INTRODUCTION

About a third of patients with SLE may have ocular involvement. The majority have the complication of dry eye syndrome, which may cause discomfort but is usually responsive to treatment and rarely affects vision. A significant minority may have sight-threatening complications, such as retinal vaso-occlusive disease, scleritis, or severe ocular surface disease. In addition, these serious ocular complications may indicate significant disease activity elsewhere. Thus, the ophthalmologist may play a valuable part both in recognizing and managing the SLE patient’s ocular disease and in warning of increasing systemic disease activity. Vigilance and appropriately aggressive therapy may be life saving as well as vision-preserving.

CLASSIFICATION AND ASSESSMENT OF DISEASE ACTIVITY

Although ocular involvement is not one of the 11 features in the American College of Rheumatologists classification criteria for SLE,¹ recognizing ocular manifestations may be a useful marker of disease activity. In particular, severe retinopathy strongly correlates with active CNS disease.² The updated British Isles Lupus Assessment Group disease activity index (BILAG 2004) includes the “ophthalmic system” as one of the nine categories considered. In their validation study, good reliability and physician agreement were seen for the ocular activity index in the one series that was sufficiently powered for ocular patients.³

CLINICAL PRESENTATION

External and Anterior Segment

Keratoconjunctivitis Sicca

Keratoconjunctivitis sicca (KCS, or “dry eye syndrome”) due to secondary Sjögren syndrome is the most common ocular manifestation of SLE, affecting about 25% of patients. Secondary Sjögren syndrome is strongly associated with HLA-DRw52 and the autoantibodies anti-Ro (SSA) and anti-La (SSB). Symptoms may vary from slight irritation and burning in milder cases to severe pain and blurred vision in significant corneal involvement. Clinical examination using slit-lamp biomicroscopy reveals a small or absent concave tear meniscus with a tear film break-up time of under 10 seconds. Corneal abnormalities, which may be highlighted with fluorescein drops and a cobalt blue light, include punctate epitheliopathy, mucus filaments, strands, and plaques. Additional staining with Rose Bengal drops reveals a characteristic interpalpebral pattern, with greatest staining nasal and temporal to the corneal limbus.

Tear production, as measured by the Schirmer test, is reduced. Wetting of the test strip by less than 5 mm after 5 minutes in the un-anaesthetized eye indicates severe tear deficiency. In one series of patients with SLE, the median value was 7.5 mm.⁴ It should be noted that the correlation of dry eye symptoms with observed disease is poor. Many more patients report “dry eyes” than have visible disease,⁴ and many asymptomatic patients do have some degree of keratoconjunctivitis sicca.

Other Keratopathies and Anterior Segment Complications

Superficial punctate keratitis may be observed in patients with SLE in the absence of visible KCS. One series noted corneal staining in as many as 21 of 24 (88%) SLE patients.⁵ Similarly, superficial punctate keratitis (and recurrent erosions) has been noted in DLE. Interestingly, this responded well to the immunomodulator quinacrine hydrochloride, suggesting that this may be a direct autoimmune phenomenon. Deeper corneal involvement may occasionally occur, with both interstitial keratitis and keratoendotheliitis reported. In the latter, polyrefringent crystals in the deep stroma with associated edema are seen. Other rare anterior segment complications include iris neovascularization (rubeosis iridis, usually indicating severe retinal ischemia) and uveitis.

Episcleritis and Scleritis

Episcleritis is observed in 1 to 2% of SLE patients. Patients present with a red eye with mild, if any, discomfort. Upon examination, either sectoral or diffuse injection of the superficial vessels is seen. The superficial nature of the inflammation may be confirmed by the instillation of topical 10% phenylephrine. When only the more superficial vessels are injected (as occurs in episcleritis), constriction of these vessels will result in visible blanching. This can helpfully distinguish the condition from scleritis, where deeper vessels would be unaffected and the redness would be maintained. Although not serious in itself, episcleritis may indicate increased systemic activity. (See Box 39.1.)

Scleritis is observed in 1% of SLE patients, and may be the first manifestation of their systemic disease.⁶ The more common anterior scleritis usually presents with a severely painful red eye, which may be so severe that it wakes the patient up at night. Upon examination, the deeper vascular plexus is injected. This may be widespread (diffuse non-necrotizing scleritis) or focal and associated with a nodule (nodular non-necrotizing scleritis). Necrotizing scleritis is rare. It is important to also examine the eye in day or room light, as the bright light of the slit lamp often underestimates the degree of scleral inflammation (and thinning). Posterior scleritis may present with mild to severe ocular pain (which may be referred to brow or jaw), reduction of vision, hypermetropic shift (i.e., becoming more long-sighted), photopsia, and diplopia.

Ocular signs include choroidal folds or detachment (may be annular), exudative retinal detachments, and edema of the macula or optic disc. In addition, there may be associated periocular and orbital signs, such as lid edema, proptosis, lid retraction, and restricted ocular motility. B scan ultrasound is the investigation of choice (see “Investigations”). Scleritis may be sight threatening and is an indicator of significant systemic activity requiring commencement or increase of systemic therapy (as “Treatment”). Conversely, the scleritis improves as the systemic disease is brought under control. As the scleritis resolves, it becomes thinner and allows the blue-black color of the uvea to show through. Scleral thinning may induce high degrees of astigmatism, and in necrotizing disease possibly globe perforation. Scleritis requires urgent referral to an ophthalmologist.

Lid Disease

Both SLE and DLE may involve the eyelids, resulting in raised scaly lesions resembling chronic blepharitis.⁷ Lid biopsy may be necessary to confirm the diagnosis. This shows hyperkeratosis, focal intracellular edema and degeneration of the basal layer, and lymphocytic infiltrates (especially around the vessels). Interestingly, a mouse model for SLE inoculated with human monoclonal anti-DNA antibodies demonstrated acute and chronic inflammation of the lids with immune complex deposition. The lids may also be involved in the classic malar rash of SLE.

Orbital Disease

Uncommonly, SLE may be associated with orbital inflammation or periorbital edema. Orbital inflammation may present with acute proptosis, lid edema, conjunctival injection and chemosis, reduced motility, and raised intraocular pressure. It may be misdiagnosed as orbital cellulitis, thyroid eye disease, or another form of orbital inflammation. Orbital inflammation may include myositis or rarely panniculitis (lupus erythematosus profundus). Myositis may be demonstrated by imaging using CT and B scan ultrasound showing enlargement of extraocular muscles, and upon biopsy. Episodes of orbital myositis may occur concomitantly with a generalized myositis.⁸ Orbital inflammation may also be associated with acute ocular ischemia and posterior scleritis.⁹ Rare complications include episodic periorbital edema and septic cavernous sinus thrombosis in the presence of severe immunosuppression. (See Box 39.2.)

Posterior Segment

Classic Lupus Retinopathy

Bergmeister first described retinal involvement in SLE in 1929. He noted cotton-wool spots and other lesions arising several weeks after a flare-up of the patient’s cutaneous manifestations. The retinopathy is usually bilateral, but may be asymmetric. The presence of retinopathy is commonly associated with systemic activity, active systemic disease being present in 88% of one series of retinopathy patients.¹⁰

Although older series reported retinopathy in up to 28% of SLE patients, more recent studies suggest that its prevalence is nearer 10% in adults ¹¹ and in children. This reduction is likely to reflect the overall improved control of systemic SLE. Mild retinopathy is usually asymptomatic, but severe disease (and its complications) may cause reduced visual acuity, field defects, distortion, or floaters. The classic clinical picture is of cotton-wool spots and retinal hemorrhages with abnormalities of the vasculature, such as arterial narrowing, capillary dilation, venous dilation, and tortuosity (see Figs. 39.1, 39.2, and 39.3). Additional features include retinal edema, hard exudates, and microaneurysms.

Fig. 39.1 Acute lupus retinopathy with cotton-wool spots, arterial narrowing, venous dilation, and tortuosity.

Fig. 39.2 Fundus fluorescein angiography of the same patient: (A) early, (B) arteriovenous, and (C) late phases demonstrating capillary “drop-out,” vessel wall staining, and leakage.

Fig. 39.3 Detail of the same patient showing venous beading.

Severe Vaso-occlusive Retinopathy (“Retinal Vasculitis”)

The more severe vaso-occlusive retinopathy of SLE is much less common. Significant visual loss is reported in up to 80% of such patients, with final acuity of <20/200 in 50%.² In addition, severe vaso-occlusive retinopathy is strongly associated with the life-threatening complication of CNS lupus.² The risk of vaso-occlusive disease (ocular and CNS) is increased in the presence of antiphospholipid antibodies, with some observers noting a fourfold increase for ocular disease.¹² Interestingly, most of the features seen in SLE-associated retinopathy may occur in the presence of antiphospholipid antibodies without SLE (primary antiphospholipid syndrome or Hughes syndrome). Cotton-wool spots are, however, less common.

This form of retinopathy is often termed retinal vasculitis, although true vasculitic changes are often not present upon histologic examination. It is characterized by widespread arteriolar occlusions and capillary nonperfusion with subsequent neovascularization in 40 to 72% of cases.² Such proliferative retinopathy may in turn be complicated by vitreous hemorrhage (up to 63%), retinal traction, and retinal detachment (up to 27%).² Rarely, frank vasculitis does occur. Reports include a “frosted branch”-type periphlebitis with exudative maculopathy.

Fluorescein angiography may reveal areas of arterial and capillary nonperfusion, staining of vessel walls, and leakage notably from neovascular fronds (see Figs. 39.4 and 39.5). Angiography commonly shows more extensive disease than clinically suspected. At the histologic level there is hyaline thrombus formation with thickening of the vessel walls and perivascular infiltrate, but inflammation of the vessel wall itself is not seen, in contrast to a “true” vasculitis.¹³ Immune complex deposition containing IgG, C1q, and C3 may be seen upon immunofluroescence staining.