Immunosuppressive Therapy of Ocular Disease W. Benton Boone, MD, and Lewis Slater, MD Long Beach and Irvine, California
Care and caution are required in using immunosuppressive agents to combat sight-threatening ocular disease. Informed consent of the patient and the active participation of a knowledgeable internist are mandatory in view of the known potential consequences of therapy. These consequences or side effects include specific and general problems, and before initiating therapy the cost/benefit ratio must be considered. Although the most commonly used agents are nonspecific, some drugs appear more beneficial in certain conditions than others, as is the case of chlorambucil in Behcet disease. It is a policy at the Uveitis Clinic of the University of California, Irvine, to institute immunosuppressive therapy early enough for conservation of useful vision, yet late enough so that it is clear that moderate to heavy steroid therapy cannot prevent blindness. In the event of failure of the "conventional" immunosuppressive therapy, plasmapheresis may prove a helpful adjunct. The etiologies are unknown for many inflammatory processes involving uveal tissue; for that reason it is not surprising that treatment of these conditions is nonspecific and often inadequate. Even though an immunological cause cannot be definitely ascribed, some uveal inflammations seem to be associated with excessive immune responses. It is easy to see how the concept evolved that these disorders might be beneficially treated with substances that suppress immune mechanisms. The method of action of the immunosuppressive drugs used in ophthalmology is varied. Among other things, they interrupt protein synthesis. and nucleic acid production, and thereby inhibit segments of the immune responses at different levels. Another mode of action has to be considered. It is widely known that many of these agents have anti-inflammatory properties, and that these may be a major factor in their efficacy. In fact, it is not altogether clear whether it is the antiinflammatory component or the im-
Presented in part at the Ocular Drug Therapy Update, September 1978, Newport Beach, California. From the Veteran's Administration Medical Center, Long Beach, and the University of California, Irvine, California. Requests for reprints should be addressed to Dr. W. Benton Boone, Veteran's Administration Hospital, 5901 East 7th Street, Long Beach, CA 90822.
munosuppressive component of these agents that is of most therapeutic value. The use of immunosuppressives in ophthalmology follows their extensive use as cancer chemotherapeutic agents,1 and some of these are used more frequently than others. Currently in vogue in ophthalmology are azathioprine, cyclophosphamide, cblorambucil, and methotrexate. Certain antimetabolites inhibit the biosynthesis of nucleic acids through interruption in the formation of the essential components of DNA and RNA. Methotrexate is an antimetabolite which inhibits folic acid reductase to block the reduction of folic acid to tetrahydrofolic acid. This results in blockage of the methylation of deoxyuridylic acid to thymidylic acid, an essential component of DNA. Azathioprine, a derivative of 6-mercaptopurine, prevents both purine ring biosynthesis and interconversion of the purine bases. The alkylating agents chlorambucil and cyclophosphamide interfere with the structure of DNA; this disorganizes and disrupts the cell. Vogt-Koyanagi-Hard4 disease, Behcet disease, sympathetic ophthalmitis, pars planitis, and lens-induced uveitis are examples of diseases of the uvea associated with immunological phenomena. When they fail to respond to systemic steroid therapy alone, these diseases may be treated with immunosuppressants in addition to the steroids.
JOURNAL OF THE NATIONAL MEPICAL ASSOCIATION, VOL. 71, NO. 9, 1979
Certain diseases appear to respond better to particular drug treatments than to others. Chlorambucil, for example, seems to cause a favorable response in Behcet disease where other agents have failed. In three studies, a total of 39 out of 41 patients suffering from Behcet have shown an "improved" response after treatment with chlorambucil (Table 1).2-4 Cyclophosphamide has been reported by Buckley and Gills to produce strikingly good results in pars planitis,5'6 and methotrexate and azathioprine have both been used in the treatment of sympathetic ophthalmitis with improvement.7'8 In the majority of these patients, the immunosuppressant therapy was carried out in conjunction with the steroid treatment and allowed the later reduction or discontinuation of corticosteroids. There is extensive information about the side effects of these drugs. There are at least four general problems associated with the agents discussed: 1. Bone marrow suppression is a serious potential problem, which can occur early in therapy or after prolonged administration of these drugs and result in serious thrombocytopenic bleeding and a serious granulocytopenic infection. Bone marrow suppression is reversible and can generally be avoided by close surveillance of peripheral blood and platelet counts during therapy. 2. Another important complication is sterilization; both aspermia and lack of oogonia have been reported. Infertility may be reversible when the medicine is stopped, but reversibility is unpredictable. 3. A very obvious danger in the use of these agents is their mutagenic potential; therefore, when treating individuals of childbearing age, it is wise to have the persons involved undergo contraceptive counseling. The use of an intrauterine device seems a reasonable solution to this problem.9" 0 4. The last of these problems involves the well established fact of increased incidence of cancer in individuals subjected to immunosuppres837
Table 1. Immunosuppressive Prescriptions in Uveitis Agent
Dose
Chlorambucil Chlorambucil
0.1-0.2 mg/kg/day 6-8 mg/day >2 mg/day Chlorambucil Cyclophosphamide 50-200 mg/day Methotrexate 25 mg/sq yd/q4D Azathioprine 1.5-3.0 mg/kg/day
sive therapy. Theoretically, there is probably little question that these agents might reduce immune surveillance against cancer, and thereby augment neoplasia.9 All of these complications of therapy are potentially serious. In addition, there are certain characteristic potential complications of some of these agents, eg, methotrexateinduced cirrhosis, osteoporosis, or pulmonary fibrosis; azathioprine-induced rash and urticaria; and cyclophosphamide-induced alopecia or hemorrhagic cystitis. To minimize the occurrence and/or effect of these, the active participation in the care of patients is required of an internist or hemotologist familiar with the use of these agents.
A New Use An interesting and perhaps important new method of "immunosuppression" has been introduced in the treatment of myasthenia gravis.'1 It is fairly certain that myasthenia gravis is a disease caused by an autoantibody to acetylcholine receptors. Plasmapheresis has been combined with prednisone and azathioprine, in order to reduce the level of autoantibody, and has been found to produce striking improvement in myasthenic patients. At the Uveitis Clinic of the University of California at Irvine, the authors are examining this method of reducing autoantibodies and its ability to produce clinical improvement in patients with "autoimmune" uveitis. 838
Disease
Number of Prescriptions
Author
Behcet Behcet Behcet Pars Planitis Sympathetic Ophthalmitis Sympathetic Ophthalmitis
Bietti2 Mano3 O'Connor Buckley & Gills5 Leopold Moore8
Case Report B. F. is a 30-year-old female who presently has a visual acuity of light perception and count fingers vision at one foot. She has carried the diagnosis of Vogt-Koyanagi-Harada disease for six years. The diagnosis was made on the basis of the appearance of viteligo, poliosis, and anterior and posterior uveitis, in the face of frequent severe headaches. Throughout the history of this chronic uveitis, the patient has been treated with cytoxin, azathioprine, and steroids. Ultimately, anterior and posterior uveitis was controlled with a dosage as high as 100 mg of prednisone and 100 mg of azathioprine daily. Any attempt to reduce the steroid dosage below 60 mg of prednisone daily resulted in a flare-up of the uveitis. Because of this, with the patient's fully informed consent, it was decided to make an attempt at immunosuppression through the use of plasmapheresis. The rationale for this was to remove the presumably injurious circulating autoantibodies. The patient underwent plasmapheresis twice a week for six weeks. Plasma (2000 cc or more) was removed at each procedure and replaced wit\h saline and albumin. The dosage of prednisone and azathioprine was maintained at 100 mg each, daily. Prior to the plasmapheresis, indirect immunofluorescence gave minimal evidence of IGA antibody present in the patient's blood to uveal tissue. The authors were not able to demonstrate this antibody after plas-
16 20 5 9, 12 2 1
Number Improved 16 19 4 9, 12 2 1
mapheresis. The pre-plasmapheresis immunofluorescence was minimal and, therefore, this test was nonconclusive. Subsequently, the patient's azathioprine dosage has been reduced to 40 mg daily, and the prednisone dosage to 10 mg daily with maintenance of the visual acuity and without recurrence of the uveitis. It has been necessary for the patient to undergo one further plasmapheresis in order to continue the reduced dosage of azathioprine and prednisone.
Literature Cited 1. Krakoff l: Cancer chemotherapeutic agents. CA 27:130-143, 1977 2. Bietti G, Cerulli L, Pivetti-Pezzi P: Behcet's disease and immunosuppressive treatment. Mod Probl Ophthalmol 16:314-323, 1976 3. Mano J: Treatment of Behcet disease with chlorambucil. Arch Ophthalmol 94:580583, 1976 4. Nozik RA, Godfrey WA, Epstein WV, et al: Immunosuppressive treatment of uveitis. Mod Probi Ophthalmol 16:305-308, 1976 5. Buckley C, Gills J: Cyclophosphamide therapy of peripheral uveitis. Arch Intern Med 124:29-35, 1969 6. Gills J, Buckley C: Oral cyclophosphamide in the treatment of uveitis. Trans Am Acad Ophthalmol Otolol 74:505-508, 1970 7.. Lazor M, Weiner M, Leopold I: Treatment of uveitis with methotrexate. Am J Ophthalmol 67:383-387, 1969 8. Moore C: Sympathetic ophthalmitis treated with azathioprine. Br J Ophthalmol 52:688-690, 1968 9. Steinberg AD, Plotz PH, Wolff SM, et al: Cytotoxic drugs in treatment of nonmalignant diseases. Ann Intern Med 76:619-642, 1972 10. Schein P, Winokur S: Immunosuppressive and cytotoxic chemotherapy: Long-term complications. Ann Intern Med 82:84-95, 1975 11. Dau PC, Lindstrom JM, Cassel CK, et al: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N EngI J Med 297:1134-1140, 1977
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 9, 1979
Care and caution are required in using immunosuppressive agents to combat sight-threatening ocular disease. Informed consent of the patient and the active participation of a knowledgeable internist are mandatory in view of the known potential consequences of therapy. These consequences or side effects include specific and general problems, and before initiating therapy the cost/benefit ratio must be considered. Although the most commonly used agents are nonspecific, some drugs appear more beneficial in certain conditions than others, as is the case of chlorambucil in Behcet disease. It is a policy at the Uveitis Clinic of the University of California, Irvine, to institute immunosuppressive therapy early enough for conservation of useful vision, yet late enough so that it is clear that moderate to heavy steroid therapy cannot prevent blindness. In the event of failure of the "conventional" immunosuppressive therapy, plasmapheresis may prove a helpful adjunct. The etiologies are unknown for many inflammatory processes involving uveal tissue; for that reason it is not surprising that treatment of these conditions is nonspecific and often inadequate. Even though an immunological cause cannot be definitely ascribed, some uveal inflammations seem to be associated with excessive immune responses. It is easy to see how the concept evolved that these disorders might be beneficially treated with substances that suppress immune mechanisms. The method of action of the immunosuppressive drugs used in ophthalmology is varied. Among other things, they interrupt protein synthesis. and nucleic acid production, and thereby inhibit segments of the immune responses at different levels. Another mode of action has to be considered. It is widely known that many of these agents have anti-inflammatory properties, and that these may be a major factor in their efficacy. In fact, it is not altogether clear whether it is the antiinflammatory component or the im-
Presented in part at the Ocular Drug Therapy Update, September 1978, Newport Beach, California. From the Veteran's Administration Medical Center, Long Beach, and the University of California, Irvine, California. Requests for reprints should be addressed to Dr. W. Benton Boone, Veteran's Administration Hospital, 5901 East 7th Street, Long Beach, CA 90822.
munosuppressive component of these agents that is of most therapeutic value. The use of immunosuppressives in ophthalmology follows their extensive use as cancer chemotherapeutic agents,1 and some of these are used more frequently than others. Currently in vogue in ophthalmology are azathioprine, cyclophosphamide, cblorambucil, and methotrexate. Certain antimetabolites inhibit the biosynthesis of nucleic acids through interruption in the formation of the essential components of DNA and RNA. Methotrexate is an antimetabolite which inhibits folic acid reductase to block the reduction of folic acid to tetrahydrofolic acid. This results in blockage of the methylation of deoxyuridylic acid to thymidylic acid, an essential component of DNA. Azathioprine, a derivative of 6-mercaptopurine, prevents both purine ring biosynthesis and interconversion of the purine bases. The alkylating agents chlorambucil and cyclophosphamide interfere with the structure of DNA; this disorganizes and disrupts the cell. Vogt-Koyanagi-Hard4 disease, Behcet disease, sympathetic ophthalmitis, pars planitis, and lens-induced uveitis are examples of diseases of the uvea associated with immunological phenomena. When they fail to respond to systemic steroid therapy alone, these diseases may be treated with immunosuppressants in addition to the steroids.
JOURNAL OF THE NATIONAL MEPICAL ASSOCIATION, VOL. 71, NO. 9, 1979
Certain diseases appear to respond better to particular drug treatments than to others. Chlorambucil, for example, seems to cause a favorable response in Behcet disease where other agents have failed. In three studies, a total of 39 out of 41 patients suffering from Behcet have shown an "improved" response after treatment with chlorambucil (Table 1).2-4 Cyclophosphamide has been reported by Buckley and Gills to produce strikingly good results in pars planitis,5'6 and methotrexate and azathioprine have both been used in the treatment of sympathetic ophthalmitis with improvement.7'8 In the majority of these patients, the immunosuppressant therapy was carried out in conjunction with the steroid treatment and allowed the later reduction or discontinuation of corticosteroids. There is extensive information about the side effects of these drugs. There are at least four general problems associated with the agents discussed: 1. Bone marrow suppression is a serious potential problem, which can occur early in therapy or after prolonged administration of these drugs and result in serious thrombocytopenic bleeding and a serious granulocytopenic infection. Bone marrow suppression is reversible and can generally be avoided by close surveillance of peripheral blood and platelet counts during therapy. 2. Another important complication is sterilization; both aspermia and lack of oogonia have been reported. Infertility may be reversible when the medicine is stopped, but reversibility is unpredictable. 3. A very obvious danger in the use of these agents is their mutagenic potential; therefore, when treating individuals of childbearing age, it is wise to have the persons involved undergo contraceptive counseling. The use of an intrauterine device seems a reasonable solution to this problem.9" 0 4. The last of these problems involves the well established fact of increased incidence of cancer in individuals subjected to immunosuppres837
Table 1. Immunosuppressive Prescriptions in Uveitis Agent
Dose
Chlorambucil Chlorambucil
0.1-0.2 mg/kg/day 6-8 mg/day >2 mg/day Chlorambucil Cyclophosphamide 50-200 mg/day Methotrexate 25 mg/sq yd/q4D Azathioprine 1.5-3.0 mg/kg/day
sive therapy. Theoretically, there is probably little question that these agents might reduce immune surveillance against cancer, and thereby augment neoplasia.9 All of these complications of therapy are potentially serious. In addition, there are certain characteristic potential complications of some of these agents, eg, methotrexateinduced cirrhosis, osteoporosis, or pulmonary fibrosis; azathioprine-induced rash and urticaria; and cyclophosphamide-induced alopecia or hemorrhagic cystitis. To minimize the occurrence and/or effect of these, the active participation in the care of patients is required of an internist or hemotologist familiar with the use of these agents.
A New Use An interesting and perhaps important new method of "immunosuppression" has been introduced in the treatment of myasthenia gravis.'1 It is fairly certain that myasthenia gravis is a disease caused by an autoantibody to acetylcholine receptors. Plasmapheresis has been combined with prednisone and azathioprine, in order to reduce the level of autoantibody, and has been found to produce striking improvement in myasthenic patients. At the Uveitis Clinic of the University of California at Irvine, the authors are examining this method of reducing autoantibodies and its ability to produce clinical improvement in patients with "autoimmune" uveitis. 838
Disease
Number of Prescriptions
Author
Behcet Behcet Behcet Pars Planitis Sympathetic Ophthalmitis Sympathetic Ophthalmitis
Bietti2 Mano3 O'Connor Buckley & Gills5 Leopold Moore8
Case Report B. F. is a 30-year-old female who presently has a visual acuity of light perception and count fingers vision at one foot. She has carried the diagnosis of Vogt-Koyanagi-Harada disease for six years. The diagnosis was made on the basis of the appearance of viteligo, poliosis, and anterior and posterior uveitis, in the face of frequent severe headaches. Throughout the history of this chronic uveitis, the patient has been treated with cytoxin, azathioprine, and steroids. Ultimately, anterior and posterior uveitis was controlled with a dosage as high as 100 mg of prednisone and 100 mg of azathioprine daily. Any attempt to reduce the steroid dosage below 60 mg of prednisone daily resulted in a flare-up of the uveitis. Because of this, with the patient's fully informed consent, it was decided to make an attempt at immunosuppression through the use of plasmapheresis. The rationale for this was to remove the presumably injurious circulating autoantibodies. The patient underwent plasmapheresis twice a week for six weeks. Plasma (2000 cc or more) was removed at each procedure and replaced wit\h saline and albumin. The dosage of prednisone and azathioprine was maintained at 100 mg each, daily. Prior to the plasmapheresis, indirect immunofluorescence gave minimal evidence of IGA antibody present in the patient's blood to uveal tissue. The authors were not able to demonstrate this antibody after plas-
16 20 5 9, 12 2 1
Number Improved 16 19 4 9, 12 2 1
mapheresis. The pre-plasmapheresis immunofluorescence was minimal and, therefore, this test was nonconclusive. Subsequently, the patient's azathioprine dosage has been reduced to 40 mg daily, and the prednisone dosage to 10 mg daily with maintenance of the visual acuity and without recurrence of the uveitis. It has been necessary for the patient to undergo one further plasmapheresis in order to continue the reduced dosage of azathioprine and prednisone.
Literature Cited 1. Krakoff l: Cancer chemotherapeutic agents. CA 27:130-143, 1977 2. Bietti G, Cerulli L, Pivetti-Pezzi P: Behcet's disease and immunosuppressive treatment. Mod Probl Ophthalmol 16:314-323, 1976 3. Mano J: Treatment of Behcet disease with chlorambucil. Arch Ophthalmol 94:580583, 1976 4. Nozik RA, Godfrey WA, Epstein WV, et al: Immunosuppressive treatment of uveitis. Mod Probi Ophthalmol 16:305-308, 1976 5. Buckley C, Gills J: Cyclophosphamide therapy of peripheral uveitis. Arch Intern Med 124:29-35, 1969 6. Gills J, Buckley C: Oral cyclophosphamide in the treatment of uveitis. Trans Am Acad Ophthalmol Otolol 74:505-508, 1970 7.. Lazor M, Weiner M, Leopold I: Treatment of uveitis with methotrexate. Am J Ophthalmol 67:383-387, 1969 8. Moore C: Sympathetic ophthalmitis treated with azathioprine. Br J Ophthalmol 52:688-690, 1968 9. Steinberg AD, Plotz PH, Wolff SM, et al: Cytotoxic drugs in treatment of nonmalignant diseases. Ann Intern Med 76:619-642, 1972 10. Schein P, Winokur S: Immunosuppressive and cytotoxic chemotherapy: Long-term complications. Ann Intern Med 82:84-95, 1975 11. Dau PC, Lindstrom JM, Cassel CK, et al: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N EngI J Med 297:1134-1140, 1977
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 9, 1979
