BASICS

DESCRIPTION

• Multisystem autoimmune disease

• Chronic course with relapses and remissions

• Organ systems most frequently involved: skin, joints, kidneys, blood, and CNS

• Diverse manifestations in eye:

– Discoid lesions of eyelids

– Keratoconjunctivitis sicca (dry eye)

– Episcleritis

– Scleritis

– Cranial neuropathy

– Optic neuropathy

– Retinal vasoocclusive disease

– Choroidopathy

– Antimalarial drug toxicity

EPIDEMIOLOGY

Incidence

• Approximately 250,000 people have systemic lupus erythematosus (SLE) in the US (1)[B]

• Up to 1/3 of patients with SLE have ocular manifestations.

– Ocular surface disease: up to 30%

– Retinal manifestations: 3–30% (depends on systemic disease activity)

– Optic nerve involvement: 1%

RISK FACTORS

• Gender: female 9:1

• Age: peak incidence 2nd–4th decade

• Race: African-American and Asian descent

• Family history

• Environmental factors: hormones, sunlight

• Drug-induced lupus: procainamide, hydralazine, quinidine, chlorpromazine, methyldopa, isoniazid

Genetics

• Twin studies support genetic predisposition.

• Linkage studies have identified many candidate genes, particularly on chromosome 1q

• Associated with HLA-A1, HLA-B8, and HLA-DR3

PATHOPHYSIOLOGY

• Autoimmunity may be triggered by autoantigen exposure during apoptosis.

– Autoantibody production

– Immune complex deposition

• Lupus retinopathy associated with immune complex–mediated arteriolar occlusion and thrombosis

COMMONLY ASSOCIATED CONDITIONS

• Secondary Sjögren’s syndrome

• Antiphospholipid antibody (APA) syndrome (found in 77% of SLE patients with retinal or optic nerve disease vs. 29% of other SLE patients) (2)[B]

DIAGNOSIS

SLE is diagnosed by at least 4 of the 11 following American College of Rheumatology (ACR) criteria:

• Malar rash

• Discoid rash

• Oral ulcers

• Arthritis

• Serositis (pleuritis, pericarditis)

• Renal disorder (proteinuria or cellular casts)

• CNS disorder (seizures, psychosis)

• Hematologic disorder (anemia, leucopenia, thrombocytopenia, lymphopenia)

• Immunologic disorder

– Antidouble-stranded DNA (anti-dsDNA)

– APAs

– Anti-Sm

– False-positive RPR or VDRL

• Antinuclear antibody (ANA) positive

HISTORY

• Photophobia

• Redness

• Pain

• Diplopia

• Floaters

• Visual decline

PHYSICAL EXAM

• Ocular adnexa—edema, mass, proptosis

• Motility–-myositis, cranial neuropathy, intranuclear ophthalmoplegia

• Eyelids—discrete, scaly lesions (discoid lupus)

• Conjunctiva—inflammation (noninfectious conjunctivitis)

• Sclera

– Episcleritis (superficial, blanches with topical phenylephrine)

– Scleritis (deep, does not blanch with topical phenylephrine, nodular or diffuse, anterior or posterior)

• Cornea

– Reduced tear film, punctate keratopathy, filaments (dry eye, Sjögren’s syndrome)

– Interstitial keratitis (rare)

– Peripheral ulcerative keratitis (rare)

– Vortex keratopathy (verticillata)

Associated with antimalarial drug use

Rarely visually significant

Reversible with cessation of treatment

• Anterior chamber

– Cell and flare (iritis)

– Hypopyon uveitis (rare)

• Lens (cataract)

– Especially posterior subcapsular

– Associated with chronic steroid use

• Vitreous—inflammation (posterior uveitis)

• Retina

– Lupus retinopathy

– Cotton–wool spots (nerve fiber layer infarcts)

– Intraretinal hemorrhages

– Microaneurysms

– Exudates

– Vascular tortuosity

– Vasoocclusive retinopathy (more severe)

– Capillary nonperfusion

– BRVO, CRVO, BRAO, CRAO

– Neovascularization of disc and retina

– Vitreous hemorrhage

– Traction retinal detachment

– Choroid

– Uveal effusion

– Serous retinal detachment

– Choroidal infarction

– Choroidal neovascular membrane

– Optic nerve

– Neuropathy

– Neuritis

– Papilledema (intracranial hypertension)

– CNS

Intranuclear ophthalmoplegia

Retrochiasmal infarcts

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• Anti-dsDNA (highly specific)

• ANA (sensitive)

• CBC

Follow-up & special considerations

• Other autoantibodies

– APA (anticardiolipin and lupus anticoagulant)

– Anti-Ro

– Anti-La

– Anti-c1q

– Anti-Sm

– Anti-nucleosome

– Anti-N-methyl-d-aspartic acid (NMDA)

– Anti-alpha actinin

Imaging

Initial approach

• Fluorescein angiography to assess retinal and choroidal circulation

– ICG to assess choroidal circulation

– OCT to assess for macular edema or serous retinal detachment

– B-scan ultrasonography to assess vitritis and for retinal detachment

Follow-up & special considerations

Retinal vasculitis is associated with CNS lupus involvement. Consider CNS imaging with MRI/magnetic resonance angiography (MRA) to evaluate for thrombotic events.

Pathological Findings

• Biopsies of eyelid lesions show immunoglobulin deposition at the junction of epidermis and dermis on immunohistochemical staining.

• Orbital and adnexal involvement can also be confirmed by biopsy.

DIFFERENTIAL DIAGNOSIS

• Discoid lupus on the eyelids should be distinguished from blepharitis.

• Optic neuritis in SLE can resemble demyelinating disease but is often more severe.

• Lupus retinopathy resembles diabetic and hypertensive retinopathy.

• Patients with SLE on immunosuppressive therapy often present with new ocular complaints. It is important to rule out an infectious etiology before continuing or accelerating immunosuppressive therapy. Consider:

– Herpetic retinitis (herpes simplex virus [HSV], herpes zoster virus [HZV], cytomegalovirus [CMV])

– Tuberculosis

– Toxoplasmosis

– Lyme disease

TREATMENT

MEDICATION

First Line

• Artificial tears for episcleritis, dry eye

• Oral prednisone for more severe ocular manifestations: 1–2 mg/kg/day

Second Line

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Antimalarials:

– Chloroquine

– Hydroxychloroquine

• Steroid-sparing immunosuppressive agents:

– Azathioprine

– Cyclosporine

– Mycophenolate mofetil

– Cyclophosphamide

– Methotrexate

• Plasmapheresis

• Intravenous immunoglobulins

• Newer biologic agents:

– Rituximab (Rituxan)

– Anticytokine agents

ADDITIONAL TREATMENT

General Measures

Care should be taken to prevent and manage side effects of immunosuppressive therapy such as gastric prophylaxis, blood sugar and blood pressure monitoring, and purified protein derivative (PPD) tuberculosis screening.

Issues for Referral

Systemic treatment of ocular manifestations should be comanaged with the patient’s primary doctor and/or rheumatologist.

Additional Therapies

• Anticoagulation for vasoocclusive disease or APA syndrome

– Aspirin

– Warfarin

SURGERY/OTHER PROCEDURES

• Treat complications of proliferative retinopathy:

– Panretinal photocoagulation

– Vitrectomy

IN-PATIENT CONSIDERATIONS

Initial Stabilization

Consider inpatient admission for pulse IV methylprednisolone: 1g/day

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

• The antimalarial agents are associated with bull’s eye maculopathy leading to impairment of visual acuity, color vision, and visual field.

• All patients initiating antimalarial therapy should receive counseling about risk of retinopathy and have baseline eye exam: visual acuity, dilated fundus examination, Amsler, Humphrey 10-2, optional tests (color, fundus photos, fluorescein angiography, multifocal electroretinogram [ERG])

• Risk factor for complications include dose >6.5 mg/kg hydroxychloroquine, >3 mg/kg chloroquine, duration >5 years, renal or liver disease, preexisting retinal disease, and age >60 years.

– Low-risk patients do not require additional screening exams.

– High-risk patients should have annual screening exams.

• Cessation of treatment may halt or even reverse sight-threatening complications.

PROGNOSIS

• Vision loss in 55% of patients with severe vasoocclusive retinopathy (4)[B]

• Optic neuritis outcomes highly variable, appear to improve with early initiation of steroid treatment (5)[B]

COMPLICATIONS

Visual loss, retinal detachment, optic neuropathy

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