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Ciclosporin Pharmacodynamics

Cyclosporine Pharmacodynamics

Primary Mechanism of Action

  • Calcineurin inhibition: Cyclosporine binds to cyclophilin (an intracellular protein) forming a complex that inhibits calcineurin, a calcium-dependent phosphatase

  • NFAT inhibition: Prevents dephosphorylation and nuclear translocation of Nuclear Factor of Activated T-cells (NFAT)

  • Gene transcription blockade: Inhibits transcription of several cytokine genes, primarily interleukin-2 (IL-2)

Cellular Effects

  • T lymphocyte inhibition: Primarily affects T-helper cells (CD4+)

    • Blocks activation and proliferation of T-cells

    • Suppresses production of IL-2, IL-3, IL-4, IFN-γ, TNF-α

    • Impairs generation of cytotoxic T-cells

  • Minimal impact on B-cells: Limited direct effect on antibody production

  • Leaves hematopoiesis intact: Unlike many immunosuppressants, cyclosporine preserves bone marrow function

Additional Pharmacodynamic Effects

  • Renal effects: Vasoconstriction of afferent arterioles leading to reduced GFR

    • Mediated through increased endothelin-1 and thromboxane

    • Decreased nitric oxide and prostaglandin production

  • Nervous system: Increases neuronal excitability through GABA modulation

  • Endocrine system: Impairs insulin secretion and peripheral insulin sensitivity

  • Cardiovascular system: Increases sympathetic tone and arterial pressure

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Dose-Response Relationship

  • Therapeutic window: Narrow therapeutic range necessitating careful monitoring

  • Concentration-effect curve: Sigmoidal relationship between blood levels and immunosuppression

  • Temporal dynamics: Maximum immunosuppressive effect lags behind peak blood concentration

Differences Between Formulations

  • Conventional formulation (Sandimmune): Variable absorption and bioavailability

  • Microemulsion formulation (Neoral): More consistent pharmacodynamic profile due to improved bioavailability

Clinical Implications of Pharmacodynamics

  • Onset of action: Rapid inhibition of T-cell function (within hours)

  • Achievement of steady-state effects: 2-3 days

  • Immunosuppressive selectivity: More selective than older agents like azathioprine

  • Reversibility: Effects are generally reversible upon discontinuation

  • Combination therapy: Often used with other immunosuppressants due to complementary mechanisms

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​Absorption

  • Bioavailability: Highly variable (20-50%) due to several factors:

    • Poor aqueous solubility (hydrophobic cyclic peptide)

    • P-glycoprotein efflux in intestinal epithelium

    • CYP3A4 metabolism in gut wall

    • Bile-dependent absorption

  • Formulation differences:

    • Original oil-based formulation (Sandimmune): More variable absorption (F~30%)

    • Microemulsion formulation (Neoral): Improved absorption characteristics (F~40-50%)

    • SMEDDS (Self-Microemulsifying Drug Delivery System) technology in newer formulations

  • Food effects:

    • High-fat meals increase AUC by 10-30%

    • Greater effect on conventional formulations than microemulsions

    • Grapefruit juice significantly increases bioavailability by inhibiting intestinal CYP3A4

Distribution

  • Volume of distribution: 3-5 L/kg (extensive tissue distribution)

  • Protein binding:

    • 90-98% bound, primarily to lipoproteins (HDL, LDL)

    • Only 10-20% bound to albumin (unlike many other drugs)

    • Temperature-dependent binding (increases with lower temperatures)

  • Blood distribution:

    • 33-47% in plasma

    • 41-58% in erythrocytes

    • 5-12% in leukocytes

    • Blood/plasma ratio approximately 2:1

  • Tissue distribution:

    • High concentrations in adipose tissue, liver, pancreas

    • Lower concentrations in kidney, lung, heart

    • Very low CNS penetration (<1% of blood levels)

Metabolism

  • Primary enzymes: CYP3A4 and CYP3A5 in liver and intestinal mucosa

  • Metabolic pathways:

    • N-demethylation

    • Hydroxylation

    • Cyclization

    • Oxidation

  • Major metabolites:

    • AM1 (1-hydroxy): Retains ~20% of parent immunosuppressive activity

    • AM9 (9-hydroxy): Minimal immunosuppressive activity

    • AM4N (4-N-demethylated): ~5-10% of parent activity

  • Metabolite excretion: >25 metabolites identified in bile, feces, and urine

Elimination

  • Clearance rate: 5-7 mL/min/kg (primarily hepatic)

  • Half-life phases:

    • Distribution phase: 1-2 hours

    • Elimination phase: 10-27 hours (average ~19 hours)

  • Excretion routes:

    • Biliary: >90% of dose as metabolites

    • Renal: <1% unchanged, ~6% as metabolites

    • Fecal: Primary elimination route

  • Special populations:

    • Hepatic impairment: Decreased clearance, increased half-life

    • Renal impairment: Minimal effect on parent drug clearance

    • Elderly: Reduced clearance (~25-30%)

    • Children: Increased clearance (may require higher weight-adjusted doses)

Pharmacokinetic Variability

  • Interindividual variability:

    • Trough concentrations can vary up to 10-fold on the same dosage

    • Genetic polymorphisms of CYP3A4/5 and P-glycoprotein (ABCB1)

    • Expression level of metabolizing enzymes in intestine and liver

  • Intraindividual variability:

    • Day-to-day variability of 10-35% in absorption

    • Time post-transplant affects clearance (typically increases over time)

    • Gastrointestinal transit time variability

​Drug Interactions

  • CYP3A4 inhibitors (increase cyclosporine levels):

    • Azole antifungals (ketoconazole, itraconazole)

    • Macrolide antibiotics (erythromycin, clarithromycin)

    • Calcium channel blockers (diltiazem, verapamil, nicardipine)

    • HIV protease inhibitors

    • Grapefruit juice (intestinal CYP3A4 inhibition)

  • CYP3A4 inducers (decrease cyclosporine levels):

    • Anticonvulsants (carbamazepine, phenytoin, phenobarbital)

    • Rifampin, rifabutin

    • St. John's Wort

    • Efavirenz, nevirapine

Therapeutic Drug Monitoring

  • Target concentrations (vary by indication and time post-transplant):

    • C₀ (trough): Generally 100-400 ng/mL depending on transplant type

    • C₂ (2-hour post-dose): Often better correlates with AUC

  • Sampling considerations:

    • Temperature affects erythrocyte partitioning (sample handling important)

    • Time of sampling relative to dose is critical

    • EDTA anticoagulant preferred for some assays

  • Assay methods:

    • Immunoassays (EMIT, FPIA, CEDIA) - may detect some metabolites

    • LC-MS/MS - more specific for parent compound

    • Differences between assays can be up to 20%

Chronopharmacokinetics

  • Diurnal variation in absorption (morning vs. evening dosing)

  • Circadian rhythm affects clearance and metabolism

  • May be clinically relevant for twice-daily dosing regimens

Ciclosporin Pharmacokinetics

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Ciclosporin Pivotal Studies - UC

These pivotal studies established cyclosporin as a rapid-acting rescue therapy for severe steroid-refractory UC, with efficacy comparable to infliximab in the short term. They also defined optimal dosing (2 mg/kg/day IV) and demonstrated the importance of transitioning to maintenance therapy (typically thiopurines) to prevent relapse after initial response.

Lichtiger et al. (1994) - The First Landmark RCT

  • Study design: Double-blind, randomized, placebo-controlled trial

  • Patients: 20 patients with severe, steroid-resistant UC

  • Intervention: IV cyclosporin (4 mg/kg/day) vs. placebo

  • Primary outcome: Clinical response at 7 days

  • Results:

    • Response rate: 82% (9/11) cyclosporin vs. 0% (0/9) placebo

    • Study terminated early due to clear efficacy

  • Significance: First controlled trial demonstrating cyclosporin efficacy in severe UC

D'Haens et al. (2001) - Oral vs. IV Formulation

  • Study design: Randomized controlled trial

  • Patients: 29 patients with severe UC

  • Intervention: IV cyclosporin (4 mg/kg/day) followed by oral vs. oral cyclosporin alone

  • Results: Similar clinical response rates between groups (approximately 80%)

  • Significance: Demonstrated potential efficacy of oral formulation

 

 

Van Assche et al. (2003) - Low vs. High Dose

  • Study design: Randomized, controlled trial

  • Patients: 73 patients with severe steroid-refractory UC

  • Intervention: IV cyclosporin 2 mg/kg/day vs. 4 mg/kg/day

  • Results:

    • Similar response rates: 85% (2 mg/kg) vs. 84% (4 mg/kg)

    • Fewer adverse events in low-dose group

  • Significance: Established 2 mg/kg as standard dosing with improved safety profile

CYSIF Trial (Laharie et al., 2012)

  • Study design: Randomized, open-label trial

  • Patients: 115 patients with severe steroid-refractory UC

  • Intervention: IV cyclosporin (2 mg/kg/day) vs. infliximab (5 mg/kg at weeks 0, 2, 6)

  • Results:

    • Similar 7-day response: 85.4% cyclosporin vs. 85.7% infliximab

    • Similar colectomy rates at day 98: 17% vs. 21%

  • Significance: First head-to-head comparison with biologics showing similar short-term efficacy

CONSTRUCT Trial (Williams et al., 2016)

  • Study design: Randomized, open-label, pragmatic trial

  • Patients: 270 patients with steroid-resistant acute severe UC

  • Intervention: IV cyclosporin (2 mg/kg/day) vs. infliximab (5 mg/kg at weeks 0, 2, 6)

  • Results:

    • Similar colectomy rates at 3 months (15% vs. 10%) and 1 year (24% vs. 17%)

    • No significant difference in quality of life measures

    • More serious adverse events with cyclosporin

  • Significance: Confirmed comparable efficacy but slight safety advantage for infliximab in longer follow-up

Long-term Follow-up Studies

  • Cohen et al. (1999):

    • Long-term colectomy rate: 58% after 7 years

    • Identified factors predicting relapse after initial response

  • Moskovitz et al. (2006):

    • 5-year colectomy rate: 88% monotherapy vs. 59% with thiopurine maintenance

    • Established importance of maintenance therapy after cyclosporin induction

 

Ciclosporin Adverse Effects

Nephrotoxicity

  • Acute nephrotoxicity:

    • Dose-dependent vasoconstriction of afferent arterioles

    • Reduced glomerular filtration rate

    • Usually reversible with dose reduction

  • Chronic nephrotoxicity:

    • Interstitial fibrosis and tubular atrophy

    • Arteriolar hyalinosis

    • Can lead to irreversible kidney damage

    • Associated with prolonged use (>1 year)

Hypertension

  • Occurs in 50-70% of transplant recipients

  • Mechanisms include:

    • Increased sympathetic tone

    • Impaired vasodilation due to decreased nitric oxide

    • Sodium retention

    • Activation of renin-angiotensin system

  • May require antihypertensive therapy (calcium channel blockers preferred)

Neurotoxicity

  • Tremor (most common, 20-40% of patients)

  • Headache

  • Paresthesias

  • Serious manifestations (rare):

    • Seizures

    • Posterior reversible encephalopathy syndrome (PRES)

    • Confusion, hallucinations

    • Cortical blindness

 

Metabolic and Endocrine Effects

  • Hyperglycemia/diabetes (10-30% of patients)

    • Reduced insulin secretion

    • Increased insulin resistance

  • Hyperlipidemia (45-60% of patients)

    • Increased LDL and total cholesterol

    • Moderate increase in triglycerides

  • Hyperuricemia and gout

  • Hypomagnesemia

  • Hyperkalemia

Gastrointestinal Effects

  • Nausea and vomiting (10-30%)

  • Gingival hyperplasia (10-15%)

  • Diarrhea

  • Hepatotoxicity (mild, transient liver enzyme elevations)

  • Anorexia

Dermatologic Effects

  • Hirsutism (excess hair growth, 50-70%)

  • Acne

  • Skin thickening and coarsening

  • Sebaceous gland hyperplasia

Increased Malignancy Risk

  • Lymphoproliferative disorders (increased risk 10-30 fold)

    • Often associated with EBV infection

  • Skin cancers (particularly squamous cell carcinoma)

  • Solid organ tumors (modest increased risk)​​

Increased Infection Risk

  • Opportunistic infections

  • Viral infections (CMV, HSV, VZV)

  • Fungal infections (Candida, Aspergillus)

  • Pneumocystis jirovecii pneumonia

  • Bacterial infections

Cosmetic Effects

  • Facial features alteration with long-term use

  • Cushingoid appearance (especially with concurrent steroids)

Hypersensitivity Reactions

  • Anaphylaxis (rare, more common with IV formulation)

  • Flushing and warmth during infusion

  • Urticaria

Formulation-Specific Effects

  • IV formulation:

    • Anaphylactoid reactions due to Cremophor EL vehicle

    • Thrombophlebitis at injection site

  • Oral formulation:

    • Greater variability in absorption

    • GI side effects more common

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Ciclosporin Drug Monitoring

Cyclosporin Drug MonitoringTherapeutic drug monitoring (TDM) is essential for cyclosporin (ciclosporin) due to its narrow therapeutic index and high inter- and intra-patient pharmacokinetic variability. Proper monitoring helps maximize efficacy while minimizing toxicity.

Monitoring Approaches

Trough Concentration (C₀)

  • Standard method: Blood sample drawn 12 hours after dose (immediately before next dose)

  • Target ranges (vary by indication and time post-transplant):

    • Kidney transplant: 150-300 ng/mL (early); 100-200 ng/mL (maintenance)

    • Liver transplant: 200-300 ng/mL (early); 100-200 ng/mL (maintenance)

    • Heart transplant: 250-350 ng/mL (early); 150-250 ng/mL (maintenance)

    • Autoimmune disorders: 100-200 ng/mL

  • Limitations: Correlates poorly with AUC and clinical outcomes in some patients

2-Hour Post-Dose Concentration (C₂)

  • Rationale: Better correlates with AUC₀₋₁₂ than trough levels

  • Target ranges:

    • Kidney transplant: 800-1500 ng/mL (early); 400-800 ng/mL (maintenance)

    • Liver transplant: 800-1200 ng/mL

  • Advantages: Better predictor of acute rejection in some studies

  • Limitations: Requires precise timing of sample collection

Limited Sampling Strategies

  • Abbreviated AUC: Using 3-4 time points (e.g., C₀, C₁, C₃, C₄)

  • Formula-based approaches: Mathematical algorithms to estimate AUC from limited samples

  • Benefits: More accurate than single time points with less burden than full AUC

Monitoring Considerations

Sample Handling

  • Blood matrix: Whole blood (EDTA) preferred over serum or plasma

  • Temperature effects: Keep at room temperature before analysis

    • Cooling causes redistribution from erythrocytes to plasma

  • Stability: Stable for 7 days at room temperature, 14 days refrigerated

Timing of Monitoring

  • First measurement: Usually 3-5 days after starting therapy

  • Steady state: Achieved in 2-3 days

  • Frequency:

    • 2-3 times weekly immediately post-transplant

    • Weekly for first month

    • Biweekly for 2-3 months

    • Monthly thereafter

    • After any dose change or potential drug interaction

Special Populations

  • Pediatrics: May require higher weight-adjusted doses

  • Hepatic impairment: Lower doses, more frequent monitoring

  • Cystic fibrosis: Often require higher doses due to malabsorption

Complementary Monitoring

Pharmacodynamic Monitoring

  • Calcineurin activity: Direct measurement of target enzyme inhibition

  • NFAT-regulated gene expression: Measures functional effect at cellular level

  • Research-stage approaches: Not yet widely implemented clinically

Clinical Parameter Monitoring

  • Renal function: Serum creatinine, BUN, GFR

  • Blood pressure: Regular measurements

  • Electrolytes: Particularly potassium, magnesium

  • Lipid profile and glucose: Monitor metabolic effects

  • Liver function tests: For hepatotoxicity

  • Complete blood count: For hematologic effects

Microemulsion Formulation Considerations

  • Neoral vs. Sandimmune: Different pharmacokinetic profiles

  • Bioequivalence: Not interchangeable without monitoring

  • AUC: Less variable with microemulsion (Neoral)

Interpretation Challenges

  • Assay variation: Results can differ by up to 20% between methods

  • Time-dependent variability: Circadian rhythm affects levels

  • Food effects: High-fat meals can increase absorption by 10-30%

  • Drug interactions: May require preemptive dose adjustments

Ciclosporin Drug Drug Interactions

Cyclosporin (ciclosporin) is susceptible to numerous clinically significant drug interactions due to its narrow therapeutic index and its metabolism primarily via CYP3A4. 

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Medications That Increase Cyclosporin Levels

CYP3A4 Inhibitors

Antifungals

  • Ketoconazole: 2-5 fold increase; dose reduction of 70-80% recommended

  • Itraconazole: 1.7-2.5 fold increase; dose reduction of 50% recommended

  • Fluconazole: Moderate increase; dose reduction of 20-30% recommended

  • Voriconazole: Significant increase; careful monitoring required

Antibiotics

  • Erythromycin: 1.5-2.5 fold increase

  • Clarithromycin: 1.5-2 fold increase

  • Azithromycin: Minor increase (less than other macrolides)

  • Chloramphenicol: Moderate increase

  • Doxycycline: Minor increase

Calcium Channel Blockers

  • Diltiazem: 1.5-2 fold increase

  • Verapamil: 1.3-2 fold increase

  • Nicardipine: 1.3-1.8 fold increase

  • Amlodipine: Mild to moderate increase

  • Nifedipine: Less significant than other CCBs

Antivirals

  • HIV protease inhibitors (ritonavir, saquinavir): 2-5 fold increase

  • Cobicistat: Substantial increase

Other

  • Amiodarone: Moderate increase; slow onset (weeks)

  • Metoclopramide: Increases absorption

  • Methylprednisolone (high dose): Increases levels by 50-60%

  • Allopurinol: Moderate increase

  • Colchicine: Moderate increase

Food/Supplements

  • Grapefruit juice: 1.5-2 fold increase; inhibits intestinal CYP3A4

  • Pomegranate juice: Moderate increase

  • Cannabidiol (CBD): Potential CYP3A4 inhibition

Medications That Decrease Cyclosporin Levels

CYP3A4 Inducers

Anticonvulsants

  • Carbamazepine: 30-70% decrease

  • Phenytoin: 30-50% decrease

  • Phenobarbital: 30-50% decrease

  • Oxcarbazepine: Less pronounced than carbamazepine

Antimicrobials

  • Rifampin (rifampicin): 40-70% decrease; avoid combination if possible

  • Rifabutin: 15-30% decrease

  • Nafcillin: Moderate decrease

Other

  • Bosentan: 30-50% decrease

  • Modafinil: Moderate decrease

  • Efavirenz: 25-45% decrease

  • Nevirapine: 20-40% decrease

Herbal Products

  • St. John's Wort: 30-60% decrease; contraindicated

  • Ginseng: Minor to moderate decrease

  • Echinacea: Possible moderate decrease

Medications With Bidirectional or Complex Interactions

  • Tacrolimus: Competitive interaction, monitor both drugs

  • Sirolimus: Increased levels of both drugs

  • Everolimus: Increased levels of both drugs

Medications That Increase Nephrotoxicity Risk

  • NSAIDs: Enhanced nephrotoxicity

  • Aminoglycosides (gentamicin, tobramycin)

  • Amphotericin B

  • Acyclovir/valacyclovir (high doses)

  • Vancomycin

  • Cisplatin

  • Melphalan

  • ACE inhibitors/ARBs

  • Trimethoprim-sulfamethoxazole

  • Foscarnet

Medications With Other Risk-Enhancing Effects

  • Statins: Increased risk of myopathy/rhabdomyolysis

    • Simvastatin, lovastatin: >5-fold increased exposure

    • Atorvastatin: 2-3 fold increased exposure

    • Rosuvastatin, pravastatin: Less affected but still increased

  • Colchicine: Increased toxicity risk

  • Eplerenone: Increased risk of hyperkalemia

  • Potassium-sparing diuretics: Increased risk of hyperkalemia

  • Repaglinide: Increased hypoglycemia risk

  • Digoxin: Increased digoxin levels in some patients

  • Oral contraceptives: Potential decreased efficacy

Displacement From Protein Binding

  • Sulfonamides

  • Salicylates (high dose)

  • Phenytoin

Vaccines

  • Live vaccines: Potentially reduced immune response and increased risk with live vaccines

  • Inactivated vaccines: Generally safe but may have reduced efficacy

Management Strategies

  1. Preventive dose adjustment: Preemptive cyclosporin dose change when starting/stopping interacting medications

  2. Increased monitoring frequency: More frequent levels when initiating, stopping, or changing dose of interacting drugs

  3. Alternative medication selection: Choose drugs with less interaction potential when possible

  4. Temporary therapy interruption: In some cases with strong inducers/inhibitors

  5. Timing separation: For interactions affecting absorption (not metabolism)

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Ciclosporin in Pregnancy

FDA Pregnancy Category

  • Classified as Pregnancy Category C

  • Animal studies have shown adverse effects on the fetus

  • No adequate well-controlled studies in pregnant women

  • Potential benefits may warrant use despite potential risks

Transplant Registry Data

  • The National Transplantation Pregnancy Registry (NTPR) has collected data on >500 pregnancies exposed to cyclosporin

  • Most comprehensive source of information on outcomes

Maternal Risks

  • Hypertension: Increased risk of pregnancy-induced hypertension and preeclampsia (30-40% vs 5-10% in general population)

  • Renal function: May exacerbate pregnancy-related decline in renal function

  • Gestational diabetes: Slightly increased risk due to cyclosporin's effects on insulin secretion

  • Infection risk: Immunosuppression may increase susceptibility to certain infections

Breastfeeding

  • Cyclosporin is excreted in breast milk

  • Concentrations in milk approximately 50-70% of maternal blood levels

  • Potential for immunosuppression and other adverse effects in nursing infants

  • Generally not recommended during breastfeeding by most guidelines

Fetal/Neonatal Risks

  • Placental transfer: Cyclosporin crosses the placenta, with fetal concentrations approximately 30-50% of maternal blood levels

  • Birth weight: Increased incidence of low birth weight (approximately 40-50% of infants)

  • Prematurity: Higher rates of preterm birth (45-60% vs 10-15% in general population)

  • Congenital malformations:

    • No specific pattern of malformations identified

    • Overall incidence similar to general population (3-5%)

    • No confirmed teratogenic effect

  • Immune system effects: Transient lymphopenia and potential immune suppression in newborns reported

Management Recommendations

  • Pre-conception counseling: Discuss risks and benefits prior to pregnancy

  • Dose adjustments:

    • Pregnancy may alter cyclosporin pharmacokinetics (increased volume of distribution)

    • Increased monitoring frequency recommended (every 4-6 weeks)

    • May require dose increases of 20-40% during later stages of pregnancy

  • Monitoring parameters:

    • Blood pressure monitoring (weekly to biweekly)

    • Renal function (every 4-6 weeks)

    • Cyclosporin blood levels (every 4-6 weeks)

    • Glucose monitoring

    • Fetal growth monitoring (ultrasound every 4 weeks)

  • Post-partum management:

    • Reduction of cyclosporin dose to pre-pregnancy levels

    • Close monitoring for rejection in transplant patients

Compared to Other Immunosuppressants

  • Tacrolimus: Similar profile but possibly lower rates of hypertension; classified as Pregnancy Category C

  • Azathioprine: More extensive pregnancy safety data; Category D but considered safer option in many cases

  • Mycophenolate mofetil: Contraindicated due to confirmed teratogenicity (Category D)

  • mTOR inhibitors (sirolimus, everolimus): Limited data; generally avoided during pregnancy

Disease-Specific Considerations

  • Transplant patients: Benefit of preventing rejection generally outweighs risks

  • Autoimmune diseases: Consider disease-specific risks vs. medication risks

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CiclosporinGeneral References

Pivotal Clinical Trials

  1. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330(26):1841-1845.

  2. D'Haens G, Lemmens L, Geboes K, et al. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology. 2001;120(6):1323-1329.

  3. Van Assche G, D'Haens G, Noman M, et al. Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology. 2003;125(4):1025-1031.

  4. Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet. 2012;380(9857):1909-1915.

  5. Williams JG, Alam MF, Alrubaiy L, et al. Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial. Lancet Gastroenterol Hepatol. 2016;1(1):15-24.

Meta-Analyses and Systematic Reviews

  1. Narula N, Marshall JK, Colombel JF, et al. Systematic review and meta-analysis: infliximab or cyclosporine as rescue therapy in patients with severe ulcerative colitis refractory to steroids. Am J Gastroenterol. 2016;111(4):477-491.

2. Komaki Y, Komaki F, Ido A, et al. Efficacy and safety of tacrolimus and cyclosporine A for refractory ulcerative colitis: a meta-analysis. J Gastroenterol Hepatol. 2016;31(1):69-81.

​

3. Scholz T, Berg E, Schuller A, et al. Systematic review and meta-analysis: Rescue therapy with cyclosporine or tacrolimus in acute or steroid-refractory ulcerative colitis. United European Gastroenterol J. 2021;9(9):1065-1082.

​

Long-term Outcomes and Maintenance Therapy

  1. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999;94(6):1587-1592.

  2. Moskovitz DN, Van Assche G, Maenhout B, et al. Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4(6):760-765.

  3. Cheifetz AS, Stern J, Garud S, et al. Cyclosporine is safe and effective in patients with severe ulcerative colitis. J Clin Gastroenterol. 2011;45(2):107-112.

Adverse Effects and Safety

  1. Sternthal MB, Murphy SJ, George J, et al. Adverse events associated with the use of cyclosporine in patients with inflammatory bowel disease. Am J Gastroenterol. 2008;103(4):937-943.

  2. Scaldaferri F, Pizzoferrato M, Lopetuso LR, et al. Use and predictors of failure of rescue therapies in outpatients with steroid-refractory ulcerative colitis. Minerva Gastroenterol Dietol. 2016;62(4):275-280.

Comparative Studies with Other Therapies

  1. Rolny P, Vatn M. Cyclosporine in patients with severe steroid refractory ulcerative colitis in the era of infliximab. Review article. Scand J Gastroenterol. 2013;48(2):131-135.

  2. Ordás I, Domènech E, Mañosa M, et al. Long-term efficacy and safety of cyclosporine in a cohort of steroid-refractory acute severe ulcerative colitis patients from the ENEIDA Registry (1989-2013): a nationwide multicenter study. Am J Gastroenterol. 2017;112(11):1709-1718.

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