immunosuppressive agent used in children and has been reported to be an effective treatment for the uveitis associated with juvenile idiopathic arthritis. Azathioprine is associated with more severe side-effects compared to other antimetabolite agents, which limits its use.

ALKYLATING AGENTS

Cyclophosphamide and chlorambucil are termed alkylating agents due to their ability to alkylate nucleic acids. As a result, DNA to DNA intrastrand crosslinking and DNA to protein crosslinking occur, which lead to interference in DNA and RNA replication and transcription. This process results in cell death, because the cells are unable to replicate. They are cytotoxic to both resting and dividing lymphocytes. So the number of activated T and B lymphocytes decreases, and T-helper lymphocyte function and cytokine production are suppressed.

vasculitis and ocular cicatricial pemphigoid. The most common sideeffects observed were fatigue (63%), nausea (32%), and headache (22%). None required permanent discontinuation of therapy.

Efficacy and comparison with other agents

Ozyazgan et al.25 conducted a single masked trial of CsA, 5 mg/kg/ day, versus monthly 1 g intravenous boluses of cyclophosphamide in 23 patients with Behçet’s syndrome and active, potentially reversible uveitis. During the initial 6 months the visual acuity significantly improved in the CsA group whereas this was not observed in the cyclophosphamide group. The subsequent follow-up of patients up to 24 months suggested that the initial improvement in visual acuity with CsA was not sustained.

Drug mechanism, systemic and ocular complications and toxi­ city, drug interactions, and contraindications are summarized in Table 36.3.2,6,8

CYCLOPHOSPHAMIDE

Key features, introduction, and history

Cyclophosphamide is a nitrogen mustard-alkylating agent, a prodrug of several alkylating agents which are formed as hepatic metabolites. The first drug clinical trials were published at the end of the 1950s. The drug use in uveitis has been described since 1969.

CHLORAMBUCIL

Key features, introduction, and history

Chlorambucil is a nitrogen mustard alkylating agent which substitutes an alkyl group for hydrogen ions in organic compounds. The drug use in uveitis has been described since 1970.

Pharmacology

Cyclophosphamide is well absorbed and is enzymatically converted by the hepatic enzymes to multiple metabolites. It is extensively metabolized before excretion, primarily by the kidney, with less than 25% remaining unchanged in the urine. One of these metabolites, acrolein, is thought to be responsible for the urologic toxicity. The use of 2- mercaptoethane sulfonate may detoxify acrolein and reduce bladder toxicity. Cyclophosphamide reaches its peak plasma level within 1 hour and has a plasma half-life of 4–10 hours.6

Drug effects in human nonocular diseases

Cyclophosphamide is FDA-approved as an adjunct for the treatment of lymphomas, some forms of leukemia, some solid tumors, and “minimal-change” nephrotic syndrome in children. It is also used in systemic lupus erythematosus and Wegener granulomatosis.

Drug use in retinal diseases

Akpek et al.23 reported on 9 patients with active, vision-threatening serpiginous choroiditis who had progressive inflammation while on steroids and/or immunosuppressive agents other than alkylating agents, who were treated with either chlorambucil or cyclophosphamide. During a follow-up time of between 15 and 96 months, no patients had recurrences while on therapy and no further visual loss was encountered after starting the therapy. Six of the patients regained vision. All but 2 patients achieved prolonged drug-free remissions. Side-effects included transient bone marrow suppression, nausea, and fatigue. Secondary malignancy was encountered in 1 patient, whose carcinoma of the urinary bladder was treated successfully.

Durrani et al.24 assess the efficacy and short-term safety of pulse intravenous cyclophosphamide therapy in the treatment of 38 patients with severe or treatment-resistant autoimmune ocular inflammatory disease. Improvement of ocular inflammation occurred in 68% of patients, with 55% achieving complete quiescence. A steroid-sparing effect was achieved in all patients previously on systemic steroid, allowing successful discontinuation of the drug in 41%. Visual acuity was maintained in 66% and improved in 21% of involved eyes. Panuveitis with concurrent retinal vasculitis and ocular cicatricial pemphigoid were the most common disease entities treated. Scleritis seemed to be the most responsive to treatment, followed by panuveitis with retinal

Pharmacology

Chlorambucil is rapidly and completely absorbed from the gastrointesinal tract and food increases its bioavailability. Peak plasma levels are reached within 1 hour and estimated half-life is 1.5 hours. Chlorambucil undergoes rapid metabolism to phenylacetic acid mustard, the major metabolite. The combined urinary excretion of chlorambucil and phenylacetic acid mustard is extremely low – less than 1% in 24 hours.6

Drug effects in human nonocular diseases

Chlorambucil is FDA-approved for the treatment of chronic lymphocytic leukemia, Hodgkin and non-Hodgkin lymphoma. It is also used in rheumatic diseases but less frequently than cyclophosphamide, and in Behçet’s disease.

Drug use in retinal diseases

Tessler et al.26 treated 5 patients with intractable sympathetic ophthalmia and 6 patients with severe Behçet’s disease by high-dose, shortterm chlorambucil therapy. Among the Behçet’s disease group the average duration was 23 weeks and the average total dose was 2.2 g. Among the sympathetic ophthalmia group the average duration was 11 weeks and the total average dose was 0.9 g. After termination of therapy all 11 patients had a sustained remission of their eye disease. Unless subretinal neovascularization was present, all had a final visual acuity of 20/50 or better. In addition concomitant systemic corticosteroids were discontinued within 6–8 weeks. Malignancy has not developed in any of the cases, with a follow-up ranging from 6 months to 12 years (mean, 4.5 years).

Mudun et al.27 evaluated the effects of short-term chlorambucil therapy (23 weeks) in the management of 44 patients with refractory uveitis associated with Behçet’s disease. The therapy was judged to be effective if the patient had ≤1 attack a year and/or ≥1 year between the attacks. The mean follow-up time was 51.4 ± 32.5 months (range, 13–122 months). Following the therapy, the mean frequency of attacks per year had significantly decreased from 4.9 ± 2.3 to 0.9 ± 1.4 and the mean longest period between the attacks was significantly prolonged from 4.4 ± 2.3 to 25.7 ± 23.1 months. The ratio of severe attacks had decreased from 74.1 ± 34% to 51.3 ± 36.6%. New attacks were seen in 56.8% of patients and another immunosuppressive agent or agents was given to 40.9% of the patients 1–8 months after treatment. No serious side-effects