Figure 1. An isolated cotton-wool spot in a patient with systemic lupus erythematosus.

The first use of the term “lupus,” which is Latin for wolf, is attributed to the 12th-century physician Rogerius to describe the classic malar rash that resembles the pattern or fur on a wolf’s face. Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production and deposition of autoantibody immune complexes in tissues throughout the body.¹ In the United States, the annual incidence is 5.1 per 100,000 persons with a reported prevalence of 52 cases per 100,000 population.² There exists a racial predilection, as the prevalence of SLE ranges from 40 cases per 100,000 persons among northern Europeans to more than 200 per 100,000 persons among blacks.³ Lupus tends to be more common among women by a factor of 9:1.⁴

Systemic lupus erythematosus can affect virtually any organ in the body, and the American College of Rheumatology has set criteria for the diagnosis of SLE (Table 1). Although ocular manifestations are not part of the diagnostic criteria, they are common and can be observed in up to one-third of patients with SLE.⁵ Anterior segment findings in SLE include keratoconjunctivitis sicca, conjunctivitis, episcleritis, anterior scleritis, keratitis and iritis.⁵ It is important to recognize SLE-associated posterior segment disease and its association with CNS disease as a significant cause of patient morbidity.

• Retinopathy. The retinopathy associated with SLE is the most common type of posterior segment finding and the risk of retinal involvement varies with disease control. It may range from 3 percent in well-controlled patients to 29 percent in patients with more active systemic disease.^6,7 The most common retinal manifestation is cotton wool spots (See Figure 1), although frank phlebitis and arteritis also occur, often producing venous or arteriolar occlusion, respectively (See Figure 2, p. 43). Other manifestations may include microaneurysms, vascular tortuosity, arteriolar narrowing, retinal edema or exudates. Retinal microangiopathy associated with SLE is thought to represent immune complex-mediated vascular injury and microvascular thrombosis.⁸ Fortunately, most patients with mild retinopathy are at low risk for vision loss.⁶

Table 1. American College of Rheumatology Criteria for the Diagnosis of Systemic Lupus Erythematosus  Criterion Definition 1. Malar Rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds. 2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging (Atrophic scarring may occur in older lesions) 3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician 5. Arthritis Nonerosive arthritis involving ≥two peripheral joints, characterized by tenderness, swelling or effusion 6. Serositis A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or evidence of plural effusion, or B) Pericarditis: Documented by electrocardiogram or rub or evidence of pericardial effusion 7. Renal disorder A) Persistent proteinuria >0.5 g/d or >3+ if quantitation not performed or B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular or mixed 8. Neurological disorder A) Seizures: In the absence of offending drugs or known metabolic derangements, or B) Psychosis: In the absence of offending drugs or known metabolic derangements 9. Hematological disorder A) Hemolytic anemia: With reticulocytosis, or B) Leukopenia: <4,000mm3 total on ≥two occasions, or C) Lymphopenia: <1,500mm3 on ≥two occasions, or D) Thrombocytopenia: <100,000mm3 in the absence of offending drugs 10. Immunological disorder A) Anti-DNA: Antibody to native DNA in abnormal titer, or B) Anti-Sm: Presence of antibody to Sm nuclear antigen, or C) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serological test for syphilis known to be positive for at least six months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption tests 11. Antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome Abbreviations: g = grams; d = deciliters; mm = millimeters; DNA = deoxyribonucleic acid; Sm = Smith; IgG = immunoglobulin G; IgM = immunoglobulin M. (Chart modified from Tan, et al.24)

Systemic lupus erythematosus can be diagnosed if any four or more of the 11 criteria are present serially or simultaneously, during any interval of observation.

In contrast, SLE associated vaso-occlusive disease characterized by widespread capillary non-perfusion of the retina (See Figure 3) has been associated with a worse visual prognosis. Up to 55 percent of patients may have vision worse than 20/200, and 40 percent of patients may go on to develop retinal neovascularization and vitreous hemorrhage.⁹ Patients often require panretinal photocoagulation to treat areas of capillary non-perfusion. Some patients can develop anterior segment rubeosis, tractional retinal detachment⁹ or macular infarction¹⁰ leading to significant vision loss and morbidity. Increasing evidence suggests that this more severe vaso-occlusive form of lupus-related retinopathy may be associated with the presence of antiphospholipid antibodies, including the presence of anti-cardiolipin (aCL) or lupus anti-coagulant antibodies (LAC).¹¹

There exists a relationship between SLE and the antiphospholipid antibody syndrome (APS). The “classical” clinical manifestations of APS, also known as Hughes’ syndrome,¹² include deep venous thrombosis, cerebral arterial thrombosis, pulmonary emboli, recurrent fetal loss (predominantly in the second and third trimesters) and thrombocytopenia. Patients with at least one classical clinical manifestation of APS, along with the presence of antiphospholipid antibodies such as aCL and/or LAC antibodies in at least two samples taken three months apart, may be diagnosed with APS. Patients with APS may have SLE. However, if patients with APS do not meet the American College of Rheumatology criteria for SLE diagnosis, they can be diagnosed as having lupus-like disease (LLD) or primary APS.

The pathogenesis of antiphospholipid antibody-induced vascular thrombosis is not entirely understood, but the presence of aPL may increase plasma levels of endothelin 1 (ET-1), which could affect arterial tone and contribute to the occurrence of thrombosis.¹³ Severe vaso-occlusive retinopathy, including central or branch retinal artery and vein occlusion with extensive retinal capillary nonperfusion, in patients with SLE with positive aPL or primary APS has been coined Hughes’ retinopathy.¹⁴ Patients with APS generally require anticoagulation to maintain a therapeutic international normal ratio (INR) of ≥3 to have adequate prophylaxis in preventing recurrent thrombosis. Cerebrovascular disease seems to be the most associated finding seen in SLE patients with Hughes’ retinopathy,¹⁴ and proper neurological workup should be taken into consideration. Some recommend that patients with SLE and antiphospholipid-associated Hughes’ retinopathy should be started on anticoagulation in addition to treatment of the underlying rheumatological disease.¹⁴

Figure 2. Peripheral phlebitis with venous occlusion (left) and posterior arteritis with arteriolar occlusion (right) in two separate patients with systemic lupus erythematosus.

• Posterior scleritis. Posterior scleritis can occur in patients with SLE and may sometimes be the presenting sign of systemic disease.¹⁵ Symptoms may include vision loss, red eye and/or pain in one or both eyes. Ocular signs suggestive of posterior scleritis include exudative retinal detachment, thickened posterior sclera and fluid seen in sub-Tenon’s space on ocular ultrasonography (See Figure 4). Though rare, one case of SLE presenting as giant nodular scleritis has been reported, and this finding may mimic a choroidal melanoma.¹⁵ With prompt treatment with systemic or periocular corticosteroids, visual prognosis can be good.

• Choroidopathy. Choroidopathy in SLE may present as multiple, serous detachments of the retinal pigmented epithelium and the neurosensory retina (See Figure 5).^16-18 Visual loss can occur if the detachment affects the macula. In some cases, the subretinal fluid can progress to large, bullous exudative retinal detachments. Treatment of underlying active disease often results in resolution of the choroidopathy and associated subretinal fluid. Once the fluid resolves, the fundus may be left with a mottled appearance to the pigmented epithelium. Patients with SLE-associated choroidopathy tend to have associated systemic vascular disease either from systemic hypertension or lupus nephritis, vasculitis or a combination of these.¹⁷ 

Figure 3. Color photographs (A,B) and early-phase fluorescein angiograms (C,D) showing extensive arteriolar occlusions with bilateral macular infarctions in a patient with systemic lupus erythematosus. Vision loss was the presenting sign of lupus in this patient.   Figure 4. Posterior scleritis in a patient with systemic lupus erythematosus. Optic disc hyperemia and retinal striae were evident clinically (A, B). B-scan ultrasonography showed posterior eye wall thickening with retrobulbar fluid producing the so-called “T-sign” (C).

Suspected pathogenesis may be due to a microangiopathy caused by a mononuclear inflammatory infiltrate of the choroid, immunoglobulin and complement deposition in the choroidal blood vessels and damage to the overlying RPE.¹⁷ It is postulated that systemic hypertension may contribute to the serous detachments by providing a hydrostatic force across and into the detachment.¹⁷ Of course, many patients with SLE are treated with systemic corticosteroids, and the relationship between corticosteroids and serous retinal detachment can be complex. That said, choroidopathy has been reported in SLE without prior exposure to corticosteroids,19 and the majority of cases of SLE-choroidopathy resolve with treatment with systemic immunosuppression including corticosteroids.¹⁷

• Optic neuropathy. While the involvement of the CNS occurs in nearly 39 percent of patients with SLE,^20,21 the estimated prevalence of optic neuropathy in SLE is 0.7 percent.²⁰ Though rare, the clinical features of optic neuropathy in patients with SLE have been described, and its presentation can be highly variable. For example, a patient may present with painless vision loss, arcuate visual field defects and optic disc swelling when seen with anterior ischemic optic neuropathy, or rather with significant orbital pain associated with optic neuritis or papillitis.²² Reported ocular findings may include optic neuritis, ischemic optic neuropathy, retrobulbar optic neuropathy and optic atrophy, and optic nerve disease can affect one or both eyes.^22,23 Corresponding visual field deficits, depressed visual evoked responses and afferent pupillary defects have been observed. Visual prognosis may also be variable as well, ranging from 20/20 to NLP vision depending on the extent of optic nerve damage, and this may be corticosteroid-responsive.²² The pathogenesis is thought to be related to small-vessel occlusive disease of the optic nerve, where milder cases show demyelination from mild ischemia and more severe cases exhibit significant axonal damage and necrosis.²² Of import is the association of optic nerve disease and associated CNS lesions in patients with SLE. Central nervous system lesions have been estimated to be in 54 percent of patients with lupus optic neuropathy, most commonly affecting the spinal cord.²²

Managing posterior segment disease typically involves the use of systemic immunosuppression with corticosteroids in the acute setting, followed by non-corticosteroid immunosuppresive agents. For severe posterior segment involvement, intravenous corticosteroid pulse therapy may be needed acutely. In some cases, local treatment with periocular corticosteroid injection may be useful. Patients with severe vaso-occlusive disease, particularly with the presence of antiphospholipid antibodies, may benefit from additional anticoagulation and/or anti-platelet treatment. In patients with profound retinal ischemia, panretinal photocoagulation and vitrectomy surgery may be needed to address complications from anterior or posterior segment neovascularization.

Retinal specialists serve an important role in the overall care of patients with SLE. One large prospective study showed that 88 percent of SLE patients with retinopathy had active systemic disease.⁷ The SLE patients who developed retinopathy had a lower overall survival rate as compared to patients without retinopathy over the same time period. Moreover, active CNS involvement of lupus, a significant cause of patient morbidity, is found more often in patients with active retinopathy,^7,14 retinal vaso-occlusive disease9 and optic neuropathy.²² Therefore, the presence of posterior segment findings in patients with SLE should prompt the retinal specialist to communicate with the general internist and/or rheumatologist regarding the activity and severity of their mutual patients’ disease.  REVIEW

Figure 5. Serous retinal detachments in a patient with systemic lupus erythematosus choroidopathy. Similar findings were present in the fellow eye.

Dr. Wong sees patients at Austin Retina Associates, Austin, Texas. Dr. Cunningham is the director of the Uveitis Service at California Pacific Medical Center, San Francisco; an adjunct clinical professor of ophthalmology at Stanford University School of Medicine, Stanford, Calif.; and sees patients at West Coast Retina Medical Group, San Francisco. Contact Dr. Wong at robertwongmd@gmail.com.