Psoriasis Heartbreak

• The Therapeutic Ladder

• The Role of Biologic Therapy

Christopher G. Nelson, M.D.

Clinical Professor

Emeritus Director of Clinical Research

MINI-SYMPOSIUM

Potential Conflicts of Interest

• Abbvie

• Amgen

• Celgene

• Eli Lilly

• Galderma

• Genentech

• Leo Pharma

• Maruho

• PharmaDerm

• Regeneron

I am on advisory boards, am a paid lecturer, or have

done clinical trials for the following companies:

I HAVE NO FINANCIAL INTEREST IN ANY OF THEM

Impact in the U.S.

• May affect more than 7 million Americans¹

• 150,000-260,000 new cases per year¹

• Annual cost for care $112 - 135 billion2

• Chronic; may require lifelong care

• May affect people physically, psychologically, and socially3

1. 1American Academy of Dermatology

2. 2JAMA Dermatology, Jan 7, 2015

3. 3Clark, A. Feldman, S. Cos Derm. 1999;12;27-30

n=504

Impact of Psoriasis vs Other Diseases

on Patient-Reported Physical

Outcomes

Adapted from table 2 in Rapp SR, et al. J Am Acad Dermatol. 1999;41:401-407.

55.3

45.1

45.0

44.3

43.1

42.6

42.3

41.5

41.2

34.5

0 10 20 30 40 50 60

Healthy adults

Cancer

Depression

Hypertension

Arthritis

Myocardial infarction

Chronic lung disease

Diabetes

Psoriasis

CHF

Me

an

SF

-36

Sc

ore

Lower scores reflect worse patient-reported outcomes

Physical Component Summary Score

n=216

n=317

n=541

n=107

n=826

n=2089

n=105

n=468

n=1825

n=182

Impact of Psoriasis vs Other

Diseases on Patient-Reported

Mental Outcomes

53.4

51.7

52.2

51.9

50.4

48.8

48.8

45.7

44.5

34.8

0 10 20 30 40 50 60

Healthy adults

Myocardial infarction

Hypertension

Diabetes

CHF

Cancer

Arthritis

Psoriasis

Chronic lung disease

Depression

Me

an

SF

-36

Sc

ore

Lower scores reflect worse patient-reported outcomes

n=504

n=317

n=826

n=105

n=216

n=541

n=2089

n=107

n=468

Mental Component Summary Score

n=182

Adapted from table 2 in Rapp SR, et al. J Am Acad Dermatol. 1999;41:401-407.

Psoriasis – more than skin deep• Abdominal obesity

• Atherogenic dyslipidemia

•high triglycerides

•low HDL cholesterol

•high LDL cholesterol

• Elevated blood pressure

• Insulin resistance or glucose intolerance

• Prothrombotic state (e.g., high fibrinogen or

plasminogen activator inhibitor–1 in the blood)

• Proinflammatory state (e.g., elevated C-

reactive protein in the blood)

• ? Increased risk of malignancy

Psoriasis in Pregnancy

• May have 3 to 4 times higher incidence of:

– Spontaneous abortion

– Preterm birth

– Pre-eclampsia

– Placenta previa

– Ectopic pregnancy

2010 AAD, Lima et. al., Harvard University

National Psoriasis Foundation

www.psoriasis.org

Clinical Features

• Sharp demarcation

• Noncoherent silvery scales

• Glossy, homogenous erythematous base

• Auspitz sign

• Koebner phenomenon

Trigger Factors

• Trauma

• Endocrine factors

• Drugs

• Alcohol and smoking

• Infection

• Metabolic factors

• Psychogenic factors

• AIDS

• Sunlight

Triggers - Drugs

• β-Blockers - 75% worsened¹

• Lithium

• NSAIDS

• Systemic steroid withdrawal

• Pregnancy and progestational OC’s

¹Gold, MH, et.al., JAAD, 1988; 19:837-841

Onychopathic Clinical Features

• Morphologic alterations reflect influence of process

on various portions of nail organ

• Pitting or flaking of the nail surface

– Dorsal aspect of proximal nail fold

• Yellow macules (“oil drop change”) or onycholysis

– Nail bed

• Onychodystrophy

– Nail matrix

Other Types of Psoriasis

• Guttate

• Pustular psoriasis– Localized– Generalized

• Acute (von Zumbusch)• Chronic

• Erythrodermic

• Inverse (sebopsoriasis)

Guttate Psoriasis

• Unstable form

• Small, drop-like

lesions

• Associated with

infection

• Pharyngitis

• Other systemic

• Skin

Complications

• Pruritus

• Infection

• Arthritis

• Apical pulmonary fibrosis

• Amyloidosis

• Nephritis/renal failure

• Hepatic failure

Psoriasis Treatments

and Severity of DiseaseSystemic treatments

• Cyclosporine

• Methotrexate

• Oral retinoids

• Biologics

Phototherapy

• UVB, PUVA

Topical treatments

• Vitamin D analogues

• Steroids

• Coal tar

Mild

Psoriasis

Moderate

Psoriasis

Severe

Psoriasis

Source: van de Kerkhof PCM. Comparisons and combinations. In: van de Kerkhof PCM, ed. Textbook of Psoriasis. Osney Mead,Oxford: Blackwell Science Ltd; 1999:275-283.

What Is Severe Psoriasis?

• NPF: Greater than 5% body surface area

– 1% BSA = palm and thumb of the patient

• Others say greater than 10%

• Even more important: Quality of life

– DLQI

Statistics on Psoriasis

Treatments

• 39% of patients with severe psoriasis are not

receiving any treatment at all

• 57% of patients with severe psoriasis are

receiving topical treatment only

National Psoriasis Foundation, presented at the American Academy of Dermatology,

2007

Topical Therapy - Old

Keratolytics• Salicylic acid

– β-hydroxy acid– Keratolytic and anti-inflammatory– Can be compounded into topicals or prescribed in

cream or ointment – 2 - 10%– Enhances the penetration of topical steroids– Soak affected area, apply and occlude if desired– Blocks UVB; don’t apply before phototherapy

• α-Hydroxy acids– Glycolic and lactic– Available in moisturizers and emollients

Tar

• Products of distillation of oil, coal or wood

• Messy and smelly; not suitable for monotherapy

• May be compounded into medications (eg, 5% liquor carbonis detergens (LCD) may be added to a topical corticosteroid)

• Topical tar gels (OTC) may be used prior to exposure to natural sunlight

Topical Corticosteroids• Age of patient

• Treatment site

• Extent/severity of disease

• Duration of treatment

• Potency

• Formulation

• Cost

30 grams to cover the average adult

Topical Therapy – How Much?

• Average amount to cover a person – 30gm.

• 1% body surface area = size of the patient’s palm

and thumb, minus the fingers.

• Add these to get approximate BSA involved, and

do the math to figure quantity you need to prescribe

Topical Therapy - New

• Vitamin D3 analogs (calcipotriene and calcitriol)

• Retinoids (tazarotene)

• Topical immunomodulators (TIM’s) – OFF LABEL

– Tacrolimus

– Pimecrolimus

Calcipotriene, Calcitriol • Principles of treatment

– Use BID as monotherapy

– Once daily in combination with corticosteroid

– Calcipotriene 0.005% ointment, cream and sol’n.

– Calcitriol 0.003% ointment (limit 200gm/wk)

• Application

– Chronic plaque psoriasis

– Scalp and nail psoriasis (solution)

• Adverse Effects

– Local irritation/facial rashes

Tazarotene (TazoracTM)

• Principles of therapy:

– Best used in combination with corticosteroid because of irritation

– Available as .05% or .1% cream or gel

• Application

– Chronic plaque psoriasis

– Nail psoriasis

• Adverse effects

– Irritation

– Cost

Calcineurin Inhibitors (TIM’s)

• Tacrolimus and pimecrolimus

• Off label for psoriasis

• Work best in intertriginous areas (inverse or

sebopsoriasis)

• Eliminate the sequelae of topical steroids

• Not as useful on chronic plaque psoriasis – need to

occlude

Phototherapy• OLD

– Goeckerman

– Heliotherapy

– Dead Sea

• NEW

– Psoralen + UVA (PUVA)

• Systemic

• Localized

– nUVB (313nm)

– Excimer laser (308nm)

Principles of Treatment

• Educate

• Lubricate

• Utilize polytherapy

Polytherapy – Topical

• Tazarotene + topical steroid¹

– One in the AM, the other at hs

– Lessens irritation

– Better than either one alone

• Vitamin D analog + topical steroid2

– Combination is better than either one alone

– Goal: maximize strengths; minimize limitations

1. Lebwohl, M et al, JAAD; 39:5990, 1998

2. Koo, J, Skin and Aging, 6; 43-46, 1998

Sequential Therapy (Koo)

• PHASE I – CLEARING – 2 WEEKS– DovonexTM (calcipotriene) qAM

– HalobetasolTM (ultrapotent corticosteroid) q hs

• PHASE II – TRANSITIONAL – 2-4 WEEKS– Calcipotriene BID Monday-Friday

– Corticosteroid BID Weekends

• PHASE III (MAINTENANCE)– Calcipotriene BID every day

Koo, J. Skin and Aging, 1998; 6:42-44, 46.

Calcipotriene + Betamethasone

• Taclonex™

• Ointment

• Suspension

• Enstilar™

• Foam

.

Nail Psoriasis

• Systemic therapies are fairly good (Humira™ has an indication)

– Not worth the risk for nail treatment only

• Intralesional steroid into posterior nail fold helps:

– Disease located in the posterior nail fold (pits)

– Disease in the nail matrix (onychodystrophy)

– NOT nail bed disease (onycholysis; oil drop change)

• Topical steroids

– Potent solutions (eg, clobetasol .05%)

• Calcipotriene solution

• Tazarotene gel

• No really good treatment

Inverse Psoriasis (Sebopsoriasis)• Intertriginous areas

• R/O candidiasis, tinea, and erythrasma

• Rx:

– Pimecrolimus cream or tacrolimus ointment (Off label)

• Apply BID

– Cautious low-potency corticosteroids

Scalp Psoriasis• Use keratolytics

– Salicylic acid shampoo

– Salicylic acid scalp treatment at bedtime

• Topical steroid solutions, sprays and foams

– Fluocinolone .05% in a hapten free peanut oil base

DermaSmoothe/FSTM or generic – softens scale

• Apply to dampened scalp at hs

• Occlude with shower cap

– Clobetasol .05% sol. – alcohol base; not greasy

– Triamcinolone .1% (KenalogTM) spray

• Tube applicator keeps medication off hair

• Calcipotriene solution

Therapeutic Shampoos• Rx

– Clobetasol

– Fluocinolone

– Ciclopirox

– Ketoconazole 2%

– Selenium sulfide 2.5%

• OTC

– Ketoconazole 1%

– Tar

– Zinc

– Selenium sulfide 1.25%

Systemic Therapy - Old

• Methotrexate

• Cyclosporine

• Hydroxyurea

• Mycophenolate mofeteil

• Retinoids (acitretin or isotretinoin)

• Fumaric acid esters

• Avoid systemic corticosteroids (rebound!!)

Methotrexate

• Given as a single weekly dose – p.o. or IM

• Dose varies, up to 25mg

– Usual is about 12.5 – 15mg per week

• Monitor liver enzymes

• Consider liver biopsy when cumulative dose

reaches 15gm.

• 6 months to see response

Acitretin (SoriataneTM)

• Long acting systemic retinoid

• Palmo-plantar psoriasis

• Teratogenic – no pregnancy for at least 3 years

– I don’t use it in any female of child bearing potential

• 10 and 25mg capsules

– I start 25mg every other day, check lipids in 2

weeks and advance to 25mg daily.

– Can increase to 50mg/day (sequelae dose related)

• Xerosis, cheilitis, arthralgias, ↑ lipids

Cellular Immune Abnormalities

• Increased Th1 (IL-2, TNF-, INF-)

• Decreased Th2 (IL-4, IL-5, IL-6, IL-10, IL-13)

• Increased ELAM-1, VCAM-1, ICAM-1

Immunopathology of Psoriasis

Immunopathology

• T cell activation

• Activated T cells traffic to skin

• Activated T cells release cytokines (TNFα and

others) that injure cells and activate keratinocytes

• Proliferative response by skin results in psoriasis

• Activated keratinocytes release proinflammatory

cytokines and chemotaxins that create a vicious

cycle feedback loop

Manipulation of Psoriasis

NEW – Oral therapy• Apremilast (Otezla™) 30mg BID

• Blocks PDE4

– Blocks hydrolysis of cAMP to AMP

– Cuts off the “energy” to produce inflammatory cytokines

• Low incidence of nausea and diarrhea, which

resolves in about 2 weeks (use starter pack)

• ?? <1% incidence of depression at first, but not wth

prolonged treatment

• Weight loss

– Ave. 1kg at 16 weeks, 1.5kg at 52 weeks

Apremilast

• No routine lab monitoring recommended

• No reactivation of TB

• No opportunistic infections

• No hepatic dosing

• If Creatinine clearance ≤ 30, halve the dose

• Safe with hx of cancer

• No rebound if D/C; 5-20 wks to regain response

• Supplied through specialty pharmacies

ACTUALLY, THEIR OVARIES!

BIOLOGIC THERAPY AND

CHINESE HAMSTERS

What’s In a Name?

• -mab = monoclonal antibodies made in genetically engineered Chinese hamster ovary (CHO) cells

• -ximab = chimeric antibody - fused hamster plus human

• -zumab = humanized antibody – human backbone, segments from hamsters

• -mumab = fully human antibody

• -cept = receptor-antibody fusion protein; targets the receptor

PASI 75 at Week 12Etanercept (Enbrel™): 40-50%

Adalimumab (Humira™): 60-70%

Infliximab (Remicade™): 75-80%

Ustekinumab (Stelara™): 65-75%

Secukinumab (Cosentyx™): 80%

Ixekizumab, Brodalumab, Guselkumab 90%

0

10

20

30

40

50

60

70

80

90

100

Workup For Biologics

• Baseline labs

– PPD (or Quantiferon®-Gold)

– Chest X-Ray

– CBC

– CMP

– Hepatitis panel

• Annually thereafter or more frequently as

needed.

Stopping Biologics

• Generally, no rebound

• Evidence that taking time off (“rest periods”)

allows antibody formation, and future courses

of the drug may not be as effective.

• In the case of infliximab (Remicade),

restarting after time off increases the chance of

infusion reations and serum sickness.

Myocardial Events

• With anti-TNFα drugs (etanercept,

adalimumab, infliximab), possibly a 50%

decrease in MI’s over time.

• With Stelara, ? Slight increase during the first

12 weeks, then a decrease over the expected

incidence

• Efficacy

• Duration of Benefit

• Safety Profile

• Convenience and Administration

• QOL Considerations

• Cost/Reimbursement

– Topicals and most biologics are all covered as pharmacy benefit (“drug plan”)

– Infliximab – medical benefit

– Ustekinumab - depends on plan

Factors Influencing Clinical

Decisions

Patient Characteristics Rx History / Options

Insurance Considerations

• Demographics

• Disease Severity

• Convenience &

Compliance Issues

• Prior Rx History

• Response to Prior Rx

• Existing Medical

Conditions

• Private, Medicare / Medicaid

• Extent / Type of Coverage

• Ability to cover copays /

coinsurance

Patient Selection

Considerations

Topicals

PUVA,

nUVB,

laser

Biologic

or

apremilast

Biologic,

apremilast

+ systemic

Biologic,

apremilast

+ UV

Systemic

Biologic,

apremilast

+ topical

SEVERITY