Mooren ulcer is a progressive corneal ulcer of unknown cause that occurs in the peripheral cornea. It is also called rodent corneal ulcer. It is considered an autoimmune disease against some corneal antigen. Type II allergic mechanism involving autoantibodies against corneal epithelial cells is central to the pathogenesis.
A gray swelling within 2–3 mm of the corneal margin occurs in the superficial one-third of the cornea, progressing circumferentially and centrally over 4–12 months 1). The leading edge of the ulcer has a prominent undermined, deep trench-like edge. The absence of a clear zone between the limbus and the ulcer is an important distinguishing feature from catarrhal corneal ulcer.
Blood vessels invade the ulcer base and extend toward the base of the undermined edge 1). However, they do not extend beyond the advancing edge of the ulcer. Corneal destruction is generally limited to the stromal tissue, leaving Descemet’s membrane and endothelium intact 1).
There is no inflammation in the adjacent sclera. This is the most important distinguishing feature from peripheral corneal ulcers associated with collagen diseases such as rheumatoid arthritis.
It is a rare disease, with an estimated incidence of about 0.03% in China 2). It is more common in the Southern Hemisphere, such as southern and central Africa and India, suggesting a genetic or geographic predisposition 2). The ICD-10 code is H16.0.
According to the Watson classification, it is classified into the following three types. Type 1 (unilateral) occurs in people aged 60 years or older and is accompanied by severe pain. Type 2 (bilateral aggressive) occurs in young people aged 14 to 40 years, is treatment-resistant, and has a poor prognosis. Type 3 (bilateral slowly progressive) occurs in the mid-50s, with mild inflammation and may heal spontaneously 1).
Severe eye pain is the main complaint. It is accompanied by photophobia, tearing, and conjunctival injection 3). Visual loss is due to iritis, central corneal lesions, or irregular astigmatism. About one-third of cases are bilateral 3). It often has a sudden onset in young to middle-aged patients and progresses rapidly.
As it progresses, it becomes a complete peripheral ulcer that completely surrounds the corneal periphery, leaving a cloudy “central island” 3). Eventually, the corneal stroma is replaced by a fibrovascular membrane. In advanced cases, corneal perforation may occur. Srinivasan et al. classified the progression patterns of the ulcer into three types: partial peripheral, complete peripheral, and total corneal ulcer 3).
Type 1: Unilateral
Age of onset: 60 years or older
Characteristics: Extremely severe pain. Spreads around the cornea, leaving a thick opaque central cornea
Vascular findings: Non-perfusion of superficial vessels is characteristic. Severe leakage from deep limbal vessels is observed
Prognosis: Pain decreases after stromal loss, but recurrence is common after corneal transplantation
Type 2: Bilateral aggressive
Age of onset: 14 to 40 years
Characteristics: Pain is milder than in Type 1. Gray spots aggregate in the corneal stroma, forming a typical ulcer
Vascular findings: Superficial vascular plexus dilates but blood flow is maintained. Leakage and neovascularization from deep vessels are observed
Prognosis: Treatment-resistant, frequent perforation, poor prognosis
Type 3 (bilateral slowly progressive) develops in the mid-50s and presents with corneal furrowing without inflammation. It progresses slowly, but spontaneous healing may occur1).
Anterior segment optical coherence tomography (AS-OCT) is useful for evaluating patterns of corneal thinning (arcuate, crab claw). It is also used for monitoring treatment response4).
The etiology of Mooren’s ulcer is unknown, but evidence suggesting an autoimmune basis has accumulated. Classically, it is considered a type II allergic reaction involving autoantibodies against corneal epithelium.
An autoimmune reaction against calgranulin C expressed by corneal stromal keratinocytes is thought to play a central role5). Normally a hidden antigen, calgranulin C becomes exposed after trauma or infection, leading to sensitization. This molecule is also present in polymorphonuclear leukocytes in the circulation5).
Associations with specific HLA alleles have also been reported. In a study by Taylor et al., 83% of Mooren’s ulcer patients were HLA-DR17 positive and 83% were HLA-DQ2 positive, significantly higher than the control group (5–40%) 6). HLA-DQ5 is also frequent in Mooren’s ulcer patients 6). Recent proteomics studies suggest anti-citrullinated protein antibodies (ACPA, anti-CCP antibodies) as an immunological feature of Mooren’s ulcer 7).
By definition, Mooren’s ulcer is a peripheral corneal ulcer without underlying collagen disease. Peripheral corneal ulcers associated with collagen diseases such as rheumatoid arthritis are a different group of diseases to be differentiated, distinguished by the presence of scleritis, immune complex deposition (type III allergy), and vasculitis 11). Mooren’s ulcer is thought to involve type II allergy (autoantibodies to corneal epithelium), and its pathological mechanism differs from that of collagen disease-associated peripheral ulcers.
The diagnosis of Mooren’s ulcer is one of exclusion 3). It requires the absence of ocular infections and systemic diseases that cause peripheral corneal ulcers. Slit-lamp microscopy reveals a crescent-shaped peripheral corneal ulcer with an undermined central edge, and serological testing excludes collagen disease.
To exclude other causes of peripheral ulcerative keratitis (PUK), the following tests are performed11).
Peripheral corneal ulcerative diseases have various etiologies, and it is important not to overlook systemic vasculitis11).
| Differential Diagnosis | Key Points for Differentiation |
|---|---|
| Terrien marginal degeneration | Non-inflammatory, clear zone, lipid deposition |
| Catarrhal corneal ulcer | Clear zone 1–2 mm, associated blepharitis |
| Rheumatoid arthritis-associated PUK | Associated scleritis, corneal melting |
| Granulomatosis with polyangiitis (GPA) | GPA-associated PUK, recurrence of scleritis/orbital inflammation 9) |
| Systemic lupus erythematosus | ANA positive, multi-organ involvement |
| Polyarteritis nodosa | Vasculitis, retinal artery occlusion |
| Relapsing polychondritis | Auricular/nasal cartilage inflammation |
| Pellucid marginal degeneration | Inferior corneal thinning, non-inflammatory |
| Senile furrow degeneration | Elderly, thinning between arcus senilis and limbus |
Terrien marginal degeneration is a painless, non-inflammatory peripheral corneal thinning that differs greatly from Mooren’s ulcer. Terrien degeneration usually begins in the superior cornea and has a clear zone between it and the limbus. It shows superficial neovascularization and lipid deposition but no epithelial defect. Progression is also slow. Mooren’s ulcer is accompanied by severe pain and inflammation, has no clear zone, and presents with an undermined ulcer edge.
Treatment starts with topical therapy and progresses stepwise to systemic therapy and surgery depending on the response. In refractory cases, treatment intensification is necessary within weeks to months.
First-line treatment is steroid eye drops. Immunosuppressive eye drops or subconjunctival injections may be used to reinforce therapy.
Indicated when progression cannot be controlled with topical therapy or in bilateral cases.
Surgery is performed when remission cannot be achieved with local or systemic therapy.
After surgery, topical and systemic steroids and immunosuppressants are continued to prevent rejection. Long-term use of therapeutic soft contact lenses is required, and monitoring for epithelial rejection and steroid-induced glaucoma is performed.
Brown surgery is a conjunctival resection along the ulcer. The hyperemic conjunctiva is resected approximately 2 clock hours from each end of the ulcer, 3–4 mm wide from the limbus. In Mooren’s ulcer, immune cell infiltration from conjunctival tissue promotes ulcer progression, so cutting off its supply controls disease activity. Keratoepithelioplasty has been reported as an adjunctive method to block re-invasion of pathological conjunctiva15).
An autoimmune reaction against calgranulin C, a hidden antigen expressed by corneal stromal keratinocytes, plays a central role in the development of Mooren’s ulcer 5). Calgranulin C is also present in polymorphonuclear leukocytes in the circulating blood.
When calgranulin C is exposed after corneal trauma, infection, or surgery, antigen-presenting cells at the corneal limbus present it to T cells via HLA class II molecules, leading to sensitization 5). In predisposed individuals, spontaneous antigen exposure may occur with aging.
Receptors for calgranulin C have been found on the surface of helminths, and molecular mimicry through cross-reactivity with helminth antigens has been suggested 5). A study in South India showed that hookworm infection is a significant risk factor for Mooren’s ulcer 19). Strong associations with HLA-DR17 and HLA-DQ2 indicate a genetic predisposition 6).
After sensitization, both humoral and cellular immune responses destroy the cornea. Circulating IgG against corneal and conjunctival epithelium is found in patient sera, and antibodies and complement bound to conjunctival epithelium have also been detected 17). Elevated serum IgA levels have also been reported.
Complement activation leads to neutrophil infiltration, degranulation, and release of collagenase 18). Collagenase destroys the corneal stroma, and degenerated corneal antigens are further exposed, creating a positive feedback loop that perpetuates the immune response. Collagenase activity has been experimentally shown to be suppressed by steroids, providing the pharmacological basis for steroid therapy 18).
In conjunctival and corneal specimens, in addition to lymphocyte infiltration, neutrophils, eosinophils, plasma cells, and mast cells are observed 7). High levels of proteolytic enzymes are detected in affected conjunctival tissue. Increased NF-κB activity has also been reported.
In the superficial stroma, infiltration of plasma cells and lymphocytes and neovascularization are observed. In the middle layer, disorganization of collagen lamellae and hyperactive fibroblasts are seen. In the deep stroma, macrophage infiltration is present 7). Neutrophil infiltration with degranulation is a characteristic finding at the advancing edge of the ulcer. Adjacent conjunctiva shows epithelial hyperplasia and subconjunctival infiltration of lymphocytes and plasma cells.
