2-5 % Europeans A distressing, life-long, inflammatory disease Impairs patients Quality of Life

Transcription

1 Psoriasis: 2-5 % Europeans A distressing, life-long, inflammatory disease Impairs patients Quality of Life 15-25%: moderate-to-severe disease - candidates for systemic therapies - often difficult to manage effectively - many not using the most aggressive treatment - larger, negative impact on Quality of Life

2 Definitions of severity of psoriasis Severity of psoriasis is linked to how the disease alters the quality of life: Impact on daily physical activities Impact on social activities Impact on psychological aspects

3 Mild Psoriasis Disease does not alter the patient's quality of life Patients can minimize the impact of disease; may not require treatment Treatments have no known serious risks Generally less than 5% of body surface is involved with disease PASI < 8-10

4 Moderate Psoriasis Disease does alter the patient s quality of life (QOL) The patient expects therapy will improve the QOL Therapies used for moderate disease have minimal risks Generally between 2% and 20% of the body surface is involved with disease PASI 10-20

5 Severe Psoriasis Disease alters the patient s quality of life Disease does not have a satisfactory response to treatments Patients are willing to accept life-altering side effects to achieve less disease or no disease Generally more than 10% of body surface is involved with disease Other factors: face, hands, genitals, joints, etc. involve PASI > 20

6 Psoriatic body surface area 10 % 30 % 20 % 40 %

7 PASI P A S I Sample PASI Scores PASI score: 18.3 PASI score: 30.6

8 Psoriasis : Mild (PASI <10)

9 Psoriasis : Moderate (PASI 10-50)

10 Psoriasis : Severe (PASI > 50)

11 Moderate to Severe (PASI 10-72)

12 H I S T O R I C A L T H E R A P I E S Historical Psoriasis Treatment Strategy Topical Therapy Phototherapy Systemic Therapy

13 Historical Treatment Paradigm: Stepwise For many clinicans, psoriasis management has typically followed a progression in which patients fail the previous before treatment with a more aggressive (and more toxic) therapy is initiated. Step 1 Topical Therapy Over-the-counter products Emollients Other Topical steroids Vitamin D analogs Topical retinoids Step 2 Phototherapy Broadband UVB Narrowband UVB PUVA Laser Step 3 Systemic Therapy Ciclosporin A Methotrexate Retinoids Systemic steroids Ashcroft DM et al. J Clin Pharm Ther. 2000;25:1-10.

14 H I S T O R I C A L T H E R A P I E S Topical Therapy Anthralin Bath solutions Coal tar Moisturizers Nonprescription medications Occlusion therapy Salicylic acid Sunlight Topical calcipotriene Topical retinoids Topical corticosteroids Topical immunomodulators Intralesional steroids Odom RB, et al. In: Andrews Diseases of the Skin: Clinical Dermatology. WB Saunders Company; 2000:

15 H I S T O R I C A L T H E R A P I E S Phototherapy Goeckerman regimen Day treatment program PUVA Ultraviolet B (UVB) light Narrowband (NB-UVB) Broadband Laser Odom RB, et al. In: Andrews Diseases of the Skin: Clinical Dermatology. WB Saunders Company; 2000:

16 H I S T O R I C A L T H E R A P I E S Systemic Therapy Cyclosporine Methotrexate Retinoids (acitretin, isotretinoin) Other therapies used rarely Thioguanine Azathioprine Mycophenolate mofetil Odom RB, et al. In: Andrews Diseases of the Skin: Clinical Dermatology. WB Saunders Company; 2000:

17 T O P I C A L A G E N T S Mechanisms of Action Agent Topical corticosteroids Anthralin and tars Topical vitamin D analog (calcipotriene) Retinoid (tazarotene) Mechanism of Action Unknown; thought to be induction of phospholipase A2 inhibitory proteins Unknown; appear to involve expression of genes for cytokines and cell adhesion molecules Unknown; appears to slow excessive growth of skin cells Unknown; may induce a growth suppressor gene in human keratinocytes White GM, et al. In: Diseases of the Skin. Mosby; 2000: Fritz KA, et al. Ann Allergy. 1983;50: Geilen CC, et al. Clin Exp Rheumatol. 2002;20(suppl 28):S81-S87.

18 T O P I C A L A G E N T S Efficacy Agent Topical corticosteroids Anthralin and tars Topical vitamin D analog (calcipotriene) Retinoid (tazarotene) Efficacy* Range from class 1 (superpotent) to class 7 (weak); duration of effect and onset of response vary depending on severity of disease, potency, area of body, occlusion; duration of effect generally short; tachyphylaxis may develop Ingram regimen: requires weeks of therapy; onset of response seen in 20 days Short-Contact Anthralin Therapy (SCAT) regimen: effective in a large number of mild-to-moderate cases Onset of response seen after 2 weeks; full effect requires 8 weeks; effective in a large number of mild-to-moderate cases After 12 weeks produces reduced plaque thickness and some improvement in erythema and scaling *At the time these drugs were evaluated, there was no standardized measure of efficacy. Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

19 T O P I C A L A G E N T S Side Effects/Safety Issues Agent Topical corticosteroids Anthralin and tars Topical vitamin D analog (calcipotriene) Retinoid (tazarotene) Side Effects/Safety Issues Skin thinning/telangiectasia; rebound; possible HPA axis suppression Staining and skin irritation Minor skin irritation in 10%-15% of patients; risk of hypercalcemia; pregnancy category C Persisting erythema, burning; should not be used by women who may become pregnant (pregnancy category X) Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

20 T O P I C A L A G E N T S Dosage and Administration Agent Topical corticosteroids Anthralin and tars Topical vitamin D analog (calcipotriene) Retinoid (tazarotene) Dosage and Administration Varies from QD or BID or more often, depending on potency of agent Ingram regimen: combines anthralin paste, a coal tar bath, and UV exposure Short-Contact Anthralin Therapy (SCAT): can be administered at home; good for localized areas; may be used with PUVA or UVB Can be used in combination with other topical agents and phototherapy Used topically once a day Hall JC, et al. In: Sauer s Manual of Skin Diseases. Lippincott Williams & Wilkins; 2000: Cornell RC, et al. Arch Dermatol. 1985;121: Nicol NH. The Nurse Practitioner. 2000;25:58-76.

21 T O P I C A L A G E N T S Advantages and Disadvantages of Topical Agents Advantages Widely available Limited systemic toxicity Efficacy in mild/localized psoriasis Disadvantages Lack of efficacy in moderate-to-severe/generalized psoriasis Messy Cutaneous side effects Patient compliance issues Potential for HPA axis suppression Tachyphylaxis Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

22 P H O T O T H E R A P Y Mechanisms of Action Therapy PUVA UVB Narrowband UVB Mechanism of Action Unknown; may involve intercalation of psoralen methoxsalen into DNA, forming crosslinks between DNA strands that interfere with DNA synthesis and block cell proliferation; may also suppress cellmediated responses in involved skin Unknown; may reduce DNA synthesis of epidermal cells or alter immune reactions in the skin Unknown; may reduce DNA synthesis of epidermal cells or alter immune reactions in the skin Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

23 P H O T O T H E R A P Y Efficacy Therapy PUVA UVB Narrowband UVB Efficacy* Significant number of patients have a long duration of effect; slow onset of response Somewhat less effective than PUVA; can be improved with addition of other systemic therapies; slow onset of response May be more effective than UVB *At the time these therapies were evaluated, there was no standardized measure of efficacy. Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

24 P H O T O T H E R A P Y Side Effects/Safety Issues Therapy PUVA UVB Narrowband UVB Side Effects/Safety Issues Nausea, headache, itching, redness, lentigines, aging of skin, increased risk of skin cancer Can burn, possible long-term skin cancer risk Can cause freckling, skin aging Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

25 P H O T O T H E R A P Y Dosage and Administration Therapy PUVA UVB Narrowband UVB Dosage and Administration More than 20 treatments with 2 to 3 visits/week for clearing, followed by maintenance treatments at varying intervals 3 visits/week for 3 months for clearing, followed by maintenance treatments at varying intervals 3 visits/week for 3 months for clearing, followed by maintenance treatments at varying intervals Odom RB, et al. In: Andrews Diseases of the Skin: Clinical Dermatology. WB Saunders Company; 2000:231.

26 P H O T O T H E R A P Y Advantages of Phototherapy Useful for generalized disease Efficacious Long duration of effect Useful in combination with other agents Retinoids Methotrexate Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

27 P H O T O T H E R A P Y Disadvantages of Phototherapy Risk of skin cancer (PUVA, UVB) Squamous cell carcinoma Melanoma concerns Requires frequent patient visits (PUVA, UVB, narrowband UVB) Cost and availability (PUVA, UVB, narrowband UVB) Slow onset of response (PUVA, UVB) Photodamage Lentigines (PUVA) Burns Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

28 S Y S T E M I C A G E N T S Mechanisms of Action Agent Methotrexate Cyclosporine Acitretin Mechanism of Action Immunomodulatory; interferes with DNA synthesis, repair, and cellular replication Prevents action of T lymphocytes via specific and reversible inhibition of immunocompetent lymphocytes in the G 0 and G 1 phase of the cell cycle Unknown; may slow cell replication by modulating the cellular differentiation of the epidermis Odom RB, et al. In: Andrews Diseases of the Skin: Clinical Dermatology. WB Saunders Company; 2000:232. Nicol NH. The Nurse Practitioner. 2000;25: Neoral package insert. Novartis Pharmaceuticals Corporation; 2002.

29 S Y S T E M I C A G E N T S Efficacy Agent Efficacy* Methotrexate 26% of patients achieve PASI 75 response at 24 weeks; onset of response seen in 4-6 weeks; time on treatment limited to alleviate safety concerns Cyclosporine Callis KP, et al. SID Meeting 2002; Poster 220. Ellis CN, et al. N Engl J Med. 1991;324: %-85% of patients achieve PASI 75 response at 12 weeks; after therapy discontinuation, disease returns in 7 weeks; onset of response seen as early as 4 weeks; time on treatment limited to alleviate safety concerns Acitretin Works slowly; onset of response seen at 8-16 weeks; time on treatment limited to alleviate safety concerns *At the time these drugs were evaluated, there was no standardized measure of efficacy.

30 S Y S T E M I C A G E N T S Side Effects/Safety Issues Agent Methotrexate Cyclosporine Acitretin Side Effects/Safety Issues Long-term risk of liver damage, birth defects, bone marrow toxicity; nausea, tiredness, insomnia; contraindicated in patients with alcoholism or liver disease Decreased renal function; hypertension, skin cancer risk, hyperlipidemia Hyperlipidemia, retinoid mucocutaneous side effects, alopecia; risk of birth defects; alcohol consumption is contraindicated for women taking acitretin; depression and/or other psychiatric symptoms, such as aggressive feelings or thoughts of self-harm, have been reported Lebwohl M, et al. J Am Acad Dermatol. 2001;45: Leucovorin package insert. Roxane Laboratories Inc; 2002.

31 S Y S T E M I C A G E N T S Dosage and Administration Agent Methotrexate Cyclosporine Acitretin Dosage and Administration Once a week orally Once or twice a day orally Once a day orally Odom RB, et al. In: Andrews Diseases of the Skin: Clinical Dermatology. WB Saunders Company; 2000:232. Soriatane package insert. Roche Pharmaceuticals; 2001.

32 S Y S T E M I C A G E N T S Advantages and Disadvantages of Systemic Agents Advantages Efficacious for generalized disease Easy to administer Disadvantages Organ toxicity limits duration of therapy renal toxicity (cyclosporine); hepatotoxicity (methotrexate, acitretin) Monitoring required mucocutaneous side effects (acitretin); hyperlipidemia (acitretin, cyclosporine); blood pressure, creatinine, and blood urea nitrogen levels (cyclosporine) Inappropriate for patients with concomitant disease alcoholism (methotrexate, acitretin); hypertension (acitretin, cyclosporine); depression (acitretin) Bone marrow toxicity (methotrexate) Potential for drug-drug interactions Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

33 H I S T O R I C A L T H E R A P I E S Unmet Medical Needs of Psoriasis Therapies Topical Agents Phototherapy Systemic Agents Long-term safety Pregnancy restriction HPA axis suppression Cutaneous atrophy Carcinogenicity Photodamage Renal toxicity Hepatotoxicity Carcinogenicity Teratogenicity Long-term efficacy Limited efficacy for extensive disease Tachyphylaxis Slow onset of response Slow onset of response Limited by cumulative toxicity Convenience Messy Time consuming Skin staining and irritation Access Frequent visits Complex monitoring required Odom RB, et al. In: Andrews Diseases of the Skin: Clinical Dermatology. WB Saunders Company; 2000: Hall JC, et al. In: Sauer s Manual of Skin Diseases. Lippincott Williams & Wilkins; 2000: White GM, et al. In: Diseases of the Skin. Mosby; 2000: Lebwohl M, et al. J Am Acad Dermatol. 2001;45: Lebwohl M, et al. J Am Acad Dermatol. 2001;45:

34 H I S T O R I C A L T H E R A P I E S Weight of Evidence for Historical Psoriasis Therapies Lack of consistent measurements More than 40 efficacy end points found in literature search of 249 randomized controlled trials (RCTs) Lack of patient-reported outcomes data Only 1 of 249 studies assessed quality of life Small number of psoriasis patients assessed per RCT Median: N=40 Short duration of therapy Median: 7 weeks Naldi L, et al. J Invest Dermatol. 2003;120:

35 P S O R I A S I S T R E A T M E N T O V E R V I E W Historical Psoriasis Treatment Strategy Cyclical therapy Periodic discontinuation and monitoring for serious side effects Restrictions for certain patient types Inconvenient regimens

36 The Goal of Psoriasis Therapy and the Changing Treatment Paradigm Improved patient safety No interruptions in control Appropriate for a broad range of patients Convenient dosing and administration