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

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

PsoriasisPsoriasisPsoriasisPsoriasis

Dermatologic and Ophthalmic Drugs Advisory Committee Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004July 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?What is Psoriasis?What is Psoriasis?What is Psoriasis?


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)




• 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


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 cells

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 cells


• 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



PrevalencePrevalencePrevalencePrevalence

• 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


Symptoms of Chronic Plaque Symptoms of Chronic Plaque PsoriasisPsoriasis

Symptoms of Chronic Plaque Symptoms of Chronic Plaque PsoriasisPsoriasis

• 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


Psoriasis: TreatmentPsoriasis: Treatment Psoriasis: TreatmentPsoriasis: 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


Treatment of PsoriasisTreatment of PsoriasisTreatment of PsoriasisTreatment 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


Topical TreatmentTopical TreatmentTopical TreatmentTopical Treatment

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Topical TherapiesTopical TherapiesTopical TherapiesTopical Therapies

– Topical corticosteroids– Topical vitamin D3 analogues– Topical retinoids– Topical emollients– Topical salicylic acid ointment– Photo chemotherapy– Tar– Excimer laser

– Topical corticosteroids– Topical vitamin D3 analogues– Topical retinoids– Topical emollients– Topical salicylic acid ointment– Photo chemotherapy– Tar– Excimer laser


CorticosteroidsCorticosteroidsCorticosteroidsCorticosteroids The most widely prescribedmedications 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 prescribedmedications 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


CorticosteroidsCorticosteroids CorticosteroidsCorticosteroids


• 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


Side effects Side effects Side effects 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


Topical Vitamin DTopical Vitamin D33 Analogues AnaloguesTopical Vitamin DTopical Vitamin D33 Analogues 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


Topical Vitamin DTopical Vitamin D33 Analogues AnaloguesTopical Vitamin DTopical Vitamin D33 Analogues 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


Topical RetinoidsTopical RetinoidsTopical RetinoidsTopical Retinoids

• Vitamin A derivatives

• MOA:1.Normalization of abnormal

keratinocyte differentiation2.Reduction in keratinocyte

proliferation3.Reduction in inflammation

• Vitamin A derivatives

• MOA:1.Normalization of abnormal

keratinocyte differentiation2.Reduction in keratinocyte

proliferation3.Reduction in inflammation


Topical RetinoidsTopical RetinoidsTopical RetinoidsTopical 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


PhototherapyPhototherapyPhototherapyPhototherapy


Photo-chemotherapyPhoto-chemotherapyPhoto-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


Side effects with PsoralenSide effects with PsoralenSide effects with PsoralenSide 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


Coal Tar Coal Tar الفحم Coal Tar Coal Tar قطران الفحم قطران

Old topical medication MOA: Decreases epidermal cell mitosis and scale

development (anti-scaling properties)Reduces sebum productionAnti-inflammatory effects5% 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 productionAnti-inflammatory effects5% coal tar concentration most effective

(1%-6%)Used together with salicylic acid

(keratolytic) for psoriasis of the scalp Tar baths and shampoos are helpful


Coal TarCoal TarCoal TarCoal 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,


Emollients and MoisturizersEmollients and MoisturizersEmollients and MoisturizersEmollients 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


Topical salicylic acidTopical salicylic acidTopical salicylic acidTopical 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


Systemic TreatmentSystemic TreatmentSystemic TreatmentSystemic Treatment

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• 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 medication

– Pregnancy must be avoided for the majority of these treatments

• 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 medication

– Pregnancy must be avoided for the majority of these treatments


AcitretinAcitretinAcitretinAcitretin

• 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


Acitretin - ContraindicationsAcitretin - ContraindicationsAcitretin - ContraindicationsAcitretin - 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.


Oral PUVAOral PUVAOral PUVAOral 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


Drugs affectingDrugs affecting the immune response the immune response

Drugs affectingDrugs affecting the immune response 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

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MethotrexateMethotrexateMethotrexateMethotrexate• 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


Methotrexate: PrecautionsMethotrexate: PrecautionsMethotrexate: PrecautionsMethotrexate: 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)


MethotrexateMethotrexateMethotrexateMethotrexate

• 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)

.


CyclosporinCyclosporinCyclosporinCyclosporin

• 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


TacrolimusTacrolimusTacrolimusTacrolimus

• 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


Mycophenolate mofetil Mycophenolate mofetil Mycophenolate mofetil 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

•


Monoclonal antibodiesMonoclonal antibodiesMonoclonal antibodiesMonoclonal antibodies

• Several monoclonal antibodies (MAbs)

(infliximab) work against TNF-alphaimmunomodulators

• Several monoclonal antibodies (MAbs)

(infliximab) work against TNF-alphaimmunomodulators

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

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