eMedicine Specialties > Ophthalmology > Cornea
Peripheral Ulcerative Keratitis: Treatment & Medication
Updated: Dec 8, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Local treatment 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 in the treatment of patients with PUK associated with systemic disease because it may aggravate corneal melt due to collagen synthesis inhibition.
- Systemic collagenase inhibitors (tetracycline 250-mg tab qid or doxycycline 100-mg tab bid) may help slow the progression.
- There is limited experience in the use of topical cyclosporine19 and topical tacrolimus.20 Topical cyclosporine combined with lamellar keratoplasty (see Surgical Care) was noted to improve the healing rate in Mooren ulcer.21 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, WG, 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.22 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.23,24
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.
- 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.25 Amniotic membranes have properties that promote rapid healing and reduce ocular surface inflammation.26 However, they may have a limited role in treating eyes with severe ischemia (eg, rheumatoid arthritis).27
- 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.
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
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Systemic corticosteroids
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.
Adult
1 mg/kg/d PO initially; not to exceed 60-80 mg/d; adjust dose based on clinical response and adverse effects
Pediatric
Not established
Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; long-term systemic steroids can cause glaucoma and cataracts
Immunosuppressant agents
Inhibit key factors that mediate immune response.
Tacrolimus (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.
Adult
Apply 0.02% ointment qd/qid
Pediatric
None reported
For systemic administration, drugs that affect cytochrome P-450 (verapamil, diltiazem, ketoconazole, fluconazole, itraconazole, danazol, bromocriptine, metoclopramide, erythromycin, methylprednisolone, rifampin, phenytoin, phenobarbital, carbamazepine); synergistic nephrotoxicity with aminoglycosides, amphotericin B, ketoconazole, vancomycin, melphalan, cimetidine, ranitidine, trimethoprim/sulfamethoxazole, ciprofloxacin, and NSAIDs
For systemic administration, known hypersensitivity; uncontrolled systemic hypertension, hepatic and renal disease, pregnancy
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
For systemic administration, uncontrolled systemic hypertension, hepatic and renal disease; caution in mothers who are breastfeeding
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.
Adult
7.5-12.5 mg/wk PO/IM/SC single dose initially; not to exceed 40 mg/wk; adjust dose based on clinical response and adverse effects
Pediatric
Not established
Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase MTX plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines
Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Monitor CBCs monthly; monitor liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occur; fatal reactions reported when administered concurrently with NSAIDs
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.
Adult
1-3 mg/kg/d PO initially; adjust dose based on clinical response and adverse effects
Pediatric
Not established
Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of MTX metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Documented hypersensitivity; low levels of serum TPMT
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy; monitor liver, renal, and hematologic function; pancreatitis rarely associated
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.
Adult
2.5-5 mg/kg/d PO divided bid initially; not to exceed 10 mg/kg/d; adjust dose based on clinical response and adverse effects
Pediatric
Not established
Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UV-B radiation in psoriasis since it may increase risk of cancer
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO
Cyclophosphamide (Cytoxan)
Nitrogen mustard derivative, which affects cell replication by alkylating purines in DNA and RNA.
Adult
Initial dose is 2 mg/kg/d PO; not to exceed 3 mg/kg/d; adjust dose based on clinical response and adverse effects
Pediatric
Not established
Long-term treatment with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; may potentiate effects of succinyl chloride
Documented hypersensitivity; breastfeeding; immunosuppression; leukopenia or thrombocytopenia
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Bone marrow depression may occur requiring regular blood count monitoring; long-term oral therapy may lead to myelodysplasia; hemorrhagic cystitis is uncommon, but advise all patients to increase fluid intake; monitoring with urinalysis may help by early detection of microscopic hematuria; malignancy, ovarian suppression, testicular atrophy, azoospermia, alopecia, nausea, vomiting, and lymphopenia with resultant opportunistic infections may occur
Chlorambucil (Leukeran)
Slow-acting nitrogen mustard derivative, which interferes with DNA replication, transcription, and nucleic acid function by alkylation.
Adult
0.1 mg/kg/d PO initially; not to exceed 0.2 mg/kg/d; adjust dose based on clinical response and adverse effects
Pediatric
Not established
None reported
Documented hypersensitivity; previous resistance to medication
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Teratogenic and should be avoided in pregnant women; bone marrow suppression is reversible and may be avoided by routine blood count monitoring; opportunistic infections, nausea, sterility, and amenorrhea may occur; some studies have shown a dose-related increased risk of developing myeloproliferative malignancies later in life
Disease modifying agents
These agents alter the immune response to diverse stimuli.
Infliximab (Remicade)
Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-a and inhibits its binding to TNF-a receptor. Reduces infiltration of inflammatory cells and TNF-a production in inflamed areas. Used with methotrexate in patients who have had inadequate response to methotrexate monotherapy.
Adult
Follow guideline for treatment of rheumatoid arthritis: 3 mg/kg IV single dose, follow by additional 3 mg/kg at 2 and 6 wk after first dose; repeat q8wk thereafter
Pediatric
Not established
None reported
Documented hypersensitivity; infections; congestive heart failure
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
TNF alpha modulates cellular immune responses; anti-TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; more cases of lymphoma were observed in TNF alpha-blockers compared to controlled groups; may increase risk of reactivation of tuberculosis in patients with particular granulomatous infections
More on Peripheral Ulcerative Keratitis |
| Overview: Peripheral Ulcerative Keratitis |
| Differential Diagnoses & Workup: Peripheral Ulcerative Keratitis |
 Treatment & Medication: Peripheral Ulcerative Keratitis |
| Follow-up: Peripheral Ulcerative Keratitis |
| Multimedia: Peripheral Ulcerative Keratitis |
| References |
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References
Mondino BJ. Inflammatory diseases of the peripheral cornea. Ophthalmology. Apr 1988;95(4):463-72. [Medline].
Shiuey Y, Foster CS. Peripheral ulcerative keratitis and collagen vascular disease. Int Ophthalmol Clin. Winter 1998;38(1):21-32. [Medline].
Messmer EM, Foster CS. Vasculitic peripheral ulcerative keratitis. Surv Ophthalmol. Mar-Apr 1999;43(5):379-96. [Medline].
Foster CS, Sainz de la Maza M. Immunological considerations of the sclera. In: Foster CS, ed. The Sclera. ed. New York: Springer-Verlag; 1993:33-58.
Gregory JK, Foster CS. Peripheral ulcerative keratitis in the collagen vascular diseases. Int Ophthalmol Clin. Winter 1996;36(1):21-30. [Medline].
Eiferman RA, Carothers DJ, Yankeelov JA Jr. Peripheral rheumatoid ulceration and evidence for conjunctival collagenase production. Am J Ophthalmol. May 1979;87(5):703-9. [Medline].
Brown SI, Grayson M. Marginal furrows. A characteristic corneal lesion of rheumatoid arthritis. Arch Ophthalmol. May 1968;79(5):563-7. [Medline].
Tauber J, Sainz de la Maza M, Hoang-Xuan T, et al. An analysis of therapeutic decision making regarding immunosuppressive chemotherapy for peripheral ulcerative keratitis. Cornea. Jan 1990;9(1):66-73. [Medline].
Hoang-Xaun T, Foster CS, Rice BA. Scleritis in relapsing polychondritis. Response to therapy. Ophthalmology. Jul 1990;97(7):892-8. [Medline].
Watson PG, Hazelman BC. The Sclera and Systemic Disorders. Philadelphia: WB Saunders Co; 1976:241.
Sangwan VS, Zafirakis P, Foster CS. Mooren's ulcer: current concepts in management. Indian J Ophthalmol. Mar 1997;45(1):7-17. [Medline].
Tabbara KF. Mooren's ulcer. Int Ophthalmol Clin. Winter 1986;26(4):91-8. [Medline].
Chawla B, Agarwal P, Tandon R, et al. Peripheral ulcerative keratitis with bilateral optic nerve involvement as an initial presentation of acute lymphocytic leukemia in an adult. Int Ophthalmol. Nov 16 2007;[Medline].
Carson DA. Rheumatoid factor. In: Kelley WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of Rheumatology. 3rd ed. Philadelphia: WB Saunders Co; 1989:664-679.
Lüdemann G, Gross WL. Autoantibodies against cytoplasmic structures of neutrophil granulocytes in Wegener's granulomatosis. Clin Exp Immunol. Aug 1987;69(2):350-7. [Medline].
Savage CO, Winearls CG, Jones S, et al. Prospective study of radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet. Jun 20 1987;1(8547):1389-93. [Medline].
Nolle B, Specks U, Ludemann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med. Jul 1 1989;111(1):28-40. [Medline].
Squirrell DM, Winfield J, Amos RS. Peripheral ulcerative keratitis 'corneal melt' and rheumatoid arthritis: a case series. Rheumatology (Oxford). Dec 1999;38(12):1245-8. [Medline].
Liegner JT, Yee RW, Wild JH. Topical cyclosporine therapy for ulcerative keratitis associated with rheumatoid arthritis. Am J Ophthalmol. May 15 1990;109(5):610-2. [Medline].
Miyazaki D, Tominaga T, Kakimaru-Hasegawa A, et al. Therapeutic effects of tacrolimus ointment for refractory ocular surface inflammatory diseases. Ophthalmology. Jun 2008;115(6):988-992.e5. [Medline].
Chen J, Xie H, Wang Z, et al. Mooren's ulcer in China: a study of clinical characteristics and treatment. Br J Ophthalmol. Nov 2000;84(11):1244-9. [Medline].
Clewes AR, Dawson JK, Kaye S, et al. Peripheral ulcerative keratitis in rheumatoid arthritis: successful use of intravenous cyclophosphamide and comparison of clinical and serological characteristics. Ann Rheum Dis. Jun 2005;64(6):961-2. [Medline].
Thomas JW, Pflugfelder SC. Therapy of progressive rheumatoid arthritis-associated corneal ulceration with infliximab. Cornea. Aug 2005;24(6):742-4. [Medline].
Atchia II, Kidd CE, Bell RW. Rheumatoid arthritis-associated necrotizing scleritis and peripheral ulcerative keratitis treated successfully with infliximab. J Clin Rheumatol. Dec 2006;12(6):291-3. [Medline].
Lambiase A, Sacchetti M, Sgrulletta R, et al. Amniotic membrane transplantation associated with conjunctival peritomy in the management of Mooren's ulcer: a case report. Eur J Ophthalmol. Mar-Apr 2005;15(2):274-6. [Medline].
Prabhasawat P, Tesavibul N, Komolsuradej W. Single and multilayer amniotic membrane transplantation for persistent corneal epithelial defect with and without stromal thinning and perforation. Br J Ophthalmol. Dec 2001;85(12):1455-63. [Medline].
Tseng SC. Amniotic membrane transplantation for persistent corneal epithelial defect. Br J Ophthalmol. Dec 2001;85(12):1400-1. [Medline].
Bullen CL, Liesegang TJ, McDonald TJ, et al. Ocular complications of Wegener's granulomatosis. Ophthalmology. Mar 1983;90(3):279-90. [Medline].
Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosuppression. Ophthalmology. Oct 1984;91(10):1253-63. [Medline].
Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. Oct 2000;130(4):492-513. [Medline].
Robin JB, Schanzlin DJ, Verity SM, et al. Peripheral corneal disorders. Surv Ophthalmol. Jul-Aug 1986;31(1):1-36. [Medline].
Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol. Mar 1976;60(3):163-91. [Medline].
Further Reading
Keywords
peripheral ulcerative keratitis, peripheral corneal ulceration, PUK, marginal corneal ulcer, corneal stroma, corneal perforation, rheumatoid arthritis, RA, vision loss, blindness
