Cyclosporine

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Cyclosporine


Chemical Names

Cyclosporine is also known as ciclosporin or cyclosporin A and may be abbreviated as CsA.

Mechanism of Action

Cyclosporine is a neutral lipophilic polypeptide with an amino acid side chain. It is an immunomodulatory agent that belongs to the calcineurin inhibitors group and has a major effect in T cell activation, which is known to play a predominant part in the pathogenesis of noninfectious uveitis [1].

Its major ability is to block the activation of the nuclear factor of activated T cells (NF-AT) required for transcription of cytokine genes namely the gene that encodes interleukin-2 (IL-2). IL-2 is a major enhancer for T-cell activation and recruitment. Other proposed mechanism reports than cyclosporine blocks the release of IL-2 or the acquisition of IL-2 receptors on T-cells thereby preventing their activation [2].

Pharmacokinetics

Cyclosporine is metabolized by the cytochrome P450 enzyme system. Bioavailability depends on dietary fat intake because of its lipophilic nature and on liver first-pass effect (27%). Cyclosporine half-life varies between 6-24 hours [3]. In uveitic patients receiving systemic cyclosporine treatment, 40% of cyclosporine serum concentration is found in the aqueous humor [4]. Metabolites are mostly eliminated by the biliary system.

Indications

Topical cyclosporine has been used in the treatment of ocular surface disease [5]. In regards to ocular inflammation, systemic cyclosporine may used in combination with other immunosuppressive agents particularly for uveitic conditions requiring long-term corticosteroid-sparing immunosuppression [4][6][7].

It has been suggested that the most ideal candidates for treatment with cyclosporine are individuals under 50 years of age with good renal function and no history of poorly controlled or severe hypertension [7].

Uses in Various Types of Ocular Inflammation

For years studies supported cyclosporine prescription in numerous types of ocular inflammation. Good visual and clinical outcomes regarding severity and frequency of attacks and inflammation control were reported.

One of the first publications concerning this issue in 1983 described improvement of visual acuity and resolution of ocular inflammation in seven of eight patients with bilateral sight-threatening noninfectious posterior uveitis unresponsive to other drugs. A 10mg/kg/day initial dose was used [8]. At the same time, Nussenblatt et al. described visual acuity improvements of more than two lines in 12 of 16 patients with active noninfectious uveitis. While renal toxicity occurred as a side effect, renal function returned to normal when the dose of cyclosporine was decreased [9].

1) Juvenile Idiopathic Arthritis (JIA)-associated uveitis

In refractory cases of uveitis in JIA, systemic immunosuppressive agents are required. Combination therapy with cyclosporin and methotrexate or a tumor necrosis factor alpha inhibitor has been noted to be an option [7][10] .

A study using cyclosporine in 15 children and adolescents with severe bilateral intermediate or panuveitis reported a 82% improvement in ocular inflammation and a good tolerability [11].

2) Intermediate Uveitis/Pars Planitis

Nussenblat et al. was the first to demonstrate responsiveness of pars planitis to cyclosporine at a dose of 10mg/kg/day [12]. Other authors have suggested that cyclosporine may be used alone or in combination with other immunosuppressive medications in patients requiring long-term therapy or in recalcitrant inflammation as a second-line therapy [13][14].

Nussenblatt et al. also described a case of success in a patient with multiple sclerosis who presented improvement in visual acuity, vitreous haze severity and macular edema [15].

3) Behçet Disease

Systemic immunosuppressives are accepted as the initial agent for posterior uveitis in Behçet’s disease [16]. Studies report good clinical results [17][18][19] with cyclosporine with reduction of severity and frequency of attacks. Concerns about recurrence after cyclosporine suspension or dose lowering were present.

Infliximab or cyclosporine 2-5 mg/kg/day in combination with azathioprine and systemic steroids is suggested by European League Against Rheumatism (EULAR) for severe eye disease defined as > 2 lines reduction in visual acuity and/or retinal disease (macular involvement or retinal vasculitis) [16]. Despite cyclosporine’s efficacy in Behçet disease, case reports and small retrospective studies suggest that infliximab may be more effective in reducing acute episodes of refractory uveitis during the initial 6 months of treatment. [20] Currently, new expert panel recommendations state that anti-tumor necrosis factor alpha inhibitors, including infliximab and adalimumab, as first line therapy for ocular manifestations of Behçet disease.

4) Sympathetic Ophthalmia

Leznoff et al. demonstrated good and complete response in 3 of 4 patients with severe and progressive inflammation due to sympathetic ophthalmia with the other patient only responding partially [13]. He also reported a positive result in a patient with severe corneal graft failure.

5) Vogt-Koyanagi-Harada (VKH)

For years, the gold standard therapy for VKH has been high-dose corticosteroids. However half of individuals treated in this manner can develop ocular and systemic corticosteroid-related side effects. Therefore the American Uveitis Society and the International Uveitis Study Group strongly recommends the use of immunomodulatory drugs for inflammation control and corticosteroid sparing-effect [21].

A triple immunosuppressive scheme combining cyclosporine, prednisone and azathioprine has been reported to induce a rapid clinical remission and reduce the possibility of recurrence in some cases [22].

6) Serpiginous Choroiditis

While first-line therapy for serpiginous choroiditis typically involves the use of systemic corticosteroids, long-term systemic immunossupression with a corticosteroid-sparing agent can include cyclosporine. A case series of 14 eyes with serpiginous choroidopathy used cyclosporine with 6 of 7 patients experiencing remission and no further recurrences [23]. Cyclosporine can also be used in combination with other immunosuppressant agents (particularly antimetabolites) such as mycophenolate mofetil or azathioprine for severe inflammation or as monotherapy for maintenance of remission [10].

7) Birdshot Retinochoroidopathy

As serpiginous choroiditis, acute birdshot retinochoroidopathy first line treatment lies on the use of periocular or systemic corticosteroids. Corticosteroid administration and associated complications are concerns given disease chronicity and long-term steroids use. Also it does not show a strong positive result on disease control [24].

Cyclosporin combined with corticosteroids has generally resulted in a higher percentage of vitreous inflammation control and improvement in visual acuity compared to corticosteroid monotherapy[25].

8) Others

Ciclosporin has also demonstrated positive results in some cases of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and sarcoid uveitis [10].

Therapeutic Scheme

Because of renal toxicity observed with doses at 10mg/kg/day, it is recommended that cyclosporine be prescribed at a starting dose of up to 5 mg/kg/day (7 mg/kg/day in specific cases in which particularly low bioavailability is verified) once or twice daily regimen, the second predisposing to less renal toxicity. When monotherapy is unsatisfactory it is usually combined with prednisone 10-20 mg/day [4].

If ocular inflammation remains controlled, cyclosporine can be progressively reduced although recurrence of inflammation has been reported [26]. A reduction of 50-100 mg/day to a maintenance dose 0.5 mg/kg/day is advisable and serum creatinine levels should not rise more than 30% from de baseline [4].

Initial Evaluation/ Precautions

  • Before initiating systemic cyclosporine patients should be evaluated for renal disease and serum creatinine levels should be examined
  • Poorly controlled hypertension and neurotoxicity are also concerns and its use should be avoided in patients with CNS involvement
  • Active or latent infectious disease should be ruled out
  • Use of cytotoxic agents should be discontinued 1 month before its start.

Secondary Effects

The most common side effects listed are renal toxicity, hypertension, paresthesia/hyperesthesia and mild anemia [27].

Nephrotoxicity

Some degree of renal toxicity, such as significant elevations of the mean serum creatinine levels, is reported in 75-100% of patients using 10 mg/kg/day [4], twice the dose recommended nowadays. Nephrotoxicity occurs usually 1–3 months after initiating cyclosporine and is the most common cause of dose reduction [28].

The effects on the kidney are both functional and structural. Reversible and irreversible lesions can ensue.

Mild type IV renal tubular acidosis [28], other tubulointerstitial lesions/dysfunction, interstitial fibrosis, and tubular and glomerular atrophy/sclerosis were found in renal biopsies of cyclosporine treated individuals [29][30][31]. Renal vascular alterations as luminal narrowing and arteriole wall thickening have also been reported [29][30][31][32]. Progressive renal injury can be seen even when renal function is normal and despite cyclosporine dose reduction [29][32].

There is no strong evidence between nephropathy and dose dependency. A higher initial dose, an increase in the serum creatinine concentration ,and age are independent variables for toxicity.

Other Side Effects

Other side effects are listed as following [33]:

  • Fatigue
  • Epigastric burning
  • Hyperuricemia without clinical gout
  • Hypertrichosis and hirsutism
  • Gingival hyperplasia
  • Breast tenderness/ fibroadenoma
  • Liver toxicity: unspecific abnormality of the liver injury tests and mild cholestatic liver injury is an asymptomatic self-limited common finding [34];
  • Reduced appetite;
  • Hidradenitis;
  • Neurologic alterations as tremor; there is also a case report of aseptic meningitis.

Cyclosporin-treated individuals have not shown differences in overall and cancer-related mortality rates compared with others not exposed to immunosuppressive therapy [26]. Opportunistic infections have not been a major problem either [4].

Drug Interactions

Cyclosporine is metabolized by the cytochrome P450 enzyme system. Over one hundred drugs are identified as having major interactions with ciclosporin [35]. Some examples of commonly used drugs with those major interactions are listed:

  • Analgesics: tramadol
  • Antibiotics: sulfamethoxazole/trimethoprim (Bactrim); erythromycin; clarithromycin; ketoconazole; itraconazole; voriconazole
  • Anticoagulants: dabigatran; edoxaban
  • Antiepileptic drugs: carbamazepine
  • Antiretroviral drugs: adefovir; cidofovir; indinavir; lamivudine/tenofovir
  • Biologics: infliximab; natalizumab
  • Immunomodulators: tacrolimus
  • Live attenuated vaccines
  • Statins: atorvastatin; pitavastatin; rosuvastatin; simvastatin

Other Cyclosporine Formulations

Besides oral and topical cyclosporine (which can also be compounded at concentrations greater than 0.05%) , a slow release insert was previously investigated. A pilot study in humans has reported no clinical effects and the tolerability was doubtful. Systemic therapy was needed for disease control [4][7].

Topical cyclosporine is not effective in the management of uveitis.

References

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