What is the role of cyclosporin (CsA) in the treatment of severe chronic plaque psoriasis?

Cyclosporine in Chronic Plaque Psoriasis

Cyclosporine is highly effective for severe chronic plaque psoriasis, achieving 50-70% PASI 75 response at 2.5-5 mg/kg/day within 8-16 weeks, but should be used as short-term interventional therapy (optimally ≤12 weeks per course) rather than continuous treatment due to nephrotoxicity and hypertension risks. 1

Indications and Patient Selection

Cyclosporine is FDA-approved for adult, nonimmunocompromised patients with severe, recalcitrant psoriasis, defined as extensive or disabling plaque disease that has failed at least one systemic therapy or where other systemic therapies are contraindicated or not tolerated. 1

The drug demonstrates particular efficacy in crisis situations:

• Erythrodermic psoriasis with dramatic improvement within 2-3 weeks 2, 3, 4
• Generalized pustular psoriasis requiring rapid control 1
• Palmoplantar psoriasis 1

Dosing Strategy

Two evidence-based approaches exist, with the rapid induction method preferred for severe disease:

Rapid Induction Approach (Preferred for Severe Disease)

• Start at 5 mg/kg/day divided into two doses for swift control 1, 2
• 65% of patients achieve clear or almost clear results after 8 weeks at this dose 1
• Reduce by 0.5-1.0 mg/kg when clearance is achieved 1

Conservative Escalation Approach

• Start at 2.5-3.0 mg/kg/day divided twice daily 1, 2
• Increase gradually if needed after 4 weeks 1
• 36% achieve clear or almost clear results at 3 mg/kg/day after 8 weeks 1

Critical dosing principle: The modified microemulsion formulation (Neoral) is required and is not interchangeable with unmodified cyclosporine (Sandimmune). 1

Treatment Duration and Maintenance

Short-term intermittent courses are strongly preferred over continuous therapy:

• Optimal duration: 8-16 weeks per treatment course 1
• Maximum FDA-approved duration: 1 year continuous treatment in the US; 2 years in non-US countries 1
• Maintenance dosing: 3.0 mg/kg/day maintains 58% of patients through 24 weeks after initial clearance 1, 5

Tapering Protocol to Minimize Relapse

When discontinuing after achieving ≥90% clearance, gradual tapering delays relapse by only 4 days compared to abrupt cessation but is still recommended:

• Reduce by 1 mg/kg/day weekly until complete cessation 2, 6
• Median time to relapse: 113 days with gradual taper vs. 109 days with abrupt cessation (statistically significant, P=0.038) 2, 6
• Initiate alternative therapy before completing taper to maintain disease control 2

Common pitfall: Abrupt discontinuation leads to rapid relapse, typically within 3 months, and may precipitate rebound erythrodermic or pustular flares. 1, 2

Efficacy Data

Short-term results (8-16 weeks):

• 50-70% achieve PASI 75 1
• 30-50% achieve PASI 90 at 3 mg/kg/day 1
• 80-90% show dramatic improvement at approximately 5 mg/kg/day 1, 5

Long-term intermittent therapy (2-year data):

• Patients remain in remission 56-62% of the time over 2 years 6
• Treatment required only 43% of the time during 2-year period 6
• Median time to relapse progressively shortens after multiple courses 6

Mandatory Monitoring Requirements

Baseline Assessment

• Blood pressure (must be normal; uncontrolled hypertension is absolute contraindication) 1
• BUN and serum creatinine (abnormal renal function is absolute contraindication) 1
• Urinalysis 1
• CBC, LFTs, lipid profile, magnesium, uric acid, potassium 1, 2
• Pregnancy test if applicable 1
• Consider PPD for tuberculosis screening 1

Ongoing Monitoring

• Every 2 weeks for first 3 months: Blood pressure, BUN, creatinine 1, 2
• Monthly thereafter: Blood pressure, BUN, creatinine 1
• Monthly throughout: CBC, LFTs, lipid profile, magnesium, uric acid, potassium 1

Critical monitoring principle: Perform laboratory tests at least 4 days after dosing to avoid making adjustments based on transient elevations. 1

Absolute Contraindications

• Abnormal renal function 1
• Uncontrolled hypertension 1
• Active malignancy 1
• Hypersensitivity to cyclosporine 1
• Concomitant use with PUVA, UVB, methotrexate, other immunosuppressive agents, or coal tar 1, 2
• History of ≥200 PUVA treatments or radiation therapy 1

Use with extreme caution in:

• Major active infection 1
• Poorly controlled diabetes 1
• Obesity (significant correlation with cyclosporine-induced side effects) 7
• Age >70 years (increased risk of adverse effects) 7
• Pre-existing controlled hypertension (higher risk of worsening) 7
• Metabolic syndrome 7

Adverse Effects and Management

Nephrotoxicity (Most Significant Long-Term Risk)

• Occurs in up to 71% of patients on long-term therapy 8
• Management: Reduce dose by 0.5-1.0 mg/kg if creatinine increases >30% from baseline 1, 7
• Discontinue if creatinine elevation persists despite dose reduction 7, 8
• Renal impairment typically stabilizes or improves after dose reduction or discontinuation 7, 8

Hypertension

• Develops in 40-57% of patients 7, 8
• Management: Use calcium channel blockers, particularly isradipine 2
• Avoid: Thiazide diuretics and potassium-sparing diuretics 2
• Reduce cyclosporine dose by 0.5-1.0 mg/kg if blood pressure becomes uncontrolled 1

Drug Interactions (Critical to Review)

Cyclosporine is metabolized by CYP3A4, leading to numerous interactions: 2

• Avoid: Aminoglycosides, amphotericin, trimethoprim, ketoconazole, phenytoin, rifampin, isoniazid, NSAIDs 2
• Avoid: Grapefruit juice (increases cyclosporine levels) 1

Special Populations

Pregnancy (Category C):

• Lower birth weight and shorter pregnancy duration reported in transplant patients 1
• Not teratogenic based on transplant experience 2
• Avoid unless benefits clearly outweigh risks 2

Breastfeeding:

• Mothers should not breastfeed while taking cyclosporine 1, 2

Pediatric patients:

• Effective and generally well tolerated in children at 2-5 mg/kg/day 1
• 77% of pediatric patients achieve excellent response with clearance in mean 4 weeks 1
• Children may require higher weight-based doses than adults due to faster clearance 1

Practical Risk Minimization Strategies

Use intermittent short courses (2-12 weeks) rather than continuous therapy to minimize cumulative toxicity. 2, 6 Only 8% of patients discontinue due to adverse effects with this approach. 2

Combine with topical treatments to reduce required cyclosporine dose and duration. 2

Transition to alternative maintenance therapy (biologics, methotrexate, or acitretin) before completing cyclosporine taper. 2

Never combine with phototherapy (PUVA or UVB) due to increased photocarcinogenesis risk. 1, 2

Comparative Context

While cyclosporine achieves 50-70% PASI 75 at 8-16 weeks, biologics demonstrate superior efficacy: infliximab (80% PASI 75), adalimumab (75%), and ustekinumab (67%). 1 However, cyclosporine remains valuable for rapid crisis management and as a bridge to longer-term therapies, with significantly lower cost than biologics (approximately $10,000 annually at 5 mg/kg/day). 2