Rheumatology 2007;46:17571762

Advance Access publication 5 August 2007

doi:10.1093/rheumatology/kem173

Review

Ocular manifestations of systemic lupus erythematosus

R. R. Sivaraj1, O. M. Durrani1, A. K. Denniston1, P. I. Murray1 and Caroline Gordon2
Ocular manifestations of lupus are fairly common, may be the presenting feature of the disease and can be sight-threatening. Almost any part
of the eye and visual pathway can be affected by inflammatory or thrombotic processes. Ocular pain and visual impairment require urgent
assessment by an ophthalmologist. Infection should be excluded. Optic neuritis and ischaemic optic neuropathy may be difficult to
distinguish. Scleritis and severe retinopathy require systemic immunosuppression but episcleritis, anterior uveitis and dry eyes can usually
be managed with local eye drops. Vaso-occlusive disease, particularly in the presence of antiphospholipid antibodies, requires treatment with
anticoagulation and proliferative retinopathy is treated with laser therapy. Hydroxychloroquine rarely causes ocular toxicity at doses under
6.5mg/kg/day. When this has occurred, it has been associated with more than 5 years of drug exposure.
WORDS:

Lupus, Ocular, Ophthalmic, Retinal, Scleral, Corneal, Optic.

Introduction

Diagnosis and assessment of disease activity

Systemic lupus erythematosus (SLE) is a chronic, autoimmune,

multisystem disease which may affect the eyes and/or visual
system in up to a third of patients. These ocular manifestations
cause significant morbidity in their own right, but can also be a
useful indicator of underlying systemic disease activity. Although
early recognition and treatment have led to a reduction in severe
ocular complications, ocular involvement in SLE is still a
potentially blinding condition.

The diagnosis of SLE is essentially clinical and is generally based

on the presence of four or more of the 11 features listed by the
American College of Rheumatology classification criteria (ACR/
ARA) [2]. The course of disease is highly variable with many
patients having remissions between exacerbations. Assessment of
disease activity by a validated activity index helps in monitoring
and provides a more reliable basis for therapeutic intervention.
Ophthalmic problems may be an important part of overall disease
activity, and are thus featured in the latest version of the British
Isles Lupus Assessment Group index of disease activity (BILAG
2004) [3].

Methods
In addition to the authors personal knowledge of the subject, we
performed a comprehensive literature search using PubMed,
medline and dialog datastar from 1966 to present using key
words lupus, SLE, eye, orbit, conjunctiva, cornea, glaucoma,
iridocyclitis, retina, choroid, neuro ophthalmology and treatment.
We also mined the bibliographies of the included publications for
additional relevant publications. It should be noted that there is a
paucity of controlled studies addressing the prevalence and
treatment of ophthalmic manifestations of SLE.

Presentation of ophthalmic disease

Ocular manifestations in SLE are fairly common, potentially sight
threatening and may be the presenting feature of their disease
[4, 5]. SLE may affect almost any part of the eye and visual
pathway. Additionally drugs used in the treatment of SLE may
cause ocular problems such as cataract or retinopathy.
The patient will usually be aware that there is an eye problem,
and will report it to their rheumatologist (or General
Practitioner). It is therefore important that the implications of
these symptoms are recognized and appropriate help is sought. In
general terms, pain (often accompanied by visible inflammation or
redness) usually indicates significant external/anterior segment
disease, whereas problems with vision (blurring, distortion, double
vision usually indicates posterior segment/neuro-ophthalmic
disease (Tables 1 and 2). All such complaints warrant urgent
referral to an ophthalmologist for more detailed assessment.

Pathophysiology of ocular disease

SLE may cause ocular disease by a number of mechanisms
including immune complex deposition and other antibody related
mechanisms, vasculitis and thrombosis. Immune complex deposition has been identified in blood vessels of the conjunctiva, retina,
choroid, sclera, ciliary body, in the basement membranes of the
ciliary body and cornea, in the peripheral nerves of the ciliary
body and conjunctiva [1]. Antibody dependent cytotoxicity may
cause retinal cell death and demyelination of the optic nerve.
Pathogenic circulating antibodies include anti-phospholipid antibodies (APA) and antineuronal antibodies. Similar mechanisms
centred on the lacrimal gland may result in secondary Sjogrens
syndrome with consequent dry eyes (keratoconjunctivitis sicca)
due to inadequate tear production; this is in marked contrast to
most cases of dry eyes in the general population where it is
primarily a problem of disturbance of the lipid layer of the tear
film resulting in increased tear evaporation.

External eye disease

Eyelid disease. SLE (and discoid lupus erythematosus) can
present with a discoid lupus-type rash over the eyelids. These
discrete raised scaly lesions must be distinguished from the much
more common chronic blepharitis (inflammation of lid margins).
These lesions usually respond well to systemic but not topical antiinflammatory therapy [6].
Lacrimal system disease. Dry eye syndrome (keratoconjunctivitis sicca) is the most common ocular feature of SLE (around a
third of patients) and is often associated with secondary Sjogrens
syndrome [7, 8]. Usually, symptoms are relatively mild (irritation,
redness) but severe pain and visual loss may occur. A reduced tear
film and corneal changes are evident on slit-lamp examination.
Tear production can be assessed by the Schirmer test which

Academic Unit of Ophthalmology and 2Department of Rheumatology, Division of

Immunity and Infection, University of Birmingham, UK.
Submitted 12 January 2007; revised version accepted 25 May 2007.
Correspondence to: C. Gordon, Rheumatology (East Wing), Division of
Immunity and Infection, The Medical School, University of Birmingham,
Vincent Drive, Birmingham B18 7QU, UK. E-mail: p.c.gordon@bham.ac.uk

1757
The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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KEY

R. R. Sivaraj et al.

1758
TABLE 1. Causes of red eye in SLE
Common

Dry eye (kerato-conjunctivitis sicca)

Less common

Episcleritis
Scleritis
Conjunctivitis (non-infective)
Keratitis (other than kerato-conjunctivitis sicca)
Anterior uveitis

Rare

TABLE 2. Causes of loss of vision in SLE

Severe kerato-conjunctivitis sicca

Lens

Cataract (secondary to inflammation and/or

corticosteroids)
Vitreous haemorrhage (secondary to
proliferative retinopathy)
Severe vaso-occlusive retinopathy
Central retinal vein occlusion (CRVO)
Branch retinal vein occlusion (BRVO)
Central retinal arteriole occlusion (CRAO)
Branch retinal arteriole occlusion (BRAO)
Exudative retinal detachment
Toxic maculopathy (secondary to anti-malarial treatment)
Lupus choroidopathy
Choroidal effusion
Choroidal infarction
Choroidal neovascular membranes
Optic neuritis
Anterior ischaemic optic neuropathy
Posterior ischaemic optic neuropathy
Optic chiasmopathy
Cortical infarcts

Vitreous
Retina

Choroid

Neuro-ophthalmic

measures the wetting of a test strip hung over the lower lid for a
period of 5 min.
Milder forms of dry eye can be treated with artificial tear drops.
The choice of treatment depends on balancing the disadvantages
of frequent instillation required for low viscosity preparations
(such as hypromellose) with the blurred vision caused by more
viscous preparations (such as liquid paraffin). Often a medium
viscosity drop (e.g. a carbomer) or a combination (low viscosity
during the day, high viscosity at night) is preferred. In more severe
cases, drainage of tears may be reduced by temporary or
permanent occlusion of the puncta.

Orbital disease. Rare ocular presentations include orbital

masses, periorbital oedema, orbital myositis, panniculitis, acute
orbital ischaemia and infarction are rare presentations of SLE.
A biopsy is often necessary to confirm the diagnosis. Treatment is
with systemic immunosuppression [912].
Anterior segment disease
Corneal disease. Although the most common, the changes of
dry eye syndrome are not the only corneal manifestation of SLE.
Recurrent corneal erosions (large breaks in the corneal epithelium) typically present as a painful watery eye that comes on at
waking and improves over the course of the day. Another corneal
presentation is punctate epithelial loss. This may respond to
systemic antimalarials suggesting that this may be an autoimmune
rather than a dry eye phenomenon [13]. Peripheral ulcerative
keratitis is rare and is an ominous marker of the presence of active
systemic vasculitis [14]. Acute unilateral corneal stromal infiltration and oedema has been reported and responds rapidly to
topical corticosteroid therapy.
Episcleral and scleral disease. Episcleritis (superficial) and
scleritis (deeper inflammation of the sclera) are both seen in SLE,
and may be the presenting feature of the disease [15]. Episcleritis
usually presents with mild, if any, irritation and redness due to

FIG. 1. Necrotizing anterior scleritis resulting in scleral thinning. Areas of scleral

thinning appear dark due to visualization of the underlying uveal tissue.

injection of the superficial blood vessels. Since only the superficial

blood vessels are affected, a drop of phenylephrine (e.g. 2.5%) will
cause visible blanching of the vessels, so confirming the diagnosis.
Episcleritis is usually self-limiting.
Scleritis is much more painful, may be sight threatening and
requires urgent assessment by an ophthalmologist. The pain is so
severe that it can wake the patient from sleep; it may be described
as an ache or boring and may be generalized to the whole eye or
the side of the face. In anterior scleritis there is redness due to
injection of the deeper episceral vessels (which do not blanch on
the phenylephrine test); the sclera itself is avascular. The redness
may be concealed under the upper lid so it is worth examining this
area by lifting the lid, whilst asking the patient to look down. It is
usually unilateral and is not associated with discharge. Anterior
scleritis may be diffuse or nodular in distribution. Rarely it may
result in significant destruction (necrotizing scleritis) leaving an
area of scleral thinning (Fig. 1). Posterior scleritis does not cause a
red eye (unless it extends anteriorly) but may cause visual
problems, with blurring, change in refraction and double vision
[16]. Although features may be present on fundoscopy (oedema,
choroidal detachments, exudative retinal detachments), the
diagnosis is most easily confirmed on B-scan ultrasonography.
Episcleritis does not usually require treatment, although
artificial tears may be soothing. Suspected scleritis should be
referred to an ophthalmologist. The presence of scleritis may
indicate activity of the underlying disease and requires systemic
therapy, ranging from non steroidal anti-inflammatory drugs like
flurbiprofen to corticosteroids and other immunosuppressive
agents (e.g. cyclophosphamide, azathioprine, methotrexate, ciclosporin or mycophenolate).

Other anterior segment complications. Conjunctival

inflammation is uncommon. It presents with irritation, redness
and may be associated with lid follicles.
Anterior uveitis (intraocular inflammation of the anterior part
of the eye) seldom occurs in isolation. It is more commonly
associated with scleritis or posterior intraocular inflammation.
It is rarely of sufficient severity to be associated with a hypopyon.
Posterior segment disease
Retinal disease. Retinal disease affects around 10% of SLE
patients, reflecting a reduction in frequency associated with
improved control of systemic disease. Mild retinopathy may be
asymptomatic but more severe disease may cause loss of vision,
field defects, distortion or floaters. Such visual symptoms are
therefore an indication for urgent ophthalmic review. The retinal
signs often parallel the severity of systemic inflammation, and may
indicate inadequate control of the systemic disease [17, 18]. The
presence of APA is associated with more severe retinopathy and
vascular occlusions [19].
Mild lupus retinopathy consists of cottonwool spots, perivascular hard exudates, retinal haemorrhages and vascular tortuosity
[20] (Figs 2 and 3). Moderately severe cases may also have focal
or generalized arteriolar constriction and venous tortuosity.

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Anterior segment

Ocular manifestations of SLE

1759

New vessels

Cotton-wool spots

Venous dilation

Haemorrhages

FIG. 2. Acute lupus retinopathy with cotton wool spots, haemorrhages, arterial
narrowing, venous dilation and tortuosity.

New vessels

8p2.119

Capillary drop-out

Vessel wall staining

FIG. 6. Branch retinal arteriole occlusion in a patient with SLE and antiphospholipid
syndrome.

Leakage

FIG. 3. Fundus fluorescein angiography of a patient with acute lupus retinopathy

demonstrating capillary drop-out, vessel wall staining and leakage. Phases
(i) early, (ii) arteriovenous and (iii) late.

FIG. 7. Acute retinal necrosis secondary to varicella zoster virus in a patient

with SLE.

FIG. 4. Disc new vessels (proliferative retinopathy) in a patient with lupus

vaso-occlusive retinopathy.

There are some similarities to both hypertensive retinopathy and

diabetic retinopathy; when these conditions occur concurrently,
disease monitoring and treatment can be challenging. At the
severe end of the spectrum there is occlusion of retinal arterioles
and consequent retinal infarction, termed vaso-occlusive

retinopathy or retinal vasculitis [21, 22]. Proliferative retinopathy

may occur in up to 72% of such cases, often with ensuing
vitreous haemorrhage, retinal traction and retinal detachment
(Figs 4 and 5). Other retinal presentations include large vessel
occlusions (central and branch retinal vein occlusions, central and
branch retinal arteriole occlusions) that are more common in the
presence of APA (Fig. 6), pigmentary changes (pseudo-retinitis
pigmentosa) and exudative retinal detachments secondary to
choroidal disease. In the immunosuppressed state, rare retinal
infections may occur: retinal necrosis due to herpes simplex,
varicella zoster (Fig. 7) and cytomegalovirus are all reported.
The mainstay of treatment for significant retinal disease
is systemic immunosuppression, but laser therapy and anticoagulation also have a role. Initial treatment is usually with

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FIG. 5. New vessels elsewhere (proliferative retinopathy) in a patient with lupus

vaso-occlusive retinopathy. Images: (i) suspicious fundal appearance, (ii) new
vessels leaking on late phase of fundus fluorescein angiogram, (iii) vessels
regressed after laser treatment (photocoagulation).

1760

R. R. Sivaraj et al.

oral corticosteroids (e.g. prednisolone 1 mg/kg/day), but may be

preceded by intravenous methylprednisolone (e.g. 500 mg1 g
daily for 3 days). This is then supplemented with, or replaced
by, other immunosuppressive agents as part of a steroid-sparing
strategy or for resistant disease. In unilateral or asymmetric
disease, regional corticosteroid injections are sometimes used in
addition.
In the presence of significant vaso-occlusive disease (particularly when APA are present), anti-coagulation and the addition of
low dose acetylsalicylic acid may be beneficial. Proliferative
retinopathy usually requires treatment with laser (panretinal
photocoagulation) akin to the treatment of proliferative diabetic
retinopathy [23].

Neuro-ophthalmic disease
Optic nerve disease. Optic nerve disease occurs in around 1%
of patients with SLE [3032], and includes optic neuritis and
ischaemic optic neuropathy (anterior or posterior). Optic neuritis
presents acutely with unilateral loss of vision associated with pain
that is worse with eye movements. In the absence of other features
of SLE, it can be very difficult to distinguish this from the typical
optic neuritis of demyelinating disease [3234]. However, the
prognosis is worse in SLE associated optic neuritis, with more
than half having a persistent central scotoma and progressing to
optic atrophy. Pathological studies demonstrate infarction of the
optic nerve secondary to extensive arteriolar fibrinoid necrosis
[35]. Acute optic neuritis may also be bilateral and associated with
transverse myelopathy.
In contrast to optic neuritis, optic neuropathy in SLE typically
presents with bilateral, acute painless loss of vision associated with
an altitudinal or arcuate field defect, with or without optic disc
swelling. This is due to occlusion of the small vessels of the optic
nerves, which leads to demyelination in mild cases or axonal
necrosis in more severe cases. Unilateral optic neuropathy appears
to reflect a focal thrombotic event and is associated with the
presence of APA. Bilateral optic neuropathy that improves with
immunosuppressive treatment is suggestive of a more generalised
CNS vasculitic pathology [32, 36].
Visual prognosis following optic neuropathy is generally poor,
although good outcomes have been reported. Recurrence usually
worsens the prognosis. Occasional improvement following early
treatment with corticosteroids or pulsed cyclophosphamide
have been reported [30, 31], with some patients needing anticoagulation in addition to immunosuppression.
Cranial nerve disease and other disorders of ocular
motility. Ocular motor abnormalities are not uncommon in
SLE with one series reporting a rate of 29.2% [37]. Diplopia may
be transient and indeed is not always present. The motility

Other neuro-ophthalmic manifestations. Pupillary abnormalities such as light near dissociation (reduced pupillary light reflex
but preserved near reflex), Horners syndrome [37], Adies pupil
and abnormal pupillary reflexes have all been described in SLE.
Blepharospasm is also reported and may be troublesome.
Retrochiasmal disease can also present with headache, lethargy,
dizziness, alterations in memory and consciousness, seizures, other
cranial nerve palsies, ataxia, papilloedema, amaurosis fugax
(transient monocular blindness), nystagmus, field defects, cortical
blindness and coma. Transient monocular blindness was observed
11 times more commonly among patients with SLE than the
normal population [42]. Idiopathic intracranial hypertension has
been reported in both children and adults with SLE, and may be
the presenting feature of the disease [43, 44].
Ophthalmic disease and the role of anti-phospholipid
antibodies
The presence of APA is associated with vaso-occlusive disease
(both retinal and CNS) in SLE [45, 46]. Interestingly retinal
vascular occlusions and even a similar retinopathy may also be
seen in primary anti-phospholipid syndrome. In general, the
presence of APA is linked to focal thrombotic events that may
prompt the use of anti-coagulation or low dose aspirin in addition
to immunosuppression.

Ophthalmic disease in drug induced lupus

Ocular complications are rare in drug-induced lupus, although
retinal vasculitis and occlusive disease have been reported in
hydralazine and procainamide induced lupus syndrome.

Ophthalmic disease as a side-effect of treatment

The agents used in the treatment of SLE can themselves cause
significant ophthalmic morbidity. Corticosteroids are commonly
used in SLE and may cause cataract formation. Although steroid
induced glaucoma does occur with patients taking oral corticosteroid, it is more frequent in those patients using topical
corticosteroids. The introduction of other immunosuppressive
agents in steroid-sparing regimes has resulted in reduced
corticosteroid exposure for most patients.
Other immunosuppressive agents are usually more costly, have
their own side-effects and need careful monitoring. Overwhelming
septic cavernous sinus thrombosis has been reported after a
combination of high dose steroid and intravenous cyclophosphamide therapy for lupus nephritis [47].
The aminoquinolones, chloroquine and, to a lesser extent,
hydroxychloroquine can cause reversible visually insignificant
changes in the cornea (vortex keratopathy) and, more importantly, an irreversible sight-threatening maculopathy. Initial
changes are subtle (loss of foveal reflex and a fine granular
appearance) and often asymptomatic, but can progress to a bulls
eye maculopathy and even generalized atrophy of the retina and
optic nerve [48]. This retinopathy may continue to progress
despite cessation of the drug. Although both drugs can cause
identical changes the risks are much lower with hydroxychloroquine, particularly at recommended doses of up to 6.5 mg/kg/day
[49, 50]. Below this level, hydroxychloroquine, toxicity is
extremely rare. One prospective cohort study of 400 patients
receiving long-term hydroxycholoroquine of up to 6.5 mg/kg/day

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Choroidal disease. Choroidal disease is less common than

retinopathy but is probably underdiagnosed as a cause of visual
loss in SLE. Angiography of the fundus with fluorescein and
indocyanine green often demonstrates disease not detectable on
clinical examination. This may include leakage into uni/multifocal
retinal detachments and choroidal ischaemia. Other complications
include choroidal effusions (which have been reported to cause
secondary angle closure [24]), choroidal infarction and choroidal
neovascular membranes [25]. In the immunosuppressed state, rare
choroidal infections may occur: both a nocardia choroidal abscess
[26] and tuberculous granulomas [27] with associated pulmonary
disease have been reported.
Treatment is with systemic immunosuppression. However, in
some patients, corticosteroids may themselves induce central
serous chorioretinopathy, in which case alternative agents should
be used [28]. Pulsed methylprednisolone and cyclophosphamide
have been reported to be effective in treating bilateral exudative
retinal detachment secondary to ischaemic choroidopathy [29].

abnormalities usually arise from vasculitic or ischaemic events

within the brainstem and are frequently associated with both
cranial nerve and long tract signs.
Occasionally disorders of conjugate gaze such as internuclear
ophthalmoplegia (unilateral [38] or bilateral [39]) and one a half
syndrome (internuclear ophthalmoplegia with ipsilateral horizontal gaze palsy [40]) are seen. Other reported complications include
nystagmus and Miller Fisher syndrome [41].

Ocular manifestations of SLE

Conclusion
Eye manifestations in SLE may be sight-threatening and can be an
indicator of active systemic disease. Significant ocular pain or
reduction of vision are serious symptoms requiring urgent
assessment by an ophthalmologist. The serious ocular manifestations of SLE (such as scleritis and lupus retinopathy) generally
require systemic immunosuppression. Future research will hopefully provide more evidence on which to base treatment choice.
Early recognition by the rheumatologist, prompt assessment by
the ophthalmologist and coordinated treatment strategies are key
to reducing the ocular morbidity associated with this disease.
Disclosure statement: The author have declared no conflicts of
interest.

Rheumatology key messages

 Ocular pain and visual impairment require urgent assessment by
ophthalmologist.
 Scleritis and lupus retinopathy usually require systemic
immunosuppression.
 Anti-phospholipid antibodies may cause vaso-occlusive disease
affecting the retina.

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found only two patients to be affected, in both cases only after

6 yrs of treatment [51]. Indeed Lee [52] estimated that at these
recommended levels there have been only 20 affected cases in over
a million patients receiving the drug; all 20 cases had been taking
the drug for over 5 yrs.
In the UK, the Royal College of Ophthalmologists
(in conjunction with representatives from the Royal College
of Physicians Rheumatology Committee, the British society of
Rheumatology and the British Association of Dermatologists)
have advised that the prescribing rheumatologist should carry out
the baseline assessment of lean body weight (if overweight), renal
and liver function, asking about any visual impairment which is
not corrected by glasses and testing reading vision [49]. Any
apparent visual impairment or eye disease should be first
confirmed by an optometrist, and then referred on to the local
ophthalmologist before starting treatment. If visual problems
occur once treatment has started, patients should be advised
to stop treatment, attend their optometrist and seek advice
from the prescribing physician who would refer on to the
ophthalmologist. Annual evaluation should be by the prescribing
rheumatologist and includes enquiry about visual symptoms and
measuring reading acuity [49]. In the USA, screening by an
ophthalmologist is recommended for those patients on hydroxychloroquine who are at higher risk: dose >6.5 mg/kg/day,
duration of treatment >5 yrs, renal or hepatic disease, pre-existing
retinal disease or age >60 yrs [50].
Chloroquine has a less clear safety profile and should be
avoided where possible. All patients taking chloroquine should
have regular ophthalmic examination according to locally
arranged protocol.

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