The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides—Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome—can present with various ophthalmic manifestations. In a subset of patients, these findings may be the earliest indicators of systemic disease. Orbital and anterior segment findings are most common, whereas posterior segment complications such as retinal vasculitis and optic neuropathy occur much less frequently. This article describes the distinguishing features of associated ophthalmic disease, focusing on the manifestations clinicians are most likely to encounter and those with the most significant ocular morbidity. Although the ANCA-associated vasculitides require systemic workup and treatment, this article discusses diagnostic and therapeutic modalities often used concurrently for ophthalmic disease.
Vasculitis is characterized by blood vessel inflammation and necrosis of vascular endothelium. End-organ damage is the result of the destruction and occlusion of blood vessels. The antineutrophil cytoplasmic antibody (ANCA) associated vasculitides—Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS)—are diseases in which small to medium-sized blood vessels are affected. ANCAs not only serve as a marker for disease but are also thought to play a major role in disease pathogenesis. Proteinase-3 and myeloperoxidase, the two antigens that are the targets of ANCAs observed in these diseases, are found within the neutrophil, and degranulation of these leukocytes is thought to initiate the cascade of destruction.
Of the three ANCA-associated vasculitides, WG is the most common. In a population-based study from Norfolk, England, the incidence of WG was 8.5 cases per million. The reported incidences of MPA and CSS were 3.6 cases and 2.4 cases per million, respectively. Ophthalmologic findings, with ocular blood vessels as the target of disease, can be common, particularly in WG. They can sometimes be the presenting finding. Ocular or orbital involvement has been reported to occur in 29% to 52% of patients with WG. In one cohort of 158 patients, 15% presented with ocular manifestations at diagnosis. Ocular or orbital disease occurs less frequently in MPA and CSS. In a cohort of 85 patients with MPA, confirmed in most on biopsy, only one had ocular manifestations. However, ocular findings can still be the initial presenting sign in these diseases.
Therefore, the ability to recognize the ocular manifestations of vasculitis and associate them with the underlying systemic disease is important so that treatment can be initiated promptly to prevent morbidity and mortality. The systemic findings of WG, MPA, and CSS are described in other articles within this issue (see the articles by Chung and Seo; Baldini and colleagues; Holle and colleagues elsewhere in this issue for futher exploration of this topic). This article describes ocular and orbital findings ( Table 1 ). However, one must be aware that many of the findings described and illustrated here are not pathognomic for ANCA-associated vasculitis and may be seen in other vasculitic, inflammatory, or infectious processes.
| Wegener’s Granulomatosis | Microscopic Polyangiitis | Churg-Strauss Syndrome | |
|---|---|---|---|
| Conjunctivitis Episcleritis Scleritis | 4%–16% + 16%–38% | + + + | + + – |
| Peripheral ulcerative keratitis | + | + | + |
| Retinal vasculitis | + | + | + |
| Orbital disease Mass/myositis/dacryoadenitis | + | – | + |
| Nasolacrimal obstruction | 7%–10% | – | – |
| Neuroophthalmic manifestations | + | − | + |
Conjunctival, episcleral, and scleral disease
These manifestations can sometimes be difficult to distinguish from each other because they all can present with ocular redness and discomfort. The key to distinguishing them is recognizing the depth of tissue involvement associated with the blood vessel plexus ( Fig. 1 ). For example, in episcleritis, the superficial episcleral plexus is thought to be affected by the vasculitis process (see Fig. 1 B), in contrast to scleritis, in which the deep episcleral plexus is affected (see Fig. 1 C).
Conjunctival disease has been reported to occur in 4% to 16% of patients with WG. Early disease presents with conjunctival hyperemia. Granulomas can also be present and disease is often bilateral. Progressive disease is characterized by cicatrizing conjunctivitis, which may result in symblepharon, or bands of fibrovascular tissue stretching across the ocular surface to the eyelids; entropion with an in-turning eyelid; and trichiasis with eyelashes directed against the globe ( Fig. 2 ). The palpebral surface of the upper eyelid is most commonly involved. Ocular exposure may occur, increasing the risk of secondary infectious keratitis. Exposure is often exacerbated by a tear deficiency caused by loss of the mucin-producing conjunctival goblet cells and destruction of lacrimal glands. Symptoms of conjunctival disease often include ocular redness, foreign body sensation, blurred vision from tear dysfunction, and possibly bloody tears.
The first reported case of MPA involving the conjunctiva and eyelid was in a 23-year-old black woman with renal failure and ulcerative skin and conjunctival nodules. Laboratory testing was positive for perinuclear ANCA (p-ANCA) and the patient experienced response to treatment with cyclophosphamide. Several cases of conjunctival involvement in CSS have been reported, including a 30-year-old woman with adult-onset asthma, a lung mass, peripheral eosinophilia, and a conjunctival nodule responding to oral corticosteroids.
Conjunctival biopsy may be helpful in diagnosis because specimens may show evidence of necrosis and occlusive vasculitis. The differential diagnosis includes more common causes of conjunctivitis, such as allergies or infections, including adenovirus. More severe cicatrizing conjunctivitis can also be found in diseases such as ocular cicatricial pemphigoid and trachoma. Treatment often requires aqueous tear replacement and surgical intervention involving lysis of adhesions with removal of scar tissue, and ocular surface reconstruction with either mucous membrane or amniotic membrane grafts.
Episcleritis also presents with ocular redness. It can be unilateral or bilateral, diffuse or sectoral, or nodular in presentation. Dilated blood vessels typically appear in a radial pattern emanating from the corneoscleral limbus, and the redness blanches with application of topical 2.5% phenylephrine drops ( Fig. 3 ). In addition, because the lesions occur in the loose connective tissue overlying the sclera, the lesions are mobile. The ocular morbidity of episcleritis is minimal. This condition is usually idiopathic, with systemic associations such as ANCA-associated vasculitis in approximately one-third of cases. In most instances these cases are associated with bilateral involvement and recurrent symptoms.
Scleritis, in contrast to episcleritis, can cause serious ocular morbidity. It often presents with deeper, boring pain and photophobia. The affected eye can be very tender to palpation. Dilated blood vessels have a crisscross or network-like appearance. The redness is not mobile and does not blanch with phenylephrine drops. Scleritis may be associated with a keratitis or iritis (as discussed later). Anterior scleritis may be diffuse, sectoral, nodular, or necrotizing, a classification scheme first described by Watson and Hayreh ( Fig. 4 ). In necrotizing disease, the underlying pigmented uveal tissue of the choroid and retina will appear bluish in the areas of scleromalacia.
The risk of scleral thinning and perforation can be exacerbated by secondary infection. Severe ocular complications occur in more than 90% of patients, often resulting in blindness. In addition to systemic immunosuppression to treat the underlying disease, patients with necrotizing scleritis often require aggressive topical antibiotic therapy and possibly even scleral patch grafts. Scleritis may also involve the posterior sclera. In these cases, patients may present with an atypical, nonlocalizing “odd” pain with ocular movement and decreased vision from exudative retinal detachments. Choroidal folds may be seen on dilated funduscopic examination and ocular ultrasound may show thickening of the posterior globe (see Fig. 4 D).
Scleritis is associated with an underlying systemic disorder in up to 50% of patients. The differential diagnosis for scleritis is broad and includes numerous rheumatologic and inflammatory diseases, such as rheumatoid arthritis, relapsing polychondritis, systemic lupus erythematosus, Behçet’s syndrome, inflammatory bowel disease, psoriatic arthritis, and sarcoidosis, and infectious processes caused by bacterial, fungal, and parasitic infection. These diseases must be considered and excluded based on history, clinical examination, and laboratory findings.
Scleritis has been reported to occur in 16% to 38% of patients with WG. Necrotizing scleritis has a much higher association with systemic disease, and is seen in more than half of the patients with ocular WG. Mortality has been reported to be as high as 54% in patients with necrotizing scleritis who are not undergoing immunosuppressive therapy.
Cases of scleritis in MPA have also been reported, mostly from Japan. In one case, a 60-year-old woman presented with renal failure and bilateral scleritis, which responded to intravenous corticosteroid treatment. Another report described a 79-year-old man with bilateral scleritis, fatigue, and pulmonary disease, also responsive to systemic corticosteroids.
The onset of scleritis in a patient with vasculitis is a serious ophthalmic manifestation. It is either the first manifestation of the disease or a marker that systemic disease is active and aggressive therapy must be implemented to prevent not only ocular morbidity but also systemic multiorgan complications.
Corneal manifestations
Corneal findings of the ANCA-associated vasculitides are often present in concert with other anterior segment manifestations, particularly necrotizing scleritis. Conjunctival scarring with resultant tear deficiency, entropion, trichiasis, and poor eyelid closure can produce an exposure keratopathy, secondary infectious ulceration, and even corneal perforation. Proptosis from orbital disease (as discussed later) can also cause exposure and its sequelae.
In addition to these secondary corneal findings, inflammatory disease may specifically target the cornea, resulting in a condition known as peripheral ulcerative keratitis (PUK). This condition is typically unilateral and sectoral, although bilateral disease can occur in up to 40% of patients. The lesions usually are found within 2 mm of the corneoscleral limbus, and the adjacent limbal tissue and sclera show evidence of vasculitic disease ( Fig. 5 ). The affected corneal stroma can be markedly thin as keratolysis progresses to potential corneal perforation either spontaneously or with minor ocular trauma. An epithelial defect may be present, predisposing patients to secondary infection. Patients typically present with pain, injection, photophobia, and decreased vision from corneal opacities or induced astigmatism.
PUK is typically associated with an underlying systemic disease, most commonly rheumatoid arthritis followed by WG. Peripheral keratitis, although nonulcerative in appearance, was reported as a presenting sign of MPA in a 16-year-old girl who subsequently developed renal failure. Recurrent PUK has also been described in a 44-year-old woman with asthma, hemorrhagic skin lesions, peripheral eosinophilia, and positive ANCA titers, confirming the diagnosis of CSS. Concurrent scleritis is found in approximately one-third of patients with PUK. Conversely, only 14% of patients with scleritis have PUK. In those with both conditions, the scleritis is necrotizing in nearly 60% of cases.
The differential diagnosis for PUK includes all conditions listed earlier for scleritis, in addition to localized inflammatory conditions such as rosacea. Other disease entities may resemble PUK. Mooren’s ulcer has a similar appearance, but no systemic or local associations exist except for possible hepatitis C exposure. Terrien’s marginal degeneration also presents with peripheral corneal thinning. However, this condition is noninflammatory and very slowly progressive. A line of lipid is present at the leading edge of the area of thinning and, unlike PUK, the epithelium remains intact. Dellen or localized corneal dehydration and thinning related to tear film irregularities can be caused by an adjacent site of tissue elevation.
Definitive treatment of PUK requires systemic immunosuppression, but adjunctive local therapies may be beneficial. Because corneal epithelial breakdown is common, topical antibiotic coverage and aggressive tear replacement should be instituted. Matrix metalloproteinases (MMPs) are believed to play a role in keratolysis, and elevated levels of these enzymes have been found in the tears and corneal tissue of patients with PUK. Doxycycline, which has been shown to inhibit MMP activity, may therefore be helpful in limiting corneal melts. Topical medroxyprogesterone acetate has also been shown to limit collagenase activity and is often used in these settings.
In one series, impending or frank corneal perforation was reported to occur in one-third of patients with PUK. In another series of patients with scleritis-associated PUK, 100% were in danger of perforation. Imminent or overt corneal perforation can be managed by placement of cyanoacrylate glue or a contact lens as a bandage. Larger corneal defects may require the use of corneal patch grafts or therapeutic corneal transplants. The failure rate of these grafts is extremely high, because the persistence of inflammatory mediators increases the likelihood of graft rejection and may lead to progressive melting of the transplanted tissue. Because the cornea is an avascular structure, and the inflammatory mediators of tissue destruction are thought to travel into the cornea from the dilated blood vessels in paralimbal tissues, conjunctival resection has been advocated in the management of PUK. This procedure, however, remains controversial.
Corneal manifestations
Corneal findings of the ANCA-associated vasculitides are often present in concert with other anterior segment manifestations, particularly necrotizing scleritis. Conjunctival scarring with resultant tear deficiency, entropion, trichiasis, and poor eyelid closure can produce an exposure keratopathy, secondary infectious ulceration, and even corneal perforation. Proptosis from orbital disease (as discussed later) can also cause exposure and its sequelae.
In addition to these secondary corneal findings, inflammatory disease may specifically target the cornea, resulting in a condition known as peripheral ulcerative keratitis (PUK). This condition is typically unilateral and sectoral, although bilateral disease can occur in up to 40% of patients. The lesions usually are found within 2 mm of the corneoscleral limbus, and the adjacent limbal tissue and sclera show evidence of vasculitic disease ( Fig. 5 ). The affected corneal stroma can be markedly thin as keratolysis progresses to potential corneal perforation either spontaneously or with minor ocular trauma. An epithelial defect may be present, predisposing patients to secondary infection. Patients typically present with pain, injection, photophobia, and decreased vision from corneal opacities or induced astigmatism.
