Immunosuppressive drugs in immune and inflammatory ocular disease

SURVEY OF OPHTHALMOLOGY

VOLUME 35. NUMBER 5. MARCH-APRIL 1991

THERAPEUTIC

REVIEW

JOEL MINDEL AND SAIICHI MISHIMA, EDITORS

Immunosuppressive Ocular Disease RAMZI HEMADY, M.D., JOSEPH

Drugs in Immune and Inflammatory TAUBER,

M.D., AND C. STEPHEN

Immunology and Cornea Services, Massachusetts Eye and Ear Infirmq, Boston, Massachusetts

FOSTER, M.D.

Harvard Medical School,

Abstract. Advances in immunology, particularly ocular immunology, have been accompanied by

the emergence of safer, more specific immunosuppressive drugs, notably, cyclophosphamide, chlorambucil, methotrexate, azathioprine, cyclosporine A, bromocriptine, dapsone, and colchitine. These drugs have become an important, and often essential, part of the ophthalmologist’s armamentarium against inflammatory and immune-mediated ocular diseases. In order to better acquaint the ophthalmologist with the properties of the most commonly used immunosuppressive drugs, we review the literature Ophthalmol 35:369-385, 1991)

Behcet’s disease cyclitis inflammation rheumatoid arthritis

Key words.

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and relate our own experience

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immunology immunosuppressive drugs systemic lupus erythematosus uveitis l

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The eye is susceptible to the deleterious effects of an unchecked immune response. Structural alterations of ocular tissues such as cornea or retina result in permanent loss of function due to loss of clarity, improper anatomic organization, or impaired physiologic functions. Appropriate suppressors of the immune inflammatory response to infections, trauma, surgery, and stimulation by foreign or self-antigens is critical to the preservation of the transparency of ocular media and the integrity of the visual system. Developed in the 195Os, topical and periocular steroid preparations dramatically changed the outcome of many previously blinding conditions.s0*81 For many years, however, these synthetic corticosteroids were the only therapeutic agents available for effective suppression of ocular inflammation. In the 1960s other immunosuppressors came to occupy an increasingly important role in the manage-

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ment of ocular inflammatory and immune-mediated diseases, as reported by Newe11,‘4’*142Wong,217-221 and others. The armamentarium of the physician who manages inflammatory and immunologic ocular diseases has greatly increased over the past three decades; this expansion became possible, in part, because of improved understanding of the immune system’s complicated role ‘in certain “local” ocular diseases and in the ocular manifestations of systemic diseases.6g*g5*102*20g The immune system can be involved in protection from, recovery from, or production of inflammatory or immunologic diseases. For example, antibodies against ocular tissue have been identified in experimental models of uveitis; increased peripheral blood lymphocyte blastogenesis to retinal-S antigen has been demonstrated in patients with birdshot choroidopathy; and a role for T-helper, cytotoxic, or suppressor cells has been 369

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postulated in several uveitis entities (sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome).“gs g5~‘02In addition, the pharmacologic and therapeutic properties of many immunosuppressive drugs, which were originally designed for treating malignant neoplasms, have been better elucidated. Improved understanding of their complex properties has prompted their use in managing other diseases. Meanwhile, more specific immunosuppressive drugs, such as cyclosporine, have emerged and found a role in ophthalmic practice. Initially, concern about the low therapeutic index of immunosuppressive drugs limited their use to the treatment of corticosteroid-resistant, sightthreatening ocular diseases or cases in which corticosteroids had produced unacceptable adverse effects. As experience in using these drugs increased, however, they gained recognition as the treatment of choice for a number of diseases, such as Wegener’s granulomatosis and Behset’s syndrome, for which they may effect longterm remission or cure. In fact, when administered at properly adjusted doses by physicians trained in their use and monitoring, these potentially toxic agents appear to produce fewer adverse effects than does chronic treatment with corticosteroids which commonly produce secondary diabetes mellitus, peptic ulcer disease, osteoporosis, hypertension, myopathy, Cushing’s syndrome, psychosis, and other adverse effects 32.187204 The purpose of this review is to familiarize ophthalmologists with immunosuppressive drugs available for the treatment of ophthalmic diseases and to discuss their unique properties.

I. Immunosuppressive

Drugs

A. CYCLOPHOSPHAMIDE 1. Class and Mechanism Cyclophosphamide (Cytoxan@) is the most widely used nitrogen mustard derivative. It is an alkylating agent that has its active moieties generated in viva by the hepatic microsomal system. The resulting metabolites undergo strong electrophilic chemical reactions with nucleophilic substances resulting in the formation of covalent linkages (alkylation).” By primarily targeting the 7-nitrogen atom of guanine, cyclophosphamide leads to the formation of guanidine-thymidine linkages with resultant DNA miscoding; various other reactions are also possible.” Resistance and cross-resistance to the actions of cyclophosphamide occur by mechanisms which are still unclear.” Earlier reports stressed the inhibitory effects of cyclophosphamide on the humoral immune system, with resultant suppression of primary and sec-

HEMADY ET AL It is now ret_ ondary antibody responses. 121~189~198~218 ognized that cyclophosphamide also suppresses the cellular immune system. In animal models, low doses of cyclophosphamide preferentially suppress T-suppressor cells, and result in the expression of immunoreactivity, whereas higher doses suppress both T-suppressor and T-helper cells, and result in suppression of delayed-type hypersensitivity (DTH) responses and suppression of T-cell mediated humoral responses, respectively.6~‘8g~200In mice, antigen-specific cytotoxic T-cell (CTL) functions are enhanced by pretreatment with low doses of cyclophosphamide; this is probably secondary to cyclophosphamide-induced suppression of T-suppressor cell activity.‘78,‘7g 2. Indications The pioneering work of Fauci and Wolff established cyclophosphamide as the treatment of choice for Wegener’s granulomatosis.53’54*2’6 Before the introduction of cyclophosphamide, the prognosis for these patients was extremely grave; the use of cyclophosphamide, in combination with corticosteroids, markedly improved survival. In an excellent review in 1974, *I6 Wolff demonstrated that remissions correlated with the level of lymphopenia and that profound leukopenia was not necessary for induction of remissions. Clinical improvement was noted at total white blood cell counts of 3000 and neutrophil counts of 2000. The risk of infection at these neutrophil counts is low. Several authors in addition to Wolff and Fauci have demonstrated that cyclophosphamide, alone or in combination with corticosteroids, is superior to corticosteroids alone in controlling the ocular manifestations, especially the necrotizing scleritis, of Wegener’s granulomatosis (Fig. 1) 30.59,96.193 Cyclophosphamide is also used in the management of rheumatoid arthritis and its associated ocular manifestations.56’60’99 Its use correlates favorably with the survival of patients with active systemic and necrotizing rheumatoid arthritis.60 Our group found that cyclophosphamide controlled inflammation in a group of five patients suffering from necrotizing scleritis associated with relapsing polychondritis that had not responded to corticosteroids, dapsone, and other immunomodulating agents.88 Cyclophosphamide has achieved encouraging results in controlling the inflammatory activity of cicatricial pemphigoid affecting the eyes. In a ramdomized, double-masked, clinical trial, Foster demonstrated superior control of inflammation using cyclophosphamide with prednisone versus therapy reprednisone alone. 58Cyclophosphamide sulted in diminished conjunctival shrinkage in the

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Fig. I. A: Patient with Wegener’s granulomatosis related diffuse, anterior scleritis prior to initiation of therapy. B: Same patient after administration of cyclophosphamide, 100 mg orally for one month, showing marked resolution of inflammation and an area of scleral thinning.

Fig. 2. A: Peripheral cornea1 thinning, inflammatory cell infiltration, and redness, in a patient with Mooren’s peripheral cornea1 ulceration. B: Same patient after six weeks of cyclophosphamide, 125 mg given orally, showing halting of ulceration and absence of infiltration in an uninflamed eye.

series of patients with cicatricial pemphigoid reported by Mondino and Brown,“‘j although disease progression was noted in some eyes. Foster’s group reported that four of eight patients with Behcet’s syndrome responded favorably to treatment with cyclophosphamide; two had had persistent inflammation when treated with chlorambucil, but responded to intravenous cyclophosphamide.’ Gills and Buckley reported that a patient with BehCet’s syndrome who had not responded to corticosteroids alone showed ocular and systemic improvement after treatment with oral cyclophosphamide. ” Oniki et al found cyclophosphamide to be superior to corticosteroids in controlling the ocular inflammation associated with BehGet’s syndrome. 15’ Mooren’s ulcer is a rare but potentially blinding disease of the cornea. Prior to the use of cyclophos-

phamide, therapy often failed to halt the progressive cornea1 destruction characteristic of the bilateral form of this disease. Foster and colleagues reported excellent recovery rates,57 and Brown and Mondino” reported improved prognosis in cases of bilateral Mooren’s ulceration when cyclophosphamide was used (Fig. 2). Scattered reports describe the efficacy of cyclophosphamide in the treatment of sympathetic ophthalmia,‘28 ocular and systemic manifestations of polyarteritis nodosa52~‘17 and relapsing polychondritis g4~18’~p24 orbital vasculitis,” peripheral uveitis refraitory to corticosteroids,5’*76 and experimental cornea1 ulceration.63 3. Dose and Route The recommended dose of cyclophosphamide to treat ocular diseases is l-2 mg/kg/day, adminis-

IMMUNOSUPPRESSIVE DRUGS IN OPHTHALMOLOGY our patients. The mechanism(s) of these ocular side effects is unclear; furthermore, there is no evidence that they are causally related to therapy with cyclophosphamide. B. CHLORAMBUCIL 1. Class and Mechanism Chlorambucil (Leukeran’a), the slowest-acting nitrogen mustard derivative, shares many properties with cyclophosphamide. 2. Indications After a favorable report by Mamo and Azzam appeared in 1970, ‘X chlorambucil gained popularity among ophthalmologists and rheumatologists for the treatment of Behcet’s syndrome, a potentially blinding and lethal disease. With the notable exception ofTabbara’s report in 1983,“’ many reports by different authors subsequently confirmed these resome reporting longterm sults 14,22,78.145.156~~68,192,907 remissions and cures.2’4g These events prompted many to recommend chlorambucil as the first line of therapy in patients with BehGet’s syndrome. Although we have not found a single therapeutic agent to be efficacious in all our patients with BehGet’s syndrome, we agree that chlorambucil may be the single most efficacious agent. Eight of 29 patients with Behcet’s syndrome were treated with chlorambucil; longterm control of inflammation was achieved in all but one (Fig. 3).’ and, more recentGodfrey et al, 78S’45Martenet,’ ly, Jennings and Tessler” have presented data suggesting that chlorambucil may be of use in the treatment of sympathetic ophthalmia. Ocular inflammation associated with juvenile rheumatoid arthritis is often relentless and unresponsive to treatment. Kanski reported encouraging results in five out of six patients with ocular inflammation associated with juvenile rheumatoid arthritis treated with chlorambucil,‘03 and Godfrey et al reported intermediate results in one patient.78 We observed favorable responses in two patients with iridocyclitis associated with juvenile rheumatoid arthritis, one of whom had been unresponsive to topical and systemic corticosteroids, nonsteroidal antiinflammatory agents, azathioprine, or methotrexate.“’ 3. Dose and Route Several dosages have been advocated. Godfrey recommended 2 mg/day (administered orally), increased each week by an additional 2 mg/day to a maximum of 10-12 mg/day, or until a favorable response was achieved (typically 34 weeks after initiation of therapy). If no response was observed at this dosage and no adverse effects were noted,

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Godfrey recommended increasing it up to as much as 22 mglkglday. 78 We recommend a dose of 0.1 mg/kg/day, with adjustments every three weeks based on clinical response and tolerance, and a maximum daily dose of 18 mg/day (used only to treat severe, sight-threatening inflammation in patients who are tolerating the drug well). We emphasize that safe use of chlorambucil requires close attention: the potential for adverse effects, particularly bone marrow suppression, increases exponentially at doses above 10 mgiday; abrupt and profound leukopenia can occur. 4. Toxicity Tabbara reported significant interference with spermatogenesis in all his male patients treated with chlorambucil, and irreversible azoospermia in some.“’ Callis reported minimal effects on the male reproductive system if the dosage was less than 0.2 mg/kg/day, and if treatment lasted no longer than six weeks.” In addition, recovery of spermatogenesis was possible within three years after discontinuation of therapy if the total accumulated dose did not exceed 400 mg. Moderate, but rapid, myelosuppression necessitates careful monitoring of hematologic parameters. Although chlorambucil-induced myelosuppression reversible,‘* we have is often encountered two patients in whom relative leukopenia persisted for months after withdrawal of chlorambucil. Therapy was discontinued in one of the two because of profound leukopenia. A patient in the series reported by Colvard et al in 1977 died with severe pancytopenia two years after cessation of chlorambucil therapy.3g Malignancies, mostly leukemias, were reported when chlorambucil was used for prolonged periods in the treatment of myeloproliferative disorders.‘g,34*‘g5 Other less common adverse effects are possible.‘* C. METHOTREXATE 1. Class and Mechanism The antimetabolite methotrexate (Folex@, Mexate@) was first introduced in 1958 for the treatment of leukemias. The FDA approved its use for the treatment of psoriasis in 197 1; more recently it has been used to treat other nonmalignant conditions, such as adult and juvenile rheumatoid arthritis. Methotrexate is a folic acid analog. Its primary site of action is the enzyme dihydrofolate reductase (DHFR), which catalyses the reduction of folate to tetrahydrofolate, a compound essential for the synthesis of DNA and RNA. Both B and T cell functions are suppressed. 79,2’3 Three mechanisms of resis-

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tance to methotrexate have been described.‘3 When methotrexate is given in high doses (as in the treatment of malignancies), Folinic acid (Leucovorin@), a fully reduced and metabolically functional folate coenzyme, is also administered to protect normal tissues from the effects of the drug.73 2. Indications In the mid- 196Os, Wong et al administered intravenous methotrexate to 10 patients with cyclitis that was not responding to corticosteroids or other conventional therapeutic measures; favorable and prompt responses were reported in nine patients.“7~“0 Reversible hepatotoxicity and mild hematologic toxicity were documented. The same authors successfully used intravenous methotrexate to treat a patient with sympathetic ophthalmia that was responding poorly to corticosteroids.“’ McMaster et al also demonstrated that methotrexate prevented the development of experimental uveitis in guinea pigs. ‘33 Lazar and coworkers confirmed Wong’s observations, achieving good results in 14 out of 17 patients with various corticosteroidresistant uveitis syndromes treated with intravenous methotrexate.“5 Four patients with sympathetic ophthalmia responded particularly well. Significant complication rates were reported, however; gastrointestinal complications developed in 13 patients, stomatitis in 11. Secondary infections, including one case of varicella zoster,“4 developed in four patients. Laboratory evidence of liver damage was also found in four patients. Concern about adverse effects has limited the role of methotrexate in the treatment of ocular diseases. We used it to treat patients with scleromalacia, necrotizing scleritis, and episcleritis with mixed results; inflammation was controlled in some cases, but scleritis, complicating relapsing polychondritis, failed to respond in two patients.” In two of our four juvenile rheumatoid arthritis patients, iridocyclitis that had not responded to conventional therapy was well controlled by weekly intramuscular doses of methotrexate (unpublished data). 3. Dose and Route Several excellent reviews in the dermatologic literature, most notably a cooperative study published in 1973, recommend infrequent, low doses of methotrexate given orally, intravenously, or intramuscularly (lo-25 mg divided over 36-48 hours, every l-4 weeks). *‘* This schedule leads to significantly less hepatotoxicity, a potentially serious adverse effect of methotrexate, and does not necessitate rescue with leukovorin. Most is excreted unchanged in the urine.” Methotrexate is rapidly

HEMADY ET AL absorbed

when given orally.

4. Toxicity Methotrexate-induced hepatic fibrosis and cirrhosis are of significant concern, especially in the presence of other conditions affecting the liver (alcoholism, obesity, diabetes mellitus). Hepatotoxicity is also related to the total dose of methotrexate. Pretreatment and follow-up (every six months or yearly) liver biopsies are indicated if the patient has preexisting liver disease; otherwise every two to three years (or every 1500 mg cumulative dose), since serum liver function tests are unreliable indices of methotrexate-induced hepatotoxicity ‘8*42~‘75~2”~2’2 (Health and Public Policy Committee, American College of Physicians). Ulcerative stomatitis and diarrhea are common complications that can be sources of significant concern and of discomfort for the patient4’,‘**; a reduction in dose may be helpful. Bone marrow suppression and other side effects are relatively uncommon. Pancytopenia, however, was recently reported with low-dose methotrexate therapy.‘44*‘g’ Methotrexate-induced interstitial pneumonitis leading to pulmonary fibrosis may occur at any dose. Should this occur, methotrexate should be discontinued. Ocular effects are not uncommon. Ocular irritation, aggravation of seborrheic blepharitis, photophobia, and tearing develop in 25% of patients.65 These problems usually improve with time and do not necessitate termination of therapy. D. AZATHIOPRINE 1. Class and Mechanism Azathioprine (Imuran@), a derivative of 6-mercaptopurine,48*74 was one of the first immunosuppressants used in the treatment of ocular immune-mediated disorders. It is a purine analog that is activated in the liver. The metabolites produced interfere with the synthesis of purine bases and are incorporated into DNA and RNA.74 The drug is relatively selective in its toxicity to T-helper/inducer cells. Seven mechanisms of resistance to azathioprine have been described.74 2. Indications Azathioprine has been extensively used to prevent renal graft rejections. The efficacy of azathioprine in the management of autoimmune diseases, especially systemic lupus erythematosus (SLE) and Wegener’s granulomatosis was substantiated by Corley,40 and later Bouroncle.** Subsequent reports in the ophthalmic literature described successful control of corticosteroid-resistant uveitis

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syndromes (peripheral uveitis, Behcet’s syndrome) with azathioprine, alone or in combination with corticosteroids or other immunosuppressives. Watson recommended azathioprine as a steroid-sparing agent for the control of scleritis,210 and Koyama et al recommended it for the control of the destructive ocular and systemic manifestations of Wegener’s granulomatosis.“’ Hoang-Xuan et al reported that two of three patients with scleritis associated with relapsing polychondritis responded favorably to azathioprine.” Several studies have produced conflicting results. Newell treated 20 patients with uveitis of different etiologies with azathioprine; results were most remarkable in those with pars planitis.14’ Andrasch and colleagues treated 22 patients suffering from various uveitis syndromes with azathioprine and corticosteroids3 Responses were favorable in 12 patients, but azathioprine was discontinued in four patients because of inadequate response and in six because of gastrointestinal distress. In contrast, Mathews et al, in a controlled, double-blind study, showed that azathioprine was no more effective than a placebo in controlling the inflammatory activity of iritis or iridocyclitis.‘30 Using a combination of corticosteroids and azathioprine, Moore in 1968 apparently arrested the inflammatory activity of sympathetic ophthalmia in and Newell and a child.13’ Reports by Martenet”’ Krill,14’ however, did not corroborate his success. Leibowitz and Elliott,“s~“g Polack,16g and, later, Barraquer” reported that azathioprine prolonged cornea1 graft survival in an animal model and in humans. In a recent superb, double-masked, randomized, controlled study, azathioprine (2.5 mg/kg/day) prevented the development of new eye disease and decreased recurrences of ocular and systemic inflammation in patients with Behget’s syndrome.2’5 Serious adverse effects were not encountered. In earlier reports, Rosselet et al,lso FranGois and Van Oye,64 and Bietti et al** had noted favorable outcomes in patients with Behcet’s syndrome treated with azathioprine, whereas results reported by Aoki and Sugiura4 and Martenet”’ had been unimpressive. Foster’s group recently reported mixed results among eight patients with Behcet’s syndrome: Inflammation was controlled in one patient receiving azathioprine and corticosteroids, and in two patients receiving azathioprine and cyclosporine; severe leukopenia developed in one patient, which necessitated withdrawal of treatment.’ Azathioprine is effective in controlling the inflammatory activity associated with cicatricial pemphigoid if used as an adjunctive agent, but not as the first line of therapy.“’

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3. Dose and Route A single or divided oral dose of azathioprine, totaling l-2.5 mg/kg/day is suggested. This amount should be reduced by 25% if allopurinol is used concomitantly (allopurinol inhibits the enzyme xanthine oxidase, thus impairing the conversion of azathioprine to inactive metabolites).74 4. Toxicity Most reports in the ophthalmic literature claim minimal complications with azathioprine. Careful monitoring of the complete blood cell count, white blood cell differentials, and platelet levels is essential, however, because bone marrow suppression and leukopenia are common. Monitoring of blood cell counts should follow the guidelines suggested above for cyclophosphamide. Gastrointestinal distress is a relatively common adverse effect; others include secondary infections, stomatitis, and alopecia.74 Two patients with SLE treated by Foster with azathioprine developed arthritis that responded to discontinuation of the drug (unpublished data). Newell and Krill reported transient arthralgias in two patients.14’ No ocular toxicities have been reported yet. E. CYCLOSPORINE

A

1. Class and Mechanism Cyclosporine (Sandimmune@), an oil-soluble fungal metabolite, was isolated from extracts of Tolypoclad&m injlatum Gams cultures in 1970.25 In 1972, Jean Bore1 and coworkers were the first to demonstrate the profound immunosuppressive properties of this cyclic endecapeptide, which has become one of the most important immunosuppressant agents pharmacology in use today. 26 The immunology, and clinical uses of cyclosporine were the subject of an excellent review in Survey of Ophthalmology several years ago.14’ Despite extensive study, the drug’s mechanism of action remains incompletely understood; it apparently involves numerous sites related to the process of T cell activation. Cyclosporine interferes with receptors on the surfaces of T lymphocytes that recognize the DR (Ia-like) antigens present, most notably, on antigen-presenting cells.27~“‘~‘5s Thus, cyclosporine inhibits the responses of T lymphocytes, especially T-helper cells, to antigen presentation and to interleukin-1 (IL-l), processes that are central to T cell activation and the subsequent production of interleukin-2 (IL-2). The responsiveness of primed T lymphocytes is, however, unimpaired.“’ Cyclosporine interferes also with the expression of IL-2 receptors on the surface of T lymphocytes and with IL-2 release.85 Some evidence

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Fig. 4. A: Patient with birdshot retinochoroidopathy showing a hazy vitreous with a poor view of retinal details. B: Same patient showing marked clearing of vitreous infiltrates three weeks after initiation of cyclosporine, 400 mg/day, orally.

indicates that it blocks transcription of mRNA specific for the production of lymphokines.‘~‘00~‘73 Preliminary reports suggest that cyclosporine might have an inhibitory effect on mast cells.206 Larson and Russell and colleagues, in several reports, suggest that cyclosporine induces its immunosuppressive action through specific blockade of the prolactin receptor on lymphocytes (prolactin being a potent immunostimulator).“3~‘82-‘84 Lymphocyteprolactin binding is enhanced at low cyclosporine doses (causing immunostimulation), and inhibited at high therapeutic doses (resulting in immunosuppression). ’ I3 The effects ofcyclosporine on the immune system might be mediated by the binding of cyclosporine to the cytosolic proteins calmodulin and cyclophilin.38,s2*‘7’ More recently, the work of Emmel and colleagues suggests that cyclosporine inhibits the function of nuclear proteins critical to T lymphocyte activation or inhibits the action of a more proximal member of the signal transmission cascade leading from the antigen receptor to the nucleus.50 The bone marrow, T-suppressor lymphocytes, and B lymphocytes are relatively spared from the effects of cyclosporine.27~“’ 2. Indications Systemically administered cyclosporine inhibited experimental autoimmune uveitis in rats.‘52-‘54 Cyclosporine has been used to treat a wide variety of ocular immune-mediated conditions. Nussenblatt and colleagues at the National Institutes of Health published several reports attesting to the efficacy of cyclosporine, at doses of 8-10 mg/kg/day, in patients with uveitis of noninfectious causes (including Behcet’s syndrome, birdshot retinochoroidopathy,

sarcoidosis, pars planitis, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, and idiopathic vitritis) that was refractory to corticosteroids and cytotoxic agents (Fig. 4).“6,‘48~14g~‘5’~‘”Results were especially impressive in patients with Behset’s syndrome.‘48,‘50 Unfortunately, this dosage was later found to be profoundly nephrotoxic. Little is known about the efficacy of the low-dose cyclosporine therapy (maximum, 7 mg/kg/day) recommended to reduce nephrotoxicity.“‘*‘“O Binder’s results in patients with Behset’s syndrome were disappointing; recurrences were frequent and often more severe when cyclosporine dosage was below 7 mg/kg/day. 23Towler et al documented improved visual acuity in 11 of 15 patients with various uveitis syndromes, including one patient with Behcet’s syndrome and two patients with sarcoidosis, after treatment with low doses of cyclosporine. Improvement in ocular inflammation did not correlate with improvement in acuity, however.*05 In a study by Baer, Foster, and Raizman, 10 of 29 patients with Behget’s syndrome received cyclosporine at a dose of 5 mg/kg/day, with or without bromocriptine.’ Inflammation was controlled in three patients, two of whom were receiving azathioprine concomitantly. Cyclosporine was discontinued in five because of therapeutic failure, and in two because of adverse effects. Two reports have supported the efficacy of systemic cyclosporine in halting cornea1 melting associated with Wegener’s granulomatosis.‘Og~’ lo Three publications have reported favorable results with topical cyclosporine therapy for cornea1 ulceration with or without scleral melting.8g~‘47~2’4Holland et al recently reported successful use of topical cyclosporine to treat ligneous conjunctivitis in two patients.gO These reports, however, were all uncon-

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trolled studies and involved small numbers of patients. A pilot study by BenEzra et al indicated that topical cyclosporine alleviates the symptoms of vernal Using a canine model of keratoconjunctivitis.‘5 spontaneous keratoconjunctivitis sicca, Kaswan et al recently showed that topical application of 2% cyclosporine increased tear production, decreased cornea1 neovascularization, and increased healing of cornea1 ulcers. lo4 Double-blind, masked trials are currently in progress at our institution to evaluate the efficacy of topical cyclosporine in vernal keratoconjunctivitis and keratoconjunctivitis sicca in humans. An exciting area of research is the use of cyclosporine in the management of high-risk penetrating keratoplasty. A host of uncontrolled studies by many authors have indicated that systemic or topical cyclosporine prolongs survival of cornea1 transplants in animal-models of high risk cornea1 transHill87 and plantation. 13,41~55~91~92~101~‘27~143~186 Similarly, Miller et a1’34 reported impressive graft survivals in high-risk patients treated with systemic cyclosporine. Topically administered cyclosporine also appears to aid graft survival in high risk patients.‘2,7g A multicenter trial of topical cyclosporine in the prevention of rejection following high risk cornea1 transplantation has begun. Its findings could present an important breakthrough in the pharmacotherapy of cornea1 transplant patients. 3. Dosage Absorption following oral administration is variable, incomplete, and slow; peak blood levels are achieved 2-4 hours after ingestion.2’*222 Cyclosporine undergoes slow oxidation by the hepatic cytochrome P-450 system into metabolites that include some active immunosuppressants.67 Most of the metabolites are excreted in the bile, and 6% is excreted by the kidneys.222 Animal studies have shown excellent cornea1 absorption of topical cyclosporine, with significantly lower levels in the conjunctiva, aqueous, and deeper intraocular tissues.‘38*‘43*‘46,2’5Depending on the specific vehicle employed, significant tissue levels may be maintained for 12 to 24 hours.‘38’43 Recent studies in humans and rabbits revealed insignificant plasma levels of cyclosporine after topical application of 1% or 2% solutions.46*‘38 Although oral cyclosporine dosage was as high as 10 mg/kg/day in early therapeutic trials,‘48,‘5’*‘64 the discovery of cyclosporine-induced toxicities prompted a reduction in the recommended dosage to 5-7 mg/kg/day. Renal function should be carefully followed. 23*205Serum drug levels should be monitored, since these findings correlate with immuno-

suppressive activity and renal toxicity.226 Authors disagree as to the best method for monitoring serum cyclosporine levels, however. Radioimmune assay (RIA) which determines levels of certain metabolites as well as the parent compound, yields levels 30-100% higher than does high-performance liquid chromatography (HPLC), which determines levels of the parent compound on1y.‘20*‘g7Keown et al, using RIA and determination of systemic immune parameters, found trough levels of 0.1-0.4 ug/ml to be ideal for immunosuppression.‘06 Little has been published about the optimal topical dosage with cyclosporine, but most animal studies utilize a 1% or 2% solution administered up to five times daily,g’,‘04~‘g0and human studies have all utilized a 2% solution.12’15 4. Toxicity Cyclosporine is no safer than other immunosuppressive drugs and requires expert management. Nephrotoxicity is the most serious adverse effect of systemic cyclosporine use. Some alteration in renal function was detected (decreased glomerular filtration rate, reduced creatinine clearance, increased blood urea nitrogen) in virtually 100% of patients treated with cyclosporine at doses of 10 mglkgiday. ” Most early nep hrotoxicity appears to be physiologic rather than morphologic (possibly resulting from an imbalance between glomerular arteriolar constrictors and dilators) and is reversed by lowering dosage; however, chronic, irreversible interstitial fibrotic and atrophic changes have also Although the immune_ been reported. ‘6,98.99*‘39,‘59 suppressive activity of cyclosporine is directly related to serum drug levels, therapeutic efficacy might be preserved at dosages as low as 2-5 mg/kg/ which limit nephrotoxicity. These results day, ‘07~‘60 require further confirmation. Parasthesias, temperature hypersensitivity, nausea, and vomiting are common, but rarely require discontinuation of therapy.45*83~gg~147*‘63 Mild to moderate hypertrichosis commonly occurs during the first months of therapy and can be distressing to female and pediatric patients.gg~‘47~‘63Gingival hyperplasia, similar to that induced by phenytoin, occurs in as many as 25% of patients after the third month of therapy and is exacerbated by poor oral hygiene.‘47s223 Neurotoxicity has been detected in 25% of patients after liver transplantation; difficulties include fine hand tremors and a reversible myopathy.83,gg Laboratory findings include mild anemia in 5-25% of patients, and increased erythrocyte sedimentation rate.16’ Dose-dependent, reversible hepatotoxicity occurs in 3449% of transplant patients receiving cyclosporine,gg*‘24 but this is less common

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in patients treated for ocular inflammation.“j’ Among renal transplant recipients, hyperuricemia is a common complication (occurring in 30-84% of patients), and gouty arthritis appears to cause significant morbidity. “’ C yclosporine was also recently shown to elevate total serum cholesterol levels in renal transplant recipients, possibly by increasing light-density lipoprotein levels8 Hypertension develops or is exacerbated in 15-25% of patients using cyclosporine. This effect can be reversed by lowering of dosage and the use of antihypertensive agents.45 Anecdotal reports of lymphomas in patients using cyclosporine have been published, but no convincing data support this association.36*203 None have been reported in the ophthalmic literature. Topical preparations of cyclosporine commonly cause redness, itching, tearing, burning, which are probably reactions to the vehicle. No reports associate elevated intraocular pressure, cataracts, or retinal disease with topical cyclosporine. A moderate increase in the number of goblet cells in rabbit conjunctiva was reported after topical application of a 4% solution of cyclosporine.24 F. BROMOCRIPTINE 1. Class and Mechanism Bromocriptine (Parlodel@) is a semisynthetic ergot alkaloid widely used in the management of patients with Parkinson’s disease and hyperprolactinemit conditions.208 It decreases both cellular and humoral immunoreactivity in animals and inhibits inflammation in animal models of autoimmune diseases, especially when used with other immunosuppressive drugs.‘7*‘40,‘6’ The exact mechanism(s) of bromocriptine’s effects on the immune system are unclear. A dopamine agonist, bromocriptine inhibits the secretion of prolactin. Prolactin is a potent immunomodulator1’3,‘55 that binds to receptors on B cells, and competes with cyclosporine for receptors on T cells.‘82-‘84 Bromocriptine thus increases the effectiveness of a given dose of cyclosporine. 2. Indications In 1985 Hedner and Bynke reported that four patients with steroid-dependent iridocyclitis of various causes were treated with bromocriptine for Parkinson’s disease or hyperprolactinemia. The iridocyclitis was controlled, and the steroids were withdrawn. Inflammation resumed when bromocriptine was discontinued.84 Subsequently, Nussenblatt and Palestine found bromocriptine to be an effective adjunct to low-dose cyclosporine in treating Behcet’s syndrome and in controlling experimental autoimmune uveitis in rats.‘61,165 In a small

randomized, double-masked study, however, the same authors could not demonstrate efficacy ofbromocriptine alone in the treatment of recurrent anterior uveitis,16’ although inflammatory activity in certain cases was controlled. Recent reports by Lopatynsky and Krohel’*’ and by Kazeev et allo5 described successful control of thyroid ophthalmopathy with bromocriptine. 3. Dose and Route Bromocriptine is given orally, 2.5 mg, three or four times a day (see section 4 below for initiation of therapy).'23.'61."08 It is rapidly but incompletely absorbed; metabolism is rapid (half-life, three hours) and excretion is mostly in the stools.*” 4. Toxicity Early adverse effects, including nausea, vomiting, and postural hypotension,208 can be reduced by starting with a low dose (1.25 mg) at bed time, with food; dosage is increased gradually. A first-dose phenomenon of cardiovascular collapse can occur.*08 Although longterm complications are also possible, tolerance often develops. Dry eye symptoms secondary to bromocriptine have been reported.68 G. DAPSONE 1. Class and Mechanism Dapsone possesses antibacterial properties similar to those of the sulfonamides and is widely used in the treatment of leprosy and dermatitis herpetiformis.44,“2 It is the most commonly used sulfone. The mechanisms by which dapsone influences the inflammatory and immune systems are unclear, but evidence suggests that it stabilizes lysosomal membranes, decreasing the release of lysosomal enzymes.gs’12 Dapsone also suppresses Arthus reactions and interferes with the myeloperoxidaseH,O,-halide-mediated cytotoxic system of polymorphonuclear leukocytes’12*‘g6; additional effects are possible.“* 2. Indications Person and Rodgers found dapsone to be beneficial in controlling the systemic and ocular inflammatory activity of cicatricial pemphigoid, a disease that can lead to blindness and death.‘@‘,l” The experience of Foster and coworkers, who treated more than 130 patients with cicatricial pemphigoid confirmed favorable systemic and ocular outcomes in those treated with dapsone;58~62~202 approximately 70% of patients responded well (Fig. 5). Although recurrences commonly occurred after cessation of therapy, Foster et al recommend dapsone as the drug of choice if the inflammatory activity is not

IMMUNOSUPPRESSIVE DRUGS IN OPHTHALMOLOGY

379

Fig. 5. A: Patient with active cicatricial pemphigoid stage 2 (Foster’s staging). B: Same patient five weeks after beginning 50 mg/day dapsone showing uninflamed conjunctiva.

extreme, the disease progression is not rapid, and the patient has normal levels of glucose-6-phosphate dehydrogenase (G-6PD).*‘* Response is usually observed within four weeks of initiation of therapy. Recently, dapsone has been reported to be useful for treating the systemic manifestations of relapsing polychondritis,10~12g~176but its effects on the ocular manifestations of the disease are still uncertain.g4*19’ Foster and coworkers used dapsone, with or without corticosteroids, to treat 11 patients with scleritis associated with relapsing polychondritis, favorable responses were observed in six.88 The possible benefits of dapsone in other immune-mediated diseases, such as systemic lupus erythematosus,185 are unclear.

result from dapsone’s ability to oxidize intracellular glutathione, the reduced form of which is essential to the protection of red blood cells from hemolysis. Other possible adverse effects include an infectious mononucleosis-like syndrome (which can be fatal), methemoglobinemia, gastrointestinal upset, blurred vision, reversible peripheral neuropathy, and psychosis.44,‘12 Although none of Foster’s 20 cicatricial pemphigoid patients that were treated with dapsone were G-6PD deficient, anemia developed in all, nausea in four, abdominal pain in two, hepatitis in one, and reversible peripheral neuropathy in one.58

3. Dose and Route

Colchicine is an antiinflammatory agent best known for its use in the treatment of gout.**’ By binding to microtubular proteins, it interferes with the function of the mitotic spindle and causes depolymerization and disappearance of fibrillar microtubules in granulocytes and other motile cells.47* ‘25~167Thus, it inhibits migration of granulocytes, which release lactic acid and inflammatory enzymes, to sites of inflammation. A role for colchicine as an antimitotic agent has been proposed since its prevention of spindle formation can arrest cell division in metaphase.75 Cells with the highest rate of division are affected earliest.

Therapy begins with an oral dose of 25 mg given twice a day for one week. This dosage is increased to 50 mg twice a day, with further adjustments depending on therapeutic response and drug tolerance.58 Orally administered dapsone is slowly, but almost completely, absorbed and is acetylated in the liver; approximately 80% is excreted in the urine.“* 4. Toxicity Dose-dependent hemolytic anemia is the most common adverse effect of dapsone44*112 and is invariably present if the daily dose equals or exceeds 200-300 mg.44 Anemia usually does not occur for three to four weeks after therapy is started in normal individuals. However, since hemolysis is more common, more severe, and occurs earlier and at lower drug doses in individuals with G-6PD deficiency, G-6PD levels must be determined before the initiation of therapy.44*“2 Hemolysis is thought to

H. COLCHICINE 1. Class and Mechanism

2. Indications Alone or in combination with other agents, chicine has proven effective in controlling the lar and systemic manifestations of Behcet’s drome.66~86~1s2~‘95~‘7* Mizushima et al reported 104 of 13 1 patients with Behcet’s syndrome

colocusynthat re-

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TABLE 1

TABLE 2

Summary of Immunosufipressives: Class, Route, and DosaKe

Summary of Immunosup@essives: Major Indications

Route and Dosage

Class Cyclophosphamide Chlorambucil Methotrexate

Alkylating

agent

Alkylating agent Antimetabolite

Azathioprine

Antimetabolite

Cyclosporine

Antibiotic

Bromocriptine

Ergot alkaloid

Dapsone

Sulfone

Colchicine

Antiinflammatory

P.O., I.V., l-2 mglkglday P.O., 0.1 mg/kg/day P.O., I.V., I.M., lo-25 mg every l-4 weeks, over 3648 hrs. P.O., l-2.5 mg/kg/day P.O., 5-7 mg/kg/day topical, 5 x /day P.O., 2.5 mg, 3-4 x /day P.O., 25-50 mg, 2-3 x /day P.O., 0.5-0.6 mg, 2-3 x /day

sponded to colchicine,rs5 probably because of the drug’s inhibition of leukocyte migration and chemotaxis. Baer et al used colchicine in the treatment of 19 patients with Behcet’s syndrome.’ Three with mild disease responded to colchicine alone, without further flare-ups; concomitant immunosuppressive therapy was required in 15. Colchicine was withdrawn from one patient because of diarrhea. In two patients with relapsing polychondritis, three attacks (one with associated episcleritis) responded to treatment with colchicine.5 This finding has not been confirmed by other reports.

Cyclophosphamide

Chlorambucil Methotrexate Azathioprine

Cyclosporine

Bromocriptine Dapsone Colchicine

4. Toxicity Colchicine is well tolerated in moderate doses, although gastrointestinal upset is a common adas hemorverse effect. 75 Acute toxicity manifests rhagic gastroenteritis, nephrotoxicity, vascular damage, muscular depression, and ascending paralysis of the central nervous system.75 Chronic administration can lead to agranulocytosis, aplastic anemia, alopecia, myopathy, and azospermia.75

II. Conclusions and Future Considerations Advances in diagnostic approaches to immunemediated diseases and increased knowledge of ba-

Behset’s syndrome, cicatricial pemphigoid, Wegener’s granulomatosis Mooren’s ulceration, rheumatoid arthritis, sympathetic ophthalmia Behfet’s syndrome, sympathetic ophthalmia Sympathetic ophthalmia, scleritis Behcet’s syndrome, systemic lupus erythematosus, scleritis, Wegener’s granulomatosis, cicatricial pemphigoid Behcet’s syndrome, birdshot retinochoroidopathy, cornea1 graft rejection Adjunct to cyclosporine, anterior idiopathic uveitis Cicatricial pemphigoid Behcet’s syndrome

TABLE 3 Summary of Immunosuppressives: Major Adverse Reactions

Drug

Adverse Reactions

Cyclophosphamide

Hemorrhagic cystitis, bone marrow suppression, secondary malignancies

Chlorambucil

Bone marrow suppression, gonadal dysfunction, secondary malignancies Hepatotoxicity, ulcerative stomatitis, diarrhea, bone marrow suppression Bone marrow suppression (luekopenia), nausea, secondary infections Nephrotoxicity, hypertension, hyperuricemia, hepatotoxicity Nausea, vomiting, postural hypotension Hemolytic anemia, nausea Nausea, vomiting, bone marrow suppression

Methotrexate

Azathioprine

3. Dose and Route The recommended dose is 0.5-0.6 mg, 2-3 times/ day given orally. 66~‘s5,172 The drug is well absorbed; most of it is excreted in the stools, and the rest, via the kidneys.75

Indications

Drug

Cyclosporine Bromocriptine Dapsone Colchicine

sic immune responses have permitted a better understanding of immune-mediated ocular diseases, characterization of specific uveitogenic antigens, and determination of the role of specific immune responses in the development of ocular diseases. This knowledge has allowed the design of new, more specific treatment strategies. Corticosteroids, although still key agents in the management of ocular inflammatory and immune-mediated diseases,

IMMUNOSUPPRJBSIVE

DRUGS IN OPHTHALMOLOGY

are now supplemented and at times supplanted by immunosuppressive agents. Tables l-3 list the immunosuppresive drugs in use today, with recomindimended dosage, route of administration, adverse effects. Intimate cation, and major knowledge of the characteristics of each of these potentially toxic agents is essential to their safe use for the treatment of nonmalignant and frequently nonlethal diseases. The detection and management of adverse effects requires much more than following up laboratory results. The patients must be carefully examined and interviewed so that changes in mood, psyche, appearance, color, appetite, and other subtle changes can be detected. Ophthalmologists not specifically trained in using immunosuppressives are strongly urged to consult a fellow ophthalmologist or a chemotherapist who has expertise in their use. The physician must carefully explain the myriad toxicities of these drugs to the patients before therapy is begun. Research in the fields of monoclonal antibodies against specific targets (such as class-II antigens), antigen specific immunomanipulation, manipulation of immune response mediators (interleukins, lymphokines), and the development of new immunosuppressives (cyclosporin-G, mizoribine, substance FK 506, and others) will undoubtedly result in the development of more specific and safer immunosuppressive drugs.

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Supported in part by the Fogarty International Program of the NIH, and the Susan B. Hilles Fund. Reprint address: C. Stephen Foster MD, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.