Psoriasis Heartbreak • The Therapeutic Ladder • The Role of Biologic Therapy Christopher G. Nelson, M.D. Clinical Professor Emeritus Director of Clinical Research MINI-SYMPOSIUM
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