MTX is the only clinically useful folic-acid inhibitor. MTX differs from folic acid in that methyl and amino groups replace a hydrogen atom and hydroxyl group. MTX inhibits dihydrofolic acid reductase and thus interferes with DNA synthesis, repair, and cellular replication, with actively proliferating cells being relatively more sensitive to its action.¹⁵ MTX is cytotoxic only when cells are actively dividing, acting as it does predominantly during the S-phase of the cell cycle. Because protein and RNA synthesis also are affected by this agent, cell entry into the S-phase can be slowed, and the medication has been referred to as being self-limiting.⁵ The exact mechanism of its action in autoimmune diseases is currently uncertain.^5,14 MTX is available in oral or injectable forms and has been used extensively in various ocular inflammatory conditions as one of the first-line immunosuppressive drug options.

Pretreatment assessment includes a complete blood count with differential, hepatic enzymes, and renal function tests. Periodic monitoring of these serum chemistry and blood counts are required: CBCs at least monthly, and renal and liver function tests every 1 to 2 months. Caution should be used when nonsteroidal anti-inflammatories (NSAIDs) or cyclosporine are administered concomitantly with MTX due to the risk of renal toxicity. This is commonly the case when treating juvenile idiopathic arthritis (JRA)-associated uveitis. Because folate-deficient states increase MTX toxicity, daily folic acid (1 mg or more) is essential while MTX is prescribed. MTX is excreted via the kidney; it is not dialyzable. The physician must inform the patient about dosing guidelines as well as provide counseling on the need for contraception if either partner is on the medication. The FDA classifies MTX as pregnancy category X (absolutely contraindicated) due to its teratogenic potential (Table 31.2). Patients must be cautioned that MTX is a weekly, not daily, formulation. MTX toxicities include stomatitis, gastritis, anemia (reflecting bone marrow suppression), hepatonecrosis and fibrosis,^15,16 renal toxicities, and idiosyncratic pulmonary toxicity, occasionally progressing to pulmonary fibrosis.

Several nonrandomized, uncontrolled studies document the utility of MTX in ocular inflammatory diseases, and one particular case series tended to favor its use in ocular sarcoidosis.^5,17 Historically, MTX has been an agent of choice in juvenile idiopathic arthritis. However, it has been our experience that generally MTX appears to more effective when added to another agent (such as low-dose prednisone [<10 mg/day] or anti–tumor necrosis factor [TNF] agents). Anti-TNF drug antibody formation may be favorably influenced by the addition of MTX¹⁵. Some evidence suggests that MTX may be preferentially concentrated in the aqueous ¹⁸.

In a meta-analysis of 160 patients on systemic MTX for noninfectious uveitis, the incidence of adverse events was less than 20%, but of these only 8% had potentially serious adverse reactions¹⁹. In this study, no long-term morbidity or mortality was caused by MTX.

Although the clinical effects of MTX typically are manifest after 4 to 6 weeks of therapy, its effect on the blood counts may be visible as early as 1 week after initiation of therapy. MTX is well absorbed, although variably orally—bioavailability and clinical efficacy may be increased when injected subcutaneously or intramuscularly.²⁰ The maximum dosage used in uveitis ranges from 10 to 20 mg/m²/week (roughly equivalent to 15 to 25 mg/week for a person who weighs 60 kg). It is initiated at a lower dose; as patient tolerance increases, the dose is increased by 2.5 to 5 mg/week until efficacy is achieved. As with all drugs, if MTX does not produce the desired effect at recommended dosages after 3 to 4 months, the addition of another agent or replacement options should be considered. As with any of the potent agents described in this chapter, the working diagnosis itself should be reevaluated prior to additional therapy at every stage of treatment.

Since the initial studies by Hitchings and colleagues²¹, investigators have been interested in the broad therapeutic applications of the analogs of purine bases. These drugs exert a number of therapeutic effects, including control of uric acid production (allopurinol), antiviral activity, and immunosuppressive actions as an antimetabolite. AZT (Imuran) is the most widely used immunosuppressive medication in its class.

AZT is believed to be a prodrug that reacts with sulfhydryl compounds and then slowly releases 6-mercaptopurine. This is advantageous, because it decreases the rate of 6-mercaptopurine inactivation by methylation, nonenzymatic oxidation, and by conversion to the inactive 6-thiouric acid by the xanthine oxidase present in high quantities in the liver. Additionally, AZT is better absorbed than 6-mercaptopurine and causes less gastrointestinal distress.

Although both 6-mercaptopurine and AZT have been studied extensively, their modes of action are still unclear. It does appear that these agents alter both RNA and DNA metabolism by their conversion to the ribonucleotide 6-thioinosine-5-phosphate (T-IMP) by the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT).^21,22,23 The accumulation of T-IMP intracellularly affects the synthesis of nucleic acids,²³ probably by incorporation into nucleic acids. Nucleotides of 6-methylmercaptopurine ribonucleoside have been demonstrated in patients treated with these purine analogs. T cells appear to be considerably more sensitive to these agents than are B cells. 6-Mercaptopurine and AZT have been reported to inhibit antibody production in vitro and in vivo. However, antibody responses to thymus-independent antigens are highly resistant to those compounds when compared to the responses of the thymus-dependent group. This selectivity is further demonstrated by the inhibitory effects of the thiopurines on experimental allergic encephalomyelitis, delayed hypersensitivity, and rejection of xenogeneic grafts, all of which are T cell–mediated immune processes.^22,23 However, AZT was not particularly effective in preventing predominantly antibody-mediated autoimmune disease in NZB mice.²⁴ Thus, AZT is an immunosuppressive, with greater suppressive effects on delayed hypersensitivity and cellular cytotoxicity than on antibody production at the recommended doses.

A complete general examination, including serum blood chemistries and complete blood count should be performed. Abnormalities, especially hematologic, must be resolved prior to AZT initiation. A history of liver disease (active or quiescent) or systemic cancers are contraindications for this agent.

Both the immunosuppressive and therapeutic effects are dose-related but an optimal dose must be individually tailored. AZT is a slow-acting drug (4 to 6 weeks), and its clinical and adverse effects may persist in the absence of its use.^24,25,26 The adverse effects of AZT include bone marrow depression, gastrointestinal upset, and hypersensitivity. These alterations are due partly to hepatocellular necrosis and biliary stasis. Continuation of therapy in the presence of these drug-induced abnormalities can lead to hepatic decompensation. The most serious side effect is bone marrow suppression. Leukopenia is a more frequent adverse effect than is either anemia or thrombocytopenia. In addition to bone marrow depression, rash and an increased risk for infection have been reported. An increased incidence of malignancy, especially lymphomas, also has been associated with the use of purine analogs.

AZT interacts with allopurinol, and thus the dosage of AZT must be decreased by at least 25% when the two drugs are used concomitantly. The use of angiotensin-converting enzyme (ACE) inhibitors also can increase bone marrow toxicity in certain patients. Several other drug interactions interfere with the clearance of AZT and are summarized elsewhere.^26,27

6-Mercaptopurine and AZT are thought to be effective in the treatment of a wide variety of ocular inflammatory conditions. James showed that AZT is effective in promoting successful corneal transplantation in high-risk patients.²⁸ Foster initially reported his experience with AZT in the treatment of cicatricial pemphigoid, but gastrointestinal intolerance precluded a thorough trial. More recently, however, Foster and colleagues also reported that this agent was effective in the treatment of ocular cicatricial pemphigoid.²⁹

The combination of AZT and low-dose prednisone also is effective in the treatment of chronic uveitis.³⁰ Of 22 patients with chronic uveitis, 12 had a positive therapeutic response to this regimen, with adverse effects occurring in six patients and no response in four. Additionally, AZT or 6-mercaptopurine has been used beneficially in cases of sympathetic ophthalmia,³¹ Vogt-Koyanagi-Harada disease,³² and pars planitis.³⁰ Aoki and Sugiura found that more than half of 25 patients with Behçet syndrome treated with AZT had an improvement in their ocular disease³³. In a double-masked trial, Yazici and colleagues showed that AZT was superior to placebo in the prevention of new eye disease in patients with Behçet disease.³⁴ AZT has been used effectively in combination with prednisone and, for severe, sight-threatening uveitis, AZT has been added to regimens containing cyclosporine and prednisone. This triple immunosuppressive agent therapy was used by Hooper and Kaplan for the treatment of macula-threatening serpiginous choroidopathy.³⁵

AZT is an immunosuppressive antimetabolite that is administered orally at 1 to 3 mg/kg/day for the management of ocular inflammatory disease. AZT is well-absorbed following oral administration. Serum levels are of minimal predictive value for therapy because the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Although drug levels of AZT can vary considerably, the absolute neutrophil counts tend to correlate well with metabolite levels. About half of the absorbed dose is excreted in the urine within 24 hours of administration. AZT and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and liver; no AZT or mercaptopurine is detectable in urine after 8 hours. Renal clearance is probably not important in predicting biologic effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function. AZT is mutagenic in animals and humans, and it is carcinogenic in animals; therefore, it may increase the patient’s risk of neoplasia and is a pregnancy category D drug (Table 31.2).^26,27 A recent concern is related to reports of patients with myasthenia gravis on purine analogs developing systemic lymphoma. However, it is difficult to infer a causal relationship or whether myasthenia patients are inherently more predisposed to developing this complication.

Mycophenolic acid, the parent drug from which MMF was synthesized, is a product of the Penicillium species first extracted in 1896. Widespread clinical use of mycophenolic acid (MPA) in autoimmune disease was delayed by the need for a more effective and better-tolerated derivative. Although MPA was shown to be an effective treatment for conditions such as psoriasis, its unpredictable pharmacokinetics and unacceptable gastrointestinal toxicity hindered widespread use until the introduction of MMF. Interestingly, it may well have been that the dermatologic resynthesis of MPA from the acid glucuronide increased the effective drug availability of MPA and consequently led to its success in treating psoriasis. MMF was approved for use as a reserve drug in managing rejection in renal transplantation and was subsequently found to be equally effective in other organ transplants.

Although MMF has similarities to AZT, inherent differences prompted classifying it as a selective purine synthesis inhibitor. MMF is a morpholinoethyl ester derivative of MPA that inhibits purine synthesis of human lymphocytes and, thus indirectly, T-cell proliferation.³⁴ MMF is a more specific inhibitor than is AZT. AZT inhibits IMP dehydrogenase as well as 5- phosphoribosyl-1-pyrophosphate (PRPP)-aminotransferase and adenylosuccinate synthetase.^24,35,36 Because AZT and MMF share a similar adverse-effect profile, they must not be combined^35,36.

Because of the guanosine depletion and lack of activation of PRPP, MMF may cause a nonspecific inhibition of purine synthesis. MMF is hydrolyzed to MPA in the liver and gastrointestinal tract. The mofetil ester is almost entirely converted to the acid form, because little is detected in the blood. The mofetil ester has significantly higher bioavailability than does the acid form.^37,38,39 In healthy volunteers, the absorption was 94%. Food does not alter the extent of absorption, but the maximum concentration is decreased about 40% when MMF is taken with food. MMF levels are affected by significant drug interactions with cholesterol-binding resins and antacids (decrease) and with acyclovir (increase).^36,37,38

MMF is similar to AZT because the drugs share a common pathway.

MMF is of some utility in the treatment of a wide variety of ocular inflammatory diseases. Using data without appropriate statistical analysis, it appears that MMF, when used in the treatment of ocular diseases, probably has been associated with less adverse events, such as significant leucopenia, when compared to its use with renal patients receiving 3 g daily.^38,39. This view has been corroborated by a recent analysis by Thorne and colleagues, who recently reported 82% (based on patient numbers) treatment efficacy with relatively minimal complications ⁴⁰. It is our impression that the clinical efficacy sometimes does not compensate for its overwhelming cost versus AZT, although information from nonrandomized trials illustrate its clinical utility in scleritis as well as other ocular inflammatory diseases^36,41. MMF is pregnancy category C (see Table 31.2).

The recommended starting dose is 500 mg twice daily (15 mg/kg/day in divided doses) and escalates to a maximum of 1,000 mg twice daily over the course of a month. We believe that, at higher dosages, the risk of toxicity may outweigh benefits.

Cyclophosphamide (Cytoxan; Table 31.4) and chlorambucil (Leukoran) are the two alkylating agents used clinically. These agents are derived from sulfur mustard, which was synthesized in 1854. The use of sulfur mustard as a chemical warfare agent during World War I had devastating effects, causing leukopenia in survivors and a lymphoid aplasia in those who died.⁶