibitors, and alkylating agents, and biologics are
effective in many patients, allowing reduction in steroid dose
and preservation of visual function. Aggressive treatment
may result in fewer complications and less recurrence.
Our team has reviewed IMT drugs approved by the US
Food and Drug Administration (FDA) for use in uveitis.5
In this study, we review and summarize conventional IMT
drugs or biologics that have not received approval as an
“orphan drug” from the FDA for use in noninfectious uveitic
patients, despite having been approved for use in treating
other systemic diseases or organ transplantation.
Orphan drug status in ocular inflammatory diseases
The Orphan Drug Designation program provides orphan
status to drugs and biologics that are defined as those
intended for the safe and effective treatment, diagnosis, or
prevention of rare diseases/disorders that affect fewer than
200,000 people in the USA, or that affect .200,000 persons
but are not expected to recover the costs of developing and
marketing a treatment drug.6
Although not approved as orphan agents for uveitis, there
are many randomized clinical trials evaluating various IMT
drugs and biologics used for ocular inflammatory diseases.
These treatments have been approved as orphan drugs by
the FDA to be used in malignancies, autoimmune disorders,
and/or organ transplantation (Table 1). Table 2 shows the use
and dosage of these drugs for the treatment of uveitis.
High-dose methotrexate for use with leucovorin rescue in patients with nonmetastatic osteosarcoma who have undergone
surgical resection or amputation for the primary tumor
Prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate release formulations in
combination with other immunosuppressants; prophylaxis of organ rejection in patients receiving allogenic heart transplants
For reducing signs and symptoms, and inducing and maintaining clinical remission in pediatric patients with moderately to
severely active Crohn’s disease who have had an inadequate response to conventional therapy; for reducing signs and symptoms,
and inducing and maintaining clinical remission in pediatric patients aged $6 years with moderately to severely active ulcerative
colitis who have had an inadequate response to conventional therapy; treatment of moderately to severely active Crohn’s
disease for the reduction of the signs and symptoms in patients who have an inadequate response to conventional therapies; and
treatment of patients with fistulizing Crohn’s disease for the reduction in the number of draining enterocutaneous fistula(s)
Treatment of chronic myelogenous leukemia (interferon α-2a); treatment of selected patients with AiDS-related Kaposi’s
sarcoma (interferon α-2b [recombinant]); treatment of relapsing forms of multiple sclerosis to slow the accumulation of physical
disability and decrease the frequency of clinical exacerbations (interferon β-1a); in ambulatory patients with relapsing–remitting
multiple sclerosis to reduce the frequency of clinical exacerbations (interferon β-1b); delaying time to disease progression in
patients with severe, malignant osteopetrosis (interferon γ-1b); adjuvant treatment of melanoma with microscopic or gross
nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy (peginterferon α-2b)
Treatment of patients previously untreated for CD20-positive chronic lymphocytic leukemia in combination with fludarbine and
cyclophosphamide; for the use of Rituxan® (rituximab) in combination with glucocorticoids for the treatment of patients with
wegener’s granulomatosis and microscopic polyangiitis
Treatment of active polyarticular juvenile idiopathic arthritis in patients aged 2 through 16 years
Treatment of neonatal-onset multisystem inflammatory disease
Treatment of cryopyrin-associated periodic syndromes, in adults and children aged $4 years; treatment of active systemic
juvenile idiopathic arthritis in patients aged 2 through 16 years
The treatment of patients with B-cell chronic lymphocytic leukemia who have been treated with alkylating agents and who have
failed fludarabine therapy
Orphan drugs in noninfectious uveitis
As an antimetabolite and antifolate drug, methotrexate
(formerly known as amethopterin) is a folic acid analog
that irreversibly, competitively binds and inactivates the
enzyme dihydrofolate reductase. Methotrexate also partially,
reversibly, competitively inhibits thymidylate synthetase.
Ultimately, DNA synthesis, DNA repair, RNA synthesis,
and cell division (S-phase cell cycle specific) are inhibited.7
Methotrexate suppresses both B and T cells. At low doses,
it has little effect on cell-mediated immunity, but has been
shown to depress acute-phase reactants. Therefore, it is
suspected that the action of methotrexate is more likely
anti-inflammatory than immunosuppressive.8,9 Potential side
effects of methotrexate include nausea, diarrhea, fatigue,
minimal hair loss, mouth ulcers, hepatitis, eosinophilic
pneumonitis or inflammatory lung disease, increased risk of
sunburn, increased risk of infection, and rare mood swings
in children. In general, methotrexate is mostly well tolerated
and side effects improve with reducing dosage.
Methotrexate is used to treat leukemia, cancers (including
breast, head and neck, leukemia, lymphoma, lung,
osteosarcoma, bladder, and trophoblastic neoplasms), autoimmune
diseases (including rheumatoid arthritis, juvenile
dermatomyositis, psoriasis, psoriatic arthritis, lupus, sarcoidosis, Crohn’s
disease, eczema, and many forms of vasculitis), ectopic
pregnancy, and for the induction of medical abortions.10,11
Methotrexate is a widely used agent for ocular inflammation
because of its ease of administration and long track record.
It is often regarded as the first-line agent when starting a
patient with uveitis on IMT.
Methotrexate has been reported to be effective in treating
ocular inflammation in several uncontrolled retrospective
case studies. In the retrospective Systemic
Immunosuppression for Eye Disease Cohort Study (SITE), which included
384 patients, methotrexate was found to be moderately
effective with an overall success of 66% at 12 months for
sustained control and 58.4% for corticosteroid-sparing
control (#10 mg). From the data, it appeared to be more
successful for the treatment of anterior disease; however, the
authors caution that this observed effect may be related to the
severity of the disease. It was found to be safe, with just 16%
patients discontinuing therapy due to side effects, which were
all reversible.3 Methotrexate was reported to be one of the
agents of choice for recurrent anterior uveitis, as it was
pref81 erentially concentrated in the aqueous humor.12 Galor et al
l-2u0 reported 90 patients with inflammatory eye disease,
includ-J13 ing 21 patients with scleritis, 17 patients with intermediate
on uveitis, 43 patients with posterior/panuveitis, and 9 patients
.072 with other types, who were treated with methotrexate. They
.649 reported that the median time to treatment success was
.537 6.5 months. The proportion of patients able to discontinue
/ybom ipnremdnetihsoontreeaxfatteer g6rmouopnst.h13s of antimetabolite therapy was 6%
.rscse l.y Methotrexate is also safe, effective, and the most
comep on monly used immunosuppressive agent in children with
.vdoww lsunae JIA-associated uveitis and chronic anterior or intermediate
uveitis. In the literature on methotrexate for anterior uveitis
/:/ttsphw rrspeoo JaIsAso,cmiaetethdowtrietxhattheepseerrmonitetgedatiavdeesqpuoantedyi mlomaruthnroospuaptphrieesssaionnd
from F and was steroid sparing while maintaining disease control.14
ded In a large series of 465 patients with ocular sarcoidosis,
lnoa including 365 patients treated with methotrexate, most cases
odw respond well to IMT. This drug was both efficient and well
lygo tolerated; as 281 (77%) patients continued on methotrexate
lom therapy and only 14 (3.8%) had to discontinue it due to drug
lpO Recently, intravitreal methotrexate has shown success in
iilcnaC teryeeastmweitnht uovfe1i5ticeyceysstwoiidthmuavceuitliacr CedMemE,as(tCatMistEic).a1l6l,1y7
sFiogrntihfiecant visual improvement of 4 and 4.5 lines occurred at 3 and
6 months with no statistically significant difference in vision
when compared to previous treatment with corticosteroids
or intravitreal triamcinolone acetonide. Relapse occurred at
a median of 4 months, but reinjection had similar efficacy.18
Following intravitreal corticosteroids, methotrexate is the
most widely used intravitreal immunosuppressive agent. The
dose administrated is 400 µg/0.1 mL, being effective in
different inflammatory ocular disorders as well as in masquerade
syndromes due to intraocular lymphoma.
Tacrolimus is a macrolide antibiotic that was isolated
from the fermentation broth of Streptomyces tsukubaensis.
Tacrolimus is capable of inhibiting humoral and cellular
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immunity and alloantigen-driven proliferation across strong
In 1994, a multicenter open clinical trial in Japan
conducted on 16 patients with noninfectious uveitis studied
the clinical effects of tacrolimus. The study included eight
patients with Behcet’s disease, five patients with VKH, one
patient with sympathetic ophthalmia, one patient with retinal
vasculitis, and one patient with sarcoidosis. Results
demonstrated that tacrolimus was effective in treating noninfectious
uveitis but emphasized the necessity to closely monitor
patients for the occurrence of adverse effects.20 Tacrolimus
also showed efficacy and an excellent cardiovascular risk
profile when treating 62 patients with noninfectious uveitis (4.8%
anterior uveitis, 25.8% intermediate uveitis, 37.1% posterior
uveitis, and 32.3% panuveitis) for 4 consecutive years.21
Another publication evaluated the efficacy of tacrolimus as
monotherapy versus tacrolimus in combination with systemic
corticosteroid therapies to achieve remission of
inflammation in noninfectious posterior uveitis. This study showed
that corticosteroid therapy can be reduced and/or withdrawn
in patients treated with tacrolimus who are able to achieve
control of posterior segment intraocular inflammation.22
Tacrolimus therapy showed similar efficacy and a more
favorable safety profile compared to cyclosporine
regarding control of posterior segment intraocular inflammation.23
Furthermore, the use of topical tacrolimus ointment is
effective in controlling refractory inflammatory ocular surface
disease and can reduce the need for steroid use while reducing
Infliximab, a chimeric monoclonal antibody that binds both
circulating and membrane-bound TNF-α, has been reported
to be effective for the treatment of uveitis associated with
multiple uveitic diseases, such as human leukocyte antigen
(HLA)-B27-related anterior uveitis, pars planitis, VKH,
birdshot chorioretinopathy, recalcitrant uveitic CME, multifocal
choroiditis, sympathetic ophthalmia, serpiginous
choroidopathy, and idiopathic uveitis.25–27
In addition, infliximab has been described to be a rapid
and very effective therapy for the treatment of ABD-related
panuveitis and retinal vasculitis.28,29 Sfikakis et al reported in
a prospective study of 25 patients with ABD-related uveitis
that .90% of patients demonstrated the resolution of vitritis,
CME, retinitis, and retinal vasculitis within 4 weeks after
initiating infliximab therapy and benefit often occurred in under
1 week.29 It was shown to be more effective than conventional
immunotherapy for ABD-related retinal vasculitis.30
Infliximab also showed efficacy for JIA uveitis, with the
majority of patients experiencing rapid control of uveitis after
the second infusion.31,32 However, multiple case reports and
series suggest that TNF-α inhibitors may cause
sarcoidosislike conditions. TNF inhibitors analogously are effective for
psoriasis, but they have also been reported to cause
psoriasiform skin disease and developing drug-induced lupus.33,34
Furthermore, TNF-α inhibitors should be used with caution
in patients with serpiginous choroidopathy despite previously
negative QuantiFERON test.35
INF-α and INF-β are cytokines that have an important role
in treating severe sight-threatening uveitis. INF-α, which is
naturally secreted in response to viral infection, is categorized
into INF-α 2a (Roferon-A®) and INF-α2b (Intron-A®). INF
therapy can cause severe adverse effects including
sarcoidosis with or without uveitis.36,37 Thus, this therapy is not
recommended for the treatment of sarcoid-related uveitis.
INF-α 2a and INF-α 2b have been used for the
treatment of posterior uveitis.38 INF-α 2a has been studied
mostly in patients with ABD.39,40 It has also been reported
to treat sympathetic ophthalmia, VKH, birdshot
retinochoroidopathy, intermediate uveitis, and idiopathic panuveitis.39,41
In a prospective study on patients with sight-threatening
uveitis, subcutaneous daily use of human INF-α 2b showed
a favorable response in 83% of the patients.38 INF-α 2b
has been found to be an effective option in the treatment
of refractory CME secondary to uveitis as well.42 Finally,
INF-β has been successfully used in treating intermediate
uveitis associated with multiple sclerosis, choroiditis, and
choroidal neovascularization in chronic recurrent punctate
Rituximab (Rituxan®; Genentech, Inc., South San Francisco,
CA, USA) is a murine-human chimeric monoclonal antibody
against CD20 molecule that is expressed on B lymphocytes.
It is FDA approved for both malignant and nonmalignant
B-cell-dependent diseases. It has been used in the treatment
of lymphoma, leukemia, rheumatoid arthritis, granulomatosis
with polyangiitis, and microscopic polyangiitis.45 Side effects
of rituximab include infusion reaction, infection especially
in combination with other immunosuppressive medications,
and progressive multifocal leukoencephalopathy.
Current information about the use of rituximab in
ophthalmology is limited. Rituximab has been used
successfully in the treatment of JIA-associated uveitis, particularly
in oligoarthritic (rather than polyarthritic) JIA.46,47
In concurrence, Miserocchi et al observed long-term
remission of uveitis in patients with JIA who were treated with
rituximab.45 The efficacy of rituximab in refractory ocular
involvement of systemic lupus erythematosus,48 ABD,49
birdshot retinochoroidopathy,50 and type II essential
cryoglobulinemia refractory to steroid treated with plasmapheresis has
also been shown, although ABD is known to be a
predominantly T-cell-mediated disease.51
Tocilizumab (Actemra®; Genentech, Inc.) is a monoclonal
antibody against interleukin (IL)-6 receptors. It has been
approved for the treatment of moderate-to-severe rheumatoid
arthritis and polyarticular and systemic JIA refractory to other
biologic response modifiers.
Tocilizumab has been successfully used in refractory
JIA-associated uveitis, birdshot retinochoroidopathy, ABD,
and refractory idiopathic uveitis.52–57 Hirano et al described
a case of severe ABD-associated posterior uveitis resistant
to conventional immunosuppression and infliximab
infusions who experienced complete remission after tocilizumab
monotherapy.58 Tocilizumab was also used for a case of
multicentric Castleman disease with the resolution of uveitis
and perivascular leakage on fluorescein angiography at
3 months after treatment.59 The efficacy of tocilizumab in
noninfectious intermediate, posterior, or panuveitis and
in JIA-associated uveitis is currently being examined in
two separate ongoing phase I/II clinical trials.60 Adán et al
demonstrated the effectiveness of tocilizumab in treating
uveitic CME refractory to conventional chemotherapy.55
Tocilizumab was also reported to improve visual acuity and
decrease in macular thickness in optical coherence
tomography in birdshot retinochoroidopathy, JIA, and idiopathic
Although tocilizumab therapy is employed to improve
rheumatologic symptoms, there are two case reports in regard
to possible paradoxical inflammatory responses in patients
treated with tocilizumab. The first patient (HLA-B27-positive
ankylosing spondylitis) developed uveitis for the first time
after treatment, and the second patient (rheumatoid arthritis)
developed peripheral ulcerative keratitis for the first time
11 months after tocilizumab treatment.61
Anakinra (Kineret®; Swedish Orphan Biovitrum AB,
Stockholm, Sweden) is a short-acting recombinant naturally
occurring human IL-1 receptor antagonist, which blocks IL-1α
and IL-β binding to the IL-1 receptor. In a case series of nine
adult patients with ABD, three of four patients with recurrent
uveitis showed a complete resolution of intraocular
inflammation. Patient inflammation relapsed in an average period
of 24 weeks. Side effects were observed in three patients that
included itchy rash at the site of injection and was controlled
with topical steroids.62 There are currently three case reports
demonstrating the efficacy of anakinra in infantile posterior
uveitis63,64 and one report showing efficacy in a patient having
childhood uveitis associated with Blau syndrome.65
.720 Canakinumab (Ilaris®; Novartis Pharmaceuticals Corporation,
.694 Basel, Switzerland) is a human immunoglobulin G1
anti.735 IL-1β monoclonal antibody, which is indicated for systemic
yb JIA and cryopyrin-associated periodic syndrome in adults and
/om children aged $4 years. Its mode of action is based on the
.rscse l.y neutralization of 1β signaling, resulting in the suppression
ep on of inflammation in patients with disorders of autoimmune
.vdoww lsunae iosriwgienl.lRtoelpeorrattsefdroimn mclionsitcaplattriieanltsss,uagngdesntothsaetrciaonuaskainduvmerasbe
/:sw rseo effects have been reported. It is administered subcutaneously
tth ro or intravenously every 4–8 weeks. Its effectiveness was
from F demonstrated in a refractory case of Behcet’s
syndromeded associated uveitis with a 150-mg single infusion.
lnoa Vitale et al reported a case series of three patients (two of
odw three patients had ocular involvement, one anterior uveitis,
lygo and one panuveitis) with Behcet’s disease refractory to
lom steroid and multiple immunosuppressive therapies, who
thha responded to 150 mg of subcutaneous canakinumab
monolpO therapy every 6 weeks. One patient’s uveitis was controlled
iilcnaC abnyackainnarkaiannudmraebmaanidntehdeionthreermpiasstiieonnt aocnhcieavneadkirneummisasbioanftoenr
stopping anakinra due to side effects.66 Ugurlu et al described
a case of a 16-year-old female with severe bilateral panuveitis
with hypopyon and retinal vasculitis associated with ABD.
The patient was intolerant to INF therapy and refractory
to conventional immunosuppressive and several biologic
agents, including infliximab, adalimumab, and anakinra. The
inflammation resolved with improved visual acuity, which
was sustained for at least 8 weeks after a single infusion of
150 mg canakinumab. However, there were no long-term
outcomes presented.67 Simonini et al reported on the clinical
response to canakinumab in a 4-year-old boy with sporadic
nucleotide-binding oligomerization domain-containing
protein 2-associated pediatric granulomatous arthritis and severe
resistant panuveitis, macular edema, and retinal detachment.
In this case, canakinumab was given 2 mg/kg each month,
which led to rapid control of uveitis for at least 6 months.68
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Alemtuzumab (Campath®; Genzyme Corporation, Cambridge,
MA, USA) is a human monoclonal antibody against CD52
protein on all types of lymphocytes. Alemtuzumab has not
received FDA approval, thus it is not commercially
available but is obtainable through a restricted distribution
program by the manufacturer. Adverse effects of alemtuzumab
include significant lymphopenia; secondary autoimmunity,
specifically Graves’ disease; and idiopathic
Isaacs et al described a case of a 36-year-old male who
presented with severe panuveitis with choroiditis and retinal
vasculitis resistant to immunosuppressive agents, including
cyclophosphamide and intravenous immunoglobulin. The
patient had significant systemic symptoms, presumably from
chronic corticosteroid therapy. He was given intravenous
alemtuzumab with brief improvement of ocular inflammation.
However, the patient subsequently died with myocardial
infarction.70 Dick et al reported a series of 10 patients with
various ocular inflammatory diseases treated with intravenous
alemtuzumab (four patients with retinal vasculitis, one with
ABD-related uveitis, and one with sympathetic ophthalmia).
The first five patients had clinical improvement, but the latter
with sympathetic ophthalmia had stable inflammation without
deterioration. Half of the patients flared up during follow-up
period.71 There is a report of four cases of adult patients with
Behcet’s disease-associated uveitis, who were treated with a
single course, at the escalating regimen of 4, 10, 40, 40, and
40 mg intravenously daily, for 5 consecutive days, without
concomitant immunosuppressive agents. They reported
complete remission in two cases and partial remission in
two other cases at 6-month follow-up. However, long-term
remission was observed in only one patient.72
In conclusion, continuing evidence shows that IMT
agents and biologics orphan drugs approved by the FDA for
the treatment of systemic diseases are effective in treating
refractory and recurrent uveitis. These treatments allow for
reduction in steroid dose and preservation of visual function.
However, due to the lack of evidence from large
randomized controlled clinical trials and rarity and heterogeneity of
uveitis, the use of these drugs still remains “off-label” for
noninfectious uveitis. We hope that these restrictions and
limitations will be further addressed in near future.
Uveitis constitutes a sight-threatening disease that should be
managed according to the severity. Given our current
understanding of the immune mechanisms of uveitis, IMT drugs can
greatly reduce inflammation and minimize the use of topical
and systemic steroids. There are a number of IMT options
available that have improved outcomes of uveitic patients
when used in specific situations. These IMT orphan drugs serve
as the foundation to modern corticosteroid-sparing therapy.
Conventional IMT agents are the first steroid-sparing
options for uveitic patients with refractive active inflammation
and/or sight-threatening complications. Using IMTs in treating
autoimmune uveitis follows one of the following scenarios:
1) as a steroid-sparing agent; 2) when corticosteroids fail to
control the inflammation: persistent, recurrent, or progressing
in the same eye or bilaterally; 3) when uveitis is associated
with autoimmune systemic diseases, IMTs are used to control
both; and 4) with frequent recurrences and/or the development
of ocular or steroid-induced nonophthalmic complications.
Previous experience indicates that an alternative and/or
combined IMT regimen is the best treatment choice in cases of
worsening inflammation. In these worsening patients, a
physician can either change or add other conventional IMT drugs
and/or a biologic agent. Medications in the same group can
be replaced with each other from more aggressive treatments,
such as infusions to less aggressive ones such as subcutaneous
injections. Moreover, the failure of a biologic response
modifier in a group does not necessarily mean that similar agents
in the same group will also be ineffective. Corticosteroids are
usually modulated with IMT drugs according to the degree
of intraocular inflammation and the possible occurrence of
complications and/or relapses. In cases of ocular inflammation
improvement, corticosteroids should be gradually tapered
until final withdrawal, together with a subsequent reduction
and/or withdrawal of the use of IMT drugs.
If remission is achieved, there is no consensus on when
to stop IMT. In our experience, IMT maintenance (without
corticosteroids) while the patient is in remission should be
prolonged for a period of 2 years before considering tapering the
medication, in order to achieve stable control of the disease and
to reduce the probability of recurrence. The end point of IMT
is also determined by the presence of the underlying systemic
autoimmune disease that is being controlled by the same IMT,
which often requires coordination between the
ophthalmologist and the rheumatologist. Additional controlled trials are
needed to assess long-term remission outcomes after IMT
tapering and develop proper end points of IMT regimens.
Lack of randomized controlled clinical trials, rarity and
heterogeneity of uveitis, and the high cost of these agents
make using IMTs and biologics challenging in ophthalmology.
Among the studies referenced in this study, most are small
retrospective clinical trials, which have no standard
treatment regimen, definition of success or remission, and little
consensus on IMT end points. Nowadays, the number of
IMT therapeutic options in uveitis has expanded vastly.
It remains imperative for a clinician to diagnose the disease
early and institute aggressive therapy. Furthermore,
selection, administration, and monitoring of IMT sometimes need
coordination with a rheumatologist and/or a chemotherapist
to avoid complications.
There are many other biologic response modifiers that
have been employed for the treatment of systemic
autoimmune diseases and experimental autoimmune uveitis that
are promising for the treatment of idiopathic noninfectious
uveitis. The development of monoclonal antibodies that
recognize two or more targets at the same time, and the
development of a safe and effective local sustained-release
device delivering biologic response modifiers may be
promising approaches for treatment in the future.
As our understanding of autoimmune diseases expands,
new targets and approaches to treatment are becoming
available. We emphasize the need for the FDA to approve
“on-label” use of current orphan IMT agents and
biologics more quickly and to facilitate insurance coverage and
expanded access to uveitis patients. Further assessment of
current IMT agents and new IMT regimens is needed to
provide evidence confirming the efficacy, optimal dose, regimen,
maintenance, and end point for the treatment of uveitis.
C Stephen Foster discloses the following: Consultancies
with Aldeyra Therapeutics (Lexington, MA), Baush &
Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate
Pharma (Waltham, MA), Novartis (Cambridge, MA),
pSivida (Watertown, MA), and Xoma (Berkeley, CA).
Grants or grants pending with Alcon (Aliso Viejo, CA),
Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb
(Bridgewater, NJ), Clearside Biomedical (Alpharetta, GA),
Dompé pharmacetical (Milan, Italy), Eyegate Pharma
(Waltham, MA), Mallinckrodt pharmaceuticals (Dublin,
Ireland), Novartis Pharmaceuticals (Cambridge, MA),
pSivida (Watertown, MA), Santen (Osaka, Japan). Payment
for lectures including service on speaking bureaus: Alcon
(Aliso Viejo, CA), Allergan (Dublin, Ireland). Stock or Stock
Options: Eyegate Pharama (Waltham, MA).
There was no funding or support received for this
manuscript. The authors report no other conflicts of interest in
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