Peripheral Ulcerative Keratitis 

Updated: Jun 11, 2019
Author: Ellen N Yu-Keh, MD; Chief Editor: Andrew A Dahl, MD, FACS 

Overview

Background

Peripheral ulcerative keratitis (PUK), also known as peripheral corneal ulceration, is a potentially devastating disorder consisting of a crescent-shaped destructive inflammation at the margin of corneal stroma that is associated with an epithelial defect, presence of stromal inflammatory cells, and progressive stromal degradation and thinning. Commonly referred to as PUK, it can quickly produce progressive necrosis of the corneal stroma, leading to perforation and blindness.[1]

Pathophysiology

The peripheral cornea has distinct morphologic and immunologic characteristics that predispose it to inflammatory reactions. Unlike the avascular central cornea, the peripheral cornea is closer to limbal conjunctiva and derives part of its nutrient supply from the limbal capillary arcade, a source of immunocompetent cells, for example, macrophages, Langerhans cells, lymphocytes, and plasma cells.[2, 3] Any inflammatory stimulus in the peripheral cornea that is caused by invasion of microbial organisms (bacteria, virus, fungi, and parasites), immune complex deposition (in systemic immune diseases), trauma, malignancy, or dermatologic conditions may produce local and systemic immune responses, resulting in neutrophil recruitment and complement activation (both classic and alternative pathways) in both tissue and vessels.[2]

Activated complement components can increase vascular permeability and further generate chemotactic factors for neutrophils (eg, C3a, C5a). Neutrophils, in turn, infiltrate the peripheral cornea and release proteolytic and collagenolytic enzymes, reactive oxygen metabolites, and proinflammatory substances (eg, platelet-activating factor, leukotrienes, prostaglandins), causing dissolution and degradation of the corneal stroma.[4, 5] In addition, the inflamed limbal conjunctiva itself is capable of producing collagenase, which contributes to stromal degradation.[6]

Systemic diseases that may cause immune complex deposition at the peripheral cornea and PUK include such collagen vascular diseases as rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA; previously known as Wegener granulomatosis), polyarteritis nodosa (PAN), relapsing polychondritis (RP), and systemic lupus erythematosus (SLE). Infectious conditions, whether systemic (eg, hepatitis, syphilis) or local (eg, herpes simplex keratitis, fungal keratitis), and noninfectious local disorders (eg, Mooren ulcer, marginal keratitis) may also cause PUK.

In summary, the major pathophysiologic mechanism of PUK is a result of degradation and tissue necrosis of corneal stroma produced by degradative enzymes, which are released primarily by neutrophils attracted into the area by diverse stimuli.

Epidemiology

Frequency

United States

Peripheral ulcerative keratitis (PUK) is uncommon. RA has been reported as the most common collagen vascular disorder that causes PUK, accounting for 34% of noninfectious PUK.[6, 7, 8] PUK may be the initial manifestation of WG and PAN. PUK is rare in patients with RP; only 2 of 112 patients with RP were reported to develop PUK in a clinical review study.[9] PUK has also been reported to be associated with SLE, although this is uncommon.[3, 10] Mooren ulcer is a rare local autoimmune disease associated with PUK, with only 287 cases reported in the world literature, although some of these cases may have been the presenting manifestation of an occult systemic disease rather than true Mooren ulcer.[11]

Mortality/Morbidity

PUK produces great morbidity from the pain and resultant visual disability. It can be a harbinger of death if the underlying disease is not diagnosed and successfully treated.

Race

No good data are available on racial predilection for PUK.

Sex

Since PUK is more common in people with collagen vascular disorders (especially RA), it is more common in females than in males. However, PUK caused by Mooren ulcer is more common in males than in females.[11, 12]

Age

Age varies and is dependent on the associated systemic or local disorder.

 

Presentation

History

Peripheral ulcerative keratitis (PUK) is frequently a manifestation of an occult systemic disease. Thus, a thorough systemic history is very important and should include chief complaint, characteristics of present illness, past medical history, family history, and a meticulous review of systems.[4]

Ocular symptoms vary, but nonspecific foreign body sensation with or without eye pain, tearing, photophobia, and reduced visual acuity are the most common symptoms for patients with PUK.

Loss of vision can occur quickly when PUK progresses.

PUK associated with RA, GPA, PAN, and RP is often linked with scleritis, and eye pain may be pronounced in these individuals.[4] PUK in patients with Mooren ulcer may also produce pain, although there is no scleral involvement.

Past medical history and review of systems helps to determine the possible underlying systemic diseases. RA, SLE, PAN, GPA, or RP may present with the following symptoms, which should be emphasized in the review of systems[12] :

  • General - Constitutional symptoms, such as chills, fever, poor appetite, recent weight loss, and fatigue
  • Skin - Rashes, nodules, vesicles, ulcer, nail changes, and periungual infarcts
  • Respiratory - Coughing, wheezing, pneumonia, and shortness of breath
  • Cardiac - Chest pain or discomfort and dyspnea
  • Gastrointestinal - Abdominal pain, nausea, vomiting, difficulty swallowing, and diarrhea
  • Musculoskeletal - Muscle or joint pain, arthritis, back pain, and limitation of motion
  • Neurologic - Headaches, seizures, psychiatric, paralysis, and numbness/tingling
  • Other systemic symptoms - Deafness, swollen ear lobes, ear infections, vertigo, and noises in ears (suggestive of RP)

Physical

Examination should be complete and include an overview of the head (including the nose, mouth, and external ear), trunk, joints, and extremities.[4] Skin lesions should also be noted.

A complete ophthalmic examination should be performed with special emphasis on the conjunctiva, sclera, and cornea. Anterior chamber, vitreous, and fundus examinations are also important.

Patients with PUK typically present with decreased visual acuity (secondary to induced irregular astigmatism), tearing, and eye irritation with or without pain of variable duration.[5]

Bilateral disease may be present in 21% of patients.[13]

Slit lamp examination reveals a crescent-shaped destructive lesion of the juxtalimbal corneal stroma associated with an epithelial defect, stromal yellow-white infiltrates composed of inflammatory cells, and varying degrees of corneal stromal thinning (minimal to full thickness) adjacent to the limbus.[6]

In severe cases, the peripheral cornea is progressively destroyed circumferentially, and the central corneal is also damaged.

PUK accompanied by necrotizing scleritis almost always indicates the presence of a potentially lethal systemic disease.[4]

The anterior chamber should be evaluated for depth and inflammation.

A posterior segment examination is typically indicated to help determine the underlying etiology.

Causes

The etiologies for developing peripheral ulcerative keratitis (PUK) are multiple and extensive. Connective tissue and vasculitic diseases are the major risk factors. Other disorders that can cause PUK include systemic and local infectious conditions, as well as local degenerative disorders. Although vitamin A deficiency is commonly associated with central corneal ulceration, it has also been reported to cause peripheral ulceration with or without bacterial infection of the ulcer.[14, 15]

The differential diagnosis of PUK is outlined below.[4]

  • Noninfectious conditions

    • Systemic - RA, SLE, RP, sarcoidosis, progressive systemic sclerosis, rosacea, GPA, PAN, juvenile idiopathic arthritis,[16] giant cell arteritis, Behçet disease,[17] inflammatory bowel disease, pyoderma gangrenosum,[18] metabolic conditions, nutritional deficiencies, and drug-induced side effect (checkpoint inhibitor ipilimumab)[19]

    • Local - Mooren ulcer, marginal keratitis, blepharitis (eg, staphylococcal infection, rosacea), contact lens use, chemical injury to the eyes,[20] trauma, neurotrophic and neuroparalytic causes, keratoconjunctivitis sicca, Terrien marginal degeneration, pellucid marginal degeneration, and furrow degeneration[5]

    • Surgery - Trabeculectomy,[21] cataract surgery[22]

  • Infectious conditions

    • Systemic -Shigella species, tuberculosis, syphilis, hepatitis, HIV, gonococcus, Salmonella species, and bacillary dysentery

    • Local - Herpes simplex keratitis, varicella-zoster keratitis, bacterial keratitis, fungal keratitis, and Acanthamoeba species

  • Masquerade - Malignancy - Leukemia[23, 24]

 

DDx

 

Workup

Laboratory Studies

Laboratory tests used to evaluate peripheral ulcerative keratitis (PUK) should focus on the suspected systemic disease, as follows:[4]

  • Complete blood cell (CBC) count
  • Urinalysis (UA), blood urea nitrogen (BUN), and creatinine
  • Erythrocyte sedimentation rate (ESR)
  • Rheumatoid factor (RF); positive in 80% of patients with associated RA [4, 25]
  • Angiotensin-converting enzyme (ACE); elevated in sarcoidosis
  • Antinuclear antibodies (ANA); positive in patients with SLE and RA
  • Antibody to double-stranded DNA (anti-dsDNA); associated with SLE
  • Antibodies to small nuclear ribonucleoprotein-Sm (anti-Sm); associated with SLE
  • Antibodies to small nuclear ribonucleoproteins-RNP (anti-RNP); associated with SLE
  • Antineutrophil cytoplasmic antibodies (ANCA); C-ANCA sensitivity of 96% for active generalized GPA, 67% for active regional disease, and 32% for GPA in full remission after initial regional symptoms [4, 6, 26, 27, 28]
  • Circulating immune complex (CIC) - Raji cell assay; C-1q binding assay
  • Anti-type II antibodies; associated with RP
  • Complement - C3 and C4, CH50; consumed in patients with SLE
  • Hepatitis B surface antigen (HBsAg); present in 40% of patients with PAN
  • Fluorescent treponemal antibody-absorption (FTA-ABS) for syphilis

Imaging Studies

Local

Anterior-segment optical coherence tomography (OCT) may be used to document baseline corneal thickness and to monitor for progressive thinning.[29]

Systemic

Chest radiography and sinus CT scanning may be used to rule out GPA, sarcoidosis, and tuberculosis.

Radiography of affected joints may be performed.

Procedures

Scraping and culture of the ulcer are recommended.

Conjunctival resection/biopsy may be helpful in removing the limbal source of collagenases and other factors causing progressive ulceration.

Histologic Findings

In Mooren ulcer, corneal thickening occurs at the margin of the ulcer where inflammatory cells have invaded the anterior stromal layers. However, the inflammation is nonspecific, and no etiologic agent can be identified. Necrosis of the involved epithelium and stroma is seen. PUK associated with connective tissue disease and PUK associated with mild infections sometimes may appear similarly. Signs of vasculitis in the adjacent conjunctiva may be seen.[30]

 

Treatment

Medical Care

Local treatment of peripheral ulcerative keratitis (PUK) is aimed at preventing or reducing corneal damage. Systemic therapy is aimed at controlling the underlying disease. A goal is reepithelialization of the epithelial defect to halt progressive corneal ulceration.

Surgical care may be combined with adjunctive local therapy with topical 1% medroxyprogesterone (which inhibits collagenase synthesis) or topical 20% N -acetylcysteine (a competitive inhibitor of collagenase). Lubricating drops, gels, and ointments and antibiotic drops or ointments can be helpful in aiding reepithelialization.

Topical steroid use is not recommended and should be used with caution in the treatment of patients with PUK associated with systemic disease because it may aggravate corneal melt due to collagen synthesis inhibition. However, some physicians would recommend its use only if the extent of corneal involvement is less than two quadrants and/or if stromal thickness is more than 50%.[31]

Systemic collagenase inhibitors (tetracycline 250-mg tab qid or doxycycline 100-mg tab bid) may help slow the progression.

Some physicians recommend oral vitamin C given at 500 mg four times a day to facilitate corneal healing.[31]

There is limited experience in the use of topical cyclosporine[32] and topical tacrolimus.[33] Topical cyclosporine combined with lamellar keratoplasty (see Surgical Care) was noted to improve the healing rate in Mooren ulcer.[34] However, an underlying systemic vasculitis is not addressed with this route of treatment.

Many studies have documented that patients with PUK who have associated systemic diseases have recurrences following localized temporizing treatment unless they are given adequate systemic immunosuppressive therapy. To address the underlying problem, both systemic steroid and cytotoxic immunosuppressive medications have been used, alone or in combination, and are effective at controlling ocular and systemic inflammation. Immunosuppressive agents have been indicated for management of the following:

  • PUK associated with potentially lethal systemic vasculitic syndromes, such as PAN, RA, SLE, RP, GPA, PSS, Sjögren syndrome, allergic angiitis of Churg-Strauss, and giant cell arteritis
  • PUK associated with necrotizing scleritis with vasculitis based on histopathologic analysis
  • Bilateral and/or progressive Mooren ulcer
  • PUK unresponsive to aggressive conventional medical and surgical therapy

Cyclophosphamide is the drug of choice for almost all PUK associated with a connective tissue disorder. The intravenous route has been used with success in PUK associated with rheumatoid arthritis.[35] Methotrexate (MTX), azathioprine, cyclosporine A, and chlorambucil have been found to be effective.[8] High-dose oral prednisone may be started, while the chemotherapeutic agents take effect after 4-6 weeks. When local or systemic infectious causes are suspected, therapy must be aimed at eliminating the infectious organism using the appropriate antibiotic medications based on clinical presentation or culture.

The use of the tumor necrosis factor alpha (TNF-alpha) antagonist infliximab has been reported to be effective in rheumatoid arthritis-associated PUK cases refractory to the above conventional immunomodulatory therapy.[36, 37] For its use in treating PUK in Crohn disease, see Pham et al.[38] . Adalimumab, a human monoclonal antibody against tumor necrosis factor, has been used with success in combination with other immunosuppressives to treat RA-associated PUK.[39]

Rituximab, a chimeric monoclonal antibody directed against the CD20 protein found in B cells, has been used in treatment-resistant PUK in GPA[40] and RA[41] , and was noted to have the highest success rate in achieving steroid-free remission in GPA-associated PUK.[42]

Surgical Care

Tissue adhesives, such as cyanoacrylate glue, are recommended for use in impending perforation and perforation size smaller than 1-2 mm.[6] Adhesive application follows keratectomy and conjunctival resection to remove sources of collagenase, cytokines, and inflammatory cells from the ulcerated cornea, temporarily preventing further stromal loss.

Peripheral ulcerative keratitis in the right eye o Peripheral ulcerative keratitis in the right eye of a patient with rheumatoid arthritis. Cyanoacrylate glue has been placed.

Application of a bandage contact lens prevents discomfort and dislodging of the adhesive.[6]

Amniotic membrane transplantation has been used in the management of Mooren ulcer.[43] Amniotic membranes have properties that promote rapid healing and reduce inflammation by sequestering inflammatory cells infiltrating the ocular surface.[44, 45] However, they may have a limited role in treating eyes with severe ischemia (eg, rheumatoid arthritis).[46] .

In severe cases of peripheral ulcerative keratitis (PUK) associated with membranous endothelial exudation, anterior chamber washout may be combined with amniotic membrane transplantation.[47]

Tectonic procedures, including lamellar keratoplasty, penetrating keratoplasty, and corneoscleral patch grafts, are performed as needed to maintain the integrity of the globe when corneoscleral perforation is imminent or has occurred.

The corneoscleral rim of donor grafts have been used in partial lamellar keratoplasty and may be an alternative in areas where donor corneas are scarce.[48]

Visual results of corneal transplantation may be disappointing. However, corneal clarity may be maintained with good visual outcomes when accompanied by aggressive systemic anti-inflammatory therapy in selected patients.[13]

Consultations

Referral to an appropriate specialist may be necessary. In patients with connective tissue diseases, comanagement with a rheumatologist is necessary to address the systemic disease. Pulmonary, nephrology, cardiac, hematology, and infectious disease consults may be necessary depending on the patient's symptoms and laboratory findings. Regular consultation with an oncologist may be necessary for those patients who are receiving chemotherapy.

Activity

Decreased visual acuity and systemic disorders may be limiting factors.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Systemic corticosteroids

Class Summary

Have both anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Meticorten)

A synthetic glucocorticoid steroid with nonspecific anti-inflammatory and immunosuppressive effects.

Immunosuppressant agents

Class Summary

Inhibit key factors that mediate immune response.

Tacrolimus ointment (Protopic)

Macrolide antibiotic that shares many pharmacologic properties with cyclosporine, and is similar in effects but does not produce cytotoxicity. Tacrolimus suppresses cell-mediated immunity by inhibiting DNA translation of specific lymphokines and the expression of the interleukin-2 receptor on activated T cells.

Methotrexate (Folex PFS, Rheumatrex)

A folic acid analog. Acts on the enzyme dihydrofolate reductase, which catalyses the reduction of folate to tetrahydrofolate, a compound necessary for DNA synthesis. Actively replicating cells, such as the leukocyte, are affected and their functions suppressed.

Azathioprine (Imuran)

A purine nucleoside analog that is activated in the liver producing metabolites, which interfere with purine metabolism. T- and B-cell functions are suppressed.

Cyclosporin A (Sandimmune, Neoral, SangCyA)

An 11-amino acid cyclic peptide and a natural product of fungi. Cyclosporine acts on T-cell replication and activity.

Cyclophosphamide (Cytoxan)

Nitrogen mustard derivative, which affects cell replication by alkylating purines in DNA and RNA.

Chlorambucil (Leukeran)

Slow-acting nitrogen mustard derivative, which interferes with DNA replication, transcription, and nucleic acid function by alkylation.

Disease modifying agents

Class Summary

These agents alter the immune response to diverse stimuli.

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-α and inhibits its binding to TNF-α receptor. Reduces infiltration of inflammatory cells and TNF-α production in inflamed areas. Used with methotrexate in patients who have had inadequate response to methotrexate monotherapy.

Rituximab (Rituxan)

It is a chimeric monoclonal antibody directed against the CD20 protein, which is found primarily on the surface of B cells.

Adalimumab (Humira)

A human monoclonal antibody against tumour necrosis factor (TNF).

 

Follow-up

Further Outpatient Care

Continued, possibly lifelong, follow-up care of peripheral ulcerative keratitis (PUK) is necessary even after complete resolution since relapses may occur. Furthermore, many patients may require prolonged systemic steroid, nonsteroidal anti-inflammatory, and/or chemotherapeutic medications for the systemic disease despite a quiet eye.

Same patient as in previous image, 1 year posttrea Same patient as in previous image, 1 year posttreatment.

Complications

Ocular complications include corneal scarring and neovascularization with irregular astigmatism, corneal thinning and perforation, loss of vision, and even blindness.

Left eye of same patient as in previous images. No Left eye of same patient as in previous images. Note the corneal thinning and scarring.

Prognosis

In patients with collagen vascular diseases, peripheral ulcerative keratitis (PUK) with necrotizing scleritis is associated with poor life expectancy because of the presence of subclinical systemic vasculitis.

Patient Education

Inform patients about both ocular and systemic components of the disease, treatment options, and possible complications. Emphasize lifelong follow-up care.

For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education article Corneal Ulcer.

 

Questions & Answers

Overview

What is peripheral ulcerative keratitis (PUK)?

What is the pathophysiology of peripheral ulcerative keratitis (PUK)?

What is the prevalence of peripheral ulcerative keratitis (PUK) in the US?

What is the morbidity associated with peripheral ulcerative keratitis (PUK)?

What are the racial predilections of peripheral ulcerative keratitis (PUK)?

What are the sexual predilections of peripheral ulcerative keratitis (PUK)?

Which age groups have the highest prevalence of peripheral ulcerative keratitis (PUK)?

Presentation

Which clinical history findings are characteristic of peripheral ulcerative keratitis (PUK)?

What are the symptoms of underlying systemic disease in peripheral ulcerative keratitis (PUK)?

Which physical findings are characteristic of peripheral ulcerative keratitis (PUK)?

What causes peripheral ulcerative keratitis (PUK)?

Which conditions are included in the differential diagnoses of peripheral ulcerative keratitis (PUK)?

DDX

What are the differential diagnoses for Peripheral Ulcerative Keratitis?

Workup

What is the role of lab tests in the workup of peripheral ulcerative keratitis (PUK)?

What is the role of imaging studies in the workup of peripheral ulcerative keratitis (PUK)?

What is the role of biopsy in the workup of peripheral ulcerative keratitis (PUK)?

Which histologic findings are characteristic of peripheral ulcerative keratitis (PUK)?

Treatment

How is peripheral ulcerative keratitis (PUK) treated?

What is the role of immunosuppressive drugs in the treatment of peripheral ulcerative keratitis (PUK)?

What is the role of cyclophosphamide in the treatment of peripheral ulcerative keratitis (PUK)?

What is the role of infliximab in the treatment of peripheral ulcerative keratitis (PUK)?

What is the role of rituximab in the treatment of peripheral ulcerative keratitis (PUK)?

What is the role of surgery in the treatment of peripheral ulcerative keratitis (PUK)?

Which specialist consultations are beneficial to patients with peripheral ulcerative keratitis (PUK)?

Medications

What are the goals of drug treatment for peripheral ulcerative keratitis (PUK)?

Which medications in the drug class Disease modifying agents are used in the treatment of Peripheral Ulcerative Keratitis?

Which medications in the drug class Immunosuppressant agents are used in the treatment of Peripheral Ulcerative Keratitis?

Which medications in the drug class Systemic corticosteroids are used in the treatment of Peripheral Ulcerative Keratitis?

Follow-up

What is included in the long-term monitoring of peripheral ulcerative keratitis (PUK)?

What are the possible complications of peripheral ulcerative keratitis (PUK)?

What is the prognosis of peripheral ulcerative keratitis (PUK)?

What is included in patient education about peripheral ulcerative keratitis (PUK)?