Uveitis in Therapy Immunomodulatory• 36 chapter

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Drug effects in human nonocular diseases

Methotrexate is FDA-approved for use in the treatment of neoplastic disorders such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, carcinoma of breast, lung, head, and neck, as well as rheumatoid arthritis, juvenile idiopathic arthritis, and psoriasis. It is also used in systemic lupus erythematosus, ankylosing spondylitis, Crohn’s disease, psoriatic arthritis, and Behçet’s disease.

Drug use in retinal diseases

Samson et al.15 evaluated methotrexate treatment among 160 patients with chronic noninfectious uveitis unresponsive to steroid therapy. Control of inflammation was achieved in 76.2% of patients; the average maintenance dosage of these patients was 12.3 mg weekly. Steroidsparing effect was achieved in 56% of patients. Visual acuity was maintained or improved in 90% of patients. Side-effects requiring discontinuation of medication occurred in 18% of patients. Potentially serious adverse reactions occurred in only 8.1% of patients.

Pediatric case series

Heiligenhaus et al.16 studied the efficacy of methotrexate in the treatment of 35 patients with severe chronic juvenile idiopathic arthritisassociated iridocyclitis. Methotrexate was given at a dosage of approximately 15 mg weekly/m2 body surface, either orally or subcutaneously. Quiescence of uveitis was obtained in 21 patients with additional topical steroids and in 4 patients without additional topical steroids. Visual acuity deteriorated in 6, improved in 13, and was stable in the remaining eyes. The data suggest that methotrexate is very effective in controlling inflammation of uveitis in patients with juvenile idiopathic arthritis. However, additional topical steroids or systemic immunosuppressive drugs are often required.

Intravitreal methotrexate injection

Hardwig et al.17 published a report on intravitreal injection of 400 g methotrexate as treatment for ocular disease other than primary central nervous system lymphoma. They included 9 patients with uveitis and showed that, among 7 patients, vision improved, in 1 it deteriorated, and in 1 patient it did not change. There was no observed toxicity attributable to methotrexate in any case. The authors concluded that intraocular methotrexate is a reasonable alternative to continued use of corticosteroids in uveitis patients.

Drug mechanism, systemic and ocular complications and toxicity, drug interactions, and contraindications are summarized in Table 36.2.2,6–8

Taylor et al.18 had published recently a prospective study on the use of intravitreal methotrexate for the treatment of uveitis and uveitic cystoid macular edema on 15 patients. They showed that visual acuity improved at all time points and was statistically significant at the 3- and 6-month follow-up examinations. No statistical difference was found between the best visual acuity obtained after MTX injection and after previous corticosteroid treatment. Five patients relapsed after a median of 4 months; however a similar improvement was seen after reinjection. Ocular inflammation scores improved at all time points, and systemic immunosuppressive medication was reduced in 3 of 7 patients taking this at the start of the trial.

AZATHIOPRINE

Key features, introduction, and history

Azathioprine is a prodrug, converted to the active metabolites 6- mercaptopurine and 6-thioinosinic acid. It replaced 6-mercaptopurine as an immunosuppressive treatment for kidney transplants. The drug use in uveitis has been described since 1967.

Pharmacology

Azathioprine is well absorbed orally. Thirty percent of the drug is bound to serum proteins. It is rapidly eliminated from the blood and

cannot be detected in urine after 8 hours. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Low activity of TPMT can lead to excessive drug toxicity, thus assay of serum TPMT may be useful to prevent this complication.2

Drug mechanism

Azathioprine is a purine nucleoside analogue. It interferes with adenine and guanine ribonucleotides by suppression of inosinic acid synthesis, which in turn interferes with DNA replication and RNA transcription. It decreases the numbers of peripheral T and B lymphocytes, and reduces mixed lymphocyte reactivity, interleukin-2 synthesis and IgM production.6

Drug effects in human nonocular diseases

Azathioprine is FDA-approved as an adjunct for the prevention of rejection in renal homotransplantations and for the management of active rheumatoid arthritis. It is also used in psoriatic arthritis, Reiter syndrome, and systemic lupus erythematosus.

Drug use in retinal diseases

Yazici et al.19 conducted a 2-year randomized, placebo-controlled, double-blind trial of azathioprine (2.5 mg/kg/day) in Turkish men with Behçet’s syndrome with and without eye disease. Corticosteroid treatment remained available to all the patients. Azathioprine was superior to placebo in the prevention of new eye disease in both groups. There were fewer episodes of hypopyon uveitis, oral ulcers, genital ulcers, and arthritis. There were no serious side-effects attributable to azathioprine.

Vianna et al.20 described the clinical course of 4 patients (5 eyes) with active serpiginous choroiditis treated with azathioprine (1.5–2.0 mg/ kg/day) in combination with corticosteroids. Within 3 weeks of treatment, all patients experienced decreased ocular inflammation and improved visual acuity. One patient, however, had a recurrence in both eyes while oral prednisone was being tapered and in another patient serpiginous choroiditis recurred 40 months after the initial treatment. None of the 4 patients presented serious systemic side-effects secondary to treatment.

Kim and Yu21 evaluated treatment outcomes with low-dose azathioprine (1.0–2.5 mg/kg/day) in 16 patients with Vogt–Koyanagi–Harada disease. Six patients received azathioprine in the acute uveitic phase and 10 patients in the chronic recurrent phase. A corticosteroid-sparing effect was achieved in 86.5% of patients given azathioprine in the acute uveitic phase and 90.0% of patients given in the chronic recurrent phase. Median time to corticosteroid-sparing effect was 3.5 months. Twelve of 16 patients showed improved activity in 1 month after initiation of azathioprine therapy.

Pediatric case series

Schatz et al.22 review, with respect to etiology, the efficacy and complications of different immunosuppressants used in a steroid-sparing strategy in 40 children with uveitis. Uveitis was anterior in 55% of cases, intermediate in 2.5%, posterior in 42.5%, and bilateral in 62.5%. Where corticosteroid use was combined with azathioprine, a 61% improvement in visual acuity was achieved. However, corticosteroid therapy associated with MMF resulted in a 94% improvement.

Drug mechanism, systemic and ocular complications and toxicity, drug interactions, and contraindications are summarized in Table 36.2.2,6–8

Summary and key points

The antimetabolite agents are effective as corticosteroid-sparing drugs in the treatment of ocular inflammatory disease. The properties, dosing, and most common adverse events of the three commonly used antimetabolites are summarized in Table 36.2. MMF is effective for controlling diseases that had been refractory to treatment with other immunosuppressive agents among adults and children; it is well tolerated and has few side-effects. Methotrexate is the most common

Contraindications

Absolute:

•  Pregnancy

•  Breast-feeding

•  Avoid live vaccines

•  Avoid concomitant use with clozapine

•  Avoid concomitant use with azathioprine or methotrexate because of the potential to cause bone marrow suppression

Relative:

GI disorders due to risk of hemorrhage, ulceration, and perforation

Absolute:

•  Pregnancy

•  Breast-feeding

•  Liver disease

•  Avoid concomitant use with clozapine, nitrous oxide, azathioprine, mycophenolate mofetil

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Side-effects

Serious: Severe bone marrow suppression

Hepatoxicity Teratogenic

Opportunistic infections

Secondary malignancy:

Nonmelanoma skin cancers

Lymphoma

Common:

GI upset† Less common:

Alopecia

Rash

Fever

Arthralgia

Comments

Serum TPMT assay before starting treatment

If ALT or AST is > 1.5 times normal on two separate occasions, the dose should be reduced by 25–50 mg/ day, and the liver enzyme level reevaluated after 2 weeks

If there is marked enzyme elevation the drug should be stopped

Dosage should be decreased when given with allopurinol

Concomitant use with ACE inhibitors has been reported to induce anemia and severe leukopenia

Contraindications

Absolute:

•  Liver disease

•  Pregnancy

•  Breast-feeding

•  Avoid concomitant use with clozapine