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Scleritis Case Report
Review and Treatment of Scleritis
By:
Previous candidate. Actual case report submission
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Abstract
Purpose. To present a case study, and discussion on the medical management of Scleritis.
Case Report. A 42-year-old white female presented to the office complaining of a painful red
eye. After 11 years of various treatment modalities (topical, oral and injectable), she is finally
quiescent on an off-label use of topical cyclosporine and an oral non-steroidal medication.
Throughout her treatment, she was found to be HLA-B27 positive, ANA positive, and after years
of steroid use, developed a posterior subcapsular cataract.
Conclusions. Scleritis is a chronic condition requiring continued treatment throughout a
patient’s life. A systemic diagnosis is often delayed until years after onset. The goal of
treatment in a patient with Scleritis is to identify a potentially life threatening systemic etiology,
control ocular and systemic inflammation, make the patient comfortable, and prevent a scleral
melt. With today’s understanding of scleritis and immunosuppressant agents available, we are
better prepared to fight this disease than ever before.
Key Words: Episcleritis, Scleritis, Posterior Scleritis, Necrotizing Scleritis, Scleromalacia
Perforans
Introduction
Scleritis is an inflammation of the deep sclera and is usually a chronic, painful, progressive,
potentially blinding condition. Episcerlitis on the other hand is usually an acute, self-limiting
inflammation of the episclera, which rarely produces significant adverse ocular sequelae.
Scleritis is characterized by edema and cellular infiltration of the sclera and episclera and always
requires aggressive oral treatment. Scleral inflammation gives rise to a spectrum of conditions
ranging in severity from benign, superficial inflammation of the episclera, to vision threatening
necrosis. The prevalence of Scleritis is relatively low and has been estimated at 8 cases in
100,000 and the incidence at 1.3 cases per 100,000 person /year.1 Differentiation between
Episcleritis and Scleritis is important because there are considerable differences in clinical
features, visual prognosis, ocular morbidity, therapeutic approach, and the association with a
potentially life threatening systemic disease. In fact, up to 50% of patients with
scleritis have evidence of an underlying systemic disease.2
Case Report
Initial Visit 12/14/2004 – Stacy C, a 42-year-old white female presented complaining of a red,
painful right eye. SC could barely move the eye it hurt so badly. She described the pain as
boring, and radiated to her temple. Her ocular history was unremarkable, but reports a similar
episode in the past she did not seek treatment for that went away on its own. Her medical
history was positive for anxiety. Her family history was remarkable for glaucoma (father). Her
medications include Prozac (fluoxetine), and she reported no known medical allergies.
Best corrected visual acuity was 20/20 OD, OS. Pupils, extraocular muscles and confrontation
fields were intact. Objective testing revealed 2+ sectoral conjunctival and scleral injection OD.
The scleral injection did not blanch with 10% phenylephrine or stain with fluorescein. There
was point tenderness upon palpation of the globe. The right cornea and anterior chamber
were clear. The left anterior segment was healthy. She was dilated with 1% tropicamide and
the posterior segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3 OD,
.35 /.35 OS. Tonometry by applanation was 18mmHg OU using Fluress.
SC was diagnosed with Diffuse Anterior Scleritis OD. Treatment prescribed consisted of oral
Ibuprofen with a tapering dose over the next six weeks (800mg TID PO x 1 week, 600mg TID PO
x 1 week, 400mg TID PO x 1 week, 200mg TID PO x 1 week, 200mg BID PO x 1 week, 200mg QD
PO x 1 week), and topical Pred Forte (1% prednisolone acetate) QID x 2 weeks, BID x 2 weeks,
QD x 2 weeks. She was given an order to have blood drawn, to rule out a systemic component
(CBC, p-ANCA, c-ANCA, SSA, SSB, Lyme Titer, ACE, Serum Lysozyme, ANA, ESR, CRP, HLA-B27,
RF), and scheduled to return to the office in 2-4 weeks.
At the return visit, SC stated her eye had done well while on the ibuprofen and Pred forte and
the symptoms resolved. Although, after a month of being off treatment, her symptoms
returned and were bothersome to the point that treatment was re-initiated. The lab results
were discussed. All were normal except she was found to have the genetic marker for HLA-B27,
which was positive (potentially indicating Ankylosing Spondylitis (AS)). She was sent to have
imaging of her hands, feet and sacroiliac joints, but they were negative for AS. It was decided
to continue on oral ibuprofen 400mg TID PO and told to follow up in 3 months or sooner if the
Scleritis returns. A rheumatology consult was recommended, but the patient denied.
04/05/2006 – A couple of years after the first incidence, SC returned to the office complaining
of a non-healing Scleritis OD. She had been using the prescribed treatment plan of ibuprofen
800mg TID PO along with topical Pred Forte QID, but wasn’t getting relief. SC additionally
reported she had flared up several times over the last 2 years, which was treated with oral
NSAID’s and topical Pred Forte, but it was not helping this time.
Best corrected visual acuity was 20/20 OD, OS. Objective testing revealed 2+ sectoral
conjunctival and scleral injection OD. The scleral injection did not blanch with 10%
phenylephrine or stain with fluorescein. There was point tenderness upon palpation of the
globe. The right cornea and anterior chamber were clear. The left anterior segment was
healthy. She was dilated with 1% tropicamide and the posterior segment showed no signs of
inflammation OU, with cup to disc ratios at .3 /.3 OD, .35 /.35 OS. Tonometry by applanation
was 16mmHg OU using Fluress.
SC was diagnosed with recurrent Diffuse Anterior Scleritis OD and referred for more aggressive
treatment using oral prednisone. She was seen at the University of Minnesota Ophthalmology
clinic (90 miles away), by a neuro-ophthalmologist who concurred with our assessment of
Recurrent Scleritis OD. She was placed on oral prednisone 60mg x 3 days, 40mg x 3 days, 20mg
x 3 days, 10 mg x 3 days and discontinued. She had another lab work up and all were negative
(beside HLA-B27). Additionally, she had an MRI of the brain and orbits which was negative. If
she continued to have pain with oral steroids, the plan was to consider immunosuppression
therapy. She continued to follow up at our office for routine yearly exams.
01/26/2010 – SC did not have any significant flare ups for the next several years, but did have
minor episodes she self-medicated with the oral ibuprofen and topical Pred Forte, but did not
like the frequency or dosing.
Best corrected visual acuity was 20/20 OD, OS. Objective testing revealed normal sclera OD and
OS with no signs of active inflammation. The anterior segments were healthy OU. She was
dilated with 1% tropicamide and the posterior segment showed no signs of inflammation OU,
with cup to disc ratios at .3 /.3 OD, .35 /.35 OS. Tonometry by applanation was 16mmHg OU
using Fluress.
She was diagnosed with a history of recurrent Diffuse Anterior Scleritis OD (quiescent at this
visit), and switched from ibuprofen to the oral NSAID flurbiprofen, 100mg TID PO ongoing (1 pill
3 times a day, instead of 4 pills, 4 times a day), and again cautioned about the judicious use of
the topical steroid, and was switched to Lotemax (loteprednol), to help reduce the potential
side effects of ongoing topical steroids.
SC also took our recommendation to follow up with a local rheumatologist and had another
blood panel performed. This time the ANA was higher than normal. A thorough evaluation
showed no evidence of Lupus despite the mildly high ANA. And there were no signs of AS, but
it was recommended to continue to monitor, and stay on the oral flurbiprofen. There was a
discussion of immunosuppression, but the patient denied.
02/27/2011 – Stacy reported to the office complaining of a Scleritis flare up OD that has been
persistent despite oral flurbiprofen treatment for 3 months. She also felt the Lotemax was not
as effective as the Pred Forte, and was using that instead.
Best corrected visual acuity was 20/20 OD, OS. Objective testing revealed 1-2+ sectoral
conjunctival and scleral injection OD. The scleral injection did not blanch with 10%
phenylephrine or stain with fluorescein. There was point tenderness upon palpation of the
globe. The right cornea and anterior chamber were clear. The left anterior segment was
healthy. She was dilated with 1% tropicamide and the posterior segment showed no signs of
inflammation OU, with cup to disc ratios at .3 /.3 OD, .35 /.35 OS. Tonometry by applanation
was 18mmHg OU using Fluress.
She was diagnosed with recurrent Diffuse Anterior Scleritis OD and switched from flurbiprofen
to Celebrex (celecoxib) 100mg BID PO. Several attempts over the years had been made to
switch to Lotemax (loteprednol) vs Pred Forte to help reduce harmful side effects, but SC
claimed it did not touch her discomfort and continued on Pred Forte.
She reported back to the office after a month of Celebrex treatment stating she started to
notice some improvement. SC was continued on Celebrex 100mg BID PO long term.
04/25/2012 – After a year of Celebrex treatment, SC returned with an intense bout of redness,
pain and discomfort OD, despite treatment of Celebrex 100 mg BID PO and topical Pred Forte
QID.
Best corrected visual acuity was 20/20 OD, OS. Objective testing revealed 3+ sectoral
conjunctival and scleral injection OD. The scleral injection did not blanch with 10%
phenylephrine or stain with fluorescein. There was point tenderness upon palpation of the
globe. The right cornea and anterior chamber were clear. The left anterior segment was
healthy. She was dilated with 1% tropicamide and the posterior segment showed no signs of
inflammation OU, with cup to disc ratios at .3 /.3 OD, .35 /.35 OS. Tonometry by applanation
was 18mmHg OU using Fluress.
She was diagnosed with recurrent Diffuse Anterior Scleritis OD and referred for additional
treatment (oral steroid vs systemic immunosuppression therapy). SC requested the Mayo Clinic
(140 miles away), and was seen by a uveitis specialist who concurred with our diagnosis, and
treated SC with a sub-tenon’s injection of Kenalog (triamcinolone). She reported almost
immediate relief of her symptoms. She was to continue the oral NSAID therapy, and did not
follow up with our clinic until almost a year later.
02/18/2013 – SC reported for a complete exam stating her Scleritis has been under control with
oral NSAID’s. She self-discontinued the Celebrex due to the potential cardiac complications,
and has been using oral ibuprofen instead. She continued to use topical Pred Forte during
occasional flares. She also stated she was not seeing as well as she had in the past OD.
Best corrected visual acuity was 20/30 OD, 20/20 OS. Objective testing revealed normal sclera
OD and OS with no signs of active inflammation. She was found to have a 2+ posterior
subcapsular lens opacity OD. The anterior segment was healthy OS. She was dilated with 1%
tropicamide and the posterior segment showed no signs of inflammation OU, with cup to disc
ratios at .3 /.3 OD, .35 /.35 OS. Tonometry by applanation was 18mmHg OU using Fluress.
She was diagnosed with a history of recurrent Diffuse Anterior Scleritis OD (quiescent at this
visit), and a new posterior subcapsular cataract OD. It was discussed that years of steroids
(topical, oral and injectable), combined with her chronic inflammation, have led to a cataract in
her right eye. SC also had large shift in the manifest refraction, most likely due to the new
cataract formation, but was sent for labs (FBS and HgA1c) to rule out diabetes after years of
steroid use, and pentacam topography to rule out irregularly induced astigmatism. All were
normal.
SC was continued on oral ibuprofen. In place of her topical Pred Forte, we recommended using
a steroid sparing agent, and started her on off-label Restasis (0.05% cyclosporine) QID OU, to
help decrease the underlying inflammatory cause of her scleritis. It was discussed that several
recent case reports have shown success with this off-label regimen in controlling scleritis, and
SC agreed to try.
06/03/2015 – SC reported for complete eye exam stating her Scleritis has been holding stable
with minimal flares. She very rarely uses the topical Pred Forte, and the Restasis and oral
ibuprofen have been keeping things in check. She also reported she was recently diagnosed
with osteoarthritis, and placed on Celebrex again. Her orthopedic doctor is also suspicious for
rheumatoid arthritis and running labs.
Best corrected visual acuity was 20/30 OD, 20/20 OS. Objective testing revealed normal sclera
OD and OS with no signs of active inflammation. The 2+ posterior subcapsular lens opacity OD
was unchanged. The anterior segment was healthy OS. She was dilated with 1% tropicamide
and the posterior segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3
OD, .35 /.35 OS. Tonometry by applanation was 18mmHg OU using Fluress.
She was diagnosed with a history of recurrent Diffuse Anterior Scleritis OD (quiescent at this
visit), and a stable posterior subcapsular cataract OD. She was continued on the oral Celebrex
and Restasis QID OU. She will return in one year for a complete eye examination, unless she
has another flare, or worsening cataract complaints.
Summary of treatment:
Visits
12/14/04
Scleri
tis
Oral
Ibuprofen
800mg TID
with taper for
6 weeks
Oral
Prednisone
with taper,
Rx’ed at U of
M
Pred Forte
QID with
taper for 6
weeks
Pred Forte
QID when
flares
Treat
ment
Plan:
4/05/06
HLA-B 27+
Blood tests
found to be
HLA-B 27+
1/26/10
100 mg
Flurbiprofen
TID
Pred Forte QID
when flares
HLA-B 27+
2/27/11
200 mg
Celebrex
Pred Forte QID
when flares
HLA-B 27+
? ANA Elev
Visits
4/25/12
Scleri
tis
SubTenons
Injection OD
Rx’ed at Mayo
Treat
ment
Plan:
Pred Forte
QID when
flares
HLA-B 27+
? ANA Elev
2/18/13
6/3/15
Oral
Ibuprofen
200 mg
Celebrex
Pred Forte
QID when
flares
Pred Forte PRN
PSC OD
identified
Added off
label Topical
Cyclosporine
QID OU
Topical
Cyclosporine
QID OU
HLA-B 27+
? ANA Elev
Suspicious for
RA
HLA-B 27+
? ANA Elev
Long Term Outcome 2015
Although we do not have a definitive underlying systemic diagnosis, the positive HLA B-27 could
be the cause of her chronic inflammation. We are fortunate that SC has not developed any
additional ocular complications, aside from the PSC. And as time goes by, as it has already
shown, more will become evident. The underlying theme here is that scleritis is a chronic
condition that has no quick fix. If SC were to present today, we would start topical cyclosporine
sooner, and be more aggressive in our recommendation for immunosuppressive therapy,
followed by oral NSAID’s. Especially with the advent of today’s newer biologic agents, which
have been specifically studied for their safety and efficacy in controlling severe recalcitrant
ocular inflammation.
Discussion
Epidemiology
Scleritis can occur in patients of any age, but most commonly occurs in the fourth to sixth
decades, with the mode in the fifth decade.3 It affects more women than men in a ratio of
1.6 : 1. The condition is bilateral in 52% of patients, with half of these cases occurring in both
eyes simultaneously. Scleritis occurs in all races without any predilection.
Scleritis typically has a slow insidious onset, where the eye becomes red, painful, and swollen
within a period of 5 to 10 days. The hallmark symptom is pain of moderate to severe intensity,
with exquisite tenderness to palpation of the globe. The discomfort frequently radiates to the
forehead, jaw, temple, or sinuses. Often times, the severity of pain is out of proportion with the
clinical signs. Mild tearing and mild-to-moderate photophobia may be present. 2,3
The redness may have a bluish or violaceous tinge, with injection and dilation of the deep
episcleral blood vessels. Recurrences, not necessarily in the same location, are common over a
period of many years, and usually decrease in frequency after the first 3 to 6 years. Vision may
be affected in anterior scleritis, and is almost always involved in posterior scleritis due to
extension of the inflammatory process to adjacent ocular structures. This often results in
keratitis, uveitis, glaucoma, cataract, or fundus abnormalities.3,4
Anatomy
The sclera’s function is to provide a protective outer coat for the intraocular contents. It
makes up 90% of the outer tunic extending posteriorly from the corneal perimeter to the optic
foramen, perforated by the optic nerve. The thickness of the adult human sclera varies. It is
thickest at the posterior pole, 1-1.35mm and decreases gradually to 0.4-0.6mm at the equator
and is thinnest directly under the recti muscles, 0.3mm.4,5 From the insertion of the
extraocular muscles towards the limbus, the sclera will gradually increase in thickness up to
0.8mm, where it blends with the cornea. Women have been found to have slightly thinner
sclera than men. There is also an increase in scleral thickness and scleral opacification
(yellowing) with age.4
To help distinguish between the different layers, as you work posteriorly from the cornea, you
are first met with the bulbar conjunctiva, which is immediately followed by Tenon’s capsule,
episclera, and then sclera. The episclera is a thin, dense, well vascularized layer of connective
tissue that lies just between Tenon’s capsule and the sclera. The episcleral attachments to
Tenon’s capsule are dense near the limbus and weaken progressively toward the equator. The
episclera if firmly attached to the underlying sclera and its fibers blend imperceptibly with the
stroma of the sclera. 4 The sclera is composed of numerous bundles which run in whorls and
loops that are made of collagen types I, III and VIII, elastin and proteoglycans.5 The posterior
pole of the sclera, or lamina cribrosa, is weakened and has a sieve-like appearance where it is
perforated by the axons of the optic nerve. This is where the sclera is fused with the dura
mater and arachnoid sheaths of the optic nerve.2 The innermost part of the sclera adjacent to
the uvea is the lamina fusca, which has many grooves caused by the passage of ciliary vessels
and nerves.2 Although the sclera has many blood vessels passing through, the sclera itself is an
avascular tissue and derives it nutrition from the episclera above and choroid below. However,
it is heavily innervated with nerves, particularly in the anterior segment near the insertion of
the extra ocular muscles. It is damage to these nerves that account for the exquisite discomfort
that patients experience.2
An understanding of the anatomy of the vascular plexuses contained within the conjunctiva,
episclera, and sclera is essential in order to reliably differentiate episcleritis and scleritis. There
is a superficial vascular plexus of vessels within the conjunctiva, and two vascular layers within
the episclera, the superficial and deep. The sclera itself is avascular, and, therefore, highly
dependent on the vascular coats on either side.2 In episcleritis, the conjunctival and superficial
episcleral vascular plexuses are displaced outward from the sclera, and the underlying deep
episcleral plexus is uninvolved and flat against normal-thickness scleral tissue. In scleritis all
vascular layers may be involved, but the maximal involvement is in the deep episcleral plexus,
which is displaced outward by edematous swollen sclera. This displacement of the deep
episcleral vessels is seen only in patients with scleritis.2 The conjunctival and superficial vessels
can be blanched with 2.5–10% phenylephrine, while the deep vessels are hardly affected.
Examination
When performing a scleral examination, every attempt should be made to use natural daylight
in addition to the slit lamp examination.2,6 Examination in daylight is sometimes the only way
to distinguish episcleritis from scleritis, as the natural color of the sclera is not distorted. In
episcleritis, the eye appears pink to red; in scleritis, the eye has a deep bluish-red or violaceous
tinge. If scleral necrosis is present, blue-gray to dark-brown areas corresponding to the
underlying uvea may become visible through the translucent sclera. If tissue necrosis is
progressive, the sclera may become avascular, producing a central white area of necrotic tissue,
surrounded by a well-demarcated black or dark-brown circle.2,6 The slough may be gradually
replaced by granulated tissue, leaving the underlying uvea bare or covered by a thin layer of
conjunctiva.
Slit-lamp examination under conditions of diffuse illumination helps to detect congested
vessels, nodules, or avascular areas with necrosis, or visible uveal “show through.”2,3,6 It also
helps to differentiate the configuration of vessels; in episcleritis, congested vessels follow the
usual radial pattern while in scleritis this pattern is altered and new, abnormal vessels are
formed.
Slit lamp examination with the narrow slit beam is used to detect the depth of inflammation,
indicating which network of vessels is predominantly affected. Maximum congestion is seen in
the deep episcleral plexus, although the overlying superficial episcleral plexus is frequently
involved. The edema is localized to the scleral and episcleral tissues. The anterior and the
posterior edges of the narrow slit beam are displaced forward. Red-free light can also be
helpful in revealing areas of maximal vascular congestion, avascularity, and new vascular
channels. Again, topical application of phenylephrine will only blanch the superficial episcleral
plexus, leaving the deep episcleral plexus congested.
Evaluation of adjacent structures should be performed at every follow-up visit for a patient with
scleritis, looking for keratitis, uveitis, glaucoma, cataract, or fundus abnormalities.
Classification
In general, scleritis can be divided into two major categories based on cause; non-infectious and
infectious. Noninfectious scleritis, is most commonly caused by immune-mediated disorders
associated with inflammatory diseases. The systemic autoimmune conditions, tend to underlie
the most severe and fulminant processes that may involve the sclera. The second group,
infectious scleritis, is most commonly initiated by surgery or local extension from adjacent
ocular tissues. While the clinical presentation of infectious scleritis may be similar to that
associated with immune-mediated diseases, scleritis of infectious etiology occurs more rarely,
and their history will usually aid in differentiating the two. The challenge for the clinician is to
diagnose and treat promptly any underlying systemic disorder while preventing long-term
ocular sequelae and vision loss.
Noninfectious scleritis may be classified on the basis of clinical appearance. The most accepted
classification was proposed by Watson and Hayreh and divides scleritis into anterior and
posterior forms.7 Anterior scleritis is further divided into diffuse, nodular, necrotizing with
inflammation (necrotizing), and necrotizing without inflammation (scleromalacia perforans).
Classification can assist in determining the severity of the disease and selecting appropriate
therapy.
Diffuse anterior scleritis - The most common and least severe form of scleral disease. It can
vary from a small, sectoral area of inflammation, to involvement of the entire anterior segment.
It is characterized by diffuse involvement of the anterior sclera by edema and dilation of the
deep episcleral vascular plexus. The patient may be photophobic and the globe is usually
tender to touch. Corneal infiltrates, thinning, or stromal keratitis may be present with corneal
ulceration, but it is far less common than necrotizing scleritis. However, the underlying
trabecular meshwork may be involved (trabeculitis), with increased intraocular pressure, due to
the raised episcleral venous pressure.
Nodular anterior scleritis - Is characterized by a deep red or violaceous scleral lesion, usually
located in the interpalpebral area, about 3 to 4 mm from the limbus. The lesions are tender to
the touch, immobile, and result from a more localized area of scleral edema. Though there is
no evidence of capillary non-perfusion, and no evidence of scleral necrosis.
Necrotizing anterior scleritis - The most severe and destructive form of scleritis, and is a serious
threat to vision and the integrity of the eye. There is usually severe pain and extreme scleral
tenderness. The scleral involvement is characterized by severe vasculitis and closure of the
episcleral vascular bed, such that there are visible areas of capillary non-perfusion on clinical
examination, and infarction and necrosis of the involved sclera. Necrosis of the sclera can be
subtle or profound, localized, or generalized, and progress rapidly to expose the choroid. It
appears as white avascular areas surrounded by scleral inflammation and diffuse congestion of
the abnormal deep vascular episcleral channels. The involved tissue becomes thin, revealing
the brown color of the underlying uvea. There is commonly spread of inflammation that
involves the cornea, ciliary body, and trabecular meshwork, resulting in keratitis, anterior
uveitis, and elevated intraocular pressure, which may lead to staphyloma formation.
Necrotizing without inflammation (Scleromalacia perforans) - A rare, bilateral condition that is
seen most frequently among elderly women with severe rheumatoid arthritis. It is the result of
an obliterative arteritis involving the deep episcleral vascular plexus. And does not produce the
acute clinical signs of necrotizing scleritis, but is asymptomatic. It can present with blurred
vision from high astigmatism due to scleral thinning, which leads to loss of scleral rigidity. It is
characterized by yellow to grayish patches on the sclera that gradually develop a necrotic
slough. The sclera becomes parchment white, avascular, and thin. There may be exposure of
the choroid and a staphyloma may form if the intraocular pressure is elevated. There is no
corneal involvement except for limited peripheral corneal thinning.
Posterior scleritis - Is defined as inflammation of the sclera, posterior to the ora serrata. It can
frequently involve adjacent structures such as the choroid, retina, optic nerve, extraocular
muscles, and orbital tissues. The clinical presentation of posterior scleritis depends on the
location, extent, and severity of involvement of the posterior sclera. Posterior scleritis may
occur in association with anterior scleritis, or be isolated. In either case, the most common
presenting symptoms are decreased vision and pain. In patients with associated anterior
scleritis, the eye is red. When it occurs in isolation, the eye may be white. Ultrasonography
using a B-scan ultrasound remains the key to diagnosis and reveals a thickened posterior coat
of the eye which is usually greater than 2 mm, and a classic “T” sign.2,6 This is formed by the
sonographically empty space occupied by the optic nerve, and the edematous Tenon’s space,
adjacent to the optic nerve. When visualizing the posterior segment, it may appear normal, or
there can be a variety of signs, such as chorioretinal granulomas, and optic nerve swelling with
or without cotton-wool spots. The most common posterior segment signs are choroidal folds,
subretinal mass, disk edema, macular edema, and annular ciliochoroidal detachment. Large
serous retinal detachments can also be found due to shallowing of the anterior chamber, as
well as secondary angle-closure glaucoma from ciliary body rotation from uveal effusion.
Complications
Complications generally occur late in the disease course and are most commonly seen in
necrotizing scleritis. In a retrospective review, nearly 60% of scleritis patients developed an
ocular complication.2 Visual loss may be found in 16–37% of patients and is secondary to
uveitis, keratitis, glaucoma, cataract, or fundus abnormalities. Patients with scleritis associated
with uveitis and glaucoma often have severe visual loss, and it is these eyes that most
commonly require enucleation.3
Uveitis develops in more than one-third of patients with scleritis, arising as a direct extension of
scleral inflammation to the adjacent uveal tract. The anterior chamber reaction is usually not
severe, although anterior and posterior synechiae may develop. Uveitis is highly associated with
complications that lead to visual loss, including peripheral ulcerative keratitis and glaucoma,
and may be a poor prognostic indicator.6 Anterior uveitis is most often present in necrotizing
scleritis, whereas posterior uveitis is more common with posterior scleritis. The presence of
scleritis-associated uveitis does not seem to correlate with the presence of systemic diseases.
In general, keratitis associated with scleral inflammation involves the adjacent peripheral
cornea and may be present in 14–37% of patients.8 Peripheral corneal thinning, corneal
infiltrates, interstitial keratitis, and peripheral ulcerative keratitis are possible complications;
they may even precede the scleritis. Peripheral corneal thinning is most often seen in diffuse
anterior scleritis, but is not uncommon in patients with long-standing RA. Grayish discoloration
may occur in areas of thinning and, later, localized vascularization with subsequent lipid
deposition. Thinning can lead to irregular astigmatism and visual loss. Perforation is rare unless
the eye is traumatized. Small, superficial, peripheral corneal infiltrates are not unusual and
occur adjacent to areas of scleritis.6,8
Interstitial keratitis is characterized by corneal edema, intact epithelium, and one or more gray
opacities. It is usually peripheral, but may be central. If not treated, the opacities can progress
centrally and coalesce, resulting in a sclerotic appearance. White opacities may develop
peripheral to the advancing edge and take on a crystalline appearance. Stromal vessels
peripheral to the leading edge may become permanent, with subsequent lipid deposition in the
opacities, giving a ‘candy floss’ appearance.2 Visual loss occurs with extension into the visual
axis.
Peripheral ulcerative keratitis is the most severe form of keratitis associated with scleritis and
usually occurs in necrotizing scleritis. Progressive thinning and ulceration with vascularization,
white cell infiltration, and loss of stroma occur. Without treatment, spontaneous perforation
can occur. Visual loss can result from irregular astigmatism, progression into the visual axis, or
perforation. Peripheral ulcerative keratitis is highly associated with visual loss and occult
systemic vasculitic disease.6,8
Elevated IOP is present in approximately 13% of patients with scleritis, and may occur
transiently during acute inflammatory episodes.6 Permanent visual field changes in these
patients are less frequent. Scleral edema and increased episcleral venous pressure from
vascular congestion are probably important. However, increased IOP in this setting may also be
caused by steroid treatment, open-angle glaucoma from uveitis, or angle-closure mechanisms.
Posterior subcapsular cataract formation develops from intraocular inflammation or steroid
treatment. Cataract removal, when inflammation has resolved, must be undertaken with
caution because of the risk of recurrent scleral inflammation after surgery.
Fundus abnormalities related to scleral inflammation may occur in 6% of patients, most
commonly cystoid macular edema, optic nerve edema, retinal detachment, and choroidal folds.
Retinal pigment epithelial migration as a result of pars plana inflammation may lead to
characteristic peripheral retinal changes. Combined retinal and choroidal detachments can
arise. Choroidal folds and exudative retinal detachment may lead to relative hyperopia, which
usually resolves spontaneously with appropriate treatment. If any of these fundus changes are
long-standing, permanent visual loss can occur. Posterior segment complications are mostly
seen in posterior scleritis. Posterior segment inflammation in an eye with anterior scleritis
should raise suspicion of concomitant posterior scleral disease.
Associated Diseases
The exact pathogenic mechanisms that incite scleral inflammation are unknown, although Thelper type 17 cells (Th17 cell) have recently been implicated in the pathogenesis of human
autoimmune disease, including noninfectious scleritis.9 It is generally accepted that a
disordered immune response leads to both tissue and blood vessel damage. A large number of
connective-tissue disorders are associated with scleral disease, but the most common is
rheumatoid arthritis. Granulomatosis with polyangiitis (GPA, formerly wegener’s
granulomatosis), is the most common vasculitis associated with scleritis.2,6,8 Other systemic
diseases associated less commonly include relapsing polychondritis, inflammatory bowel
disease, systemic lupus erythematosus, and polyarteritis nodosa.
Scleritis may be the presenting clinical manifestation of a systemic disease. An associated
systemic disease is present in approximately 40% to 57% of patients with scleritis;
30% to 48% have an associated connective tissue or vasculitic disease, 5% to 10% an infectious
etiology, and 2% have atopy, rosacea, or gout.2,3,6, A systemic disease is most commonly seen
in patients with necrotizing scleritis and scleromalacia perforans, followed by those with diffuse
anterior, nodular anterior, and posterior types. Patients with scleritis and peripheral
keratopathy are especially likely to have an associated systemic disease.8 Rheumatoid arthritis
is by far the most common systemic association, followed by granulomatosis with polyangiitis,
relapsing polychondritis, systemic lupus erythematosus, and arthritis with inflammatory bowel
disease.2,3,6 Of patients with a systemic disease, 77.6% have a previously diagnosed disease,
14.0% have conditions diagnosed as a result of the initial evaluation, and 8.4% develop a
systemic disease during follow-up.2,3,6
Necrotizing scleritis is most frequently identified in patients with GPA, rheumatoid arthritis,
polyarteritis nodosa, or relapsing polychondritis, and is less likely to be seen in those with
systemic lupus erythematosus, or the seronegative spondyloarthropathies.
As with anterior scleritis, rheumatoid arthritis is the most common systemic disease association
in posterior scleritis, followed by other connective tissue diseases (systemic lupus
erythematosus, psoriatic arthritis) and systemic vasculitides (GPA, polyarteritis nodosa,
relapsing polychondritis); however, one must also consider infectious etiologies (Lyme disease,
toxoplasmosis, herpes zoster) and neoplastic masquerade syndromes.2,3,6
The diagnosis of a connective tissue or vasculitic condition in patients with scleritis carries a
guarded systemic and ocular prognosis and demands prompt and aggressive systemic therapy.
The mortality from vasculitic complications in patients with granulomatosis with polyangiitis
and polyarteritis nodosa is high in untreated patients, while the ocular morbidity and visual loss
is more prevalent given the frequent occurrence of necrotizing scleritis and peripheral
ulcerative keratitis with these diseases.2,3,6
The ocular prognosis of scleritis associated with connective tissue or vasculitic disease varies
depending on the specific entity. Scleritis associated with spondyloarthropathies
or systemic lupus erythematosus is usually a benign, self-limiting condition. That associated
with rheumatoid arthritis or relapsing polychondritis is of intermediate severity.2,3,6
Scleritis associated with granulomatosis with polyangiitis is a severe disease that can lead to
permanent blindness or even loss of the eye. Infectious scleritis, either endogenous or
exogenous, may be caused by the direct invasion of a microorganism or by the immune
response to an infectious pathogen. Historical details that raise the index of suspicion of an
infectious etiology include prior ocular trauma or surgery (especially a scleral buckling
procedure, strabismus surgery, or pterygium excision), contact lens use, systemic or local
immunosuppression, and local debilitating diseases (past history of recurrent keratitis caused
by herpes simplex virus or herpes zoster virus). All classes of microorganisms, including
bacteria, viruses, fungi, and parasites, can infect the sclera and produce a clinical picture
identical to that seen with immune-mediated disease.2,3,6
Other entities have been associated with scleritis, such as drug reactions to pamidronate
(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronic acid (Zometa), and
ibandronate (Boniva).2,3,6
Lab Testing
The presence of scleritis, even with the initial episode, requires a thorough diagnostic
evaluation, guided by the patient’s clinical presentation, history, and review of systems.
There is no single correct set of tests for every patient with scleritis. Typical initial
investigations might include a chest radiograph, urine analysis, serum chemistries (which may
indicate renal dysfunction in systemic vasculitides), syphilis serologies (FTA-ABS and RPR), and
antineutrophil cytoplasmic antibody (ANCA) testing. ANCAs are specific markers for a group of
related systemic vasculitides that include polyarteritis nodosa (PAN), granulomatosis with
polyangiitis, microscopic polyangiitis, Churg-Strauss syndrome, and pauci-immune
glomerulonephritis.2,3,6
Specifically, ANCAs are antibodies directed against cytoplasmic azurophilic granules of
neutrophils and monocytes. These antibodies may be divided into 2 classes based on the
pattern of staining seen on immunofluorescence. The cytoplasmic pattern, or c-ANCA, is
both sensitive and specific for GPA. The perinuclear pattern, or p-ANCA, is associated with PAN,
microscopic polyangiitis, relapsing polychondritis, and renal vasculitis. All positive ANCA tests
should be confirmed by testing for antibodies to proteinase-3 (PR3) and/or myeloperoxidase
(MPO). Between 85% to 95% of all ANCA found in GPA is c-ANCA with antigen specificity for
PR3, which is highly specific for the disease, while the remainder is p-ANCA directed against
MPO. In contrast, the diagnostic sensitivity of c-ANCA and p-ANCA for PAN is only 5% and 15%
respectively, while in patients with microscopic polyangiitis, p-ANCA (anti-MPO) positivity is
more common (50% to 80%) with a smaller percentage (40%) having the c-ANCA (anti-PR3)
marker.3,6
Additional testing in the appropriate clinical context might include:
• Rheumatoid factor – due to high association with rheumatoid arthritis
 Human leukocyte antigen (HLA)-B27 - in the presence of polyarthritis or
spondyloarthropathy. Testing for HLA-B27 may be helpful when considering inflammatory
bowel disease as a cause of scleritis. Other conditions associated with the B27 antigen, such
as Reiter’s syndrome and ankylosing spondylitis, are less commonly associated with scleritis.
• Lyme serology in a patient with a history of a tick bite from an endemic area
• Antinuclear antibodies in individuals where SLE is suggested on history and physical exam
• Radiographic imaging of the sinus in the presence of sinus symptomatology
• Purified protein derivative (PPD) skin test or Quantiferon gold assay with a history of
tuberculosis exposure
• Ultrasound examination in patients suspected of having posterior scleritis.
Finally, a scleral biopsy may be considered in cases where infectious scleritis, foreign body, or
masquerade syndrome is suspected; but is rarely necessary. When the sclera is biopsied, thin
regions that might be prone to uveal prolapse should be avoided. Inflamed sclera may heal
poorly after biopsy and patch grafting may be required.2,3,6
Treatment
Important considerations in the formulation of a therapeutic plan include accurate classification
of scleritis type and identification of concomitant local or systemic disease, the exclusion of
possible infectious etiologies, and the potential for medication related toxicity, and/or possible
drug interactions. Additionally, the results of the Systemic Immunosuppressive Therapy for Eye
Diseases (SITE) Cohort study, have provided an important perspective regarding outcomes
following treatment in a large number of ocular inflammation patients with anterior uveitis,
intermediate uveitis, posterior uveitis, panuveitis, mucous membrane pemphigoid, and
scleritis. The investigators of this retrospective cohort study evaluated the incidence of
successful control of inflammation, of corticosteroid-sparing benefits, and use of treatmentrelated complications managed with immunosuppressive therapy at tertiary ocular
inflammation centers across the USA.10
The first line of treatment for patients with diffuse or nodular scleritis, not associated with an
underlying systemic vasculitis, is an oral NSAIDs, with or without the use of a topical
corticosteroid.2,3,6,10 A treatment response is usually evident within 2 to 3 weeks of
commencing therapy and sequential trials of various NSAIDs may be necessary in order to find
which agent is most effective. The selective COX-2 inhibitors are advantageous in cases where
adverse gastrointestinal side effects or drug interactions might otherwise limit treatment.
Patients with associated conditions such as gout, rosacea, or atopy require specific treatment of
the underlying disease.
Therapeutic failure with oral NSAIDs requires the addition or substitution of systemic
corticosteroids, commencing at high doses (prednisone 1 to 1.5 mg/kg/day), with subsequent
taper and discontinuation as soon as is possible while maintaining clinical remission with or
without continued NSAIDs.2,3,6,10,11 Typically, a slow and steady taper (10 mg per week) is
commenced once scleral inflammation has been controlled (usually within 7 to 14 days) until a
dose of 20 mg/day of prednisone is reached. The dose may be further reduced (2.5 to 5 mg per
week), or an alternate dosage schedule may be employed in patients in whom a slower taper is
anticipated in an effort to reduce steroid-associated side effects. Alternatively, intravenous,
high-dose methylprednisolone (1 g/day for 3 days, usually administered in divided doses, as 250
mg q 6 hours or 500 mg q 12 hours), alone or in conjunction with other immunosuppressive
agents, has been shown safe and effective for the induction of disease remission in patients
with severe scleritis. This approach obviates some of the potential side effects associated with
prolonged, high-dose oral corticosteroid therapy. Periocular injections of corticosteroids have
been reported to be safe and effective, both adjunctively and as primary therapy, in the
treatment of various forms of nonnecrotizing scleritis; however, their use is controversial due
to concerns surrounding the potential exacerbation of scleral melting and/or scleral
perforation. Recent reports support a potential role for subconjunctival injection of
triamcinolone acetonide in selected cases of nonnecrotizing anterior scleritis, especially where
systemic therapy is either not desired or poorly tolerated.11
Immunosuppressive therapy is indicated in patients with severe scleritis who have failed to
respond to high dose oral or intravenous corticosteroids or in whom unacceptably high doses of
systemic corticosteroids are necessary to achieve inflammatory control. The addition of
immunosuppressive therapy is “steroid sparing,” allowing lower doses of each medication to be
used in an effort to achieve inflammatory quiescence, while minimizing the side-effects of
either agent used as monotherapy at higher doses.2,3,6,10,11 Immunosuppressive medications
which have been successful in the treatment of scleritis include methotrexate, azathioprine,
cyclophosphamide, mycophenolate mofetil, daclizumab, infliximab, and rituximab. Typically
these drugs are commenced together with oral corticosteroids.
Scleritis associated with an underlying systemic vasculitis requires systemic immunosuppressive
therapy at the outset, typically with cyclophosphamide (1 to 3 mg/ Kg/day) supplemented with
systemic prednisone. This therapy is directed not only in an effort to control scleral
inflammation, but also for the treatment of the underlying systemic vasculitis, which, if left
untreated, carries a significantly high mortality, especially for patients with GPA and
polyarteritis nodosa. A similar therapeutic strategy may be extended to patients with
noninfectious necrotizing scleritis associated with other underlying systemic vasculitic or
connective tissue disease conditions such as rheumatoid arthritis or relapsing
polychondritis.2,3,6,10,11 Collaboration with other health care professionals (oncologist,
hematologist, or rheumatologist) will be required to properly control the disease process.
Patients with diffuse or nodular scleritis, not associated with underlying systemic vasculitic
disease, who have failed therapy with NSAIDs and/or systemic corticosteroids, may be treated
with a variety of other immunomodulatory agents. Methotrexate (7.5 to 15 mg orally or 15 mg
intramuscularly or subcutaneously once weekly), together with folic acid (1 mg daily) is
probably the best initial choice as it is both efficacious and steroid sparing in the treatment of
scleritis and has a favorable side effect profile and lower oncogenic potential as compared to
cytotoxic drugs (cyclophosphamide and chlorambucil). Oral azathioprine (1 to 2 mg/kg daily),
while less effective as monotherapy than other immunosuppressive agents in controlling severe
scleritis, is most frequently used in conjunction with systemic corticosteroids as a steroidsparing agent and is generally well tolerated. Similarly, oral mycophenolate mofetil (1 g twice
daily) may be most useful as a steroid-sparing agent in patients with controlled scleral disease
rather than as adjunctive therapy in patients with severe active scleritis requiring additional
immunosuppressive therapy. Infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor, has
been shown to be effective and safe in the management of refractory scleritis when
conventional immunosuppression has failed. Daclizumab (humanized immunoglobulin G
monoclonal antibody that specifically binds CD25 of the human interleukin-2 receptor that is
expressed on activated T lymphocytes) and rituximab (anti-CD20B cell monoclonal antibody)
have also been shown to be successful in the treatment of refractory scleritis.2,3,6,10,11
Cyclosporine A, a calcineurin inhibitor, acts by specifically inhibiting the action of T
lymphocytes. This action results in the inhibition of the synthesis of interleukin-2, a growth
factor for T lymphocytes.12,13 It has been widely used in the treatment of various ocular
inflammatory diseases. Its efficacy in the treatment of severe scleritis has been shown by
numerous studies. However, long-term use of systemic cyclosporine A can lead to adverse
reactions such as renal dysfunction, tremors, hirsutism, hypertension, and gum hyperplasia.
Therefore, topical cyclosporine A can be considered due to its improved safety profile in the
treatment of a variety of ocular surface disorders including dry eye syndrome, and severe
blepharitis. Topical use of Cyclosporine-A is also becoming popular for the prevention of
allograft rejection in corneal transplants, and for controlling immunologic or allergic disorders
of the ocular surface. Clinical studies have documented that cyclosporine after topical
application accumulates at the ocular surface and cornea reaching concentrations that are
sufficient for immunomodulation.12,13 It has also been used as an alternative treatment to
topical steroids in the treatment of the inflammatory response in progressive corneal melting.
Although no long term studies have been performed, several case reports showing the efficacy
of topical cyclosporine A in scleritis have been published.12,13 The typical regimen is four times
daily of topical 0.05% cyclosporine A (Restasis, Allergan, Irvine, CA) for as long as needed to
keep the inflammation under control.
Conclusion
Scleritis is a potentially sight-threatening, severe inflammatory disease that can be
progressively destructive. It is a chronic condition requiring continued treatment throughout a
patient’s life. Furthermore, scleritis may be the presenting manifestation of a potentially lethal
systemic vasculitic disease. It is therefore extremely important that the correct diagnosis be
made, and that subsequent adequate treatment be given as early as possible. The goal of
treatment in a patient with scleritis is to identify a potentially life threatening systemic etiology,
control ocular and systemic inflammation, make the patient comfortable, and prevent a scleral
melt. With today’s understanding of scleritis and immunosuppressant agents available, we are
better prepared to fight this disease than ever before.
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