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Therapy Insight: the recognition and treatment of retinal manifestations of systemic vasculitis
Petros Aristodemou and Miles Stanford* S U M M A RY
A variety of retinal signs can occur in patients who have systemic vasculitides, or who experience complications of these diseases or their treatment. Although treatment of these retinal manifestations is usually the treatment of the systemic disease, specific treatment is occasionally indicated to preserve vision. The more prevalent of the systemic vasculitides are giant cell arteritis, polyarteritis nodosa, Wegeners granulomatosis, ChurgStrauss syndrome, relapsing polychondritis and systemic lupus erythematosus. Less frequently occurring vasculitides include Takayasus arteritis, Goodpastures disease, microscopic polyangiitis and HenochSchnlein purpura, as well as vasculitis secondary to scleroderma and rheumatoid arthritis. This article describes the pathogenesis, clinical features and treatment of retinal manifestations of systemic vasculitides.
KEYWORDS complications, diagnosis, eye, retina, systemic vasculitis

INTRODUCTION

REVIEW CRITERIA Information for this review was obtained via the MEDLINE database, from dates 1st January 1966 to 1st October 2005. The search terms were eye, retina, choroid, and optic nerve in combination with vasculitis, temporal arteritis, polyarteritis nodosa, wegeners granulomatosis, churgstrauss, relapsing polychondritis, systemic lupus erythematosus, takayasus arteritis, goodpastures disease, microscopic polyangiitis, antineutrophil cytoplasmic, pANCA, henochschnlein purpura, scleroderma and rheumatoid arthritis. Relevant cited references were also included.

Pathologically, the systemic vasculitides comprise a heterogenous group of disorders that are characterized by inflammatory cell infiltration and necrosis of blood vessel walls. This pathology can involve the blood supply to the eye, and cause retinal signs. The types of clinical signs seen in the posterior segment of the eye that relate to the various vasculitides are influenced by the diameter of vessel involved.1 These signs range from microinfarcts (cotton-wool spots, as seen in systemic lupus erythematosus) to ischemia of the whole eye (in giant cell arteritis and Takayasus arteritis). In the presence of scleral or orbital inflammation, other retinal signs can be evident. This article describes the pathogenesis of retinal signs that are associated with systemic vasculitis, and discusses their clinical features and treatment.
The blood supply to the posterior segment of the eye

The posterior segment of the eye has two discrete circulations. The inner retinal layers are supplied by branches of the central retinal artery whereas the posterior ciliary arteries supply the choroid, which nourishes the outer retinal layers. Branches of the posterior ciliary arteries also supply the optic nerve head. Both the central retinal artery and the posterior ciliary arteries are, ultimately, branches of the ophthalmic artery (Figure 1).

M Stanford holds the Chair of Clinical Ophthalmology at Kings College London and practices at the Medical Eye Unit at St Thomas Hospital, London, UK. P Aristodemou is a Specialist Registrar in Ophthalmology at the Royal United Hospital, Bath, UK.
Correspondence
*Medical Eye Unit, St Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK miles.stanford@kcl.ac.uk
Received 8 December 2005 Accepted 29 June 2006
www.nature.com/clinicalpractice doi:10.1038/ncprheum0268

PATHOGENESIS AND CLINICAL SIGNS OF RETINAL INVOLVEMENT Occlusions of the central retinal artery circulation

Cotton-wool spots are focal accumulations of axoplasmic components of the nerve fiber layer (Figure 2). Cotton-wool spots are thought to be caused by focal, inner-retinal ischemia due to terminal arteriolar occlusion, although it has been suggested that they are sentinel lesions of wider areas of retinal ischemia or of other, nonischemic pathology.2 Proximal blockage of

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Ophthalmic artery Posterior ciliary arteries

Cornea A C E G

Branches to optic disc Central retinal artery

a b c d e f g h i

I B D F H

Equator

Area supplied by the circulation of the anterior segment of the eye

Figure 1 A schematic representation of the posterior retinal circulation. Parts of the blood supply to the optic disk, and the segmentation of the choroidal circulation are illustrated. The short posterior ciliary arteries (a to i) supply segments of the choroid (A to I) posterior to the equator of the globe.

Figure 3 Giant cell arteritis. A color fundus photograph that shows a pale, swollen, optic disk with accompanying cilio-retinal artery occlusion. Note the cloudy retinal swelling (blue arrow) and break-up of the blood column in the artery (green arrow), indicating lack of flow.

through.3 Retinal vein occlusions (branch or central) can be ischemic or nonischemic. These occlusions cause a retinopathy that is characterized by flame-shaped and punctate hemorrhages and, occasionally, cotton-wool spots.2 Retinal venous disease is a rare feature of systemic vasculitis, and usually occurs in the context of long-standing systemic hypertension or abnormal coagulability, such as is present in antiphospholipid syndrome.4
Occlusions of the posterior ciliary artery circulation
Figure 2 Systemic lupus erythematosus retinopathy. A color fundus photograph that shows systemic lupus erythematosus retinopathy, manifest as cotton-wool spots in a pigmented fundus.

blood flow can take the form of occlusion of a branch of the retinal artery (Figure 3) or of a branch of the central retinal artery. As these are end arteries, occlusion leads to necrosis of the inner retina in the affected area. Acute occlusion is characterized by inner-retinal cellular edema, which is responsible for the pale, swollen and opaque appearance of areas affected by retinal arterial occlusions (cloudy swelling). In central retinal artery occlusion, the foveola is visible as a cherry-red spot, as it is solely supplied by the choroid, whose color shows

Each terminal choroidal arteriole supplies an independent lobule (segment) of the lamina choriocapillaris. Occlusion of these terminal arterioles produces a corresponding perfusion defect, and its extent depends on the shape of the affected lobule. In the posterior pole, the lobules are small and polygonal, whereas the anterior lobules are large and radially elongated.5 Choroidal infarction is clinically manifest as pigment clumping and atrophy of the overlying retinal pigment epithelium of the area supplied by the affected choroidal arteriole (spots, streaks or wedgeshaped infarcts). These changes are chronic. Since the retinal pigment epithelium lies anteriorly to the choroid, direct observation of ischemia or inflammation of the choroidal vessels is rarely possible in the acute stage. Anterior ischemic optic neuropathy (AION) occurs following hemodynamic changes in

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Table 1 Features of arteritic and nonarteritic anterior ischemic optic neuropathy.38

Features Incidence Arteritic AION The RR of GCA is 20:100,000 among people aged 50 years, and the RR of arteritic AION in GCA varies from 14% to 70% Involvement of posterior ciliary artery circulation by a vasculitic process GCA or polymyalgia rheumatica Other vasculitides are a rare cause of arteritic AION Loss of visual acuity (more than in nonarteritic AION) Dense central scotoma, pale optic disk with diffuse or segmental edema, occasionally BRAO or CWS separate from the disk Usually elevated but a normal value does not exclude arteritic AION39 Treat the underlying vasculitis with high-dose systemic corticosteroid Visual prognosis poor Without treatment, up to 70% might suffer contralateral AION within 1 week12 Nonarteritic AION 2.310.2:100,000 people aged 50 years

Pathogenesis Risk factors Presentation Signs

Decreased perfusion of optic disk Nature and location of vasculopathy is unknown Age, small optic disk, absent physiologic cup, white ethnicity, hypertension, diabetes mellitus, ischemic heart disease, smoking Variable loss of visual acuity Altitudinal visual-field defect, diffuse or segmental disk edema, which is often superior or inferior, small optic disk Normal Exclude arteritic AION and modify risk factors No established treatment Better than arteritic AION 50% have visual acuity >20/64 at 6 months Other eye involved in 15% of cases at 5 years

ESR Treatment Prognosis

Abbreviations: AION, anterior ischemic optic neuropathy; BRAO, branch retinal artery occlusion; CWS, cotton-wool spots; ESR, erythrocyte sedimentation rate; GCA, giant cell arteritis; RR, reported risk.

the posterior ciliary artery circulation, which supplies the optic nerve head. The pathophysiology of AION is not well understood, although both ischemic and reperfusion injury are thought to cause neuronal damage. In the acute phase, the optic disk is ischemic, with resulting blockage of retrograde axoplasmic flow from retinal ganglionic axons. This ischemia produces a swollen and pale optic nerve head, which is evident in the majority of patients with AION6 (Figure 3). Optic-disk atrophy ensues over the following weeks. The most common cause of arteritic AION is giant cell arteritis. Table 1 distinguishes the features of arteritic from nonarteritic AION. Fluorescein angiography is of particular diagnostic value in equivocal casesin this technique, fluorescein dye is injected into a peripheral vein and its transit through the choroidal and retinal circulations is recorded with serial photographs of the fundus. A substantially delayed choroidal filling time is observed in patients with AION caused by giant cell arteritis, compared with those who have nonarteritic AION (Figure 4).7
Ophthalmic or carotid artery compromise

This syndrome is characterized by punctate retinal hemorrhages, vascular tortuosity, cottonwool spots, arteriovenous shunts, macular edema and neovascularization of the optic disk and/or retina. Characteristically, retinal arterial pulsation at the optic disk can be elicited by exerting gentle pressure on the eye.
Scleral or orbital inflammation

Rarely, chronic ocular hypoperfusion can result from pathology of the carotid or ophthalmic artery and can cause ocular ischemic syndrome.

In posterior scleritis, thickening of the sclera can restrict the opening through which the optic nerve passes, resulting in nerve compression. Optic nerve compression can also occur in the presence of orbital inflammation, owing to the effects of increased mass in the confined orbital space. In compressive optic neuropathy, the optic disk is swollen, with flame hemorrhages, but lacks the characteristic pallor seen in AION.8 Similarly, mass effects caused by posterior scleritis or orbital inflammation can also produce forward displacement of the posterior wall of the globe. This displacement can cause choroidal folds (linear folds that occur at the posterior part of the eye caused by external compression) as shown in Figure 5, and a hypermetropic shift in refraction (compression of the back of the eye causes a flattening distortion of the globe, and blurring of vision that can be corrected by the addition of a convex lens).

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Figure 4 Fluorescein angiograms showing normal choroidal perfusion, and delayed choroidal perfusion in giant cell arteritis. (A) Normal choroidal perfusion in the early venous phase of the fluorescein angiogram. (B) Delayed perfusion in a patient with giant cell arteritis, which leads to a watershed (white arrows) that runs vertically through the optic disk.

The inflammation associated with posterior scleritis can cause retinal detachment due to the accumulation of exudate under the neural retina. Box 1 describes the principles of patient management for the retinal signs related to systemic vasculitis.

RETINAL FINDINGS IN LARGE-VESSEL VASCULITIS

Giant cell arteritis (also known as temporal arteritis) is the most common of the systemic vasculitides. This necrotizing vasculitis affects arteries with an internal elastic lamina.9 The superficial temporal, ophthalmic and posterior choroidal arteries (as well as the vertebral arteries) are commonly involved, whereas the internal carotid arteries are affected less often. Arteries distal to the dura are never involved.10 AION is the most common cause of visual loss in giant cell arteritis.6 In AION, the presence of cotton-wool spots separately from the optic disk is almost pathognomonic of arteritic AION. Other posterior-segment pathology is less common. Choroidal infarcts might also occur. Although the central retinal artery is not thought to be directly involved in giant cell arteritis, occlusion of this artery can occur owing to proximal vessel disease.11,6 AION can occur in the absence of arteritis, and the differentiation of arteritic and nonarteritic AION can be a challenge (Table 1). Fluorescein angiography can help to distinguish between arteritic and nonarteritic AION.

Systemic corticosteroids are effective in controlling the symptoms of giant cell arteritis. Patients with ophthalmic symptoms can present with unilateral, acute loss of visionwhich is in most cases irreversible. Without treatment, more than 70% of patients will suffer contralateral vision loss within 1 week,12 so immediate treatment with high-dose systemic steroids is warranted. Rarely, patients with giant cell arteritis experience symptoms of fluctuating monocular vision, which can herald imminent infarction of the optic nerve head. These patients require immediate treatment to preserve their vision.

RETINAL FINDINGS IN MEDIUM-VESSEL VASCULITIS

Vessels of medium and small caliber are affected by polyarteritis nodosa, which is a necrotizing vasculitis. The eye can be affected by the vasculitic process or by systemic hypertension. In the posterior segment, vasculitis most frequently involves the posterior ciliary arteries and choroidal vessels. This involvement can result in an anterior ischemic optic neuropathy similar to that seen in giant cell arteritis.13 Retinopathy with cotton-wool spots, exudation, macular star (a star-shaped pattern of lipid exudates at the posterior pole of the eye), and/or vascular tortuosity have all been described.14 Treatment for these retinal signs is largely treatment for the underlying disease. As with AION in giant cell arteritis, prompt, high-dose immunosuppression

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is required to prevent visual loss in the other eye (Box 1).

Systemic lupus erythematosus (SLE)

RETINAL FINDINGS IN SMALL-VESSEL VASCULITIS Wegeners granulomatosis

Retinal complications of Wegeners granulomatosis are rare, and include retinal artery occlusions, cotton-wool spots and choroidal infarcts.15 Posterior scleritis can cause choroidal folds (Figure 5), exudative retinal detachment and compressive optic neuropathy.8 An anterior ischemic optic neuropathy similar to that seen in giant cell arteritis has been reported.16 The presence of retinal signs usually signifies a major relapse in the underlying disease, and this relapse needs to be treated aggressively.
ChurgStrauss syndrome

Retinopathy in ChurgStrauss syndrome has been described in a few reports.17 This retinopathy consists of an ischemic vasculitis that gives rise to AION associated with retinal arterial or venous occlusions, and typically occurs in patients positive for serum perinuclear antineutrophil cytoplasmic antibodies (pANCA). It has been advocated that patients who are pANCA-positive should be considered for prophylactic steroid therapy, given that once this retinopathy develops, visual prognosis is poor despite steroid treatment.17 The value of this approach has not been formally tested. Nevertheless, posterior-segment complications related to ischemic vasculitis can develop even in the absence of positive pANCA titers, and these can be equally visually devastating.18
Relapsing polychondritis

Retinopathy is the second most common ophthalmic manifestation of SLE (after secondary Sjgren syndrome), with reported incidences ranging from 3% in the outpatient setting21 to 29% in admitted patients.22 SLE retinopathy is characterized by the presence of cotton-wool spots (Figure 2). Retinal hemorrhages and microaneurysms might also occur. Although SLE retinopathy has a good visual prognosis, it is associated with major relapses of systemic disease,21 and its presence warrants an immediate referral for rheumatologic consultation. An occlusive retinopathy with poor visual prognosis has been described in patients with SLE. This complication is very rare and is associated with cerebral vasculitis and increased mortality.23 Choriodopathy is a rare finding in patients with SLE, and few cases have been reported in the literature.24 Choroidopathy can be asymptomatic with no ophthalmologic signs,25 or it can result in serous detachments of the retinal pigment epithelium or the retina.26 Lupus choriodopathy indicates active disease and it is associated with cerebral vasculitis.24 A variety of presentations of optic neuropathy has been reported in association with SLE, including cases of papilledema secondary to cerebral venous thrombosis.27 The pathogenesis of SLE retinopathy and choroidopathy seems to arise from fibrinoid necrosis and vessel occlusion secondary to immune-complex deposition.28 Associated antiphospholipid syndrome is also a risk factor for occlusive disease.29,30 The retinal manifestations of other systemic vasculitides are summarized in Table 2.

Scleritis is the most common ocular manifestation of relapsing polychondritis; in one study, this sign was present in 51 out of 117 patients, and was the presenting feature in 6 patients.19 Posterior scleritis can result in choroidal folds, exudative retinal detachment, and optic nerve compression. In the aforementioned series, nine patients had retinopathy consisting of microaneurysms, hemorrhages and cotton-wool spots. Two other patients had retinal vasculitis associated with vein occlusions.19 AION can also occur in relapsing polychondritis.20 Where present, scleritis will need high-dose immunosuppression to control pain and restore vision. Ischemic complications require attention to the management of the underlying disease.

RETINAL MANIFESTATIONS OF THE COMPLICATIONS OF VASCULITIDES OR THEIR TREATMENT Hypertensive retinopathy and choroidopathy

Systemic hypertension is a common complication of systemic vasculitis. Signs of hypertensive retinopathy and choroidopathy will vary, depending on the mode of onset and the severity of hypertension.31 Severe, hypertensive retinopathy is characterized by flame hemorrhages and vascular leakage. This retinopathy results in the formation of retinal edema and hard exudates. Optic nerve swelling signifies a hypertensive crisis, and exudate can form a macular star around the fovea (Figure 6).

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Box 1 Principles of management of retinal features related to systemic vasculitis.

Cotton-wool spots Cotton-wool spots alone do not require specific treatment, although their presence can indicate recurrence of systemic disease, which might require treatment. Central or branch retinal artery occlusion The pathogenesis of vasculitic retinal artery occlusions is related to inflammation of vessel walls. Pathogenesis differs to that of the more common embolic retinal artery occlusion, for which there have been limited reports of restoration of blood flow (although the success rate of such attempts is disappointing). There are no such published cases for arteritic retinal artery occlusion and treatment in such cases is for the underlying pathology, to prevent further vascular occlusions. Choroidal ischemia There is no specific treatment for choroidal ischemia, apart from treating the underlying systemic disease. Anterior ischemic optic neuropathy See the treatment recommendations for anterior ischemic optic neuropathy secondary to giant cell arteritis. Restoration of vision is uncommon, and treatment is aimed at prevention of an attack in the uninvolved eye. Long-term treatment is for the underlying systemic vasculitis. Ocular ischemic syndrome The restoration of arterial perfusion is possible in cases such as Takayasus arteritis, in which improvement and resolution of the ocular ischemic syndrome is well documented following bypass graft surgery.41 In cases of established ocular ischemic syndrome, panretinal photocoagulation is reserved for cases where there is retinal or iris neovascularization, in an attempt to reduce production of angiogenic factors. The response to this treatment is less favorable than in patients with diabetic retinopathy. Posterior scleritis and optic nerve compression Optic nerve compression requires urgent treatment. In the case of posterior scleritis, systemic immunosuppression for the underlying systemic disease will reduce inflammation and decompress the optic nerve. Hypertensive retinopathy Treatment for systemic hypertension and underlying disease. Retinal signs do not require specific treatment.
Visual symptoms or the discovery of any of the above retinal signs should prompt consultation with an ophthalmologist for advice.

Figure 5 Posterior scleritis. A color fundus photograph that shows choroidal folds over the macula (encircled in green).

Hypertensive choroidopathy is rare, and usually occurs in the setting of a hypertensive crisis. Acute, exudative retinal detachment can result from exudation from the choroid through the retinal pigment epithelium.32 Chronic changes due to focal choroidal infarcts are recognized as small, dark spots surrounded by pale haloes, whereas choroidal vessels undergoing fibrinoid necrosis are visible as linear lesions.
Retinal effects of immunosuppression

The immunosuppressive effect of systemic drugs such as cyclophosphamide, azathioprine and corticosteroids can increase the risk of ocular infections such as toxoplasmosis, herpesvirus-related retinitis and tuberculosis. These infections can cause permanent vision loss in the absence of prompt treatment. Herpes simplex virus and varicella-zoster virus can cause a necrotizing retinitis, which starts in the fundal periphery and spreads to the center. Necrotizing retinitis is characterized by contiguous areas of white retinal necrosis, hemorrhages, and vasculitis of retinal arterioles. This clinical picture is termed acute retinal necrosis, and it can occur in both immunocompetent and immunocompromized hosts. High-dose intravenous antiviral therapy is often effective in arresting the progression of acute retinal necrosis, and in causing remission. Cytomegalovirus typically causes a retinitis that starts in the posterior pole and involves the macula and the optic nerve early in its course (Figure 7).33,34 Cytomegalovirus retinitis is treated with systemic ganciclovir or foscarnet.

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Table 2 Uncommon vasculitides and their retinal manifestations.

Type of vasculitis Takayasu arteritis Goodpastures disease HenochSchnlein purpura pANCA-associated vasculitis Scleroderma, including CREST syndrome Vasculitis associated with rheumatoid arthritis
aAll

Vessels affected Large elastic arteries, selected muscular arteries9 Small vessels1 Arterioles and venules, often small arteries and veins1 Small vessels1 Small vessels

Retinal featuresa OIS, CWS and rarely AION40

Other features OIS can resolve following bypass surgery to improve carotid flow41 None defined BRAO occurs in association with cerebral vasculitis44 None defined Choroidal perfusion abnormalities on angiography (asymptomatic and not clinically observable)47 None defined

Rarely retinal hemorrhages, subretinal neovascularization42,43 Rarely BRAO44 CWS, AION, posterior scleritis, choroiditis, CRAO45 Rarely CWS, ischemic retinopathy46 Rarely AION retinal vasculitis, choroiditis4850

Small to medium vessels

might have associated hypertensive retinopathy. Abbreviations: AION, anterior ischemic optic neuropathy; BRAO, branch retinal artery occlusion; CRAO, central retinal artery occlusion; CREST, scleroderma characterized by at least two of the following: calcinosis, Raynauds syndrome, loss of muscular control of the esophagus, sclerodactyly, telangiectasia; CWS, cotton-wool spots; OIS, ocular ischemic syndrome; pANCA, perinuclear antineutrophil cytoplasmic antibody.

Figure 6 Retinopathy in hypertensive crisis. A color fundus photograph that shows optic disk swelling, cotton-wool spots (blue arrow), hemorrhages (white arrow), retinal exudation and a macular star (green arrow).

Figure 7 Cytomegalovirus retinitis. A color fundus photograph that shows contiguous areas of white retinal necrosis (blue arrow), vascular sheathing (green arrow), and hemorrhage (white arrow) in the retinal periphery.

The clinical appearance of the retinitis is often not discriminatory, and a vitreous-humor biopsy is essential, so that polymerase chain reaction assays for viral sequences can differentiate between the various types of viral retinitis and appropriate treatment can be chosen. Indeed, toxoplasmosis of the eye, as well as syphilitic and tuberculous chorioretinitis can all mimic the clinical picture of viral retinitis, and these etiologies should be borne in mind in atypical cases, or when the polymerase chain reaction assay for viral sequences in the vitreous humor

is negative. Symptoms of floaters or reduced vision, particularly in a red eye, or the detection of retinal signs by the physician, should prompt an urgent ophthalmic referral. Optic neuropathy is a well-described adverse event caused by methotrexate-induced folate deficiency. Patients might complain of a reduction in their visual acuity. The optic nerve can be swollen and/or pale. Formal evaluation of visual fields often reveals centrocecal defects, which extend from the blind spot to involve the central point of fixation.35 Folate replacement might reverse

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this visual loss. As with all patients on long-term immunosuppression, there is an increased risk of malignancy, which might present in the eye as ocular lymphoma. It is beyond the scope of this article to discuss chloroquine-related and hydroxychloroquine-related retinal toxicity, which have been reviewed elsewhere.36,37

CONCLUSIONS

With the exception of giant cell arteritis and hypertensive retinopathy, fundal signs related to systemic vasculitides are uncommon, or even rare. The vasculitic process typically affects the retinal arteries rather than the veins, and these signs are not specific to any type of vasculitis. Often, the development of retinal signs heralds a relapse of the underlying vasculitis and urgent referral to a rheumatologist is required. Retinal signs on their own rarely require specific treatment, although complications such as neovascularization secondary to retinal ischemia (as is seen, rarely, in lupus and scleroderma) might require laser photocoagulation. Finally, the possibility that the retinal signs might be secondary to iatrogenic immunosuppression should always be borne in mind, as rapid and specific treatment for retinal infections might preserve the patients sight.

KEY POINTS
The pathology of the systemic vasculitides can involve the blood supply to the eye, causing retinal signs The types of posterior segment clinical signs relating to the various vasculitides are influenced by the diameter of vessel involved With the exception of giant cell arteritis and hypertensive retinopathy, fundal signs related to systemic vasculitides are uncommon or even rare The vasculitic process typically affects the retinal arteries rather than the veins, and these signs are not specific to any type of vasculitis Often, the development of retinal signs heralds a relapse of the underlying vasculitis, and urgent referral to a rheumatologist is required The possibility that retinal signs might be secondary to iatrogenic immunosuppression should be borne in mind, as rapid and specific treatment for retinal infections might preserve vision

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Competing interests
The authors declared they have no competing interests.

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