Cyclosporine (CsA) is a neutral lipophilic polypeptide with amino acid side chains, classified as a calcineurin inhibitor immunomodulator.
In non-infectious uveitis, T-cell activation plays a central role, and cyclosporine targets this activation.
In Japan, cyclosporine was initially indicated only for active ocular Behçet’s disease, but in 2012, its indication was expanded to include non-infectious uveitis other than Behçet’s disease (active intermediate or posterior non-infectious uveitis with risk of vision loss that is inadequately controlled by existing therapies).
The SITE study (Systemic Immunosuppressive Therapy for Eye Diseases) was a multicenter cohort study confirming the efficacy of standard immunosuppressive drugs for ocular inflammatory diseases, and cyclosporine was evaluated as one of the agents. In the cyclosporine cohort of 373 patients (681 eyes), 51.9% achieved sustained complete control of inflammation by 12 months, and 36.1% successfully tapered steroids (prednisone ≤10 mg).
For non-infectious uveitis, antimetabolites such as methotrexate and mycophenolate mofetil are currently preferred as first-line agents. In a survey of 221 uveitis specialists, only 8.1% chose cyclosporine as first-line, while methotrexate (57.0%) was the most common. Cyclosporine is positioned as a second-line agent due to toxicities such as nephrotoxicity and hypertension.
Cyclosporine itself does not cause uveitis; it is used as a treatment for uveitis. The main subjective symptoms targeted by treatment are as follows:
Target Diseases for Treatment
Behçet’s disease ocular involvement: recurrent panuveitis. Severe cases with fundus lesions (macular lesions, retinal vasculitis) are targets.
Vogt-Koyanagi-Harada disease: Used in combination with high-dose steroids to reduce steroid dosage.
Intermediate uveitis: Used alone or in combination for refractory cases requiring long-term treatment.
Birdshot retinochoroidopathy: Combination with steroids improves control of vitreous inflammation.
Adverse Effect Findings
Renal impairment: Elevated serum creatinine levels. Usually occurs within 1-3 months of starting treatment.
Hypertension: A significant adverse event and a major reason for treatment discontinuation.
Hypertrichosis and gingival hyperplasia: Known as cosmetic side effects.
Neurological symptoms: Tremor, etc. Avoid administration in patients with neuro-Behçet’s disease.
Factors associated with the risk of developing cyclosporine side effects are as follows.
The following tests should be performed before and during cyclosporine treatment.
After initiation, it is recommended to adjust the dose while regularly measuring blood trough levels. In practice, blood tests are performed at regular visits in the morning before taking the medication. The target trough level is 100–250 ng/mL, but since the incidence of renal dysfunction increases at levels above 150 ng/mL, a target of 100–120 ng/mL is often used.
Serum creatinine levels should be managed so that they do not increase by more than 30% from baseline.
Cyclosporine shows large intra- and inter-individual variability in gastrointestinal absorption, and its bioavailability fluctuates depending on diet (especially fat intake). Blood concentration monitoring helps maintain clinical efficacy while minimizing adverse events such as nephrotoxicity. The currently mainstream Neoral® is a microemulsion formulation with more stable blood kinetics than older formulations, but regular monitoring is still required.
As standard treatment in Japan, cyclosporine is usually administered orally at a daily dose of 5 mg/kg in two divided doses (commonly taken after meals at 12-hour intervals) in combination with systemic steroids. If the effect is insufficient, it may be administered before meals to increase the peak blood concentration.
The following regimen is used for Behçet’s disease.
| Phase | Drug | Dose |
|---|---|---|
| Remission phase | Colchicine (first-line) | 0.5–1.5 mg/day |
| Exacerbation phase | Neoral® | 5 mg/kg/day in 2 divided doses |
| Severe cases | Infliximab | 5 mg/kg (at weeks 0, 2, 6, then every 8 weeks) |
For Harada disease, Neoral 3 mg/kg/day (for a 60 kg patient: 180 mg/day in 2 divided doses) is used as a prescription example.
Behçet’s disease ocular involvement: Cyclosporine is introduced when colchicine alone does not sufficiently suppress inflammatory attacks. However, it should not be used in patients with suspected neuro-Behçet’s disease. With the advent of anti-TNF agents (infliximab, adalimumab), the opportunity to introduce cyclosporine has decreased.
Sarcoidosis: In steroid-resistant cases, cases with repeated relapses upon steroid tapering, or cases where oral administration is difficult due to side effects, addition of cyclosporine, methotrexate (off-label), or the TNF inhibitor adalimumab may be considered.
Intermediate uveitis: Options include oral corticosteroids (for 4 months or more), posterior sub-Tenon injection of triamcinolone acetonide, or oral immunosuppressants such as cyclosporine.
Rheumatic uveitis (collagen disease-related): When inflammation relapses repeatedly with oral tapering, combination oral cyclosporine is a treatment option.
If ocular inflammation remains controlled, cyclosporine can be gradually tapered by 50–100 mg/day, but recurrence of inflammation has been reported. It is recommended to reduce to a maintenance dose of 0.5 mg/kg/day.
The mechanism of action of cyclosporine is to inhibit calcineurin in T cells, thereby blocking the activation of nuclear factor of activated T cells (NF-AT) and suppressing the transcription of the gene encoding interleukin-2 (IL-2). Since IL-2 is a major cytokine that promotes T cell activation and recruitment, its suppression leads to inhibition of the immune response.
Cyclosporine is metabolized by the cytochrome P450 (CYP450) enzyme system. Due to its lipophilic nature, bioavailability depends on dietary fat intake and first-pass effect in the liver (approximately 27%). The half-life varies from 6 to 24 hours, and in uveitis patients receiving systemic administration, about 40% of the serum cyclosporine concentration is found in the aqueous humor. Metabolites are eliminated mainly via the biliary excretion system.
Cyclosporine absorption in the gastrointestinal tract is affected by bile acid secretion, so blood concentrations were initially unstable. Neoral®, which is now widely used, forms a hydrophilic microemulsion in the body and is stably absorbed from the intestine, resulting in more stable blood kinetics than the older formulation. However, intra- and inter-individual variability in absorption remains large, so blood concentration monitoring is essential.
Cyclosporine-induced renal injury involves both functional and structural changes. Renal biopsy shows changes such as mild type IV renal tubular acidosis, interstitial fibrosis, tubular and glomerular atrophy/sclerosis, and thickening of arteriolar walls. Progressive renal injury can occur even with normal renal function and even after cyclosporine dose reduction.
Data from the SITE trial showed that 10.7% discontinued due to toxicity within one year, and age ≥55 years was a strong predictor of discontinuation (adjusted relative risk: 3.25 for ages 55–64, 5.66 for ages ≥65).
The FAST trial (First-line Antimetabolites as Steroid-sparing Treatment) was a randomized controlled trial that showed methotrexate had a significantly higher treatment success rate than mycophenolate mofetil for posterior and panuveitis. These antimetabolites may show superior treatment outcomes compared to T-cell inhibitors (cyclosporine), potentially changing the role of cyclosporine in the future.
Current international expert panel recommendations list anti-TNF-α inhibitors, including infliximab and adalimumab, as first-line therapy for ocular symptoms of Behçet’s disease, and the role of cyclosporine is becoming limited.
Long-term administration carries a risk of irreversible kidney damage. Progressive kidney damage can occur even after dose reduction, even if kidney function is normal. Regular monitoring of serum creatinine levels is essential, and if levels rise more than 30% from baseline, dose reduction or discontinuation should be considered.
