KEY FEATURES

Corticosteroids are the mainstay of therapy for ocular inflammatory diseases and can be given by a variety of routes. However, additional immunosuppressive drug therapy may be necessary in patients with an inflammatory disease which is poorly responsive to corticosteroid treatment, a chronic or relapsing disease that requires the longterm use of systemic corticosteroids at a dose above 7.5 mg/day, which is likely to produce side-effects, or when the corticosteroid sideeffects are intolerable and result in the need for a corticosteroid-sparing agent.

For the disease patterns mentioned above, early and aggressive immunosuppressive drug therapy can be invaluable in preventing irreversible visual loss.

Because most of the immunosuppressive drugs take several weeks to have an effect, initial therapy of sight-threatening ocular inflammation is typically with high-dose oral corticosteroids due to their rapid anti-inflammatory effect. Once the disease is quiescent, the corticosteroids can either be tapered to a low level or, if possible, discontinued. Subsequently, the immunosuppressive drugs are tapered down.

CALCINEURIN INHIBITORS

Ciclosporin (CsA) and tacrolimus are termed calcineurin inhibitors due to their ability to bind to the cytosolic protein cyclophilin of immunocompetent T lymphocytes. This complex inhibits calcineurin, which under normal circumstances is responsible for activating the transcription of interleukin-2. It also inhibits product of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin-3, and interleukin-4 and therefore leads to suppression of effector T-cell function. Table 36.1 summarizes the properties and dosages of the two common calcineurin inhibitors.1,2

CICLOSPORIN (CYCLOSPORIN: CsA)

Key features, introduction, and history

CsA is a cyclic peptide of 11 amino acids produced by the fungus Beauveria nivea. Its success in preventing organ rejection was first shown in liver transplants in 1980 and it was subsequently approved for use in 1983. The use of this drug in uveitis has been described since 1987.

Pharmacology

Two oral preparations of CsA are available, Neoral and Sandimmune. Neoral, which has greater bioavailability, is used in uveitis. The drug is metabolized in the liver and excreted in the bile, with very little of the parent drug or its metabolites appearing in the urine. The average half-life of CsA is about 8.4 hours (range 5–18 hours). CsA leaves the vasculature readily and has been found in the intraocular fluids of uveitis patients. CsA crosses the placenta and is excreted in human milk.1

Drug effects in human nonocular diseases

CsA is approved by the Food and Drug Administration (FDA) for the prevention and treatment of graft rejection, rheumatoid arthritis that is poorly responsive to methotrexate, and plaque psoriasis in adults. It is also used in atopic dermatitis, ulcerative colitis, and a variety of glomerular disorders.

Drug use in retinal diseases

Ozdal et al.3 evaluated the long-term use of low-dose CsA in 52 patients (104 eyes) with ocular Behçet’s disease using CsA for at least 1 year. The initial dose was 5 mg/kg/day and the dose was tapered gradually over 2 months to a maintenance dose of 3 mg/kg/day. Prednisone was added when necessary. Visual acuity improved or stabilized in 72 (69.2%) and deteriorated in 32 (30.8%) of the 104 eyes. No ocular attacks occurred in 50% of the eyes during therapy.

Pediatric case series

Kilmartin et al.4 treated 14 patients (25 eyes) with refractory noninfectious childhood uveitis, at a maintenance CsA dose of 4.0 mg/kg/day as monotherapy or in combination with prednisolone or azathioprine. Visual acuity improved or was maintained in 23 (92%) eyes and binocular indirect ophthalmoscopy score outcomes improved in 19 (76%) eyes. Height centiles were preserved and the maintenance prednisolone dose was 6.3 mg/day, where required, in 10 (71%) patients.

EFFICACY AND COMPARISON WITH OTHER AGENTS

Ciclosporin versus tacrolimus

Murphy et al.5 compared, in a prospective randomized study, the treatment of CsA 2.5–5.0 mg/kg/day to tacrolimus 0.03–0.08 mg/kg/day in 37 patients with noninfectious posterior-segment intraocular inflammation. They showed that tacrolimus and CsA were similar with regard to efficacy for posterior-segment intraocular inflammation. However, CsA therapy was associated with a higher incidence of reported adverse effects. Mean arterial pressure and serum cholesterol level were significantly higher at 3 months in the CsA group than in the tacrolimus group.

Drug mechanism, systemic and ocular complications and toxicity, drug interactions, and contraindications are summarized in Table 36.1.2,6–8

TACROLIMUS

Key features, introduction, and history

Tacrolimus is a macrolide antibiotic produced from the fermentation broth of a strain of Streptomyces tsukubaensis, discovered by a Japanese team in 1987. Its name was derived from Tsukuba macrolide

Comments

Reduced by 25–50%:

•  Creatinine >30% baseline

•  Diastolic BP>95 mmHg

Discontinue if reversibility (within 25% of baseline) of serum creatinine is not achievable after two dosage modifications

Chronic nephrotoxicity is irreversible

Serum levels increased by grapefruit juice

Clarithromycin Erythromycin Fluconazole Ketoconazole Voriconazole Tacrolimus Diltiazem

Decreased serum levels by St. John’s wort herbal supplement Rifampicin and barbiturates

Vaccinations may be less effective

CsA in pregnancy: premature birth and low birth weight

Contraindications

Absolute:

•  Abnormal renal function

•  Uncontrolled HTN

•  Uncontrolled infections

•  Malignancy

•  Breast-feeding

•  Concomitant use of tacrolimus and rosuvastatin

•  Use of live attenuated vaccines should be avoided

Relative:

•  Liver disease

•  Abnormal CBC

•  Pregnancy

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chapter36•ImmunomodulatoryTherapyinUveitis

Comments

Administered on an empty stomach, meals with a moderate content of fat reduce absorption rate

Serum levels increased by grapefruit juice

Clarithromycin Erythromycin Fluconazole Ketoconazole Voriconazole Diltiazem

Serum levels decreased by St. John’s wort herbal supplement, rifampicin, and barbiturates

Vaccinations may be less effective

Contraindications

Absolute:

•  Hypersensitivity to macrolides

•  Abnormal renal function

•  Uncontrolled infections

•  Malignancy

•  Avoid concurrent administration with CsA

•  Pregnancy

•  Breast-feeding

•  Use of live attenuated vaccines should be avoided

Relative:

•  Liver disease

•  Abnormal CBC

•  Diabetes

•  Poorly controlled HTN