ROLE Of CYCLOSPORIN IN DERMATOLOGY

HISTORY OF CYCLOSPORIN
1970- J.F BOREL Discovered from a soil fungus TOLEPOCLADIUM INFLATUM

GAMS
1976 - immunosuppresive properties were identified 1978 -first organ transplant is succesful using cyclosporine

1979 -anti psoriatic properties were fotuitously discovered while treating a

patient with psoriatic arthritis.

1996 -1ST International conference confirmed efficacy

1997 -cyclosporine was approved by FDA for RA & PSORIASIS

2004 - International concensus conference on CSA formulated the guidelines on its use & monitoring

CYCLOSPORINE
Structure:C-62,H-111,N-11,O-12. Cyclic polypeptide consisting of 11 amino acids

Mechanism of action of CSA

CSA inhibits IL2 production by activated T cells T cell proliferation B cell proliferation Neutrophil chemotaxis Keratinocyte proliferation

CSA inhibits Antigen presentation function of Langerhans cells

CSA inhibits Mast cell degranulation & release of Histamine ,PGD2

Cyclosporine: Mechanism of Action

Complex with the Cytosolic Immunophilin and Cyclophilin which binds to and inhibits the activity of the intracellular enzyme Calcineurin phosphatase

Reduces the effect of the transcription factor in T cells nuclear factor of activated T cells (NF-AT) in regulating transcription of a number of cytokine genes, the most significant being interleukin (IL)-2

Inhibits histamine release from mast cells and down regulates various cellular adhesion molecules, adding to the prominent anti-inflammatory activity

Mechanism Of Action

Pharmacokinetics
Absorption & Bio-availabity
a. Thermodynamically stable, self-emulsifying, little effected by physiological state of GI tract. b. Faster and more consistent rate of absorption ,(Tmax) =1.5 to 2

hours.

C . peak concentration-2-4hrs & half life -5-18hrs c. Advantageous profile with regard to efficacy and tolerability. d. Clinically proved to produce a more rapid response and higher remission rate than conventional cyclosporine. e. A high fat meal , decreases the AUC by 13% and Cmax by 33%.

Metabolism
Extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the G I tract, and the kidney.

FDA Approved Indications

Prophylaxis of organ rejection in kidney, liver, and heart allogenic transplant

Severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate
Adult, non-immuno compromised patients with severe (i.e. extensive and/or disabling), Recalcitrant Plaque Psoriasis who have failed to respond to at least one systemic therapy

Indications
Psoriasis Dishydrotic dermatitis

Atopic dermatitis
Chronic urticaria Pyoderma gangrenosum SLE

Vitiligo
Scleroderma Sezary syndrome Mycosis fungoides Pemphigus pemphigoid EB Aquisita

PRP
Prurigo nodularis Behcets disease Alopecia areata

Lichen planus
Dermatomyositis Hailey Hailey Disease

Hidradenitis suppurativa
Sarcoidosis

Contraindications
Absolute: Impaired renal function Insufficient controlled BP Severe infectious diseases Malignancy PUVA therapy Relative: Previous potential carcinogenic therapies Significant hepatic diseases Hyperuricaemia Hyperkalaemia Simultaneous nephrotoxic drugs

Drug administration
DOSE 2.5-5mg/kg/day Low dose approach High dose approach
2.5 mg/kg/day 2 divided doses Increments -0.5- 1 mg/kg/day- Every 2wks

Duration of treatment

5mg/kg/day Decrements -0.5-1mg/kg/day-Every 2wks

Inter short course- 12-16 wks long term - upto 1yr -USA / upto2yrs -Uk

Cyclosporine in psoriasis
Intermittent short course therapy 2.5mg/kg -5 mg/kg Rescue therapy 5mg/kg Long term therapy 3.5mg/kg Combination therapy with top cs,anthralin, reduced vitD3derivatives,MTX, MFM, Biologicals, fumaric acid esters Rotational therapy retenoids,MTX,biologicals Sequential therapy - 12 -16wks - 12-16 wks -upto 1yr - dose can be

CYCLOSPORINE TREATMENT REGIMEN FOR PSORIASIS

Intermittent short-term therapy

Rescue therapy

Long-term therapy

Combination therapy

Rotational therapy

2.5-5 mg/kg/day for 12-16 wks, course repeated when relapse occurs. Duration: 12-16 weeks of CsA therapy

5 mg/kg/day for 12-16 wks for flaring of disease

5 mg/kg/day for up to 1 yr; reducing dose to lowest effective

Corticosteroids, anthralin, or vit D3 analogues for an improved response. MTX, fumaric acid esters, and mycophenolate Mofetil in severe cases

3-4 mg/kg/day, max 5 mg/kg/day

SEQUENTIALTHERAPY
PHASE - 1 CSA AT MAXIMUM DOSE 5mg/kg (3-4 months) PHASE - 2 Maintain CSA AT 4mg/kg/day Introduce acitretin taper off CSA PHASE - 3A MAINTAIN WITH ACETRETIN or Topical PHASE -3B MAINTAIN WITH ACETRETIN +UVB OR ACETRETIN + PUVA

Evidences reporting efficacy of Cyclosporine in Psoriasis

Study by Shupack et al 1991 provided further confirmation that cyclosporine
at a dose of 5.0 mg/kg per day is effective in treating most patients with severe recalcitrant or disabling psoriasis. The majority of patients (84%) achieved at

least a 70% decrease in BSA involvement in a median time of 8 weeks, with

improvement continuing through week 12. PASI scores decreased by 86%. In patients with psoriasis, cyclosporine has been a relatively easy drug to use during the short term. Psoriasis rapidly clears in a high percentage of patients (approximately 60% to 86% clearing at 8 to 12 weeks, respectively). These levels of clearance are generally maintained as long as the clearing dose is held relatively constant. (Lebwohl et al 1998).

When dosed at 3 mg/kg/d, cyclosporine leads to a PASI 75 response in 50% to 70% ofpatients and a PASI 90 response in 30% to 50% of patients. (Nast et al 2007).

Evidences related to safety and tolerability of Cyclosporine in Psoriasis

The study concluded that cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day. Most frequently reported adverse events in this 181 patients study were Headache 30.0%, Paresthesia 18.0%, Hirsutism 17.0%, Nausea 12.0%, Cold symptoms 11.0%, Fatigue 11.0%, Hypertension 8.8% with (mean cyclosporine dose = 5.0 mg/kg/day). (Shupack et al 1997).

Adverse Events
Renal Dysfunction Headache Hypertension Hypertriglyceridemia Hirsutism/Hypertrichosis Paresthesia /Hyperesthesia Influenza like symptoms: nausea/ vomitting Diarrhea Abdominal discomfort Lethargy Musculoskeletal or joint pain

Monitoring Patients on Cyclosporine

Initial monitoring
A complete physical examination.

Review of family history as well as drug history

A complete skin inspection. Testing for tuberculosis. History of excessive sun or psoralen plus ultraviolet A (PUVA) exposure Blood pressure measurements (on at least two occasions) Presence of any occult infection Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium, potassium, uric acid, and lipids.

Continuous monitoring

Serum creatinine and blood urea nitrogen Blood pressure CBC, uric acid, potassium, lipids, and magnesium

Serum Creatinine Monitoring

Management of Cyclosporininduced Hypertension

Treatment of HTN when pt is on CSA

Thiazides/Thiazide type diuretics:
Bendroflumethiazide , Benzthiazide , Chlorothalidone , Chlorothiazide , Hydrochlorothiazide, Hydrochlorothiazide, Hydroflumethiazide.

CCB: Amplodipine , Nicardipin , Felodipin . ACE Inhibitors: Benzapril Hydrochloride, ARBs: Candesartan, Eprosartan, Irbsartan,

Captopril, Enapril Maleate, Fosinopril Sodium, Lisinopril, Ramipril, Trandopril. Telmisartan, Valsartan, Losartan, Olmesartan.

Over Dosage
Seek emergency medical attention if you think you have used too much of this medicine.

Overdose can cause nausea, vomiting, pain in your upper stomach, loss of appetite, jaundice (yellowing of the skin or eyes), and urinating less than usual or not at all.
Forced emesis and gastric lavage is done until 2 hours after administration of Psorid. There may be nephrotoxicity. transient and reversible hepatotoxicity and

ADVANTAGES OF CsA Are: (1) safety in pregnancy (2) absence of tachyphylaxis (3) absence of rebound phenomenon

CONCLUSIONS
CSA can be recommended for short term rescue treatment of psoriasis & AD in appropriate patients CSA may be used for therapy of pyoderma gangrenosum & refractory chronic urticaria CSAin low dose with CS is effective in dermatomyositis CSA should be included in the list of systemic drugs for severe childhood psoriasis along with MTX & RETENOIDS Intermittent short course regemen is established as the ideal in clinical practice Duration of therapy should be < 2yrs & preferably 1yr Yearly estimation of GFR is advocated in pts taking CSA for >1yr

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