Cyclosporine (CsA)

Cyclosporine (CsA)

  • Pregnancy category C – Neoral 25,100 mg 
  • Sandimmune

  • Depends on dermatoses: 2.5-5 mg/kg/day orally (ideal body weight)
  • Higher Cyclosporine bioavailability if administered on an empty stomach

Main

Binds cyclophilin & inhibits calcineurin leading to decreased Nuclear factor of activated T-cells 1 (NFAT-1) dephosphorylation and subsequent Interleukin-2 levels, decreasing CD4 & CD8 T cell proliferation

Others

  • Decrease interferon-gamma (IFN-γ) leading to decreased intercellular adhesion molecule-1 (ICAM-1) and lymphocyte infiltration into tissues
  • Binds steroid receptor associated heat-shock protein 56 leading to decreased proinflammatory cytokines

FDA approved

  • Psoriasis (Pso):
    • Widespread, inflammatory, or sudden flare
    • Other systemic therapies failed contraindicated
    • Upcoming major life event e.g. wedding
    • Erythrodermic Psoriasis
    • Pustular Psoriasis

Off-label

  • Atopic dermatitis (approved in Austrasia & Europe)
  • Chronic actinic dermatitis
  • Prurigo nodularis
  • Lichen planus
  • Pityriasis Rubra pilaris
  • Papuloerythroderma of Ofuji 
  • Bullous dermatoses
  • Autoimmune connective tissue disease 
  • Morphea 
  • Neutrophilic dermatoses (pyoderma gangrenosum): 1st line therapy 
  • Alopecia areata
  • Lichen planopilaris
  • Granulomatous
  • Scleromyxedema
  • Urticaria
  • Toxic epidermal necrolysis

Absolute

  • Significant renal insufficiency 
  • Uncontrolled hypertension
  • Allergy to Cyclosporine or ingredients
  • Cured or persistent malignancy (except non-melanoma skin cancer)
  • Cutaneous T-cell lymphoma

Relative

  • Age <18 or >64 years
  • Pregnancy or lactation
  • Unreliable patients
  • Controlled hypertension
  • Active infection
  • Immune suppression
  • Planning to receive a live vaccine
  • Concomitant nephrotoxic treatment or medication interaction with Cyclosporine
  • Concomitant phototherapy, methotrexate, or immune- suppressant medication

Neurologic (#1) 

  • Headache, tremor, paresthesia, seizures, pseudotumor cerebri hypertension (25%)
  • Directly due to vasoconstriction, or indirectly due to renal insufficiency. Antihypertensive of choice: calcium channel blockers Amlodipine, Nifedipine (increase risk of gingival hyperplasia) or Isradipine, angiotensin-converting-enzyme inhibitor (only perindopril) other angiotensin-converting-enzyme inhibitor can decrease glomerular filtration rate

Gastrointestinal

  • Nausea, abdominal pain, diarrhea
  • Hyperbilirubinemia
  • Transaminitis  

Metabolic

  • Hyperlipidemia. Mange: diet & exercise, if unsuccessful then decrease Cyclosporine dose or start (“PRooF” treatment 🡪 Pravastatin, Rosuvastatin, Fluvastatin) 
  • Increase Uric acid, increase potassium, decrease magnesium

Renal

  • Due to vasoconstriction initially then fibrosis & tubular atrophy
  • If Creatinine increased by 30% (25% FDA) 🡪 repeat Creatinine in 2 week, if still high then decrease Cyclosporine by 1mg/kg/day for at least 2-4 weeks & repeat Creatinine. If Creatinine dropped to <30% above baseline, then Cyclosporine can be continued at the new dosage. If Creatinine remains >30% then decrease Cyclosporine by 1mg/kg/day or discontinue. Can restart Cyclosporine at a lower dose when Creatinine normalizes 
  • If Creatinine >50% above baseline then discontinue Cyclosporine

Skin

Hypertrichosis, gingival hyperplasia, sebaceous hyperplasia, eruptive xanthoma, pyogenic granuloma, paronychia, acneiform eruption

Malignancy

  • Increase non-melanoma skin cancer 6x & lymphoma

  • Cyclosporine is metabolized by the liver (substrate of cytochrome-P450 3A4), & excreted in the feces
  • Hepatic insufficiency increases dose
  • Cyclosporine is also a potent inhibitor of cytochrome-P450 3A4

Increased level /toxicity

  • Grapefruit
  • Macrolides
  • Quinolones
  • Azoles
  • Calcium channel blockers (Diltiazem & Verapamil) 
  • Diuretics
  • Protease inhibitors
  • Allopurinol
  • Methylpred
  • H2 antihistamines

Decreased level/effect

  • Rifampin
  • Aromatic anticonvulsants 

Synergic toxicity

  • Nephrotoxicity (Vancomycin, Septra, non-steroidal anti-inflammatory drugs (NSAIDs), Amphotericin-B)
  • Increased potassium (Angiotensin-converting-enzyme inhibitor & potassium sparing diuretics)
  • Lovastatin, simvastatin & atorvastatin (lead to rhabdomyolysis)

Baseline

  • History & physical exam (blood pressure at least 2 readings, 2 days apart)
  • complete blood count, liver function tests, creatinine/ blood urea nitrogen, urinalysis, lipid profile, magnesium, potassium, uric acid
  • Tuberculin skin test
  • Pneumococcal & Influenza vaccine

Follow-up

  • Blood pressure at every visit
  • Creatinine & blood urea nitrogen q2weeks x 2 months then q4 weeks 
  • complete blood count, liver function tests, urinalysis, lipid profile, magnesium, potassium, uric acid qmonthly 
  • Glomerular filtration rate after 1 year of continuous therapy

Therapeutic guidelines

  • For severe disease, flares & recalcitrant disease: start with a higher dose: 5mg/kg/day & once patient is stable, decrease by 1mg/kg/day q2weeks till minimum effective dose
  • For moderate disease: start with 2.5-3mg/kg/day then increase by 0.5-1mg/kg/day q2weeks till effective dose
  • Insufficient response after 3 month: add another immunosuppressant & taper Cyclosporine to discontinue 

Risk factors for developing non-melanoma skin cancer while on Cyclosporine

  • Treatment > 2years 
  • Concurrent immunosuppressive medications 
  • Previous treatment with psoralen + ultraviolet-A radiation (PUVA)
  • Baseline multiple Squamous cell carcinoma
  • Transplant patients 

Sequential therapy

  • Sequential use of Cyclosporine & Acitretin: fast onset (Cyclosporine) & good maintenance (acitretin) 
  • Cyclosporine & Methotrexate: not yet determined to be safe but is used in rheumatology patients