The Effects of Systemic Medication on Ocular Allergic Disease

Transcription

1 The Effects of Systemic Medication on Ocular Allergic Disease Gregg J. Berdy, MD, FACS Clinical Instructor in Ophthalmology, Washington University School of Medicine Key words: ocular allergic disease systemic medication. Acta Ophthalmol. Scand. 2000: 78: Copyright C Acta Ophthalmol Scand ISSN Ocular Allergy 2nd International Symposium 1999 Leeds Castle In discussing the topic of systemic treatment of immunologic disease, it is important to examine the treatment of ocular allergic disorders, Type I hypersensitivity reactions. Surgeons who perform corneal transplants and treat external ocular diseases, commonly employ systemic medications in the treatment of immune-mediated ocular diseases that are not Type I hypersensitivity diseases. There are four types of hypersensitivity reactions discussed by the Gell and Coombs and labeled as types I through IV. Specifically, Type I is associated with IgE immunoglobulin, Type II is associated with antigen-dependent cell cytotoxicity, Type III disease results from antigen-antibody complex deposition in small blood vessels, and Type IV reactions are T cell-mediated diseases. Type I diseases are typified in the eye by seasonal allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis. Type II hypersensitivity are seen in the eye as Mooren s ulceration and ocular cicatricial pemphigoid. Type III hypersensitivity reactions in the eye include rheumatoid arthritis, systemic lupus, polyarteritis nodosa, and Wegener s Granulomatosis. Lastly, type IV reactions are typified in the eye by corneal transplant rejection to endothelial cells as seen as a Khodadoust line with T lymphocytes. The differential diagnosis of allergic ocular disease is important. Seasonal allergic conjunctivitis is the most common ocular allergy and is associated with other forms of allergic diseases, such as allergic rhinitis, sinusitis, and asthma. It s usually seasonal, occurring in the fall and spring, but may be panseasonal. Additionally, it can last for many years. Typically symptoms and signs are itching, burning, redness, lid edema, and mucous discharge. Treatment of seasonal allergic conjunctivitis usually consists of topical eyedrops including antihistamines, topical vasoconstrictors, combination antihistamine and vasoconstrictor medications, mast cell stabilizers, nonsteroidal anti-inflammatory drugs, and topical steroids in very severe cases. Vernal keratoconjunctivitis is a bilateral recurrent disease seen in young males, typically between 5 and 14 years of age with associated atopic disease. Upon eversion of the upper eyelid, one can see the giant papillae or giant cobblestones. There is another subtype known as the limbal form. One can observe aggregations of eosinophils in a gelatinous configuration at the limbus known as Horner s dots or Trantas dots. Both presentations are the same disease, but the findings occur in a different location. Children can present with ptosis because the eyelids are very edematous and boggy, and hence heavy. Patients present with stringy, ropy mucous discharge, red eyes, cobblestone papillae of the upper eyelid and Trantas dots at the limbus. Additionally, patients may have corneal involvement with keratopathy as well as shield ulcerations. Patients complain of marked itching, tearing, burning, and associated atopic diseases of sinusitis and asthma. Treatment of vernal keratoconjunctivitis is typically topical, with a combination of antihistamines, mast cell stabilizers, topical steroids in pulsed doses, nonsteroidal agents, and cyclosporin A, however, one must be careful when using these in children. Systemic treatment becomes more important in this disease, with oral antihistamines and oral prednisone being added. As the diseases become more complex and threaten the cornea, the oral medications become of paramount importance. Atopic keratoconjunctivitis is a chronic disease. Unfortunately, many of these patients are diagnosed very late in life. Patients have multiple complaints such as chronic itching, burning, redness, discomfort. Slit-lamp examination demonstrates subconjunctival scarring from the chronic inflammation; the meibomian glands may become totally occluded; and the tear glands of Zeis and Wolfring may become scarred or nonfunctioning because of the subconjunctival fibrosis. Patients have chronically red eyes. As the disease progresses, one may observe the formation of corneal abrasions because of the poor tear film. The ocular symptoms in these individuals are chronic itching, burning, mucous discharge, photophobia, and tearing. The ocular signs are symblepharon formation, corneal ulcerations, dry eye, and 26

2 blepharitis. Unfortunately, patients can develop marked symblepharon with loss of the inferior fornix. Treatment of atopic keratoconjunctivitis must be multifaceted. In cases of atopic dermatitis of the eyelids, treatment with moisturizing soaps such as Dove, Eucerin cream, topical hydrocortisone creams, and antibiotic ointments may be necessary. Treatment of the ocular surface is necessary to decrease inflammation, improve lubrication and prevent infection. This can be accomplished by using a combination of topical antihistamines, mast cell stabilizers, steroids, nonsteroidal agents, antibiotics for the corneal abrasions, cyclosporin A drops and lubricant ointments. But here systemic treatment of the disease is quite important and imperative, with the use of antihistamines, antibiotics, and immunosuppression with prednisone. Currently, treatment of most of the Type I ocular diseases is with topical agents, yet treatment of most other ocular hypersensitivity reactions is with oral agents. In Mooren s ulcer patients, there is deposition of immunoglobulin and complement in the adjacent limbal conjunctiva. There is IgE deposition along the basement of the corneal epithelium. Also detected are circulating antibodies to a corneal antigen, possibly associated with helminthiasis in individuals from Africa. Treatment of Mooren s disease includes topical, systemic and surgical approaches. Initial treatment usually includes systemic immunosuppression with cytoxan in doses of 1 to 3 mg/kg/d, methotrexate 7.5 to 20 mg orally per week, or cyclosporin 3 5 mg/kg/d. Ocular cicatricial pemphigoid (OCP) is a chronic, progressive, mucous membrane cicatrizing disease where there is deposition of IgG, IgA, IgM and complement at the basement membrane of conjunctival epithelium. The disease is seen in older individuals with a predisposition to females. It is an autoimmune disease, and hence treatment must be systemic. In my experience, topical steroids do not work, but some researchers may have better results. Certainly, topical cyclosporin has been looked at in multiple studies, but the mainstay of immunosuppression is via systemic administration, because OCP is a systemic disease. If one examines the oropharynx and the buccal mucosa, one can find scarring. Treatment of OCP typically consists of Dapsone, usually starting at 50 mg per day but increasing to 150 mg, if necessary. One should test to see if the patient possesses a G-6-PD deficiency, because using Dapsone in patients with this deficiency could result in the development of a bleeding diathesis. Also, prednisone can be added to Dapsone to help control the patient s disease activity, as noted by increasing redness or subconjunctival scarring. For individuals who are resistant to treatment with Dapsone and prednisone, one can use Cytoxan A in doses of 1 3 mg/kg/d or azothiaprine, 1 3 mg/kg/d. Again, systemic diseases need treatment with systemic medications. Patients with rheumatoid arthritis may develop corneal ulcerations and scleritis with loss of scleral tissue. As is well known, rheumatoid arthritis patients have circulating immune complexes with anti-igg antibodies. This is a systemic disease which requires systemic treatment. Oral nonsteroidal agents may work well for joints, but they do not do very much for corneal melts. Treatment of these severe ocular diseases requires oral prednisone which can be augmented with methotrexate or azothiaprine. There have been some investigators in the literature who have used gold salt injections, but usually not for ocular disease, only for joint symptoms. Lastly, just to mention corneal allograft rejections, which are Type IV reactions, we use topical prednisone and topical cyclosporin. In severe cases, however, oral prednisone is required to control the rejection. So, where do we go from here with the topical treatment of ocular allergic diseases of SAC, VKC and AKC? The majority of ophthalmologists use drops such as Patanol A, which works very well, Alomide and other assorted drops. The question posed is, where do the systemic medications fit in? As is well known, the basic mechanism of the allergic response is the allergen binding to mast cells of patients who have previously been sensitized. These individuals have been exposed in the past and then are reexposed to an allergen which causes bridging of the IgE molecules attached to the high-affinity Fc receptor on the mast cell membrane. This binding of two IgE molecules causes a cross-linking and bridging, and subsequent calcium influx into the mast cell which causes degranulation of the cell and release of preformed mediators of inflammation. These preformed mediators which include histamine, tryptase, and other chemotactic factors, recruit eosinophils and other leukocytes to participate in the reaction. This triggers increasing itching, redness, and chemosis of the conjunctival tissue. These mediators actually potentiate the allergic response. However, it is not just the preformed mediators that are participating in the inflammatory cascade; there are mediators that are synthesized from the cell membranes of the eosinophils and mast cells. The cell membranes are degraded by phospholipase A 2, which breaks down the membrane into arachidonic acid. Arachidonic acid is then metabolized by cyclooxygenase into prostaglandins, specifically PGD 2 and PGE 2, which have been shown to be involved in the acute response of allergic conjunctivitis, and by lipoxygenase into leukotrienes. Prostaglandins and leukotrienes participate in the inflammation by causing vasodilation and mucous production. Ten or 15 years ago, people thought that allergy was a hocus-pocus specialty, for example if you treated a patient with an antihistamine, they got better. Allergy has always been and continues to be real science. During this meeting, we have learned about ICAMs and interleukins, and it is all very exciting. Patients with VKC and AKC, not only have abnormalities with histamine responses, but also have a T-lymphocyte regulatory dysfunction. Patients with VKC have Th2 cell abnormalities and patients with AKC have Th1 cell problems. So, the basic problem in patients with these ocular diseases is that the immune system is abnormal. The literature shows that certain medications can be used orally to treat these diseases. NSAIDs were first discussed as a treatment for ocular allergic disease by Mark Abelson in Abelson used aspirin as a therapy in an individual with VKC. Nonsteroidals have been shown to be a very effective treatment for this disease. Nonsteroidals work by blocking cyclooxygenase. Granted it only knocks out the prostaglandin and the thromboxane arm, but it works well. Chaudhary also showed improvements in patients with VKC treated with aspirin. In these two studies, aspirin was shown to improve conjunctival and episcleral redness, decrease keratitis, and help to resolve limbal infiltrates. But the one problem you must remember, if these individuals with VKC have asthma, aspirin may exacer- 27

3 Fig. 1. Types of hypersensitivity reactions. Fig. 4. Keratoconjunctivitis. Fig. 2. Seasonal allergic conjunctititis. Fig. 5. Atopic keratoconjunctivitis. Fig. 3. Vernal keratoconjunctivitis. Fig. 6. Mooren s ulcer. bate asthma symptoms. So it works, but you have got to be a little careful. Corticosteroids work by binding to intercytosolic receptors, being transported into the nucleus, and making abnormal mrna, which basically shuts the system down. In reviewing the literature, it has been shown in multiple studies and multiple papers that oral prednisone works very well in severe cases of AKC and VKC. Intranasal steroids have been shown to be, or at least have demonstrated a positive, but equivocal effect, with respect to ocular signs and symptoms in rhinoconjunctivitis. In reviewing the literature, there has been no specific study evaluating conjunctivitis alone; all of the studies evaluate rhinoconjunctivitis together, and usually there was no control group of ocular symptoms. Patients were able to use concurrent eyedrops during the studies. The conclusions of these studies were that intranasal steroids 28

4 Fig. 7. Rheumatoid arthritis. Fig. 10. Major effector cells and mediators. Fig. 8. Corneal transplant rejection. Fig. 11. Eosinophil recruitment. Fig. 9. Mast cell activation by FC g receptor triggering. Fig. 12. NSAID: Mechanism of action. allowed patients to use less ocular drops. So basically, intranasal steroids by themselves, per se, have not been evaluated in allergic conjunctivitis. Oral antihistamines have been used to treat ocular allergies. In the United States, ophthalmologists typically do not use oral antihistamines for treating allergic conjunctivitis. Allergists and primary care physicians usually use oral antihistamines. This may be explained by the different patient populations that are seen by the different subspecialties. In examining the literature on the use of oral antihistamines, treatment preferences were twofold. In their review, Hingorani and Lightman found decreased itching and redness in several studies for both seasonal, vernal, and atopic keratitis. However, the authors noted that oral medications, including Allegra A, Zyrtec A and Claritin A,maytakeupto5 days to receive the full effect on ocular tissues. It s slow, but it works. 29

5 Warner and Goldsworthy showed that oral ketotifen was very effective in treating SAC in children, but these children had a marked soporific effect. Forty-two percent fell asleep. On the other hand, when evaluating oral antihistamines, several authors believe it really doesn t make much difference as compared to topical antihistamines. Tristam showed no difference in ocular symptoms in patients treated with either oral astemizole versus topical cromolyn no difference. Abelson and Lanier demonstrated that patients treated with olopatadine experienced significant reduction in itching when patients were already using oral loratadine in a conjunctival antigen challenge. So here we have some individuals saying yes, oral medications work, but others saying there is no difference from topical. Interestingly, according to allergists, immunotherapy seems to work for allergic conjunctivitis. I typically do not see these results, but maybe I see a skewed population. Again, the literature is mixed on results. First of all, the mechanism of action is not certain, however, there are some postulates as to how immunotherapy may work. There may be production of IgG blocking antibodies, or an induction of an antiidiotypic antibody against an allergenspecific immunoglobulin. Or possibly, the ratio of the T-cell subsets may be altered, in some instances making patients less immune to the allergen. In the literature, there are three different ways immunotherapy can be used to treat ocular allergic diseases. The first is parenteral, the usual allergy shots, so to speak. And Prakash and Murthy demonstrated 62% of their patients with VKC had a positive response of reduced ocular symptoms when receiving immunotherapy. Lofkvist and his group showed that patients with perennial allergic conjunctivitis, when receiving parenteral immunotherapy, had decreased conjunctival sensitivity in a conjunctival antigen challenge model. On the other hand, using immunotherapy, Balda and his group showed no improvement in conjunctival symptoms in SAC. Juniper also found that in SAC patients immunotherapy offered no benefit to control and when using other medications. So again, these studies provide equivocal results. Two other types of immunotherapy exist. There is sublingual therapy, which consists of placing antigen under the tongue. Sabbah showed that sublingual immunotherapy statistically decreased conjunctival redness and tearing when looking at seasonal allergic conjunctivitis. Horak and his group demonstrated sublingual immunotherapy to decrease conjunctival sensitivity in patients with SAC. So this may be another mode to treat allergic conjunctivitis, although there are some side effects that one must worry about. Lastly, there is topical immunotherapy, which consists of placing antibody onto the conjunctival surface. DelPridi et al. showed a statistically significant decrease in conjunctival hyperemia and edema in patients with seasonal allergic conjunctivitis, as well as decreased conjunctival hyperemia and papillae in patients with GPC. Cyclosporin A has been discussed in the ophthalmic literature recently. Cyclosporin A works by a selective inhibitory effect on the CD4 T cells. There is decreased proliferation and inhibition of interleukin-2 production, leading to a blockade of IL-2 gene expression. Cyclosporin A also decreases HLA-DR, the major histocompatibility class II antigens on activated T cells, B cells, and antigen-presenting cells in the conjunctiva. This interferes with immunologic cooperation, antigen recognition, presentation of T cells and with the initiation of the B-cell and T- cell response, which is important in disease. Lastly, cyclosporin A decreases immunoglobulins and DNA production. Hoang-Xuan has treated four patients who were resistant to prednisone with AKC using cyclosporin A. These four individuals were treated with cyclosporin A 3 5 mg/kg/d for approximately 3 years. All patients had therapeutic serum levels of ng/ml, and in all patients ocular inflammation was controlled. In his study, the only side effect that was noted was an elevated BUN which returned to normal when the CsA was decreased. Other potential side effects include hypertension, hepatotoxicity, and renal toxicity. From my research, I have learned that there are many ways one can treat ocular allergic diseases with systemic medications. I think there is a role for systemic prednisone and systemic immunosuppressive agents. In examining the literature in regard to seasonal allergic conjunctivitis, it seems to me that the topical antihistamines and mast cell stabilizers are the mainstay of treatment, providing the safest and quickest way to make a patient happy and comfortable. References Abelson MB, Butrus SI & Weston JH (1983): Aspirin therapy in vernal conjunctivitis Am J Ophthalmol 95: Abelson MB & Lanier RQ (1999): The added benefit of local patanol therapy when combined with systemic claritin f or the inhibition of ocular itching in the conjunctival antigen challenge model. Acta Ophthal Scand. 77 (suppl 228): Abu El-Asrar AM, Tabbera KF, Gevoes K, et al. (1996): An immuno-histo chemical study of topical cyclosporin in vernal keratoconjunctivitis. Am J Ophthalmol 121: Akman A, Irkec M, Avarello A, et al. (1998): Effects of lodoxamide, disodeium cromoglycate and fluorometholone on tear leukotriene levels in vernal keratoconjunctivitis. Eye 12: Balda BR, Wolf H, Baumgarten C, et al. (1998): Tree-pollen allergy is efficiently treated by short-term immunotherapy (STI) with seven preseasonal injections of molecular standardized allergens. Allergy 53: Chaudhary KP (1990): Evaluation of combined systemic aspirin and cromolyn sodium in intractable vernal catarrh. Ann Ophthalmol 22: Del Prete A, Chiosi E, Maghi A, et al. (1992): Surgical treatment and desensitization therapy of giant papillary allergic conjunctivitis. Ophthal Surgery 23 (11): Del Prete A, Carderopoli A, Caparello O, et al. (1994): Local specific immunotherapy in allergic conjunctivitis. Acta Ophthalmol 72: El Hennawi M (1994): A double blind placebo controlled group comparative study of ophthalmic sodium cromoghycate and neducromil sodium in the treatment of vernal keratoconjunctivitis. Brit J. Ophthalmol 78: Ezra D, Bonini S, Carreres B, et al. (1994): Guidelines on the diagnosis and treatment of conjunctivitis. Ocul Inflamm 2 (suppl): Foster CS (1988): Evaluation of topical cromolyn sodium in the treatment of vernal keratoconjunctivitis. Ophthalmology 95: Hingorani M & Lightman S (1995): Therapeutic options in ocular allergic disease Drugs 50 (2): Hingorani M, Caldr VL, Buckley RJ, et al. (1999): The immunomodulatory effect of topical cyclosporin A in atopic keratoconjunctivitis. Invest Ophthalmol Vis YCI. 40: Holsclaw DS, Whitcher JP, Wong IG et al. 30

6 (1996): Supratorsal injection of corticosteroid in the treatment of refractory vernal kerato-conjunctivitis. Am J Ophthalmol 121: Horak F, Stubner P, Berger UE, et al. (1998): Immunotherapy with sublingual birch pollen extract. A short-term double-blind placebo study. Invest Allergol Clin Immunol. 8 (3): Hoang, Xuan T, Prisant O, Hannouchae D, et al. (1997): Systemic cyclosporin A in severe atopic ketatoconjunctivitis. Ophthalmology 104: Juniper EF, Kline PA, Ramsdale EH, et al. (1990): Comparison of the efficacy and side effects of aqueous steroid nasal spray (budesonide) and allergic injection therapy (Pollinex R) in the treatment of seasonal allergic rhinoconjunctivitis. J. Allergy Clin Immunol. 86: Katelaris C (1985): Drug treatment of hay fever. Austral Family Physicians 14 (6): Leonardi A, Borghesan F, Avarello A, et al. (1997): Effects of lodomaxide and disodium cromoglycate on tear eosinophil cationic protein in vernal keratoconjunctivitis. Brit J. Ophthalmol 81: Lofkvist T, Agrell B, Dreborg S, et al. (1994): Effects of immunotherapy with a purified standardized allergen preparation of Dermato phegoides forinae in adults with perennial allergic rhino-conjunctivitis. Allergy 49: Meyer E, Kraus E & Zonis S (1987): Efficacy of antiprostaglandin therapy in vernal keratoconjunctivitis. Brit J Ophthalmol 71: Prokash OM & Murthy KR (1992): Immunotherapy in allergic conjunctivitis. Ind J Ophthalmol 40 (l): Sabbah A, Hassour S, LeSellin J, et al. (1994): A double-blind, placebo controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Allergy 49: Secchi AG, Tognor MS & Leonardi A (1990): Topical use of cyclosporine in the treatment of vernal keratoconjunctivitis. Am J Ophthalmol 110: Steinberg DR, Bernstein DI, Bernstein IL, et al. (1989): Prednisone pretreatment leads to histamine airway hypo reactivity soon after resolution of the immediate allergic response. Chest 95: Tristan SJ, Harcup JW & Patel KR (1986): A comparison of oral astenized with topical sodium cromoghycate in the treatment of hay fever. Curr Med Res Op 10: Warner JO & Goldsworthy SJ (1982): Ketotifen in childhood allergic disease. Clin Allergy 12 (suppl):