Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem connective tissue disorder that affects primarily women of childbearing age, with higher incidence rates among African American and Hispanic persons in the United States. The pathogenesis of SLE is incompletely understood. It is thought to be an autoimmune disorder characterized by B-lymphocyte hyperactivity, polyclonal B-lymphocyte activation, hypergammaglobulinemia, autoantibody formation, and T-lymphocyte autoreactivity with immune complex deposition, leading to end-organ damage. Autoantibodies associated with SLE include antinuclear antibodies (ANA), antibodies to both single- and double-stranded DNA (anti-ssDNA and anti-dsDNA), antibodies to cytoplasmic components (anti-Sm, anti-Ro, and anti-La), and antiphospholipid antibodies.

• D’Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007;369(9561):587–596.

Manifestations The systemic manifestations of SLE include acute cutaneous diseases in approximately 70%–80% of patients (malar rash, discoid lupus, photosensitivity, and mucosal lesions), arthritis in 80%–85%, renal disease in 50%–75%, Raynaud phenomenon in 30%–50%, and neurologic involvement in 35%. Cardiac, pulmonary, hepatic, and hematologic abnormalities can also occur. The diagnosis is clinical and based on criteria established by the American College of Rheumatology.

Ocular manifestations occur in 50% of patients with SLE and include cutaneous lesions on the eyelids (discoid lupus erythematosus), secondary Sjögren syndrome, scleritis, cranial nerve palsies, optic neuropathy, retinal and choroidal vasculopathy, and, in rare cases, uveitis.

Lupus retinopathy, the most well-recognized posterior segment manifestation, is considered an important marker of systemic disease activity. Prevalence ranges from 3% among patients with mild disease to 29% among those with more active disease. Its clinical spectrum varies and is characterized by the following signs:

• Cotton-wool spots with or without intraretinal hemorrhages. These lesions can be seen without concurrent hypertension and are thought to be due to the underlying microangiopathy of the disease (Fig 9-1).

• Severe retinal vascular occlusive disease (arterial and venous thrombosis). Retinal vascular occlusion results in retinal nonperfusion and ischemia, secondary retinal neovascularization, and vitreous hemorrhage (Fig 9-2). More severe retinal vascular occlusive disease in SLE appears to be associated with central nervous system (CNS) lupus and the presence of antiphospholipid antibodies. Retinal vascular thrombosis is thought to be related to a hypercoagulable state induced by autoantibodies, rather than to an inflammatory retinal vasculitis. See BCSC Section 1, Update on General Medicine, for a discussion of antiphospholipid antibodies.

• Lupus choroidopathy. This entity is characterized by an immune-mediated choroidal vasculopathy, causing serous elevations of the retina and/or retinal pigment epithelium (RPE), as well as choroidal infarction and choroidal neovascularization (CNV). It almost always occurs in patients with known, and usually severe, systemic vascular disease, due to either hypertension from lupus nephritis or systemic vasculitis (Fig 9-3). SLE-induced hypertension and nephritis may also result in arteriolar narrowing, retinal hemorrhage, and disc edema.

• American College of Rheumatology. 1997 update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Available at https://bit.ly/2pYkcqJ. Accessed September 20, 2018.

Figure 9-1 Systemic lupus erythematosus fundus photograph showing multiple cotton-wool spots.

(Courtesy of E. Mitchel Opremcak, MD.)

Figure 9-2 Systemic lupus erythematosus (SLE). A, Fundus photograph showing ischemic retinal vasculitis and neovascularization in a patient with SLE. B, Fluorescein angiogram of the same patient, showing capillary nonperfusion.

(Courtesy of E. Mitchel Opremcak, MD.)

Figure 9-3 Systemic lupus erythematosus (SLE). A, Fundus photograph of multifocal choroiditis in a patient with SLE. B, Fluorescein angiogram showing multifocal areas of hyperfluorescence.

(Courtesy of E. Mitchel Opremcak, MD.)

• Jabs DA, Fine SL, Hochberg MC, Newman SA, Heiner GG, Stevens MB. Severe retinal vasoocclusive disease in systemic lupus erythematosus. Arch Ophthalmol. 1986;104(4):558–563.

• Nguyen QD, Uy HS, Akpek EK, Harper SL, Zacks DN, Foster CS. Choroidopathy of systemic lupus erythematosus. Lupus. 2000;9(4):288–298.

• Palejwala NV, Walia HS, Yeh S. Ocular manifestations of systemic lupus erythematosus: a review of the literature. Autoimmune Dis. 2012;2012:290898.

Limits to ANA testing Uveitis is not commonly associated with SLE. However, ANA testing is often done in patients with uveitis who have no systemic or ocular findings to suggest SLE. Under those circumstances, the test has a very high false-positive rate; ANA testing should be limited to use in patients with signs or symptoms suggestive of SLE or who have juvenile idiopathic arthritis (JIA), for whom the test can help determine the level of risk for uveitis.

Treatment The treatment of ophthalmic disease in SLE is directed toward control of the underlying systemic disease, which may involve corticosteroids and IMT (immunomodulatory therapy), including hydroxychloroquine. Patients with severe vaso-occlusive disease or antiphospholipid antibodies may benefit from antiplatelet therapy or systemic anticoagulation. Ischemic complications, including proliferative retinopathy and vitreous hemorrhage, are managed with panretinal photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) injections, and, in some cases, vitrectomy.

Some patients with SLE may remain on glucocorticoids for extended periods and thus need monitoring for cataracts and glaucoma. In addition, patients taking hydroxychloroquine should be informed about the ophthalmic risks and the need for regular ophthalmic examinations to screen for retinal toxicity. For further information, see BCSC Section 12, Retina and Vitreous.

• Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386–1394.

Polyarteritis nodosa

Polyarteritis nodosa (PAN) is an uncommon systemic vasculitis characterized by subacute or chronic, focal, necrotizing inflammation of medium-sized and small arteries. The disease presents in patients between the ages of 40 and 60 years and affects men 3 times more frequently than women; the annual incidence rate is approximately 0.7 per 100,000 individuals. Although there are no racial or geographic predisposing factors, 10% of patients test positive for hepatitis B surface antigen, implicating hepatitis B as an etiologic agent. Indeed, the demonstration of circulating immune complexes composed of hepatitis B antigen and antibodies to hepatitis B in vessel walls during the early stages of the disease strongly implicates immune-complex–mediated mechanisms in the pathogenesis of PAN.

Manifestations PAN most commonly affects skin, nerves, kidneys, and gastrointestinal tract. Fatigue, fever, weight loss, and arthralgia are present in up to 75% of patients. Vasculitis-induced peripheral neuropathies are also common, as are skin manifestations, which include subcutaneous nodules, purpura, livedo reticularis, and Raynaud phenomenon. Renal involvement often manifests as secondary hypertension and affects approximately one-third of patients. Gastrointestinal disease with small-bowel ischemia and infarction occurs less frequently but may lead to serious complications. Other systemic manifestations include coronary arteritis, pericarditis, and hematologic abnormalities. CNS disease associated with PAN is rare. The American College of Rheumatology has developed specific criteria for the diagnosis of PAN.

Ocular involvement is present in up to 20% of patients with PAN and arises because of the underlying vascular disease. Posterior pole manifestations include hypertensive retinopathy, characterized by macular star formation, cotton-wool spots, intraretinal hemorrhages, retinal artery occlusions, and choroidal infarcts. Patients may have a retinal vasculitis (Fig 9-4) or a vasculitis involving the posterior ciliary arteries and choroidal vessels, with resultant exudative retinal detachments. Elschnig spots—focal areas of choroidal hyperpigmentation surrounded by hypopigmentation—may be observed in the posterior pole because of lobular choroidal ischemia and infarcts (see BCSC Section 12, Retina and Vitreous). Neuro-ophthalmic manifestations include cranial nerve palsies, amaurosis fugax, homonymous hemianopia, Horner syndrome, and optic atrophy. Scleral inflammatory disease of all types, including necrotizing and posterior scleritis, has been reported. Peripheral ulcerative keratitis (PUK), typically accompanied by scleritis, may be the presenting manifestation of PAN.

• American College of Rheumatology. 1990 criteria for the classification of polyarteritis nodosa. Available at https://bit.ly/2xtKZxU. Accessed September 20, 2018.

• Perez VL, Chavala SH, Ahmed M, et al. Ocular manifestations and concepts of systemic vasculitides. Surv Ophthalmol. 2004;49(4):399–418.

• Rothschild PR, Pagnoux C, Seror R, Brézin AP, Delair E, Guillevin L. Ophthalmologic manifestations of systemic necrotizing vasculitides at diagnosis: a retrospective study of 1286 patients and review of the literature. Semin Arthritis Rheum. 2013;42(5):507–514.

Figure 9-4 Polyarteritis nodosa. Fundus photograph indicating retinal vasculitis associated with vascular sheathing (arrow) and intraretinal hemorrhage.

(Courtesy of E. Mitchel Opremcak, MD.)

Treatment and prognosis Unlike granulomatosis with polyangiitis (GPA; previously known as Wegener granulomatosis), polyarteritis nodosa is not associated with antineutrophil cytoplasmic antibodies (ANCA). The 5-year mortality rate of untreated PAN is 90%. Although systemic corticosteroid use may reduce this rate to 50%, combination therapy with IMT, such as cyclophosphamide, improves 5-year survival to 80% and may induce long-term remission of the disease. It is therefore important to consider PAN in the differential diagnosis of retinal vasculitis presenting in patients in whom an underlying necrotizing vasculitis is suspected; appropriate diagnosis and management can be life-saving. Tissue biopsy confirms the diagnosis.

• Gayraud M, Guillevin L, le Toumelin P, et al; French Vasculitis Study Group. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum. 2001;44(3):666–675.

Granulomatosis with polyangiitis

Granulomatosis with polyangiitis is a multisystem autoimmune disorder characterized by the classic triad of necrotizing granulomatous vasculitis of the upper and lower respiratory tract, focal segmental glomerulonephritis, and necrotizing vasculitis of small arteries and veins. Involvement of the paranasal sinuses is the most characteristic clinical feature of this disorder, followed by pulmonary and renal disease. Renal involvement may or may not be evident at presentation, but its early detection is important, as glomerulonephritis develops in up to 85% of patients during the course of the disease and carries significant mortality if left untreated. A limited form of this disease has been described, consisting of granulomatous inflammation involving the respiratory tract without overt involvement of the kidneys.

Another entity believed to belong to the GPA spectrum is microscopic polyangiitis (MPA). Patients with MPA may have clinical features similar to those of GPA but lack granulomatous changes on biopsy. Patients with MPA are also more likely to have ANCA directed at myeloperoxidase (MPO; discussed further shortly). There is some controversy in the rheumatologic literature about differentiating the 2 entities; however, ophthalmic involvement is much less common in MPA.

Manifestations Patients with GPA may present with sinusitis associated with bloody nasal discharge, pulmonary symptomatology, and arthritis. Dermatologic involvement is present in approximately one-half of patients, with purpura involving the lower extremities occurring most frequently; less common are ulcers and subcutaneous nodules. Nervous system involvement may occur in approximately one-third of patients. Mononeuritis multiplex is the most common, but cranial neuropathies, seizures, stroke syndromes, and cerebral vasculitis may also occur.

Ocular or orbital involvement is found in 15% of patients at presentation and in up to 50% of patients during the course of the disease. Orbital involvement is usually secondary to contiguous extension of the granulomatous inflammatory process from the paranasal sinuses into the orbit. Orbital cellulitis and dacryocystitis may arise from the involved and secondarily infected nasal mucosa. Orbital pseudotumor, distinct from the sinus inflammation, may also occur. Scleritis of any type, particularly diffuse anterior or necrotizing disease, with or without peripheral ulcerative keratitis, affects up to 40% of patients. Posterior scleritis has been reported.

Figure 9-5 Granulomatosis with polyangiitis. Fundus photograph of retinitis. The appearance of the retinitis may be similar to that of a viral retinitis.

(Courtesy of E. Mitchel Opremcak, MD.)

Approximately 10% of patients with GPA and ocular involvement have been reported to have an associated nonspecific, unilateral or bilateral anterior, intermediate, or posterior uveitis, with varying degrees of vitritis. Retinal involvement is relatively uncommon, occurring in up to 10% of patients. Retinal vascular manifestations range from relatively benign cotton-wool spots, with or without associated intraretinal hemorrhages, to more severe vaso-occlusive disease, including branch or central retinal artery or vein occlusion. Retinitis has been reported in up to 20% of patients; those with accompanying retinal vasculitis may develop retinal neovascularization, vitreous hemorrhage, and neovascular glaucoma (Fig 9-5). Orbital involvement can lead to compressive ischemic optic neuropathy. Vision loss in GPA may occur in up to 40% of patients, especially among those with long-standing or inadequately treated disease.

• Kubal AA, Perez VL. Ocular manifestations of ANCA-associated vasculitis. Rheum Dis Clin North Am. 2010;36(3):573–586.

• Pakrou N, Selva D, Leibovitch I. Wegener’s granulomatosis: ophthalmic manifestations and management. Semin Arthritis Rheum. 2006;35(5):284–292.

Diagnosis Tissue biopsy establishes the histologic diagnosis; chest radiograph may disclose nodular, diffuse, or cavitary lesions; and laboratory evaluation may reveal proteinuria or hematuria, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein levels, as well as the presence of ANCA. ANCA are antibodies directed against cytoplasmic azurophilic granules of neutrophils and monocytes that are specific markers for a group of related systemic vasculitides, including GPA, MPA, eosinophilic GPA (Churg-Strauss syndrome), renal-limited vasculitis, and pauci-immunoglomerulonephritis. Two main classes of ANCA have been described according to their immunofluorescence staining patterns:

• The cytoplasmic, or c-ANCA, pattern is both sensitive to and specific for GPA and is present in up to 95% of patients; proteinase 3 is the most common target antigen (referred to as PR3-ANCA).

• The perinuclear, or p-ANCA, pattern is associated with MPA, renal-limited vasculitis, and pauci-immunoglomerulonephritis.

Myeloperoxidase is the most common antigenic target (MPO-ANCA). Standardized testing for ANCA should include both immunofluorescence testing for c- and p-ANCA and specific antibody testing for PR3-ANCA and MPO-ANCA; the latter 2 are most specific.

Treatment Appropriate treatment of GPA mandates combination therapy with oral corticosteroids and IMT, such as rituximab and cyclophosphamide. Without therapy, the 1-year mortality rate is 80%. However, 93% of patients treated with cyclophosphamide and corticosteroids successfully achieve remission with resolution of eye disease. The ophthalmologist’s role in recognizing GPA-associated eye disease can be critical, since timely diagnosis and treatment are essential in reducing not only ocular morbidity but also patient mortality.

Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.