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Aspirin Therapy in Vernal Conjunctivitis
ASPIRIN THERAPY IN VERNAL CONJUNCTIVITIS M A R K B. A B E L S O N , M D . , S A L I M I. B U T R U S , AND J U D I T H H . W E S T O N , B.A.
M.D.,
Boston, Massachusetts
Prostaglandin D2 is a secondary mast cell mediator that causes redness, chemosis, mucous discharge, and eosinophil chemotaxis in the eye. It may play an important role in allergic ocular disease. Although histamine is a key mediator of allergic inflammation, antihistamine therapy provides only symptomatic relief. We added aspirin therapy to the treatment regimen of three patients with vernal conjunctivitis. Aspirin acetylates the enzyme cyclooxygenase, thereby preventing the formation of prostaglandin D 2 . Within two weeks after initiation of aspirin therapy, we noted dramatic improvement in conjunctival and episcleral redness and resolution of keratitis and limbal infiltration. We recommend a trial of oral aspirin as adjunctive therapy for intractable cases of vernal conjunctivitis. Vernal conjunctivitis is an allergic con dition characterized by severe itching, redness, tenacious mucous discharge, and photophobia. Cobblestone appear ance of the upper tarsus, shield-shaped corneal ulcération, punctate keratitis, and limbal infiltration often develop in this condition. In vernal conjunctivitis, conjunctival mast cells are more superficially located than in normal control tissue, 1 and the percentage of degranulated conjunctival mast cells is increased over normal con trols. 2 Degranulation is followed by eo sinophil accumulation in the deep tissue, presumably in response to the release of eosinophil chemotactic factors. 3 EosinoAccepted for publication Jan. 20, 1983. From the Department of Ophthalmology, Harvard Medical School, and the Cornea Service, Massachu setts Eye and Ear Infirmary (Drs. Abelson and Butrus); and the Department of Cornea Research, Eye Research Institute of Retina Foundation (Drs. Abelson and Butrus and Ms. Weston), Boston, Mas sachusetts. This work was supported in part by CooperVision Pharmaceuticals Inc., and the Massa chusetts Lions Eye Research Fund, Inc. Reprint requests to Mark B. Abelson, M.D., Eye Research Institute, 20 Staniford St., Boston, MA 02114. 502
phils may not always be recovered in conjunctival scrapings, although they are present in deeper biopsy specimens. 3,4 The tears of patients with vernal conjunc tivitis contain increased levels of hista mine, 5 eosinophil granule major basic protein, 6 and prostaglandin F. 7 Mastocytosis is a disorder character ized by the abnormal proliferation of tis sue mast cells. Serum levels of histamine and prostaglandin D2 are increased in affected patients. 8 Antihistamine therapy alone is insufficient; however, the addi tion of aspirin, an inhibitor of prostaglan din biosynthesis, to the treatment regi men of a patient with mastocytosis prevented attacks of flushing and hypo tension. 8 The role of prostaglandin D2 in inflam mation has been appreciated only recent ly. It is the major prostaglandin produced by the mast cell.9' 11 Prostaglandin D2 is a product of the cyclo-oxygenase pathway of the arachidonic acid cascade (Figure). Bhattacherjee, Kulkarni, and Eakins 12 showed that rabbit ocular tissues, such as the iris-ciliary body and conjunctiva, syn thesize all cyclo-oxygenase products. We have previously shown that topical appli-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 95:502-505, 1983
VOL. 95, NO. 4
VERNAL CONJUNCTIVITIS
cation of prostaglandin D2 to the eye produces dilation of the conjunctival, episcleral, perilimbal, and deep scierai ves sels, and stringy mucous discharge.13 Topical histamine, however, induces itching and a more superficial pattern of vasodilation. Current therapy of allergic ocular dis ease does not include antagonists of pros taglandin biosynthesis. Since the pathophysiology of both mastocytosis and vernal conjunctivitis involves mast cell abnormalities and aspirin therapy is ben eficial in mastocytosis, we evaluated the effectiveness of aspirin therapy in three patients with vernal conjunctivitis. CASE REPORTS Case 1—A 17-year-old girl, first examined on Oct. 10, 1980, had had conjunctival vasodilation, itching, burning, and mild photophobia for seven years; her symptoms were continuous and showed no seasonal variation. There was no family history of asthma, allergic rhinitis, eczema, or ocular allergy. Corrected visual acuity in both eyes was 20/20. The eyelids of both eyes showed evidence of neurodermatitis. Both eyes had giant papillary hypertro phy of the upper tarsal conjunctiva, an elevated and engorged corneoscleral limbus with several Trantas dots, a 360-degree peripheral corneal pannus, and inferior superficial punctate keratopathy. Conjunctival scrapings of both eyes contained an average of three eosinophils per high-power field. A biopsy specimen of the corneoscleral limbus dis closed many eosinophils in the epithelium and sub stantia propria, plasma cells, and lymphocytes. Treatment with topical prednisone 1% and antihis tamines resulted in marked improvement for two months. Then this therapy was discontinued and oral theophylline (300 mg three times a day), cromolyn sodium 4% (four times a day), and vasoconstrictors were tried, but only minimal improvement was noted. By January 1982, the patient's condition had stabi lized and all medication except cromolyn sodium was reduced and then discontinued. A flare-up two months later necessitated the addition of topical prednisone 1% to the regimen. Improvement was negligible. On April 16, 1982, oral aspirin (325 mg every two hours) was initiated. Within two weeks, there was dramatic improvement. Conjunctival red ness, itching and burning, and limbal infiltrates decreased markedly and the peripheral corneal ves sels constricted. Case 2—On Aug. 22, 1979, a 9-year-old boy com plained of blurred vision in his left eye. He had a three-year history of bilateral conjunctival redness
503
and itching with flare-ups during spring and summer. There was no family history of asthma or other allergic conditions. Visual acuity was R.E.: 20/20 and L.E.: 20/80. Examination showed mild papillary hypertrophy of the upper tarsal conjunctivas and superficial punctate staining inferiorly in both corneas, with a small inferior epithelial defect in the left cornea. The patient was fitted with a therapeutic bandage lens in his left eye and treated topically with chloramphenicol (four times a day) and a vasoconstrictor. Corneal stability was maintained for eight months; this was followed by the development of a shield-shaped ulcer in the left cornea. After treatment with medrysone 1% (every hour initially with the dosage gradually reduced to four times a day), cromolyn sodium 4%, antihistamines, and vasoconstrictors, the ulcer healed, but the redness, photophobia, and irritation persisted for four months. At that time, we added oral aspirin (81 mg every three hours). Within one week, conjunctival redness and itching decreased greatly. Case 3—A 13-year-old boy, referred to us on May 12, 1978, complained of itching, irritation, mucous discharge, and blurred vision in both eyes. His symptoms were seasonal, worsening during the warmer months. He had a history of asthma, eczema, hay fever, and allergy to dogs. Our initial examina tion disclosed cobblestone excrescences of the upper tarsal conjunctiva, Trantas dots at the corneoscleral limbus, and epithelial defects in both eyes. Correct ed visual acuity was 20/40 in both eyes. Periodic examination during the next four years showed cobblestone hypertrophy, limbal phlyctenules, and corneal epithelial defects with anterior stromal haze. Symptoms were controlled with theo phylline (300 mg three times a day) and prednisolone (up to 1% four times a day), but complete resolution never occurred; a maintenance dosage of corticosteroids was required. During remissions the lesions resolved and corrected visual acuity improved to 20/30 in both eyes. On April 23, 1982, the patient complained of conjunctival redness, itching, ocular irritation, and mucous discharge. Examination disclosed Trantas dots at the corneoscleral limbus, dilation of peripher al corneal vessels, and 4+ cobblestone response of the upper tarsal plate. The patient's medication at that time included an antihistamine/vasoconstrictor, erythromycin ointment, and dexamethasone 0.1%. The patient had previously been unresponsive to cromolyn sodium therapy. Therapy was supple mented with aspirin (650 mg three times a day). Within two days there was a noticeable decrease in conjunctival redness and discomfort and resolution of the limbal infiltration. However, gastritis developed, necessitating discontinuation of aspirin treatment and reinstitution of corticosteroid therapy. DISCUSSION
In 1971, Vane14 discovered that aspirin and other noncorticosteroidal anti-in-
504
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL, 1983
| Membrane phospholipids | Corticosteroids ι
Phospholipase
Arachidonic acid Aspirin (NSAIA) ,
Cyclo-oxygenase
Cyclic endoperoxides Prostaglandin Gg-^-Prostaglandin H2 Prostaglandin synthetase
c hydrolysis MDA, HHTJ mboxane synthetase
somerase
|Prostaglandin I2
Redu
iThromboxane A?l jProstaglandin F2d|
I Prostaglandin E2 | P r o s t a g l a n d i n D2
Figure (Abelson, Butrus, and Western). Cyclo-oxygenase pathway of arachidonic acid metabolism showing inhibition sites of corticosteroids and aspirin. Asterisk, noncorticosteroidal anti-inflammatory agent; MDA, malondialdehyde; HHT, heptadecatrienoic acid.
flammatory agents inhibit prostaglandin biosynthesis. Aspirin acetylates the active site of the enzyme cyclo-oxy genase, thereby preventing the genera tion of cyclic endoperoxides 15,16 (Figure). The systemic effect of prostaglandin syn thetase inhibitors has been demonstrated in vitro by using isolated cells such as human platelets, 17 epidermal cells, 18 dog spleen, 19 isolated gastrointestinal tissue, 20 and human rheumatoid synovium, 21,22 and in vivo in patients with mastocytosis. 8 Topical application of prostaglandin D2, the mast cell's most prevalent prosta glandin,9"11 produces mild conjunctival in jection, chemosis, and tearing in guinea pig eyes, 13 and dose-dependent vasodilation, chemosis, and mucous discharge in human eyes. 13 Topical application of ara chidonic acid, a precursor of prostaglan din D2, produces conjunctival redness and chemosis in rabbits. 23,24 Although histamine contributes to the conjunctival vasodilation and itching associated with vernal conjunctivitis, antihistamine ther apy provides only symptomatic relief and does not alter the underlying disease process. Corticosteroid treatment is ef fective, but the risks of long-term use— local immunosuppression, glaucoma, and
cataract formation—must be balanced against the need for such potent drugs. Cromolyn sodium, an inhibitor of mast cell degranulation, has been used suc cessfully to treat some cases of vernal and nonvernal ocular allergy,20,26 but some pa tients do not respond to cromolyn thera py. Thus far, no single drug has proven safe and effective for the treatment of vernal conjunctivitis. The increased percentage of degranulated mast cells found in patients with vernal conjunctivitis may be related to an overabundance of prostaglandin D2. To our knowledge, there are no agents avail able that selectively inhibit prostaglandin D 2 . Aspirin prevents the synthesis of prostaglandins by blocking the cyclooxygenase pathway. The addition of aspi rin to the treatment regimen of three patients with intractable vernal conjunc tivitis produced dramatic improvement in conjunctival and episcleral redness and resolution of keratitis and limbal infiltra tion. We recommend a trial of oral aspirin as adjunctive therapy for recalcitrant cases of vernal conjunctivitis and for those patients with vernal conjunctivitis who require long-term use or high dosag es of corticosteroids for control. Of
VOL. 95, NO. 4
VERNAL CONJUNCTIVITIS
course, the physician must be alert to the possible side effects of aspirin, such as gastritis, increased bleeding time, and Reyes syndrome. REFERENCES 1. Allansmith, M. R., Baird, R. S., and Greiner, J. V.: Vernal conjunctivitis and contact lensassociated giant papillary conjunctivitis compared and contrasted. Am. J. Ophthalmol. 87:544, 1979. 2. Henriquez, A. S., Kenyon, K. R., and Allansmith, M. R. : Mast cell ultrastructure. Comparison in contact lens-associated giant papillary conjunctivi tis and vernal conjunctivitis. Arch. Ophthalmol. 99:1266, 1981. 3. Abelson, M. B., Udell, I. J., and Weston, J. H.: Conjunctival eosinophils in compound 48/80 rabbit model. Arch. Ophthalmol. In press. 4. Abelson, M. B., Madiwale, N., and Weston, J. H.: Conjunctival eosinophils in allergic ocular disease. Arch. Ophthalmol. In press. 5. Abelson, M. B., Soter, N. A., Simon, M. A., Dohlman, J., and Allansmith, M. R.: Histamine in human tears. Am: J. Ophthalmol. 83:417, 1977. 6. Udell, I. J., Gleich, G. J., Allansmith, M. R., Ackerman, S. J., and Abelson, M. B.: Eosinophil granule major basic protein and Charcot-Leyden crystal protein in human tears. Am. J. Ophthalmol. 92:824, 1981. 7. Dhir, S. P., Garg, S. K., Sharma, Y. R., and Lath, N. K.: Prostaglandins in human tears. Am. J. Ophthalmol. 87:403, 1979. 8. Roberts, L. J., II, Sweetman, B. J., Lewis, R. A., Austen, K. F., and Oates, J. A.: Increased production of prostaglandin D2 in patients with sys temic mastocytosis. N. Engl. J. Med. 303:1400, 1980. 9. Roberts, L. J., II, Lewis, R. A., Oates, J. A., and Austen, K. F. : Prostaglandin, thromboxane, and 12-hydroxy-5,8,10,14-eicosatetraenoic acid produc tion by ionophore-stimulated rat serosal mast cells. Biochim. Biophys. Acta 575:185, 1979. 10. Lewis, R. A., Roberts, L. J., II, Holgate, S. T., Oates, J. A., and Austen, K. F.: Immunologie generation of mast cell prostaglandins and their effects on mast cell cyclic nucleotides, abstract. J. Allergy Clin. Immunol. 65:235, 1980. 11. : Prostaglandin D2 production by rat and human mast cells activated by reversed anaphylaxis, abstract. Fed. Proc. 39:905, 1980. 12. Bhattacherjee, P., Kulkarni, P. S., and Eakins, K. E.: Metabolism of arachidonic acid in rabbit ocular tissues. Invest. Ophthalmol. Vis. Sci. 18:172, 1979.
505
13. Abelson, M. B., Madiwale, N. A., and Wes ton, J. H.: The effect of topical prostaglandin D2 on the eye, abstract. Invest. Ophthalmol. Vis. Sci. 22:135, 1982. 14. Vane, J. R. : Inhibition of prostaglandin syn thesis as a mechanism of action for aspirin-like drugs. Nature 231:232, 1971. 15. Rome, L. H., Lands, W.*E., Roth, G. J., and Majerus, P. W. : Aspirin as a quantitative acetylating reagent for the fatty acid oxygenase that forms prosta glandins. Prostaglandins 11:23, 1976. 16. Roth, G. J., Stanford, N., and Majerus, P. W. : Acetylation of prostaglandin synthase by aspi rin. Proc. Nati. Acad. Sci. U.S.A. 72:3073, 1975. 17. Smith, J. B., and Willis, A. L.: Aspirin selec tively inhibits prostaglandin production in human platelets. Nature 231:235, 1971. 18. Forstrom, L., Goldyne, M. E., and Winkel mann, R. K. : Prostaglandin production by human epidermal cells in vitro. A model for studying phar macologie inhibition of prostaglandin synthesis. Pros taglandins 8:107, 1974. 19. Ferreira, S. H., Moncada, S., and Vane, J. R, : Indomethacin and aspirin abolish prostaglandin re lease from the spleen. Nature 231:237, 1971. 20. Van Nueten, J. M.: Antagonism of arachidonic acid hydroperoxide on isolated gastrointestinal tis sues as a measure of the inhibition of prostaglandin biosynthesis. Adv. Prostaglandin Thromboxane Res. 1:139, 1976. 21. Robinson, D. R. : Prostaglandins and inflam mation. New England Society of Allergy Proceedings 2:79, 1981. 22. Ehrenpreis, S., Greenberg, J., and Belman, S.: Prostaglandins reverse inhibition of electricallyinduced contractions of guinea pig ileum by mor phine, indomethacin and acetylsalicylic acid. Nature 245:280, 1973. 23. Bhattacherjee, P., Kulkarni, P. S., and Eakins, K. E.: Differential inflammatory effects of arachidonic acid or rabbit conjunctiva and iris. A possible role of lipoxygenase in the conjunctival response. Adv. Prostaglandin Thromboxane Res. 8:1727, 1980. 24. Bhattacherjee, P., and Eakins, K. E.: Inhibi tion of the ocular effects of sodium arachidonate by anti-inflammatory compounds. Prostaglandins 9:175, 1975. 25. Easty, D. L., Rice, N. S., and Jones, B. R.: Clinical trial of topical disodium cromoglycate in vernal kerato-conjunctivitis. Clin. Allergy 2:99, 1972. 26. Greenbaum, J., Cockcroft, D., Hargreave, F. E., and Dolovich, J.: Sodium cromoglycate in ragweed-allergic conjunctivitis. J. Allergy Clin. Im munol. 59:437, 1977.
M.D.,
Boston, Massachusetts
Prostaglandin D2 is a secondary mast cell mediator that causes redness, chemosis, mucous discharge, and eosinophil chemotaxis in the eye. It may play an important role in allergic ocular disease. Although histamine is a key mediator of allergic inflammation, antihistamine therapy provides only symptomatic relief. We added aspirin therapy to the treatment regimen of three patients with vernal conjunctivitis. Aspirin acetylates the enzyme cyclooxygenase, thereby preventing the formation of prostaglandin D 2 . Within two weeks after initiation of aspirin therapy, we noted dramatic improvement in conjunctival and episcleral redness and resolution of keratitis and limbal infiltration. We recommend a trial of oral aspirin as adjunctive therapy for intractable cases of vernal conjunctivitis. Vernal conjunctivitis is an allergic con dition characterized by severe itching, redness, tenacious mucous discharge, and photophobia. Cobblestone appear ance of the upper tarsus, shield-shaped corneal ulcération, punctate keratitis, and limbal infiltration often develop in this condition. In vernal conjunctivitis, conjunctival mast cells are more superficially located than in normal control tissue, 1 and the percentage of degranulated conjunctival mast cells is increased over normal con trols. 2 Degranulation is followed by eo sinophil accumulation in the deep tissue, presumably in response to the release of eosinophil chemotactic factors. 3 EosinoAccepted for publication Jan. 20, 1983. From the Department of Ophthalmology, Harvard Medical School, and the Cornea Service, Massachu setts Eye and Ear Infirmary (Drs. Abelson and Butrus); and the Department of Cornea Research, Eye Research Institute of Retina Foundation (Drs. Abelson and Butrus and Ms. Weston), Boston, Mas sachusetts. This work was supported in part by CooperVision Pharmaceuticals Inc., and the Massa chusetts Lions Eye Research Fund, Inc. Reprint requests to Mark B. Abelson, M.D., Eye Research Institute, 20 Staniford St., Boston, MA 02114. 502
phils may not always be recovered in conjunctival scrapings, although they are present in deeper biopsy specimens. 3,4 The tears of patients with vernal conjunc tivitis contain increased levels of hista mine, 5 eosinophil granule major basic protein, 6 and prostaglandin F. 7 Mastocytosis is a disorder character ized by the abnormal proliferation of tis sue mast cells. Serum levels of histamine and prostaglandin D2 are increased in affected patients. 8 Antihistamine therapy alone is insufficient; however, the addi tion of aspirin, an inhibitor of prostaglan din biosynthesis, to the treatment regi men of a patient with mastocytosis prevented attacks of flushing and hypo tension. 8 The role of prostaglandin D2 in inflam mation has been appreciated only recent ly. It is the major prostaglandin produced by the mast cell.9' 11 Prostaglandin D2 is a product of the cyclo-oxygenase pathway of the arachidonic acid cascade (Figure). Bhattacherjee, Kulkarni, and Eakins 12 showed that rabbit ocular tissues, such as the iris-ciliary body and conjunctiva, syn thesize all cyclo-oxygenase products. We have previously shown that topical appli-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 95:502-505, 1983
VOL. 95, NO. 4
VERNAL CONJUNCTIVITIS
cation of prostaglandin D2 to the eye produces dilation of the conjunctival, episcleral, perilimbal, and deep scierai ves sels, and stringy mucous discharge.13 Topical histamine, however, induces itching and a more superficial pattern of vasodilation. Current therapy of allergic ocular dis ease does not include antagonists of pros taglandin biosynthesis. Since the pathophysiology of both mastocytosis and vernal conjunctivitis involves mast cell abnormalities and aspirin therapy is ben eficial in mastocytosis, we evaluated the effectiveness of aspirin therapy in three patients with vernal conjunctivitis. CASE REPORTS Case 1—A 17-year-old girl, first examined on Oct. 10, 1980, had had conjunctival vasodilation, itching, burning, and mild photophobia for seven years; her symptoms were continuous and showed no seasonal variation. There was no family history of asthma, allergic rhinitis, eczema, or ocular allergy. Corrected visual acuity in both eyes was 20/20. The eyelids of both eyes showed evidence of neurodermatitis. Both eyes had giant papillary hypertro phy of the upper tarsal conjunctiva, an elevated and engorged corneoscleral limbus with several Trantas dots, a 360-degree peripheral corneal pannus, and inferior superficial punctate keratopathy. Conjunctival scrapings of both eyes contained an average of three eosinophils per high-power field. A biopsy specimen of the corneoscleral limbus dis closed many eosinophils in the epithelium and sub stantia propria, plasma cells, and lymphocytes. Treatment with topical prednisone 1% and antihis tamines resulted in marked improvement for two months. Then this therapy was discontinued and oral theophylline (300 mg three times a day), cromolyn sodium 4% (four times a day), and vasoconstrictors were tried, but only minimal improvement was noted. By January 1982, the patient's condition had stabi lized and all medication except cromolyn sodium was reduced and then discontinued. A flare-up two months later necessitated the addition of topical prednisone 1% to the regimen. Improvement was negligible. On April 16, 1982, oral aspirin (325 mg every two hours) was initiated. Within two weeks, there was dramatic improvement. Conjunctival red ness, itching and burning, and limbal infiltrates decreased markedly and the peripheral corneal ves sels constricted. Case 2—On Aug. 22, 1979, a 9-year-old boy com plained of blurred vision in his left eye. He had a three-year history of bilateral conjunctival redness
503
and itching with flare-ups during spring and summer. There was no family history of asthma or other allergic conditions. Visual acuity was R.E.: 20/20 and L.E.: 20/80. Examination showed mild papillary hypertrophy of the upper tarsal conjunctivas and superficial punctate staining inferiorly in both corneas, with a small inferior epithelial defect in the left cornea. The patient was fitted with a therapeutic bandage lens in his left eye and treated topically with chloramphenicol (four times a day) and a vasoconstrictor. Corneal stability was maintained for eight months; this was followed by the development of a shield-shaped ulcer in the left cornea. After treatment with medrysone 1% (every hour initially with the dosage gradually reduced to four times a day), cromolyn sodium 4%, antihistamines, and vasoconstrictors, the ulcer healed, but the redness, photophobia, and irritation persisted for four months. At that time, we added oral aspirin (81 mg every three hours). Within one week, conjunctival redness and itching decreased greatly. Case 3—A 13-year-old boy, referred to us on May 12, 1978, complained of itching, irritation, mucous discharge, and blurred vision in both eyes. His symptoms were seasonal, worsening during the warmer months. He had a history of asthma, eczema, hay fever, and allergy to dogs. Our initial examina tion disclosed cobblestone excrescences of the upper tarsal conjunctiva, Trantas dots at the corneoscleral limbus, and epithelial defects in both eyes. Correct ed visual acuity was 20/40 in both eyes. Periodic examination during the next four years showed cobblestone hypertrophy, limbal phlyctenules, and corneal epithelial defects with anterior stromal haze. Symptoms were controlled with theo phylline (300 mg three times a day) and prednisolone (up to 1% four times a day), but complete resolution never occurred; a maintenance dosage of corticosteroids was required. During remissions the lesions resolved and corrected visual acuity improved to 20/30 in both eyes. On April 23, 1982, the patient complained of conjunctival redness, itching, ocular irritation, and mucous discharge. Examination disclosed Trantas dots at the corneoscleral limbus, dilation of peripher al corneal vessels, and 4+ cobblestone response of the upper tarsal plate. The patient's medication at that time included an antihistamine/vasoconstrictor, erythromycin ointment, and dexamethasone 0.1%. The patient had previously been unresponsive to cromolyn sodium therapy. Therapy was supple mented with aspirin (650 mg three times a day). Within two days there was a noticeable decrease in conjunctival redness and discomfort and resolution of the limbal infiltration. However, gastritis developed, necessitating discontinuation of aspirin treatment and reinstitution of corticosteroid therapy. DISCUSSION
In 1971, Vane14 discovered that aspirin and other noncorticosteroidal anti-in-
504
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL, 1983
| Membrane phospholipids | Corticosteroids ι
Phospholipase
Arachidonic acid Aspirin (NSAIA) ,
Cyclo-oxygenase
Cyclic endoperoxides Prostaglandin Gg-^-Prostaglandin H2 Prostaglandin synthetase
c hydrolysis MDA, HHTJ mboxane synthetase
somerase
|Prostaglandin I2
Redu
iThromboxane A?l jProstaglandin F2d|
I Prostaglandin E2 | P r o s t a g l a n d i n D2
Figure (Abelson, Butrus, and Western). Cyclo-oxygenase pathway of arachidonic acid metabolism showing inhibition sites of corticosteroids and aspirin. Asterisk, noncorticosteroidal anti-inflammatory agent; MDA, malondialdehyde; HHT, heptadecatrienoic acid.
flammatory agents inhibit prostaglandin biosynthesis. Aspirin acetylates the active site of the enzyme cyclo-oxy genase, thereby preventing the genera tion of cyclic endoperoxides 15,16 (Figure). The systemic effect of prostaglandin syn thetase inhibitors has been demonstrated in vitro by using isolated cells such as human platelets, 17 epidermal cells, 18 dog spleen, 19 isolated gastrointestinal tissue, 20 and human rheumatoid synovium, 21,22 and in vivo in patients with mastocytosis. 8 Topical application of prostaglandin D2, the mast cell's most prevalent prosta glandin,9"11 produces mild conjunctival in jection, chemosis, and tearing in guinea pig eyes, 13 and dose-dependent vasodilation, chemosis, and mucous discharge in human eyes. 13 Topical application of ara chidonic acid, a precursor of prostaglan din D2, produces conjunctival redness and chemosis in rabbits. 23,24 Although histamine contributes to the conjunctival vasodilation and itching associated with vernal conjunctivitis, antihistamine ther apy provides only symptomatic relief and does not alter the underlying disease process. Corticosteroid treatment is ef fective, but the risks of long-term use— local immunosuppression, glaucoma, and
cataract formation—must be balanced against the need for such potent drugs. Cromolyn sodium, an inhibitor of mast cell degranulation, has been used suc cessfully to treat some cases of vernal and nonvernal ocular allergy,20,26 but some pa tients do not respond to cromolyn thera py. Thus far, no single drug has proven safe and effective for the treatment of vernal conjunctivitis. The increased percentage of degranulated mast cells found in patients with vernal conjunctivitis may be related to an overabundance of prostaglandin D2. To our knowledge, there are no agents avail able that selectively inhibit prostaglandin D 2 . Aspirin prevents the synthesis of prostaglandins by blocking the cyclooxygenase pathway. The addition of aspi rin to the treatment regimen of three patients with intractable vernal conjunc tivitis produced dramatic improvement in conjunctival and episcleral redness and resolution of keratitis and limbal infiltra tion. We recommend a trial of oral aspirin as adjunctive therapy for recalcitrant cases of vernal conjunctivitis and for those patients with vernal conjunctivitis who require long-term use or high dosag es of corticosteroids for control. Of
VOL. 95, NO. 4
VERNAL CONJUNCTIVITIS
course, the physician must be alert to the possible side effects of aspirin, such as gastritis, increased bleeding time, and Reyes syndrome. REFERENCES 1. Allansmith, M. R., Baird, R. S., and Greiner, J. V.: Vernal conjunctivitis and contact lensassociated giant papillary conjunctivitis compared and contrasted. Am. J. Ophthalmol. 87:544, 1979. 2. Henriquez, A. S., Kenyon, K. R., and Allansmith, M. R. : Mast cell ultrastructure. Comparison in contact lens-associated giant papillary conjunctivi tis and vernal conjunctivitis. Arch. Ophthalmol. 99:1266, 1981. 3. Abelson, M. B., Udell, I. J., and Weston, J. H.: Conjunctival eosinophils in compound 48/80 rabbit model. Arch. Ophthalmol. In press. 4. Abelson, M. B., Madiwale, N., and Weston, J. H.: Conjunctival eosinophils in allergic ocular disease. Arch. Ophthalmol. In press. 5. Abelson, M. B., Soter, N. A., Simon, M. A., Dohlman, J., and Allansmith, M. R.: Histamine in human tears. Am: J. Ophthalmol. 83:417, 1977. 6. Udell, I. J., Gleich, G. J., Allansmith, M. R., Ackerman, S. J., and Abelson, M. B.: Eosinophil granule major basic protein and Charcot-Leyden crystal protein in human tears. Am. J. Ophthalmol. 92:824, 1981. 7. Dhir, S. P., Garg, S. K., Sharma, Y. R., and Lath, N. K.: Prostaglandins in human tears. Am. J. Ophthalmol. 87:403, 1979. 8. Roberts, L. J., II, Sweetman, B. J., Lewis, R. A., Austen, K. F., and Oates, J. A.: Increased production of prostaglandin D2 in patients with sys temic mastocytosis. N. Engl. J. Med. 303:1400, 1980. 9. Roberts, L. J., II, Lewis, R. A., Oates, J. A., and Austen, K. F. : Prostaglandin, thromboxane, and 12-hydroxy-5,8,10,14-eicosatetraenoic acid produc tion by ionophore-stimulated rat serosal mast cells. Biochim. Biophys. Acta 575:185, 1979. 10. Lewis, R. A., Roberts, L. J., II, Holgate, S. T., Oates, J. A., and Austen, K. F.: Immunologie generation of mast cell prostaglandins and their effects on mast cell cyclic nucleotides, abstract. J. Allergy Clin. Immunol. 65:235, 1980. 11. : Prostaglandin D2 production by rat and human mast cells activated by reversed anaphylaxis, abstract. Fed. Proc. 39:905, 1980. 12. Bhattacherjee, P., Kulkarni, P. S., and Eakins, K. E.: Metabolism of arachidonic acid in rabbit ocular tissues. Invest. Ophthalmol. Vis. Sci. 18:172, 1979.
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