Background
The term "corneal ulcer" often is used interchangeably with "bacterial keratitis," although, in practice, these are 2 different entities. Bacterial keratitis denotes a bacterial infection of the eye that causes inflammation and, potentially, ulceration of the cornea, whereas corneal ulcer describes a loss of corneal tissue due to many possible causes. [1, 2] Although acute corneal ulcers in emergency settings most likely are infectious in etiology, other sterile causes of ulceration exist.
This article specifically addresses sterile corneal ulcers associated with autoinflammatory diseases.
The most common autoimmune pathologies with ocular manifestations include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), connective-tissue disorders (Sjögren syndrome, scleroderma, relapsing polychondritis), and vasculitis (granulomatosis with polyangiitis [GPA], polyarteritis nodosa, and, rarely, Behcet disease). Patients with ocular manifestations of autoinflammatory diseases often have keratoconjunctivitis sicca (dry eye syndrome), which can cause corneal ulceration. Less frequently, the autoinflammatory process also can directly attack the cornea, causing peripheral ulcerative keratitis (PUK), a condition that demands aggressive treatment.
Some cases of corneal ulcer may also be idiopathic; these are referred to as Mooren ulcers. These noninfectious ulcerations touch the peripheral cornea and have been classified into 2 clinical types. One is a milder, unilateral, less progressive form of the disease generally seen in elderly patients that responds well to therapy. The second type is a much more aggressive, frequently bilateral, relentless disease usually seen in younger patients that is poorly responsive to any therapy and often leads to corneal destruction. Increasing evidence has shown an autoimmune basis for this pathology. [3, 4]
Of note, patients with a poor corneal surface, especially those with systemic diseases in whom keratoconjunctivitis sicca (dry eye syndrome) often also is present, are at increased risk for corneal infection.
Pathophysiology
The pathogenesis of corneal ulcers associated with autoinflammatory diseases is unclear. Possibilities include immunologic responses to unknown antigens and genetic susceptibility, such as genetic predisposition to the development of defective suppressor T-lymphocyte function, production of autoantibodies (eg, antinuclear antibodies), and activation of the complement pathway.
Peripheral ulcerative keratitis (PUK) is a rare manifestation of RA characterized by a progressive thinning of the peripheral cornea. Both cell-mediated and humoral immunity play an important role. Circulating immune complexes are deposited in the limbal vessels, which leads to the activation of the classical pathway of the complement system. The result is a recruitment of inflammatory cells and production and release of matrix metalloproteinases which ends in keratolysis, with or without ulceration. [5, 6] Vasculitis also has been implicated in the appearance of PUK. Varying degrees of vaso-occlusion of the conjunctival vasculature and episclera have been found. This vasculopathy can cause resorption of stromal tissue with ulceration and necrosis. [7]
Genetic and environmental factors are associated with SLE. In a genetically susceptible individual, certain environmental stimuli, such as a viral infection or contact with certain drugs, induce alterations in DNA, immunoregulatory networks, or both, with resultant formation of autoantibodies, including antinuclear antibody (ANA).
The pathogenesis of polyarteritis nodosa is not clear, but, in some patients, it may be related to hepatitis B antigen–associated immune complex disease or other immune complexes.
Mooren ulcers are, by definition, idiopathic in origin. However, increasing evidence suggests that Mooren ulcer is, in fact, an autoimmune disease that exclusively targets the corneal stroma, and it is triggered by environmental factors in genetically susceptible individuals. [6] Associations also have been reported among Mooren ulcer, helminthiasis, [7] and ocular injuries. [8] Of note, this pathology has been previously associated with hepatitis C, [9] but more recent studies have failed to support this relationship. [10, 11]
Epidemiology
A 2014 study involving 70 patients showed that ulcerative keratitis generally affected older, predominantly female patients, about two thirds of whom had RA. [12]
Frequency
The prevalence of ulcerative keratitis in patients with RA was 1.4% in a retrospective study of 589 patients. [13]
Mortality/Morbidity
Development of a corneal ulcer associated with a connective tissue disease or a vasculitis carries a poor prognosis.
Patients who have RA with scleritis and a corneal melt die within 5 years without aggressive treatment. This type of corneal ulcer may lead to corneal thinning and perforation in the perilimbal region or paracentrally.
Ethnic groups
Wegener granulomatosis has no ethnic predilection.
Sex
RA primarily affects middle-aged females.
Scleroderma is 3 to 4 times more common in women than in men.
Polyarteritis nodosa is 2.5 times more likely to affect males than females.
No sexual predilection exists with Wegener granulomatosis.
Age
Corneal ulcer associated with autoinflammatory diseases does not affect children. Except for the malignant form of Mooren ulcer, patients with this pathology are usually older than 30 years.
Wegener granulomatosis can affect all age groups.
Scleroderma usually starts in individuals aged 30 to 50 years.
Polyarteritis nodosa is more frequent in middle-aged males.
Prognosis
RA is the most common immune condition associated with corneal ulceration. [14] The development of extra-articular features of RA has been associated with increased morbidity and mortality. [15] In RA, peripheral ulcerative keratitis commonly manifests later in the disease process rather than at disease onset, suggesting that the disease is worsening. Several early studies demonstrated an increased mortality rate among patients with RA-associated scleritis or corneal ulcers. [16, 17] A more recent study also confirmed a higher mortality rate among patients with RA who had severe corneal ulcers requiring corneal transplantation, compared with ulcer-free patients with RA. [18] However, early initiation of aggressive systemic anti-inflammatory therapy has been shown to reduce the severity and morbidity of ulcerative keratitis. [12]
