Corneal Disease Associated With Nonrheumatoid Collagen-Vascular Disease

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease of unknown etiology. It is a heterogeneous disease that is markedly more frequent in women than in men (9:1), and it can cause severe immune-mediated damage to multiple organ systems. Disease burden and mortality are especially high in young women and in black females. A genetic contribution to disease pathogenesis is suggested by association of SLE with major histocompatibility complex (MHC) class II alleles human leukocyte antigen (HLA)-DR2 and HLA-DR3. T- and B-cell hyperreactivity lead to production of autoantibodies and immune complex deposition leading to chronic inflammation and organ damage.

Clinical manifestations are multisystemic. Patients can experience arthralgias and myalgias (95%), cutaneous rashes and photosensitivity (80%), glomerulonephritis (50%), neurologic symptoms (60%), and pleuritis (60%). Fatigue, fever, anorexia, and weight loss are also common.

The American College of Rheumatology (ACR) 1997 diagnostic criteria ( Box 91.1 ) rely on clinical findings, the presence of autoantibodies on serologic testing, and persistent proteinuria or cellular casts on urinalysis. Antinuclear antibodies (ANAs) are present in 95% of patients and anti-DNAs are common (70%), with anti–double-stranded DNA being relatively specific to lupus. Numerous other autoantibodies are found as well, including anti-Ro (SSA), anti-La (SSB), anti-Sm, and anticardiolipin (lupus anticoagulant). Decreased complement levels are often associated with increased disease activity.

Ocular manifestations are seen in a minority of patients, but any portion of the eye can be affected. Cotton-wool spots, the most common retinal finding, are independent of hypertension and central nervous system involvement. Other retinal signs include exudates, nonperfusion, neovascularization, vitreous hemorrhage, and vascular thrombosis. Retinopathy parallels systemic disease activity and is associated with increased mortality and vision loss. Central nervous system involvement may accompany retinal occlusive vasculitis. Neuro-ophthalmic complications are seen in 1%–3% of patients and may warrant long-term immunosuppressive therapy (IMT).

Eyelid erythema, scaling plaques, and lash loss have been described in discoid lupus, which may present as a chronic blepharitis. Anterior segment abnormalities in lupus are infrequent, with the exception of secondary Sjögren syndrome, which develops in approximately 50% of patients. Conjunctival involvement is uncommon, although scarring and symblepharon formation have been reported, especially in discoid lupus. Conjunctival chemosis, periorbital edema, and orbital inflammation are infrequent findings but have been described. Recurrent episcleritis may occur in approximately 28% of patients. Scleritis is less common. If it occurs, it is typically nodular and may be chronic or relapsing and associated with systemic disease requiring IMT. Uveitis seldom occurs.

Corneal involvement in systemic and cutaneous lupus is uncommon. Corneal staining, usually in a nonspecific pattern, has been reported in 6.5% to as high as 88% of patients. Superficial keratopathy can occur in patients with and without tear insufficiency and in patients with discoid lupus. Asymptomatic dry eye with abnormal Schirmer testing is common. Sterile corneal ulceration following cataract surgery has been reported, possibly secondary to tear insufficiency or autoimmune pathology. Chronic ocular surface disease may also predispose patients to secondary infection. Significant late corneal scarring has been reported in a patient 1 year after photorefractive keratectomy for myopia. Stromal inflammation in SLE is rare, although there are case reports of deep stromal keratitis and deep “band-shaped” stromal infiltrates occurring with uveitis. Corneal endotheliitis, responsive to corticosteroids, and peripheral ulcerative keratitis, improving with systemic disease control, have also been described. ^,

Disease severity and organ involvement guide treatment of SLE. When possible, hydroxychloroquine therapy is recommended for every patient with lupus. For mild disease, judicious addition of nonsteroidal antiinflammatory drugs (NSAIDs) or corticosteroids may be effective. Additional immunosuppressives including leflunomide, methotrexate, and mycophenolate mofetil are often necessary to control persistent disease. High-dose corticosteroids may be used in treatment of severe disease complications such as nephritis, thrombocytopenia, hemolytic anemia, myocarditis, and CNS lupus. Rituximab and cyclophosphamide, used alone or in combination with additional immunosuppressants, are effective steroid-sparing agents for patients with severe or refractory disease. Additional immunosuppressants include azathioprine, cyclosporine, and belimumab, which was US Food and Drug Administration (FDA) approved in 2011 for treatment of active systemic lupus in adults.

Ocular disease may reflect active systemic disease and indicate need for systemic treatment. Topical therapies for ocular surface disease include lubrication, topical antiinflammatory agents, mucolytics, and autologous serum tears. Chronic blepharitis and meibomian gland dysfunction may benefit from oral tetracyclines, eyelid hygiene, and warm compresses. Additional interventions include punctal plugs, moisture chamber goggles, contact lenses, and tarsorrhaphy.

Ophthalmologists often care for lupus patients treated with hydroxychloroquine. Hydroxychloroquine can cause a “bull’s-eye” maculopathy with paracentral scotoma. The American Academy of Ophthalmology has published recommendations on screening for chloroquine and hydroxychloroquine retinopathy, which were most recently revised in 2016. A baseline complete ophthalmic exam is recommended in all patients starting therapy to rule out preexisting maculopathy. For patients on acceptable daily doses of hydroxychloroquine, less than 5.0 mg/kg of real body weight, and no major risk factors, annual screening should commence after 5 years. Major risk factors for toxic retinopathy include excessive daily dose by weight, duration of therapy greater than 5 years, renal disease, concomitant tamoxifen use, and coexisting macular disease. Baseline screening should consist of dilated fundus examination, with visual fields and spectral domain optical coherence tomography (OCT) if abnormalities are observed. At subsequent screening examinations, recommended screening tests include spectral domain OCT and automated visual fields. The 10-2 field pattern is recommended for non-Asian patients, and the 24-2 or 30-2 test patterns should be used for Asian patients. Additional useful structural and functional screening tests include multifocal electroretinogram and fundus autofluorescence imaging.

Systemic Sclerosis

Systemic sclerosis, also known as scleroderma or progressive systemic sclerosis, is a chronic multisystem autoimmune disease. The pathogenesis involves immune systemic activation, endothelial and vascular injury, and excessive fibrosis and collagen deposition. Women are more commonly affected than men (4.6:1). Fibrosis of the skin and viscera is the hallmark, and disease may be diffuse or in the limited form of skin thickening on the face and distal extremities. The epidermis is thin, skin appendages are lost, and fibrosis extending from the dermis produces skin tightening. Musculoskeletal involvement can produce disabling joint pain, tendon rubs, and contractures. Pulmonary involvement, which can include interstitial lung disease and pulmonary arterial hypertension, is the leading cause of death for patients with scleroderma. Additional visceral manifestations include esophageal dysfunction, gastrointestinal tract fibrosis, myocardial fibrosis and ventricular diastolic dysfunction, arrhythmia, pericarditis, renal vascular disease, and severe hypertension. In the limited form, visceral involvement is less common, but often features of the CREST syndrome are present, with calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. Raynaud phenomenon occurs in 95% of patients with systemic sclerosis.

The etiology of scleroderma is unknown. Laboratory findings may include an elevated sedimentation rate and elevated serum globulin levels. Rheumatoid factor is positive in 25% of patients. ANA tests are positive in up to 90% of patients. Antibodies to the nucleolus are most specific for scleroderma, as are antibodies to Scl-70, a nuclear enzyme topoisomerase-1. Varying subsets of systemic sclerosis have different ANAs, with anticentromere antibodies being seen in the CREST group and anti–RNA polymerase III in scleroderma renal crisis.

Ocular manifestations of systemic sclerosis are common. Most common signs include eyelid tightening (65%) with blepharophimosis and lid telangiectases (17%). Corneal exposure may be seen but is infrequent. Conjunctival vascular sludging and telangiectasia are frequent. Shallow fornices caused by subconjunctival fibrosis may occur. Biopsy demonstrates dense subconjunctival fibrosis around capillaries with minimal lymphocytic infiltrate, high numbers of mast cells, and attenuation in capillary walls with endothelial cell disruption and vessel occlusion.

Aqueous deficiency dry eye is very common (37%–76%). Whether to consider this a form of secondary Sjögren syndrome is uncertain. A minority of scleroderma patients show the lymphocytic infiltrate characteristic of Sjögren syndrome on salivary gland biopsy, and glandular fibrosis with impaired secretion is more frequent. ^, Conjunctival biopsies from Sjögren patients show lymphocytic infiltrate with the absence of fibrosis and the absence of the numerous mast cells seen in scleroderma. Restricted eyelid motility and eyelid inflammation can also contribute to ocular dryness in these patients.

Orbital findings are rare in systemic sclerosis. Enophthalmos from orbital fat atrophy may be seen in both the systemic and localized forms. Scleritis is very uncommon. Myositis may occur, and cases of anterior uveitis have been reported. Neuro-ophthalmic complications of intracranial aneurysms secondary to the vascular involvement of scleroderma have been reported infrequently. Retinal changes are typically those of the hypertension associated with the renal involvement.

Corneal involvement is predominantly secondary to eyelid changes and tear insufficiency. Corneal inflammatory disease is extremely unusual. A case was reported of bilateral peripheral corneal melting with perforation thought to be caused by T-cell–mediated inflammation in a patient with systemic sclerosis. Corneal superficial infiltrates were reported in a case of localized scleroderma. Increased central corneal thickness has been reported; however, a later study found no difference when compared with normal subjects. Higher intraocular pressures were observed in a series of 54 eyes of scleroderma patients compared with the control group. Fibrosis-restricted outflow, chronic steroid use, and possibly increased corneal thickness may explain this finding. In addition, vascular changes within the optic nerve may also contribute to the higher reported incidence of glaucoma in patients with scleroderma.

There are no proven disease-modifying agents for treatment of systemic sclerosis. However, the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) has developed evidence-based and consensus-driven management recommendations. Nifedipine and intravenous iloprost reduce the frequency and severity of Raynaud phenomenon attacks. Intravenous iloprost, phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil), and bosentan are efficacious for healing digital ulcers. ^, Endothelin receptor antagonists, PDE-5 inhibitors, and riociguat are effective treatments for pulmonary arterial hypertension associated with a variety of diseases and are also used for pulmonary arterial hypertension associated with systemic sclerosis. In addition, intravenous epoprostenol is effective in improving exercise capacity among patients with pulmonary arterial hypertension and systemic sclerosis. Despite its known toxicities, cyclophosphamide is considered for management of progressive lung disease, because two randomized control trials have demonstrated its efficacy in inhibiting disease progression. Hematopoietic stem cell transplantation is also a viable treatment option at experienced centers for selected patients with rapidly progressive disease. Methotrexate has been shown to improve skin findings in early disease; however, its role in treating other disease manifestations has not been established. For renal disease, experts recommend treatment with angiotensin-converting enzyme (ACE) inhibitors and careful monitoring of blood pressure and renal function. Treatments for gastrointestinal dysfunction include use of proton-pump inhibitors for reflux, prokinetic drugs for motility disorders, and intermittent antibiotics for symptomatic intestinal bacterial overgrowth.

Ophthalmic treatment is symptomatic. Treatments including lubricants, topical steroids, topical cyclosporine, serum tears, and punctal occlusion may improve signs and symptoms of dry eye disease associated with secondary Sjögren syndrome. There is a lack of convincing evidence to support whether these interventions alter disease course.

Mixed Connective Tissue Disease

Mixed connective tissue disease is a disease entity where high titers of serum autoantibodies against U1 ribonucleoprotein (anti-RNP) accompany hand edema, synovitis, sclerosis of the digits (acrosclerosis), Raynaud phenomenon, interstitial lung disease, pulmonary hypertension, and myositis. Disease features have significant clinic overlap with SLE, systemic sclerosis, and polymyositis.

Besides secondary Sjögren syndrome, ophthalmic findings are few. Severe retinal vasculopathies can occur and fluorescein leakage can be observed in up to 30% of patients. ^,