Corneal Ulcer

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.

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]

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.

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]

Patients with corneal ulcer usually experience pain, redness, foreign object sensation, tearing, photophobia, and decreased vision.

A complete systemic medical history and a review of systems are imperative in these patients, including questions regarding the presence of weight loss, malaise, muscle pain, or weakness, and symptoms involving the neurologic, respiratory, and renal systems.

A thorough physical examination should be performed, in addition to a complete ophthalmologic examination.

Keratitis sicca is quite common in patients with corneal ulcer associated with autoinflammatory diseases. Superficial punctate keratitis, chemosis, recurrent episcleritis, and scleritis also are common findings.

In the case of SLE, retinal vasculitis is evident on fluorescein angiography, with intraretinal hemorrhages and cotton-wool spots. Of patients, 95% develop arthralgia and articular findings, and 70-80% of patients develop skin lesions at some point. The butterfly rash across the nose and cheek occurs in about 30% of patients with SLE.

Mooren ulcer begins as a gray-white infiltrate in the peripheral cornea followed by epithelial breakdown and stromal melting. Eventually, it develops into a chronic, painful peripheral corneal ulcer that progresses circumferentially and centrally, creating an overhanging edge at its central border. The adjacent conjunctiva and sclera usually are inflamed and hyperemic.

Granulomatosis with polyangiitis is characterized by nasal or oral inflammation, necrotizing and granulomatous inflammation of the vessels of the upper and lower respiratory tract, glomerulonephritis, and other organ involvement with small vessel inflammation.

All the underlying systemic conditions leading to these types of corneal ulcers are likely to have an autoimmune etiology that is linked to genetic susceptibility.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common systemic disorder to involve the ocular surface. Patients with RA who have high titers of rheumatoid factor are most likely to have extra-articular manifestations, including ocular diseases such as keratoconjunctivitis sicca, episcleritis, scleritis, peripheral ulcerative keratitis (PUK), and, rarely, retinal vasculitis.[19] Patients with severe RA often present with indolent progressive ulceration of the peripheral or pericentral cornea with minimal inflammation that eventually may result in corneal perforation.[20]

Granulomatosis with polyangiitis (Wegener granulomatosis)

Granulomatosis with polyangiitis (Wegener granulomatosis) is a necrotizing granulomatous vasculitis that involves the upper respiratory tract, lungs, and kidneys. A limited form of granulomatosis with polyangiitis exists in which renal lesions are not present. Ahmed et al reported cases of very limited Wegener granulomatosis with only ocular involvement and no respiratory or renal manifestations.[21] Granulomatosis with polyangiitis is a leading autoimmune condition associated with PUK. PUK often manifests at the onset of GPA, leading to the diagnosis of the systemic condition.[22]

Sjögren syndrome

Sjögren syndrome is a multisystem disease that commonly occurs in middle-aged women but can affect both sexes and all ages and may be associated with other autoimmune disorders. It is the major cause of keratoconjunctivitis sicca (dry eye syndrome) in patients with auto-immune disorders and can lead to corneal ulceration.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that causes ocular complications in the anterior and posterior segments, including keratitis sicca, episcleritis, corneal ulceration, uveitis, and retinal vasculitis.[23, 24] Peripheral ulcerative keratitis rarely occurs in SLE, but some cases have been reported.

Polyarteritis nodosa

Polyarteritis nodosa is a vasculitis of small- and medium-sized arteries that leads to multiple organ diseases.

Scleroderma

Scleroderma is a connective-tissue disorder characterized by extreme skin tautness that results in vascular insufficiency, vasospasm, and Raynaud phenomenon.

Other causes

There are a few reports of peripheral ulcerative keratitis associated with sarcoidosis[22, 25] and Behçet disease.[26]

Relapsing polychondritis is a rare autoimmune disease characterized by episodic inflammation of cartilaginous structures in the body. PUK occurs in fewer than 10% of patients with relapsing polychondritis. A 2017 case report describes a resistant case of relapsing polychondritis with rapid corneal thinning and corneal perforation.[27]

Paracentral corneal melting has been reported in a patient with Vogt-Koyanagi-Harada syndrome, psoriasis, and Hashimoto thyroiditis.[28]

A unique case of peripheral ulcerative keratitis secondary to hepatitis B virus–associated cryoglobulinemia and vasculitis has been reported.[29]

Several cases of corneal melting associated with topically applied nonsteroidal anti-inflammatory drugs have been reported in the literature.[30, 31, 32, 33, 34] Furthermore, corneoscleral melting has been reported following amniotic membrane in a patient who had undergone multiple previous ophthalmologic surgical procedures[35] and in 14% of patients who underwent Boston keratoprosthesis.[36]

Corneal ulceration, if not managed properly and in a timely fashion, can lead to stromal necrosis, corneal perforation, and blindness. The presentation of corneal ulcer with a known or unknown systemic disease requires immediate workup and referral to a rheumatologist.

Serious systemic and local complications occur in patients with corneal ulceration due to autoimmune diseases. In many cases, these underlying conditions are associated with a high mortality rate.

The most serious ocular complications of corneal ulcer include corneal perforation with secondary infections, corneal scarring, and secondary cataract and glaucoma.

Culture of the cornea should be performed to rule out infectious etiology.

A complete laboratory evaluation for suspected systemic disorders is performed.

Laboratory studies for rheumatoid arthritis include the following:

• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP) level
• Complete blood cell (CBC) count
• Rheumatoid factor (RF) assay
• Antinuclear antibody (ANA) assay
• Anti−cyclic citrullinated peptide and anti−mutated citrullinated vimentin assays

Laboratory studies for granulomatosis with polyangiitis include the following:

• CBC: Mild normochromic normocytic anemia is present in 50% of patients; leukocytosis is common, with a neutrophil predominance
• Elevated inflammatory markers (ESR, CRP)
• Abnormal kidney function test findings (blood urea nitrogen and creatinine) and urinalysis (UA) results in patients with renal involvement
• Rheumatoid factor is positive in a low titer in two thirds of patients
• Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) directed against PR3 is most specific for GPA
• Some patients with GPA express perinuclear-staining ANCA (p-ANCA) specific for myeloperoxidase (MPO)

Mooren ulcer: In order to arrive at this diagnosis, an exhaustive laboratory examination should be performed and must be nonconclusive for other possible explanations of corneal ulcer, as follows:

• Laboratory investigations include CBC count with differential, platelet count, ESR, CRP, rheumatoid factor, ANA, ANCA, complement fixation, C3, C4, LFTs, VDRL/FTA-ABS, BUN and creatinine, serum protein electrophoresis, urinalysis, hepatitis B surface antigen, hepatitis C virus antibody, and HIV antibody.
• Cultures should be performed to rule out bacterial, fungal, and viral (eg, herpes simplex virus [HSV]) causes.
• A deficiency of suppressor T cells has been found in the serum of a patient with Mooren ulcer, while another study showed a helper T cell/suppressor cell ratio of greater than 1:1 in 6 of 9 patients with Mooren ulcer. More recent studies have shown that most of the resident cells from specimens with Mooren ulcers express the class 2 antigens, human leukocyte antigen DR (HLA-DR), or human leukocyte antigen DQ (HLA-DQ). Another study demonstrated that sera from patients with Mooren ulcer had high antibody titers to a cornea-specific stromal protein antigen. ^[6]

Systemic lupus erythematosus: Of patients with SLE, 50-60% have antibodies to cardiolipin. For the importance of the measurement of intraocular pressure, see Yazici et al.[37] The American College of Rheumatology has suggested 11 classification criteria for SLE. Patients are considered to have SLE if they meet 4 of the following criteria:

• Malar rash
• Discoid rash
• Photosensitive rash
• Oral ulcers
• Nonerosive arthritis in 2 or more joints
• Pleuritis or pericarditis
• Glomerulonephritis or proteinuria
• Seizures or psychosis
• Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia
• Immunologic laboratory abnormalities, such as antibodies to double-stranded DNA or the SM antigen or a false-positive serologic test for syphilis
• Positive ANA test that is not caused by a medication

Scleroderma: Anti-Sci-70 antibody tests and anticentromere antibodies (CREST variant)

Laboratory studies for polyarteritis nodosa include the following:

• Elevated blood urea nitrogen level or creatinine level
• Presence of hepatitis B surface antigen or antibody in serum
• Arteriographic evidence of aneurysms or occlusions (nonarteriosclerotic)

In RA-associated paracentral corneal ulcerations, sparse T-lymphocytes consistently were identified in the subepithelial areas adjacent to the ulcer, with some neutrophils and macrophages in the stroma. B-lymphocytes were not detected. On 2 specimens in this immunology study,[38] some infiltrating cells and the corneal endothelium expressed MHC class II antigens reactivity.

In granulomatosis with polyangiitis, histologic findings include necrotizing, granulomatous vasculitis with infiltrative neutrophils, lymphocytes, plasma cells, histiocytes, and giant cells.

In polyarteritis nodosa, the presence of polymorphonuclear cells in artery walls can be found on biopsy of small- or medium-sized arteries.

Ultrasonography of the eye (B-scan) can be used to evaluate for posterior scleritis, often present concurrently in patients with corneal ulcer associated with autoimmune diseases.

Pertinent imaging studies to assess for auto-inflammatory disorders include the following:

• CT scanning of the sinuses (GPA)
• Chest radiography (sarcoidosis)
• MSK radiography of affected joints (RA)

Corneal scraping for cultures may be performed when an infectious etiology is suspected. 

Immune corneal ulcers are ocular surface diseases with multiple etiologies. Immunosuppressive drugs and systemic or topical steroids may control the inflammatory process in some cases, but, in more severe cases, the ulcer may progress to melting or perforations.[15, 18, 39]

The medical treatment of corneal ulcer primarily is systemic and needs to be coordinated with a corneal specialist, rheumatologist, or internist. The ophthalmologic treatment is best approached in coordination with corneal subspecialists and with other specialists of the external disease and in collaboration with an internist, as necessary. Topically applied nerve growth factor (NGF) has been used in some patients with corneal neurotrophic ulcers and corneal melting with success.[40, 41]

Medical care for corneal ulcerations includes topical and systemic corticosteroid therapy and immunosuppressive treatment.

Topical therapy

Topical agents include the following:

• Preservative free artificial tears, used with or without punctum plug and soft contact lenses. Small corneal ulcers caused by dry eye syndrome can benefit from such treatment, promoting epithelialization of the ulcer.
• Cycloplegic agents (eg, cyclopentolate TID)
• Immunosuppressive agents (eg, topical cyclosporine 0.5% in artificial tears)
• Prophylactic broad-spectrum topical antibiotics (eg, 0.3% ciprofloxacin qid) to prevent bacterial superinfection.

Systemic immunosuppressive therapy

Systemic immunosuppressive agents must be prescribed by an ophthalmologist, rheumatologist, or internist who is familiar with their dosages and adverse effects.

Start initially with intravenous methylprednisolone (eg, methylprednisolone 1 g IV administered in 1 dose over 30 minutes) or oral prednisone (1 mg/d).

Steroid-sparing agents include antimetabolites (eg, methotrexate, azathioprine, mycophenolate mofetil), T-cell inhibitors (eg, cyclosporine, tacrolimus), alkylating agents (eg, cyclophosphamide, chlorambucil) and biologic agents (eg, infliximab, rituximab). A recent study reports a case of RA-associated PUK treated successfully with rapid healing using prednisolone, methotrexate, and adalimumab combination therapy.[42]

Biologic agents are gaining popularity for the treatment of ocular manifestations of rheumatic diseases. Studies showed that rituximab can be an effective induction therapy for refractory ocular complications of RA.[5] A case series identified rituximab as having the highest success rate (63%) for achieving steroid-free remission in patients with GPA-associated PUK. The second best medication was cyclophosphamide (31% success).[43] Rituximab was also effective in the management of severe Mooren ulcer.[44]

Mooren ulcer

A 2017 study suggested treating Mooren ulcers initially with aggressive topical medication, including 1% cyclosporine or 0.1% tacrolimus eye drops, 0.1% dexamethasone, and antibacterial eye drops 4 times daily, along with tobramycin and dexamethasone ointment at night.[13] Treatment was stepped up to systemic corticosteroid therapy and immunosuppressive treatment in cases of failure. Medication was continued at full dose for at least 3 months after complete resolution of the ulcer and was slowly tapered thereafter.[13]

Surgical care for corneal ulcer includes the following:

• Resection of adjacent conjunctival tissue to remove sources of collagenase, cytokines, and inflammatory cells from the ulcerated cornea
• Application of tissue adhesives such as cyanoacrylate glue to limit ulceration in cases of impending perforation: This may be effective only in small perforations. The opacity of the cyanoacrylate tissue adhesive can obscure visual axis, especially in central corneal lesions. ^[45]
• Amniotic membrane grafting or conjunctival flap covering can be used to treat ulcers that are relatively small and limited, with a depth of less than one half of the corneal thickness. ^{[13, 46]}
• Tectonic (reconstructive) lamellar or penetrating keratoplasty ^[47] may be performed to restore normal corneal thickness in cases of thinned or perforated cornea. These are useful therapeutic options in selected cases of corneal thinning and perforations, as they effectively restore the integrity of the eye and allow acceptable visual rehabilitation. ^[45] However, outcomes of keratoplasty performed for a sterile ulcer are not as good those for infectious corneal ulcers, probably owing to the underlying inflammatory condition interfering with the healing process. ^[48]

Patients with corneal ulcer must be treated and monitored closely by a rheumatologist because the treatment is systemic and can have serious adverse effects, and the systemic implications of these disorders can often be life-threatening.[17, 18]

Outpatient care for patients with corneal ulcers is essential with close follow-up.

Inpatient care for patients with corneal ulcers may be required in difficult cases.

Class Summary

Inhibit key factors in the immune system responsible for inflammatory responses.

Methotrexate (Folex PFS)

Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. Adjust dose gradually to attain satisfactory response.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease for a variety of organs. For children and adults, base dosing on ideal body weight. A compounded ophthalmic solution of this medication has been used experimentally (1 gtt qid) but has not demonstrated efficacy in patients with corneal ulcers.

Cyclophosphamide (Cytoxan, Neosar)

Used to control severe collagen vascular diseases. Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Class Summary

Prevent superinfection in corneal ulcers with inadequate protection against bacterial keratitis.

Ciprofloxacin ophthalmic (Ciloxan)

Inhibits bacterial growth by inhibiting DNA gyrase. Indicated for superficial ocular infections of the conjunctiva or cornea caused by strains of microorganisms susceptible to ciprofloxacin.