Key Features
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Peripheral corneal ulceration.
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Unilateral or bilateral.
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Progresses circumferentially and posteriorly and may perforate.
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May be associated with systemic collagen vascular diseases.
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Can be a presenting feature of a previously undiagnosed systemic collagen vascular disorder.
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Frequently requires systemic immunosuppressive immunomodulatory therapy.
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Imperative to exclude a primary or secondary infectious etiology.
Introduction
Peripheral ulcerative keratitis (PUK) is used to describe a group of destructive inflammatory diseases involving the peripheral cornea whose final common pathway is characterized by sloughing of corneal epithelium and keratolysis (corneal “melting”). The vast majority of cases are mediated by local and systemic immunological processes, although some cases may be infectious in origin and must be properly evaluated. PUK may be associated with systemic vasculitides, particularly the collagen vascular diseases, in about half of the noninfectious cases. Necrotizing scleritis often is associated in such cases and is suggestive of possible active vasculitis, with PUK being the presenting feature of a systemic inflammatory condition, such as granulomatosis with polyangiitis (GPA) (formerly known as Wegener’s granulomatosis) or polyarteritis nodosa. If not properly treated, PUK can progress to perforation resulting in significant ocular morbidity, and when associated with a systemic autoimmune condition, may be potentially life-threatening.
Anatomy and Pathogenesis
The unique characteristics and anatomy of the peripheral cornea contributes to the predilection of this region to be involved in both local and systemic immunological reactions. There are no clear-cut borders that delineate the peripheral cornea, with an arbitrary central limit beginning around 3.5–4.5 mm from the visual axis and extending out to the junction of the ill-defined transition between limbus and the sclera and conjunctiva. Distinct anatomical differences of the peripheral cornea include the greater thickness (up to 0.7 mm) with tight collagen bundle packing; a vascular arcade that originates from the anterior ciliary arteries and extends approximately 0.5 mm into the clear cornea (providing the nutritional supply but also access to the efferent arm of the immune response); and accompanying lymphatics, which drain to the regional lymph nodes. There also are unique immunological characteristics of the peripheral cornea compared with the central cornea, including the presence of more Langerhans’ cells, and higher concentrations of immunoglobulin M and the first component of complement (C1) (important in the activation of the classic complement pathway), likely caused by limited central diffusion from the limbal vessels resulting from the large size of the latter two molecules. Additionally, the adjacent conjunctival blood vessels and lymphatics not only provide peripheral corneal access to the afferent and efferent arcs of the immune system but may be sources of inflammatory effector cells and cytokines involved in the production of collagenase and proteoglycanase, which may contribute to corneal degradation.
Although the exact pathophysiological mechanisms of PUK are unclear, circulating immune complex deposition, autoimmune reactions to corneal antigens, and hypersensitivity reactions to exogenous antigens have been proposed, with evidence suggesting that both humoral and cell-mediated mechanisms (T cell and B cell) are involved. Locally produced or circulating immune complexes lodged in limbal or peripheral corneal blood vessels may activate the classic complement pathway in the presence of C1 (the recognition unit of the classic complement pathway). Immune vasculitis resulting in damage to the vessel wall with leakage and the chemotaxis of various inflammatory cells, proteins, and proinflammatory cytokines and the production of metalloproteinases by local resident cells may accelerate and propagate the peripheral corneal destructive process.
Ocular Manifestations
The presenting symptoms of PUK are not specific. Foreign body sensation, pain, and photophobia are seen when there is epithelial erosion and ulceration. Vision may be affected if the peripheral inflammatory process proceeds centrally or from induced astigmatism. Occasionally, an associated anterior uveitis may contribute to the photophobia with reduction of visual acuity. Pain may be severe if associated scleritis occurs.
The hallmark clinical features include epithelial loss, demonstrated with fluorescein staining, and various amounts of stromal inflammatory infiltration, and/or thinning caused by keratolysis (corneal melting), which may occur at any clock hour of the peripheral cornea, with or without an intervening clear zone from the limbus ( Fig. 4.16.1 ). The process may progress circumferentially, centrally, and posteriorly, potentially resulting in perforation ( Fig. 4.16.2 ). The specific clinical findings at presentation will depend on the severity and rate of progression of the disease, as well as the timing between the onset and clinical evaluation. Corneal melting, once initiated, may progress very rapidly. The amount of stromal loss may be underappreciated because of debris and necrotic material deposited at the base of the ulcer but may become more apparent after corneal scrapings are performed to evaluate for infectious causes. Limbal, conjunctival, and episcleral injections occur frequently. Concurrent scleritis denotes a higher likelihood of active vasculitis. The finding of PUK with scleritis portends a worse ocular and systemic outcome than when scleritis occurs alone. Cataract and glaucoma may occur as a result of the inflammatory process or the use of corticosteroids.
Systemic Associations
Nearly 50% of patients with PUK have an associated systemic disease, with the large majority of these being the collagen vascular diseases (CVDs) ( Box 4.16.1 ). Rheumatoid arthritis (RA) is the most common CVD associated with PUK, likely due to its high prevalence in the population (affecting 2.5%–3% of adults). Granulomatosis with polyangiitis (GPA) (formerly known as Wegener’s granulomatosis) and other antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides, although relatively rare, are an important cause of PUK. An associated scleritis may occur in a significant portion of patients, the presence of which, especially when necrotizing, suggests an active vasculitic process. In general, patients with rheumatoid arthritis (RA)–associated PUK usually have an established systemic diagnosis with evidence of advanced disease (subcutaneous nodules, vasculitis, cardiac involvement ) or clinical findings supportive of the diagnosis of RA. However, in up to 25% of patients, the PUK may be the initial presenting feature of potentially lethal undiagnosed systemic vasculitis, highlighting the importance of a thorough systemic evaluation. Additionally, in patients with scleritis, the additional presence of PUK portends poor ocular and systemic prognosis.
Ocular Noninfectious
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Idiopathic
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Acne rosacea (ocular)
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Mooren’s ulcer
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Traumatic, postoperative (may be a presenting feature of a systemic autoimmune disorder)
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Exposure/neuroparalytic keratopathy
Ocular Infectious
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Bacterial ( Staphylococcus , Streptococcus , Gonococcus [rare])
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Viral (herpes simplex and herpes zoster)
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Amebic ( Acanthamoeba )
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Fungal
Systemic Noninfectious
Collagen Vascular Diseases/Vasculitis
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Rheumatoid arthritis (common)
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Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides
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Granulomatosis with polyangiitis (previously Wegener’s granulomatosis) (relatively common)
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Polyarteritis nodosa (less common)
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Microscopic polyangiitis (MPA) (less common)
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Churg–Strauss syndrome (less common)
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Relapsing polychondritis (uncommon)
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Systemic lupus erythematosus (less common)
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Progressive systemic sclerosis/scleroderma (rare)
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Giant cell arteritis (very rare)
Other Systemic Autoimmune
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Cicatricial pemphigoid (especially with trichiasis) (rare)
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Inflammatory bowel disease (very rare)
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Sarcoidosis (very rare)
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Sjögren’s syndrome
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Leukemia/malignancy (very rare)
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Inflammatory bowel disease (usually associated with a nonulcerative peripheral keratitis)
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Giant cell arteritis (rare)
Systemic Infectious
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Gonorrhea
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Bacillary dysentery
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Tuberculosis
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Borreliosis (Lyme disease—very rare)
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Varicella zoster
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Helminthiasis
Differential Diagnosis
PUK is a clinical diagnosis and identifying the cause is paramount for the proper management. Infections may cause peripheral corneal inflammation and ulceration and must be rapidly recognized (see Box 4.16.1 ) because therapy is markedly different from that for PUK caused by autoimmune disease–mediated conditions ( Fig. 4.16.3 ). However, patients with autoimmune disease–associated PUK may become secondarily infected, and thus infectious causes must always be excluded in the initial workup. Local inflammatory causes include Staphylococcus marginal ulcers, which begin with an infiltrate adjacent to the limbus separated by a characteristic clear zone with progression to ulceration and rosacea-associated blepharoconjunctivitis and which may result in a peripheral keratitis with or without a clear zone.
Mooren’s ulcer is a specific form of unilateral or bilateral PUK that is characterized by a chronic, usually severely painful, single or multicentric corneal ulcer that begins in the periphery adjacent to the sclera with a characteristic steep, undermined, or overhanging central margin and occasionally infiltrated leading central border without associated scleritis (see also Chapter 4.17 ).
Noninflammatory cause of thinning of the peripheral cornea, as seen with Terrien’s marginal degeneration, pellucid marginal degeneration, and marginal furrow can be distinguished from PUK because of lack of inflammation and typically an intact epithelium.
Diagnostic and Ancillary Testing
A thorough history must be obtained about any previous history of ocular infections, including ocular and nonocular herpetic disease, contact lens wear, and current and previous medication, trauma, or surgery. Because PUK may be an initial or presenting feature of an underlying systemic collagen vascular disease (see Box 4.16.1 ), a comprehensive review of systems should be obtained, with particular questions related to various systems involved in the systemic diseases associated with PUK. A complete ophthalmic examination to exclude local pathologies is critical. A comprehensive physical examination should be performed by the appropriate specialist when an underlying systemic process is suspected.
Laboratory tests are listed in Box 4.16.2 . Appropriate testing should exclude infectious etiologies.
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CBC
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RF
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Anti-CCP
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c-ANCA and p-ANCA
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ESR and CRP, CIC
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Urine analysis
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Radiographs
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Chest
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Sinus
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ANCA, antineutrophil cytoplasmic antibody; anti-CCP, anti-cyclic citrullinated protein antibodies; c-ANCA, antineutrophil cytoplasmic antibodies/cytoplasmic staining pattern; CBC, complete count; CIC, circulating immune complexes; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MPA, microscopic polyangiitis; GPA, granulomatosis with polyangiitis; p-ANCA, antineutrophil cytoplasmic antibodies/perinuclear staining pattern; RF, rheumatoid factor.
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