Psoriasis Pathophysiology

Localized and systemic inflammation Increased antigen presentation Defects in T regulatory cells Upregulation of Th1 and Th17 cells, APCs, and cytokines Associated with increased CRP values and other markers of inflammation Epidermal hyperproliferation Clinically appreciated as scaling, cracking Associated with elevated uric acid and oxidative stress Angiogenesis Clinically appreciated as Auspitz sign Associated with increased circulating VEGF

Th = T helper; APCs = antigen-presenting cell; CRP = C-reactive protein; VEGF = vascular endothelial growth factor. Top photo courtesy of Joel Gelfand, MD, Department of Dermatology, University of Pennsylvania. Bottom photo courtesy of Rose Elenitsas, MD, Department of Dermatology, University of Pennsylvania.

Plaque Psoriasis
Most common type 80%-90% of psoriasis patients Plaques: 10 mm to several cm Well-defined Erythematous Irregular, round to oval in shape Most often located on the scalp, trunk, buttocks, and limbs, (especially elbows and knees) Have a dry, thin, silvery white or micaceous scale Tend to be symmetrically distributed over the body

Bottom right photo by Dr Joel Gelfand, used with permission. Other photos by National Psoriasis Foundation. Menter A, et al. J Am Acad Dermatol. 2008;58:826-850.

Psoriasis Risk Factors

Genetics: ~40% of people with psoriasis have a positive family history for the disease1 At least 9 chromosomal loci are linked to psoriasis (PSORS1-PSORS9)2 PSORS1 accounts for 35%-50% of heritability of psoriasis2 Environmental and behavioral triggers: Smoking3 Obesity4 Medications (eg, lithium, antimalarials, -blockers)5 Infection (streptococcal infection can trigger guttate psoriasis)5
1. Swanbeck G, et al. Br J Dermatol. 1994;131:32-39. 2. Nestle FO, et al. N Engl J Med. 2009;361:496-509. 3. Naldi L, et al. J Invest Dermatol. 2005;125:61-67. 4. Setty AR, et al. Arch Intern Med. 2007;167:1670-1675. 5. National Psoriasis Foundation. http://www.psoriasis.org/netcommunity/sublearn01_pscauses. Accessed August 27, 2009.

Guttate Psoriasis
Characterized by dew droplike, 1- to 10-mm salmon-pink papules, usually with a fine scale Common in those younger than 30 years Primarily found on trunk and proximal extremities Occurs in <2% of patients with psoriasis Often associated with upper respiratory streptococcal infection Sudden appearance of lesions may be first manifestation of psoriasis or an acute exacerbation in patients with established psoriasis

Photo by National Psoriasis Foundation. Menter A, et al. J Am Acad Dermatol. 2008;58:826-850.

Psoriasis Assessment Tools in Clinical Practice

Clinicians generally assess psoriasis severity (mild, moderate, or severe) by combining assessments of: BSA involvement, disease location, thickness, symptoms, presence/absence of PsA, presence/absence of nail involvement Impact on QOL (ie, physical, financial, and emotional impact of the disease) QOL measures may be generic (eg, SF-36 Health Survey Form) or skin-specific (eg, Dermatology Life Quality Index [SKINDEX])

Menter A, et al. J Am Acad Dermatol. 2008;58:826-850.

Differential Diagnosis of Psoriasis

Other inflammatory skin disorders Atopic dermatitis, eczema, localized scratch dermatitis (lichen simplex chronicus), nummular dermatitis Lichen planus Pityriasis rosea Pityriasis rubra pilaris Seborrheic dermatitis Stasis dermatitis Autoimmune disorders Dermatomyositis Subacute cutaneous lupus erythematosus Infections Candidiasis Onychomycosis Scabies Syphilis Tinea corporis Cancers Basal cell carcinoma Mycosis fungoides Squamous cell carcinoma Other Contact dermatitis Drug eruptions Reiter disease

http://www.mdguidelines.com/psoriasis/differential-diagnosis. Accessed August 31, 2009.

Psoriasis and CVD Risk

Presence of CVD Risk Factors in Psoriasis Patients and Controls
40 35 30 Percent 25 20 15 10 5 0
DM Hypertension Hyperlipidemia Smoking BMI 25-30 BMI >30

Controls Mild psoriasis Severe psoriasis

DM = diabetes mellitus. Neimann AL, et al. J Am Acad Dermatol. 2006;55:829-835.

Psoriasis and Increased Risks for MI and Mortality

Patients with severe psoriasis have a 50% increased risk of mortality1 Die 3.5-4.4 years younger than patients without psoriasis Psoriasis patients have an increased risk for MI2 Risk increases with increasing disease severity Relative risk of MI in psoriasis patients, adjusted for major CV risk factorsa Age, y 30 60
a

Mild Psoriasis 1.29 1.08

Severe Psoriasis 3.10 1.36

Results suggest that psoriasis may confer an independent risk for MI.

Hypertension, diabetes, history of MI, hyperlipidemia, age, sex, smoking, and BMI. 1. Gelfand JM, et al. Arch Dermatol. 2007;143:1493-1499. 2. Gelfand JM, et al. JAMA. 2006;296:1735-1741.

Psoriasis Comorbidities
Autoimmune diseases Crohns disease/ulcerative colitis1 Multiple sclerosis2 Malignancies3 Lymphoma Cutaneous T-cell lymphoma NonHodgkins lymphoma Hodgkins lymphoma
1

Najarian DJ, Gottlieb AB. J Am Acad Dermatol. 2003;48:805-821. 2Broadley SA, et al. Brain. 2000;123:1102-1111. 3. Gelfand JM, et al. J Invest Dermatol. 2006;126:2194-2201.

Psoriasis Comorbidities
PsA Inflammatory arthritis associated with psoriasis Occurs in 6%-40% of patients with psoriasis, depending on population studied1 Prevalence increases with increasing BSA affected2 Typically develops 7-10 years after onset of psoriasis, at an average age of 36 years1 May be progressive, severe, deforming
10

1. Kimball AB, et al. J Am Acad Dermatol. 2008;58:1031-1042. 2. Gelfand JM, et al. J Am Acad Dermatol. 2005;53:573-577.

PsA: Clinical Features

Stiffness, pain, swelling, tenderness of joints, ligaments, and tendons Nail disease is common Dactylitis (sausage digit) is common; usually affects feet in an asymmetric distribution

11

Photos by Dr Joel Gelfand, used with permission. Gottlieb A, et al. J Am Acad Dermatol. 2008;58:851-864.

Prevalence of Associated Diseases in Severe Psoriasis Patients vs Controls

Condition
Type 2 diabetes Hypertension (arterial) Hyperlipoproteinemia Metabolic syndrome Coronary heart disease

Psoriasis (n=581)
11.7% 21.9% 5.2% 4.3% 5.5%

Control (n=1044)
5.8% 10.2% 2.8% 1.1% 3.6%

Odds Ratioa (95% Confidence Interval)

2.48 (1.70-3.61)b 3.27 (2.41-4.43)b 2.09 (1.23-3.54)c 5.92 (2.78-12.8)b 1.77 (1.07-2.93)d

12

Common odds ratio adjusted for age and sex. bP <.0001. cP <.01. dP <.05. Sommer DM, et al. Arch Dermatol Res. 2006;298:321-328.

Natural History of Psoriasis and Comorbidities

Risk factors
Genes Environment

Outcomes
Cancer Vascular disease Metabolic disease Arthritis Mortality

Mediating factors
Pathophysiology (inflammation, hyperproliferation, angiogenesis) Treatment Psychosocial impact
13

Photo by Dr Joel Gelfand, used with permission.

Recommendations for Monitoring Psoriasis and Comorbidities

NPF Consensus Statement1 Approach psoriasis as a potentially multisystem disorder Alert patients to the potentially negative effects of psoriasis as it relates to other aspects of their health AJC Editors Consensus: Medical Evaluation of Moderate-to-Severe Psoriasis2 Medical history of CAD risk Annual physical examination and blood pressure check Blood lipids and glucose measurements

14

AJC = The American Journal of Cardiology; CAD = coronary artery disease. 1. Kimball AB, et al. J Am Acad Dermatol. 2008;58:1031-1042. 2. Friedewald VE, et al. Am J Cardiol. 2008;102:1631-1643.

General Recommendations for Topical Therapy

Most mild to moderate psoriasis can be treated with topical agents May require continuous intense regimen Patient adherence is important Treatment should be tailored to individuals needs Body location, lesion thickness, degree of erythema, amount of scaling, patient preferences May be used in combination with other agents; must be aware of possible compatibility issues Potent agents should be used short-term, then intermittently Patients who require continuous treatment should use the leastpotent agent that allows for disease control
Menter A, et al. J Am Acad Dermatol. 2009;60:643-659.

15

General Recommendations for Topical Therapy

Choice of vehicle (eg, ointment, cream, gel, foam) may alter use, penetration, and efficacy of the medication Optimal choice is vehicle the patient will most likely use Patients should receive regular examinations to assess side effects Approximately 400 g of a topical agent is required to cover the entire body surface of an average adult when used twice daily for 1 week 60-g tube = about 4% BSA per month

16

Menter A, et al. J Am Acad Dermatol. 2009;60:643-659.

Topical Therapy: Corticosteroids and Vitamin D Analogs

Corticosteroids Cornerstone of treatment for most patients Lower potency agents for face, intertriginous areas, areas with thin skin Mid-high potency agents for initial therapy Class I corticosteroids: 2-4 weeks of use Taper usage following clinical response Side effects (eg, stretch marks, atrophy) may limit use Vitamin D analogs (eg, calcipotriene, calcitriol) Most useful as a steroid-sparing adjuvant Not to exceed 100 g/wk (risk of hypercalcemia)
17

Menter A, et al. J Am Acad Dermatol. 2009;60:643-659.

Topical Therapy: Topical Retinoids and Calcineurin Inhibitors

Topical retinoids (tazarotene) Most useful as a steroid-sparing adjuvant Teratogenic/pregnancy category X Calcineurin inhibitors (tacrolimus, pimecrolimus) Useful for facial and intertriginous psoriasis Black box warning regarding malignancy Not FDA approved for psoriasis

18

Menter A, et al. J Am Acad Dermatol. 2009;60:643-659.

General Recommendations for Phototherapy

UVB Safe, effective, cost-effective Narrowband UVB More effective than broadband UVB 20 to 25 treatments, given 2 to 3 times a week, usually required for significant improvement Administered in the office or at home PUVA Very effective for most patients Potential for long remissions Long-term treatment in Caucasians is associated with an increased risk of skin cancers Induces photoaging and other skin changes Ingestion of psoralen may produce nausea/contraindicated in pregnancy Narrowband UVB therapy avoids some of the adverse side effects of PUVA, but slightly less effective than PUVA

19

Menter A, et al. J Am Acad Dermatol. 2008;58:826-850.

Conventional Systemic Therapies: Dosing and Efficacy

Methotrexate Most commonly prescribed systemic therapy Usually administered as a single weekly oral dose of 7.5 mg to 25 mg Gradually increased until optimal response is achieved PASI-75 achieved in 36%-60% of patients after 16 weeks Recommended for treatment of moderate or severe PsA Cyclosporine Use is limited to 1 year Generally prescribed for patients with severe psoriasis who have not responded to 1 other systemic therapy Dosing is given as 2.5 mg/kg to 5.0 mg/kg per day in 2 divided doses Dose is decreased when psoriasis is cleared PASI-75 achieved in 50%-70% of patients after 8-16 weeks Recommended for treatment of moderate or severe PsA Acitretin Often used in conjunction with UV light Dosing ranges from 10 mg to 50 mg per day as single dose Generally takes 3-6 months for response Efficacy is dose-dependent

20

Menter A, et al. J Am Acad Dermatol. 2009;61:451-485. Ritchlin CT, et al. Ann Rheum Dis. 2009;68:1387-1394.

Biologic Agents for the Treatment of Psoriasis

Biologic
Adalimumab

Structure
Human monoclonal antibody Human IgG1 Fc region fused to LFA-3 extracellular domain Human IgG1 Fc region fused to TNF type II receptor Chimeric monoclonal antibody Human monoclonal antibody

Target
Soluble and membrane-bound TNF- LFA-3

Dosing
80 mg SC, followed by 40 mg SC every other wk 15 mg IM weekly for 12 weeks 50 mg SC BIW for 12 wk, then 50 mg SC each wk 5 mg/kg IV at wk 0, 2, 6, then every 8 wk 45 or 90 mg SC at wk 0 and 4, then once every 12 wk

Half-Life, d
10-20

Alefacept

11.25 (IV)

Etanercept

Soluble TNF-, lymphotoxin Soluble and membrane-bound TNF- IL-12 and IL-23

4-12.5

Infliximab

8-9

Ustekinumab

15-46

SC = subcutaneously; BIW = biweekly; IV = intravenously; LFA-3 = leukocyte functionassociated antigen-3; IM = intramuscularly.

21

Kurd SK, et al. Expert Rev Clin Immunol. 2007;3:171-185. Stelara [package insert]. Horsham, PA: Centocor Ortho Biotech Inc.; 2009.

Psoriasis: Nail Involvement

May occur in all psoriasis subtypes Fingernails are involved in ~50% of patients Toenails are involved in ~35% of patients Includes pitting, onycholysis, subungual hyperkeratosis, the oil drop sign, and nail plate dystrophy Difficult to treat

Onycholysis
22

Pitting

Nail plate dystrophy

Right photo by Dr Joel Gelfand, used with permission. All other photos by DermAtlas. Menter A, et al. J Am Acad Dermatol. 2008;58:826-850.

Psoriasis: Impact on QOL vs Other Major Morbidities

QOL outcome was SF-36 physical and mental health domains
Mental Functioning
Depression Lung disease Psoriasis Arthritis Congestive heart failure MI Type 2 diabetes Healthy adults

Physical Functioning
Congestive heart failure Psoriasis Type 2 diabetes Lung disease MI Arthritis Depression Healthy adults

20

40

60

20

40

60

SF-36 = short form 36.

23

Rapp SR, et al. J Am Acad Dermatol. 1999;41:401-407.

2008 NPF Survey: Psoriasis Impact on QOL

71% report that psoriasis is a significant problem in everyday life 49% have significant pain 53% report that psoriasis significantly affects their emotional well-being 63% experience significantly self-consciousness 58% experience significant embarrassment

24

National Psoriasis Foundation. Available at: http://www.psoriasis.org/NetCommunity/Document.Doc?id=193. Accessed August 25, 2009.

Limitations of Conventional Systemic Therapies

Agent
Methotrexate

Adverse Event
Hepatotoxicity, drug interactions, immunosuppression, bone marrow suppression, pneumonitis, birth defects, decreased sperm count, miscarriage

Contraindications
Pregnancy, renal impairment, hepatitis, cirrhosis, leukemia, thrombocytopenia, alcohol abuse, unreliability in patients Acute infections, active malignancies, uncontrolled hypertension, impaired renal function Pregnancy, breastfeeding

Cyclosporine

Immunosuppression, impaired renal function, hypertension, malignancies, drug interactions

Acitretin

Birth defects, mucocutaneous effects, dyslipidemia

25

Menter A, et al. J Am Acad Dermatol. 2008;58:826-850. Menter A, et al. J Am Acad Dermatol. 2009;61:451-485.

Biologic Agents: Adverse Events

Biologic Adalimumab Common (>5%) Injection site reaction, +ANA, elevated alkaline phosphatase, cholesterol Lymphopenia Injection site reaction, +ANA Uncommon (0.1%-5%) Neutralizing antibodies, serious infections Rare (<0.1%) TB, malignancy Lupus-like syndrome, hypersensitivity, hepatitis B reactivation, demyelination, CHF, pancytopenia Malignancy, hypersensitivity TB, malignancy Lupus-like syndrome, hypersensitivity, hepatitis B reactivation, demyelination, CHF, pancytopenia Severe hepatic injury, TB, malignancy, lupus like syndrome, hypersensitivity, hepatitis B reactivation, demyelination, CHF, pancytopenia Cellulitis, injection site reactions Black Box Infection (TB, sepsis, fungal, and opportunistic)

Alefacept Etanercept

Elevated liver function test values, serious infection Serious infection

None Infection (TB, sepsis, fungal, and opportunistic)

Infliximab

Infusion reactions, +ANA, elevated liver function test values, neutralizing antibodies Nasopharyngitis

Hypersensitivity, serious infection

Infection (TB, sepsis, fungal, and opportunistic), hepatosplenic T-cell lymphoma None

Ustekinumab

Upper respiratory tract infection, headache, fatigue.

26 +ANA = positive antinuclear antibody;

Information obtained from prescribing information December 2008.

General Recommendations for Biologic Therapy

Obtain at baseline: age-appropriate history, physical examination, updated medication list, baseline laboratory studies Chemistry screen with liver function tests, complete blood cell count including platelet count, hepatitis panel, and TB testing Periodically re-evaluate for development of new symptoms including infection and malignancy Use all approaches to prevent infection, including vaccinations Administer vaccinations prior to initiating biologic therapy Biologic therapies may impair the immunologic response to vaccinations Administration of live vaccines must be avoided
27

Menter A, et al. J Am Acad Dermatol. 2008;58:826-850.