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Review

Ocular manifestations in systemic lupus

erythematosus
Sukhum Silpa-archa,1,2,3 Joan J Lee,1,2 C Stephen Foster1,2,4

studies.13 Aberrant epigenetic regulation including

1
Massachusetts Eye Research ABSTRACT
and Surgery Institution, Systemic lupus erythematosus (SLE) can involve many DNA methylation, histone modications and
Cambridge, Massachusetts,
USA
parts of the eye, including the eyelid, ocular adnexa, microRNA-mediated regulation may contribute to
2
Ocular Immunology & Uveitis sclera, cornea, uvea, retina and optic nerve. Ocular the complex array of immune abnormalities and
Foundation, Cambridge, manifestations of SLE are common and may lead to disease manifestations in SLE.14
Massachusetts, USA permanent blindness from the underlying disease or Inammation in lupus is caused by the formation
3
Faculty of Medicine, therapeutic side effects. Keratoconjunctivitis sicca is the of autoantibodies and immune complexes and can
Department of Ophthalmology,
Rajavithi Hospital, College of most common manifestation. However, vision loss may cause inammatory responses and activate the com-
Medicine, Rangsit University, result from involvement of the retina, choroid and optic plement system. This results in multiorgan damage
Bangkok, Thailand
4
nerve. Ocular symptoms are correlated to systemic that manifests as nephritis, vasculitis and arthritis.3
Harvard Medical School, disease activity and can present as an initial Immunohistochemical studies of an animal model
Boston, Massachusetts, USA
manifestation of SLE. The established treatment includes with retinal vasculitis disclosed immune complex
Correspondence to prompt systemic corticosteroids, steroid-sparing deposition within the vessel walls, which ultimately
Dr C Stephen Foster, immunosuppressive drugs and biological agents. Local caused vaso-occlusion in the eye.15 The key role of
Massachusetts Eye Research ocular therapies are options with promising efcacy. aberrant B cell autoreactivity in SLE was revealed
and Surgery Institution, 355
The early recognition of disease and treatment provides in a landmark murine study using a knockout gene
Main Street, Five Cambridge
Center, 8th Floor, Cambridge, reduction of visual morbidity and mortality. mutation to prevent lupus mice from developing
MA 02142, USA; B cells, which resulted in a lack of autoantibody
sfoster@mersi.com formation and clinical manifestations (nephritis or
INTRODUCTION vasculitis).16 Autoimmunity in SLE is a consequence
Received 12 January 2015
Revised 4 March 2015 Systemic lupus erythematosus (SLE) is a complex of the progressive adaptive immune responses to
Accepted 4 April 2015 connective tissue disorder that involves multiple autoantigens by not only B cells but also T cells.17
Published Online First organs. Lupus erythematosus was rst described There are changes in T cells in patients with SLE,
22 April 2015 and distinguished from lupus vulgaris by Cazenave which cause increase in the proinammatory Th17
and Schedel in 1833. In 1845, skin lesions were cell population and decrease in the anti-inammatory
reported by Hebra and later biopsied in 1872 by T regulatory cell population.14
Kaposi who also pointed to systemic symptoms.1
The rst report of lupus in the eye was in 1929, DIAGNOSTIC CRITERIA
and Semon and Wolff, in 1933, described the histo- The diagnostic criteria for SLE were developed by
pathological characteristics of choroiditis and sub- American College of Rheumatology (ACR).18 19 It
retinal exudation.2 Ocular involvement may was based on 4 of 11 criteria, either at the present
correlate with systemic disease activity and precede time or at some time in the past; malar rash, discoid
other systemic symptoms stressing the important rash, photosensitivity, oral ulcers, non-erosive arth-
role the ophthalmologist may play.3 ritis, serositis, renal disorder, neurological disorder
The reported prevalence of SLE in the population (seizures or psychosis), haematological disorder
is 20150 cases per 100 000.46 The prevalence of (anaemia, leucopenia, thrombocytopenia), immuno-
SLE is different between age, gender, geographic logical disorder (anti-DNA antibody, anti-Sm anti-
and racial distributions. The female-to-male ratio is body and false positive Venereal Disease Research
close to 9:1, and the estimated prevalence is 1/1000 Laboratory testing) and presence of antinuclear
among American women above the age of 17.7 8 antibodies.
Due to improved identication at mild disease stage
and better approaches to therapy, the incidence of OCULAR MANIFESTATIONS
SLE has nearly tripled over the past four decades.9 Ocular manifestations of SLE vary from patient to
patient and can correlate to the systemic disease
PATHOPHYSIOLOGY activity. Ocular involvement is moderately common
The pathogenesis of SLE is multifactorial and in SLE and can be vision threatening.20 Findings
complex. Various genetic, epigenetic, immunoregu- may include abnormalities of the eyelid, ocular
latory, environmental and infectious factors con- adnexa, keratoconjunctivitis sicca, iridocyclitis,
tribute to the susceptibility, onset, progression and retinal vasculitis, vaso-occlusive disorder, choroido-
prognosis of the clinical disease in a given pathy and optic neuropathy. Keratoconjunctivitis
patient.3 10 The concordance rate has been sicca is the most common manifestation while
reported between 24% and 57% in monozygotic retinal and choroidal involvement are most asso-
To cite: Silpa-archa S, twins, which outweighs the rate of 02% in dizyg- ciated with visual loss.21 22 Active inammation in
Lee JJ, Foster CS. Br J otic twins or siblings.11 12 Thirty-one susceptibility the retina and choroid can echo vasculitis in
Ophthalmol 2016;100: loci for SLE have been identied by genome-wide other organs, especially in cerebral vascular disease
135141. association studies and other gene mapping (table 1).2327 In addition, though uncommon,
Silpa-archa S, et al. Br J Ophthalmol 2016;100:135141. doi:10.1136/bjophthalmol-2015-306629 135
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Table 1 Association among lupus-related ocular posterior segment disorders to activity of systemic diseases and prognoses
Prognosis
Cases Association to Association to Eye as an initial for survival
Authors (n) Pathological site Visual outcome systemic lupus CNS lupus manifestation (mortality rate)

Case series
Frigui et al68 13 Optic nerve Moderate to poor Positive No Yes NA
Lanham et al63 52 Retina (mostly Good Positive No No NA
microangiopathy)
Jabs et al26 11 Retina (mostly Poor Positive Positive (73%) No NA
vaso-occlusive cases)
Stafford-Brady 550 Retina (mostly Good Positive (88%) Positive (73%) No Poor (34% died in
et al27 microangiopathy) 16 years
follow-up)
Nguyen et al25 28 Choroid Equivocal (improved Positive (100%) Positive (36%) Yes (1 case) 14%
vision after resolved
choroidopathy)
Baglio et al78 16 Choroid NA Positive (100%) NA NA NA
Case reports
Hwang and 1 Retina (combined central NA Positive No Yes NA
Kang56 retinal vein and artery
occlusion)
Giocanti- 1 Choroid Poor Positive Positive Yes NA
Auregan et al79
Wisotsky et al60 1 Choroid NA Positive NA Yes NA
NA, not available.

vision-threatening disease of the posterior segment involving the (4 according to van Bijstervelds scoring system) are important
retina and optic nerve can precede systemic features and may tests for diagnosis of dry eye syndrome associated with SS.40
aid in early diagnosis and prompt treatment of patients with However, given patient discomfort after rose bengal instillation,
SLE.2830 Early diagnosis is the key to successful treatment and lissamine green could be used as a substitute for rose bengal
better prognosis. with similar staining patterns and greater tolerability to
patients.41
External eye diseases
Orbit Anterior segment diseases
Orbital involvement is a less common manifestation in SLE. Corneal disorders
Many case reports describe bilateral orbital involvement and Corneal involvement in SLE involves the supercial epithelium
unilateral periorbital involvement despite systemic nature of manifesting as supercial punctate keratitis and may be second-
SLE.3135 Inammation manifesting as myositis and panniculitis ary to SS.42 Peripheral ulcerative keratitis rarely occurs in SLE
has been described.3234 36 Patients may present with painful or and is more commonly associated with rheumatoid arthritis.43
painless proptosis, chemosis, ptosis, lid oedema or limited However, some cases of peripheral ulcerative keratitis have been
ocular movement. Inammation can be conned to the orbit or reported in both non-inltrative and inltrative patterns.42
spread to neighbouring tissues, which may lead to vision loss
from optic neuropathy.35 Further biopsy, serological workup Episclera and sclera
and long-term follow-up are essential to facilitate the proper Episcleritis is characterised by painless or mildly uncomfortable
diagnosis.33 red eye with dilated episcleral vessels, which are non-tender and
markedly reduced by topical phenylephrine. Unlike episcleritis,
Eyelid disorders scleritis is a severe vision-threatening, progressively destructive
Discoid lupus-type rash over the eyelids typically appears in the inammatory condition, which is more often associated with
lower eyelid as an irritating, discrete, slightly raised erythema- systemic disorders. Necrotising scleritis, though rare, is the type
tous scaly plaque, which can involve the lid margin and can be of scleritis most often associated with ocular complications and
complicated by scarring and madarosis.31 37 Lid biopsy and decreased vision. We reported a series of 585 patients with scler-
direct immunohistochemistry studies are valuable in conrming itis and episcleritis. We found that disease association was
the diagnosis. Topical corticosteroids and oral antimalarial drugs observed in 35.8% of patients with scleritis versus 27.1% of
are typically effective.31 37 patients with episcleritis.44 A more recent analysis of 1358 cases
of scleritis performed by Heron et al45 reported a 2% preva-
Lacrimal system disorders lence of SLE-associated scleritis compared with 6.410.4% of
Dry eye syndrome (keratoconjunctivitis sicca) is the most rheumatoid arthritis-related scleritis.
common ocular feature of SLE (around a third of patients) and
is often associated with secondary Sjgrens syndrome (SS).38 39 Iridocyclitis
The International Dry Eye Work Shop classied Sjgrens as an There are few reports of iritis or iridocyclitis secondary to SLE
aqueous tear-decient dry eye, reecting failure of lacrimal tear particularly in adults. One adult case presented with bilateral
secretion. Schirmer I test (5 mm in 5 min) or rose bengal score keratitis and iridocyclitis and responded well to chloroquine.46
136 Silpa-archa S, et al. Br J Ophthalmol 2016;100:135141. doi:10.1136/bjophthalmol-2015-306629
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Nevertheless, visual deterioration is uncommon in isolated iritis. occur, either independently or together, and may be unilateral
The inammation in the anterior segment can present as hypop- or bilateral.54 5659 A study by Jabs et al26 disclosed 55% of
yon or brinous anterior uveitis.35 47 The inammation in the eyes with severe retinal vaso-occlusive disease suffered vision
anterior segment usually improves with the systemic immuno- loss, often due to a visual acuity of worse than 20/200. A recent
suppressants; however, atypical recalcitrant presentations have report of Purtscher-like retinopathy of 8 from 5688 patients
been reported to result in severe visual damage.47 48 with SLE revealed an association between Purtscher-like retinop-
athy with central nervous system lupus and highly active disease.
Posterior segment Visual acuity recovery was usually poor despite prompt
Retinopathy treatment.52
Lupus retinopathy is a potentially blinding ocular manifestation
of SLE. In the pre-steroid era, retinopathy was present in up to Vasculitis
half of patients with SLE.49 However, with the advent of ster- The terminology of vasculitis in lupus retinopathy can be con-
oids and immunosuppressive therapy, the incidence of retinop- founding among clinical presentation and pathogenesis. Though
athy has declined considerably. The prevalence of retinopathy immune complex deposition leading to complement activation
varies among various populations, ranging from 3% in well- is well known in lupus retinopathy, clinically presenting vascu-
controlled patients to 29% of patients with more active systemic litis is fairly uncommon. The classic sign of vasculitis is vascular
disease.50 Retinal involvement corresponded to activity of sys- sheathing, which can present in arterioles and/or venules.
temic and cerebral SLE (table 1).26 27 51 52 The major pathology Vaso-occlusion is a common end-point of vasculitis that may
of lupus retinopathy is attributed to vasculopathy, most com- alter visual function (gure 2).
monly, microangiopathy. It is thought to be an immune Renal involvement by SLE will generally lead to secondary
complex-mediated vasculopathy.15 53 hypertension. When prolonged, it usually affects retina and
The autoimmune process can affect the retina and choroid in choroid and is characterised by retinal arterial narrowing,
two ways: directly, by immune complex-mediated vasculitis, and arteriovenous crossing changes, microaneurysms, intraretinal
indirectly, by secondary hypertension from renal involvement. haemorrhages, hard exudates, disc oedema and multifocal
Hence, there are three types of direct retinal damage by lupus: serous or pigment epithelial detachment.
microangiopathy, severe vaso-occlusion and vasculitis.
Choroidopathy
Microangiopathy Lupus choroidopathy can occur either independently or with
Microangiopathy should be considered the mild form of lupus lupus retinopathy and may present with good visual acuity.
retinopathy. The classic retinal ndings are similar to diabetic Nguyen et al reported a total of 28 patients with lupus choroi-
and hypertensive retinopathy, including cotton wool spots, dopathy and found 64% of presenting visual acuity of 20/40 or
microaneurysms, hard exudates and dot haemorrhages.22 51 better. The common manifestations include single or multiple
Small intraretinal haemorrhages and cotton-wool spots account areas of serous or exudative retinal detachment (36%), detach-
for 80% of cases and are usually associated with a good visual ment of the retinal pigment epithelium (32%) or retinal
prognosis.27 pigment epitheliopathy (21%).25 Choroidal ischaemia can
present as subretinal hypopigmented patches and angiography
Severe vaso-occlusion can help conrm ischaemic areas (gure 3). Secondary angle-
This most severe form of lupus retinopathy manifests within a closure glaucoma has also been reported secondary to choroidal
wide spectrum of ischaemia, from occlusion in major vessels effusion, leading to an anterior shift of the lensiris diaphragm,
like central retinal vessels and cilioretinal artery to extensive narrow angles and increased intraocular pressure.60 61
microembolisation in small vessels presenting as Purtscher-like Appropriate immunosuppressive treatment leads to resolution of
retinopathy. lupus choroidopathy followed by recovered vision.3 25
Severe vaso-occlusive retinopathy is a rare but well-described
entity that is associated with widespread retinal capillary non- Imaging in lupus retinopathy and choroidopathy
perfusion, multiple branch retinal artery occlusions, ocular neo- Modern imaging techniques including fundus uorescein angi-
vascularisation, vitreous haemorrhage, tractional retinal detach- ography (FFA), indocyanine green (ICG) and optical coherent
ment, neovascular glaucoma and signicant resultant visual loss tomography (OCT) have played an important role in the evalu-
(gure 1).54 55 Central retinal vein or artery occlusions can also ation and monitoring of lupus retinopathy and choroidopathy.

Figure 1 Fundus photograph (left)

and uorescein angiogram (right) of a
54-year-old woman who presented
with acute severe vision loss in both
eyes. Fundus photo (left) and
angiogram (right) note extensive
retinal capillary non-perfusion and
macular ischaemia. Oral prednisone
and anticoagulant were employed
without steroid-sparing
immunosuppressant. Final visual acuity
was no light perception in 3 months
later.

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Figure 2 Fundus photograph (left)

and early-phase uorescein angiogram
(right) of a 37-year-old woman who
previously presented with lupus retinal
vasculitis and was treated with
scattered laser photocoagulation in
2006. Signicant hyperuorescent
leakage represented the recurrence of
neovascularisation. She received oral
prednisone, methotrexate and
intravenous cyclophosphamide. Initial
visual acuity and visual acuity 8 years
later were 20/60 and 20/100,
respectively.

FA ndings may help identify subclinical ndings in patients no light perception vision.69 70 Presentations can vary based on
with SLE, manifesting as leakage, retinal capillary dilatation and the location of pathology. Patients may present with painless or
microaneurysms in patients with mild-to-moderate disease activ- painful progressive visual loss, with or without pain on eye move-
ity.62 63 Choroidal pathology can also be studied with FFA by ment, optic disc swelling or pallor on examination.50 68 69 Optic
identifying delayed choroidal lling, areas of choroidal non- neuritis generally responds well to corticosteroid treatment. Visual
perfusion (gure 3) or multifocal areas of subretinal leakage prognosis following optic neuropathy is generally moderate to
with pooling corresponding to the areas of serous elevation and poor, although good outcomes have been reported.68 69 In add-
inferior retinal detachment.25 ition, for patients with SLE with suspected optic neuritis and
ICG can help to identify active choroidopathy not seen on relapsing myelitis, testing for the aquaporin-4 autoantibody would
clinical examination or FFA. It may detect focal, transient hypo- help conrm the correct diagnosis of neuromyelitis optica.71 72
uorescent areas in the early phase and spots of choroidal Ischaemic optic neuropathy73 74 and chiasmopathy69 in SLE have
hyperuorescence in the intermediate to late phase. also been described.
Interestingly, pinpoint spots of ICG choroidal hyperuorescence Eye movement abnormalities are more common in SLE and
may represent immune deposition in deeper layer of choroidal have been reported in up to 29% of patients.75 Pseudotumor
stroma or Bruch membrane.64 cerebri has been reported in both children and adults with SLE,
OCT offers a non-invasive way to follow the structural and may be the presenting feature of the disease.76 77
changes of SLE. Its advantage is apparent, especially in active
phase of disease identifying intraretinal and subretinal uid and
pigment epithelial detachment with ease. The qualitative and PROGNOSIS AND SYSTEMIC ASSOCIATIONS
quantitative evaluations of OCT are also benecial in diagnosis Table 1 shows association among lupus-related ocular posterior
and monitoring of lupus choroidopathy.65 66 segment disorders and systemic involvement including activity
and prognosis. Visual prognosis of retinal involvement depends
Neuro-ophthalmological manifestations on pattern of retinopathy, and vaso-occlusion usually leads to
Neuro-ophthalmic manifestations of lupus are not common. poor visual outcome. Two reviews of retinopathy and choroido-
The prevalence is 3.6% in adults and 1.6% in children. Findings pathy pointed out that these two entities are indicative of
are highly variable, with the most common presentation being guarded to poor survival.25 27 Unlike demyelinating processes in
optic neuritis, followed by myasthenia gravis, visual eld defects which association between optic neuritis and brain is common,
and optic disc oedema.67 Optic neuropathy, which may manifest a review of SLE presenting as optic neuropathy revealed no
as the presenting feature of disease,68 is the most common nding association to CNS disorder.68 This may reect and support the
and occurs in about 1% of patients with SLE22 67 (table 1). Initial ischaemic aetiology of SLE-related neuro-ophthalmological
visual loss can be severe in SLE-associated optic neuritis, causing disorders.

Figure 3 Fundus photograph (left)

and uorescein angiogram (right) of a
46-year-old woman diagnosed with
lupus-associated catastrophic
antiphospholipid syndrome with
bilateral choroidal infarction and
uveitis. Image from the right eye
demonstrates unremarkable retinal
vasculature and distinct geographic
subretinal patches. These
hypopigmented patches correspond to
extensive absence of choroid lling
pattern in angiogram. Given
intravenous methylprednisolone,
rituximab and anticoagulant, the
patient maintained visual acuity of
20/600 5 years later.
138 Silpa-archa S, et al. Br J Ophthalmol 2016;100:135141. doi:10.1136/bjophthalmol-2015-306629
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Treatment and needs to be investigated.88 Repeat anti-VEGF injections in

The heterogeneous nature and multisystem involvement make vaso-occlusion with macular ischaemia should be performed
treatment of SLE difcult. Nevertheless, the general goals of only if monitoring FFA can be done to prevent worsening of
therapy are to induce and maintain remission of the disease, and macular ischaemia. Finally, vitrectomy can also be helpful in
prevent relapses. Proper management requires a team approach complicated neovascularisation, vitreous haemorrhage and trac-
that may include specialists in the elds of rheumatology, neph- tion retinal detachment.54 86
rology, dermatology and ophthalmology. Treatment strategies
for SLE include non-steroidal anti-inammatory drugs, hydroxy- Future direction
chloroquine, systemic corticosteroids, immunosuppressive The future of SLE consists of newly emerging agents that specif-
therapy and biologics. The effective immunosuppressive drugs ically target mechanisms involved in the pathogenesis of SLE
include azathioprine, methotrexate, mycophenolate mofetil and and biomarkers allow physicians to adopt theranostics, a
cyclophosphamide. Increasingly, patients with lupus who do not patient-tailored approach. Hopefully in the future systemic glu-
respond to conventional immunosuppressive drugs are consid- cocorticoids will be used less and gradually replaced by early
ered for targeted biological therapies aimed at cytokines, B and commencement of other immunosuppressive or biological ther-
T lymphocytes, and B-cell-activating factors. Rituximab, apies. Among a myriad of emerging biological agents, the ones
B-cell-depleting therapy, has been used when conventional with positive outcomes in literature are belimumab, rituximab,
drugs have proven ineffective.80 Combination of rituximab and epratuzumab and sifalimumab. In spite of failure of a major
cyclophosphamide infusions employed early in the course of trial, rituximab has been considered for patients with active
retinal vasculitis and vaso-occlusive disease also granted rapid lupus nephritis refractory to conventional therapies by the ACR
resolution as well as dramatic improvement in vision.81 and the European League Against Rheumatism.80 Early treat-
Belimumab, a monoclonal human antibody that inactivates ment with rituximab showed promising efcacy and safety in
B-cell-activating factor, is the rst biologic recently approved by newly diagnosed SLE.91 The success of belimumab encourages
the US Food and Drug Administration after 50 years as an other studies of molecules that block B-cell-activating factors.
add-on therapy for active SLE.80 82 In addition, epratuzumab Both belimumab and rituximab have also provided support in
and sifalimumab, biological response modiers currently being the maintenance phase of lupus nephritis.92 93 Better insight in
investigated, also showed positive outcome. The treatment of the mechanisms and accountable biomarkers of inammation
CD22-targeted monoclonal antibody epratuzumab in adults will bring about more acceptable diagnostic criteria and success-
with moderately to severely active SLE was reportedly associated ful treatment strategies. Treatment of ocular disease in SLE is
with improvements in disease activity.83 Sifalimumab, a human based on systemic therapy. As such, local ocular therapy in lupus
anti-interferon- monoclonal antibody, was proven to be safe, is not widely investigated. While PRP still serves as an effective
and clinical activity prole supports its continued clinical devel- treatment for neovascularisation sequel, anti-VEGF therapy has
opment for SLE.80 showed additional benet in refractory cases.
Hydroxychloroquine is an effective medication for SLE. It is
now recommended long term for all patients with SLE.84
Correlation between discontinuation of chloroquine and retinal Competing interests None declared.
vaso-occlusion was described by el-Asrar et al.57 Patients must Provenance and peer review Not commissioned; externally peer reviewed.
be made aware of the possible risk of macular toxicity and have
regular eye check-up to monitor for this complication.85
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Silpa-archa S, et al. Br J Ophthalmol 2016;100:135141. doi:10.1136/bjophthalmol-2015-306629 141

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Ocular manifestations in systemic lupus

erythematosus
Sukhum Silpa-archa, Joan J Lee and C Stephen Foster

Br J Ophthalmol 2016 100: 135-141 originally published online April 22,

2015
doi: 10.1136/bjophthalmol-2015-306629

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