1. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 1 PsoriasisPsoriasis

2. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004  Psoriasis is a common chronic skin disease that affects about 2% of the population  psora = "itch"  The most common type of psoriasis is the chronic plaque psoriasis, affects about 90% of the psoriatic patient population  Psoriasis is a common chronic skin disease that affects about 2% of the population  psora = "itch"  The most common type of psoriasis is the chronic plaque psoriasis, affects about 90% of the psoriatic patient population What is Psoriasis?

3. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004  Characterized by well defined, scaly red skin patches on the body (arms, legs and trunk) and scalp  Usually distributed symmetrically  May involve the nails that can eventually progress to the joints (arthritis)  Characterized by well defined, scaly red skin patches on the body (arms, legs and trunk) and scalp  Usually distributed symmetrically  May involve the nails that can eventually progress to the joints (arthritis) PsoriasisPsoriasis

4. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 4 PsoriasisPsoriasis Auto-immune disease T-cell mediated inflammatory disease –Epidermal hyperproliferation –Altered maturation of skin –Inflammation –Vascular changes Auto-immune disease T-cell mediated inflammatory disease –Epidermal hyperproliferation –Altered maturation of skin –Inflammation –Vascular changes

5. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004  T-lymphocyte which normally help protect the body against infection become active, migrate to the dermis and trigger the release of cytokines (tumor necrosis factor- alpha TNFα) which cause inflammation and the rapid production of skin cellsdermiscytokinestumor necrosis factor- alpha  T-lymphocyte which normally help protect the body against infection become active, migrate to the dermis and trigger the release of cytokines (tumor necrosis factor- alpha TNFα) which cause inflammation and the rapid production of skin cellsdermiscytokinestumor necrosis factor- alpha

6. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 Have genetic component Nongenetic Factors: - Mechanical, ultraviolet, chemical injury - Infections: Strep, viral, HIV - Prescription Drugs, stress, endocrine, hormonal, obesity, alcohol, smoking  Drugs that are most strongly related to psoriasis are lithium, β-blockers, NSAIDs and antimalarials Have genetic component Nongenetic Factors: - Mechanical, ultraviolet, chemical injury - Infections: Strep, viral, HIV - Prescription Drugs, stress, endocrine, hormonal, obesity, alcohol, smoking  Drugs that are most strongly related to psoriasis are lithium, β-blockers, NSAIDs and antimalarials PsoriasisPsoriasis

7. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 7 PrevalencePrevalence Equal frequency in males and females May occur at any age Life-long disease –Remitting and relapsing unpredictably –Spontaneous remissions of up to 5 years have been reported in approximately 5% of patients Equal frequency in males and females May occur at any age Life-long disease –Remitting and relapsing unpredictably –Spontaneous remissions of up to 5 years have been reported in approximately 5% of patients

8. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 8 Symptoms of Chronic Plaque Psoriasis Itching Pain Excessive heat loss Patient complaints –Unsightliness of the lesions –Feelings of being socially outcast –Excessive scale Itching Pain Excessive heat loss Patient complaints –Unsightliness of the lesions –Feelings of being socially outcast –Excessive scale

9. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 9 Psoriasis: Treatment Lubrication Removal of scales Slow down lesion proliferation Pruritus management Prevent complications Lessen patient stress Season and climate Lubrication Removal of scales Slow down lesion proliferation Pruritus management Prevent complications Lessen patient stress Season and climate

10. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 10 Treatment of Psoriasis Topical and systemic Wide range of therapies for the treatment of moderate to severe psoriasis None induce a permanent remission Many have side effects that can place limits on their use Topical and systemic Wide range of therapies for the treatment of moderate to severe psoriasis None induce a permanent remission Many have side effects that can place limits on their use

11. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 Topical Treatment 11

12. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 12 Topical Therapies –Topical corticosteroids –Topical vitamin D 3 analogues –Topical retinoids –Topical emollients –Topical salicylic acid ointment –Photo chemotherapy –Tar –Excimer laser –Topical corticosteroids –Topical vitamin D 3 analogues –Topical retinoids –Topical emollients –Topical salicylic acid ointment –Photo chemotherapy –Tar –Excimer laser

13. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 13CorticosteroidsCorticosteroids  The most widely prescribed medications for plaque psoriasis MOA Reduce inflammation, itching and scaling Anti-inflammatory effect –Decrease in vascular permeability, decreasing dermal edema and leukocyte penetration into skin Antiproliferative effect Immunosuppressive effect  The most widely prescribed medications for plaque psoriasis MOA Reduce inflammation, itching and scaling Anti-inflammatory effect –Decrease in vascular permeability, decreasing dermal edema and leukocyte penetration into skin Antiproliferative effect Immunosuppressive effect

14. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 Corticosteroids Corticosteroids  These range in strength from weak (1% hydrocortisone to potent corticosteroids, such as, betamethasone)  Systemic or potent corticosteroids should be avoided (on discontinuation a rebound exacerbation of the condition may occur )  Avoid strong corticosteroids for long periods  These range in strength from weak (1% hydrocortisone to potent corticosteroids, such as, betamethasone)  Systemic or potent corticosteroids should be avoided (on discontinuation a rebound exacerbation of the condition may occur )  Avoid strong corticosteroids for long periods

15. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 15 Topical corticosteroids are available in numerous vehicles including powders, sprays, lotions, gels foams, creams, emollient creams, ointments Ointments: helps hydrate; good for dry, hyperkeratotic, scaly lesions Cream: for use on all areas, useful for infected lesions Solutions: for scalp psoriasis, often contain alcohols which can be painful with open lesions Topical corticosteroids are available in numerous vehicles including powders, sprays, lotions, gels foams, creams, emollient creams, ointments Ointments: helps hydrate; good for dry, hyperkeratotic, scaly lesions Cream: for use on all areas, useful for infected lesions Solutions: for scalp psoriasis, often contain alcohols which can be painful with open lesions

16. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 16 Side effects –Systemic absorption Suppression of the hypothalamic-pituitary-adrenal axis –Skin atrophy, burning sensation –Poor wound healing –Pyogenic infections  Tachyphylaxis ( medications that are highly effective initially, lose efficacy with prolonged use).  To avoid tachyphylaxis and the other side effects of topical corticosteroids, They are applied twice daily for 2 weeks, after which they are applied on weekends –Systemic absorption Suppression of the hypothalamic-pituitary-adrenal axis –Skin atrophy, burning sensation –Poor wound healing –Pyogenic infections  Tachyphylaxis ( medications that are highly effective initially, lose efficacy with prolonged use).  To avoid tachyphylaxis and the other side effects of topical corticosteroids, They are applied twice daily for 2 weeks, after which they are applied on weekends

17. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 17 Topical Vitamin D 3 Analogues The second most commonly used group of medications consists of the vitamin D analogues Calcipotriol is available as cream, ointment, and scalp lotion MOA: inhibition of cell proliferation and induction of cell differentiation in psoriatic skin The second most commonly used group of medications consists of the vitamin D analogues Calcipotriol is available as cream, ointment, and scalp lotion MOA: inhibition of cell proliferation and induction of cell differentiation in psoriatic skin

18. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 18 Topical Vitamin D 3 Analogues Side Effects; Burning, pruritus, skin irritation, tingling of the skin Phototherapy may inactivate vitamin D analogues and thus these topical agents should be applied after phototherapy, not before Side Effects; Burning, pruritus, skin irritation, tingling of the skin Phototherapy may inactivate vitamin D analogues and thus these topical agents should be applied after phototherapy, not before

19. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 19 Topical Retinoids Vitamin A derivatives MOA: 1.Normalization of abnormal keratinocyte differentiation 2.Reduction in keratinocyte proliferation 3.Reduction in inflammation Vitamin A derivatives MOA: 1.Normalization of abnormal keratinocyte differentiation 2.Reduction in keratinocyte proliferation 3.Reduction in inflammation

20. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 20 Topical Retinoids Tazarotene; Gel and cream a third-generation retinoid approved for the treatment of psoriasis Side Effects; itching, burning, skin irritation Contraindicated in women who are or may become pregnant Tazarotene; Gel and cream a third-generation retinoid approved for the treatment of psoriasis Side Effects; itching, burning, skin irritation Contraindicated in women who are or may become pregnant

21. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 21 PhototherapyPhototherapy

22. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 22Photo-chemotherapyPhoto-chemotherapy –Psoralen +Ultraviolet A (PUVA) – Consists of oral or topical treatment with psoralen followed by UVA (2 to 3 times per week for several months) Theories of MOA: 1.Psoralen intercalates into DNA, inhibiting DNA replication and thus, inhibiting epidermal cell hyperproliferation 2.Free radical formation damages cell membrane, cytoplasmic contents and nucleus of epidermal cells…inhibiting growth of cells 3.Increased apoptosis of activated T-cells –Psoralen +Ultraviolet A (PUVA) – Consists of oral or topical treatment with psoralen followed by UVA (2 to 3 times per week for several months) Theories of MOA: 1.Psoralen intercalates into DNA, inhibiting DNA replication and thus, inhibiting epidermal cell hyperproliferation 2.Free radical formation damages cell membrane, cytoplasmic contents and nucleus of epidermal cells…inhibiting growth of cells 3.Increased apoptosis of activated T-cells

23. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 23 Side effects with Psoralen – Pruritus – Skin ageing – Increased risk for skin cancer with long-term exposure to the drug – Pruritus – Skin ageing – Increased risk for skin cancer with long-term exposure to the drug

24. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 24 Coal Tar Coal Tar قطران الفحم  Old topical medication MOA:  Decreases epidermal cell mitosis and scale development (anti-scaling properties)  Reduces sebum production  Anti-inflammatory effects  5% coal tar concentration most effective (1%-6%)  Used together with salicylic acid (keratolytic) for psoriasis of the scalp  Tar baths and shampoos are helpful  Old topical medication MOA:  Decreases epidermal cell mitosis and scale development (anti-scaling properties)  Reduces sebum production  Anti-inflammatory effects  5% coal tar concentration most effective (1%-6%)  Used together with salicylic acid (keratolytic) for psoriasis of the scalp  Tar baths and shampoos are helpful

25. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 25 Coal Tar Use only on lesions that are well separated, not too big Problems with coal tar: –Smell –Sting ; irritation –Stain skin and fabrics –Sensitize, contact dermatitis, Use only on lesions that are well separated, not too big Problems with coal tar: –Smell –Sting ; irritation –Stain skin and fabrics –Sensitize, contact dermatitis,

26. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 26 Emollients and Moisturizers  Soothe, smooth and hydrate the skin  for dry and scaly skin  In case of scalp psoriasis, the scales may be thick and adherent  Emollients are useful with other more specific treatment  White soft paraffin ointment  Soothe, smooth and hydrate the skin  for dry and scaly skin  In case of scalp psoriasis, the scales may be thick and adherent  Emollients are useful with other more specific treatment  White soft paraffin ointment

27. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 27 Topical salicylic acid  In particular, emollients containing keratolytic agents such as salicylic acid helps remove scales and reduce hyperkeratosis Ointments containing 2%-10% salicylic acid are used with topical medications to Enhance absorption of other drugs  In particular, emollients containing keratolytic agents such as salicylic acid helps remove scales and reduce hyperkeratosis Ointments containing 2%-10% salicylic acid are used with topical medications to Enhance absorption of other drugs

28. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 Systemic Treatment 28

29. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 29 For severe, resistant, complicated forms of psoriasis –Oral retinoids; acitretin –Psoralin and UVA –Immunosuppressant therapy – Patients undergoing systemic treatment are required to have regular blood and liver function tests because of the toxicity of the medicationbloodliver function teststoxicity medication –Pregnancy must be avoided for the majority of these treatments Pregnancy For severe, resistant, complicated forms of psoriasis –Oral retinoids; acitretin –Psoralin and UVA –Immunosuppressant therapy – Patients undergoing systemic treatment are required to have regular blood and liver function tests because of the toxicity of the medicationbloodliver function teststoxicity medication –Pregnancy must be avoided for the majority of these treatments Pregnancy

30. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 30 AcitretinAcitretin Oral retinoid approved for the treatment of severe psoriasis in adults resistant to other form of therapies Significant improvement can be achieved within 8 weeks of therapy Side effects; dryness of skin, mm; conjunctiva, pruritus Oral retinoid approved for the treatment of severe psoriasis in adults resistant to other form of therapies Significant improvement can be achieved within 8 weeks of therapy Side effects; dryness of skin, mm; conjunctiva, pruritus

31. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 31 Acitretin - Contraindications Patients with severely impaired liver or kidney function Hyperlipidemia Contraindicated in pregnant females or those who intend to become pregnant. Patients with severely impaired liver or kidney function Hyperlipidemia Contraindicated in pregnant females or those who intend to become pregnant.

32. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 32 Oral PUVA Psoralen = “P” in PUVA = a photosensitizer Given 2 hours before UVA irradiation Symptomatic control of severe, disabling psoriasis, not responsive to other therapy Long-term: premature aging, cataracts, skin cancer Psoralen = “P” in PUVA = a photosensitizer Given 2 hours before UVA irradiation Symptomatic control of severe, disabling psoriasis, not responsive to other therapy Long-term: premature aging, cataracts, skin cancer

33. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 Drugs affecting the immune response Systemic drugs acting on the immune system are generally used by specialists in a hospital setting Examples:  Methotrexate  Cyclosporin  Tacrolimus  Mycophenolate mofetil Systemic drugs acting on the immune system are generally used by specialists in a hospital setting Examples:  Methotrexate  Cyclosporin  Tacrolimus  Mycophenolate mofetil 33

34. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 34MethotrexateMethotrexate For moderate-severe psoriasis non-responsive to topical treatment MOA: –binds to DHFR which leads to reduction of tetrahydrofolate, which inhibits pyrimidine synthesis, thus inhibiting DNA replication esp rapidly dividing cells as in skin –Induces apoptosis of activated T cells For moderate-severe psoriasis non-responsive to topical treatment MOA: –binds to DHFR which leads to reduction of tetrahydrofolate, which inhibits pyrimidine synthesis, thus inhibiting DNA replication esp rapidly dividing cells as in skin –Induces apoptosis of activated T cells

35. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 35 Methotrexate: Precautions Contraindicated: –Pregnancy, lactating mothers –Renal & liver problems –Preexisting severe anemia, leukopenia, thrombocytopenia –Alcoholics –Active infectious disease –Side effects : BM depression, N, V, stomatitis and development of megaloblastic anemia (Folate supplementation) Contraindicated: –Pregnancy, lactating mothers –Renal & liver problems –Preexisting severe anemia, leukopenia, thrombocytopenia –Alcoholics –Active infectious disease –Side effects : BM depression, N, V, stomatitis and development of megaloblastic anemia (Folate supplementation)

36. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 MethotrexateMethotrexate Folic acid antagonist that competitively inhibits dihydrofolate reductase effective treatment for psoriasis and psoriatic arthritis Weekly single oral dose Side effects :bone marrow depression, nausea, stomatitis and development of megaloblastic anemia (Folate supplementation). Folic acid antagonist that competitively inhibits dihydrofolate reductase effective treatment for psoriasis and psoriatic arthritis Weekly single oral dose Side effects :bone marrow depression, nausea, stomatitis and development of megaloblastic anemia (Folate supplementation).

37. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 CyclosporinCyclosporin Cyclosporin is a potent immuno-suppressant Calcineurin Inhibitor and ultimately results in inhibition of T-cell activation Hypertension and renal dysfunction are the major adverse effects Cyclosporin is a potent immuno-suppressant Calcineurin Inhibitor and ultimately results in inhibition of T-cell activation Hypertension and renal dysfunction are the major adverse effects

38. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 TacrolimusTacrolimus It is a potent macrolide immuno-suppressant traditionally used to prevent kidney, liver, and heart allograft rejection Calcineurin inhibitors, it works mainly by inhibiting early activation of T-lymphocytes Topical tacrolimus compared with topical glucocorticoids does not cause skin atrophy and therefore can be used safely in locations such as the face It is a potent macrolide immuno-suppressant traditionally used to prevent kidney, liver, and heart allograft rejection Calcineurin inhibitors, it works mainly by inhibiting early activation of T-lymphocytes Topical tacrolimus compared with topical glucocorticoids does not cause skin atrophy and therefore can be used safely in locations such as the face

39. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 Mycophenolate mofetil It is an anti-proliferative immuno- suppressant approved for prophylaxis of organ rejection in patients with renal, cardiac, and hepatic transplants It inhibits the enzyme inosine mono- phosphatase dehydrogenase thereby depleting guanosine nucleotides essential for DNA and RNA synthesis It is an anti-proliferative immuno- suppressant approved for prophylaxis of organ rejection in patients with renal, cardiac, and hepatic transplants It inhibits the enzyme inosine mono- phosphatase dehydrogenase thereby depleting guanosine nucleotides essential for DNA and RNA synthesis

40. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 Monoclonal antibodies Several monoclonal antibodies (MAbs)monoclonal antibodies (infliximab) work against TNF-alphainfliximab immunomodulators Several monoclonal antibodies (MAbs)monoclonal antibodies (infliximab) work against TNF-alphainfliximab immunomodulators