overview/epidemiologysma.org/.../2010/05/rosen_psoriasismanagement.pdf · social impact of...

Pragmatic Approach to Psoriasis Pragmatic Approach to Psoriasis 20102010

Ted Rosen, MD Professor Ted Rosen, MD Professor of Dermatology Baylor College of Dermatology Baylor College

of Medicine Houston, Texas USA of Medicine Houston, Texas USA

Conflict of Interest Disclosure

•• Honoraria for Honoraria for SpeakerSpeaker’’s Bureaus Bureau

•• AbbottAbbott

•• Amgen CanadaAmgen Canada

•• CentocorCentocor

•• Genentech Genentech (Product discontinued)(Product discontinued)

•• StiefelStiefel

What is Psoriasis?

Is it Important?

Overview/Epidemiology •• Psoriasis is a chronic Psoriasis is a chronic immuneimmune--mediatedmediated

inflammatory disease of the skin & jointsinflammatory disease of the skin & joints

•• Psoriasis affects approximately 2.2% of the U.S. Psoriasis affects approximately 2.2% of the U.S. adult population (5.8adult population (5.8––7.5 million)7.5 million)

•• Graded by severity: PASI score; Numerical reflection Graded by severity: PASI score; Numerical reflection of extent, redness & thickeningof extent, redness & thickening

•• Mild <3% BSA Moderate 3Mild <3% BSA Moderate 3--10% Severe > 10%10% Severe > 10%

•• {One palm = 1% Body surface area}{One palm = 1% Body surface area}

•• Less than one third (29%) of psoriasis patients are Less than one third (29%) of psoriasis patients are ““very satisfiedvery satisfied”” with Rx & owith Rx & over one third of people with psoriasis receive NO professional care (NPF Surveys)

Psoriasis: Erythema, Induration, ScalingBody Surface Area is NOT always accurate assessment of severity!Body Surface Area is NOT always accurate assessment of severity!

Psoriasis: Differential Diagnosis•• Seborrhea (scalp)Seborrhea (scalp)•• Contact dermatitisContact dermatitis•• TineaTinea (superficial (superficial dermatophytedermatophyte))•• OnychomycosisOnychomycosis (nails)(nails)•• PityriasisPityriasis rubrarubra pilarispilaris•• Drug eruptionsDrug eruptions•• Secondary syphilisSecondary syphilis•• CutaneousCutaneous TT--cell lymphomacell lymphoma•• Eczema (atopic, Eczema (atopic, xeroticxerotic))

Psoriasis SymptomsPsoriasis Symptoms

Krueger G, et al. Arch Dermatol. 2001;137:280-284.

100 94%

79%71%

31% 29%21% 19%

5%

Itching SkinRedness

Tightnessof Skin

Bleeding BurningSensation

Fatigue OtherScaling

Per

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f R

esp

on

den

ts

Most Frequently Experienced Symptoms

80

50

40

30

20

10

0

90

60

70

Psoriatic Emergencies

Hospitalize Consult Hospitalize Consult DermatologistDermatologist

Social Impact of PsoriasisSocial Impact of Psoriasis

Arch Dermatol 137:280-284, 2001

57%

48%

40%

0 10 20 30 40 50 60 70 80 90 100

Percentage of Respondents

Psoriasis Mistaken as Contagious

Psoriasis Mistaken as Other Disease

Trouble Receiving Equal Treatmentin Service Establishments

Psoriasis: Impact on Psoriasis: Impact on PhysicalPhysicalHealth (SF36)Health (SF36)

55

4745 45 44

43 43 42 42 41

35

30

40

50

60

Health

y ad

ults

Derm

atiti

s

Cance

r

Depre

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n

Hyper

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on

Arthrit

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-- 3636

J Am J Am AcadAcad DermatolDermatol 41:40141:401––407, 1999407, 1999

Psoriatic Emergencies Exfoliative Erythroderma

InfectionInfection

HighHigh--output CHFoutput CHF

Thermoregulatory Thermoregulatory crisiscrisis

Psoriatic Emergencies PustularPsoriasis

““ToxicToxic”” Anorexia, FebrileAnorexia, Febrile

InfectionInfection

Dehydration; ARFDehydration; ARF

KEY POINT

•• Psoriasis (including Psoriasis (including PsAPsA) is a VERY ) is a VERY significant disease for those who develop significant disease for those who develop this maladythis malady

•• We OWE our patients the BEST We OWE our patients the BEST treatment(streatment(s) available) available

•• Physicians and other healthcare providers Physicians and other healthcare providers must exercise good judgment in selecting must exercise good judgment in selecting therapy therapy

BSA = 28%

“Severe”

ElbowElbow

“I feel fine, and I’m in good health. Just fix my skin, doc.”

•• 703 x weight(lb)/height(in)703 x weight(lb)/height(in)2 2 BMI = BMI = 40.9 = morbidly obese40.9 = morbidly obese

•• BP 180/96 mm HgBP 180/96 mm Hg

•• Fasting glucose = 153mg/dLFasting glucose = 153mg/dL

•• Triglycerides = 225mg/dLTriglycerides = 225mg/dL

•• HDL = 23mg/dLHDL = 23mg/dL

•• ROS is entirely negativeROS is entirely negative

Metabolic Syndrome increased in Metabolic Syndrome increased in PsOPsOBr J Br J DermatolDermatol 157:68, 2007157:68, 2007

Increased CAD and risk of myocardial Increased CAD and risk of myocardial infarction associated with psoriasis infarction associated with psoriasis JAMA 296:1735, 2006 Br J JAMA 296:1735, 2006 Br J DermatolDermatol 156:271, 2007 156:271, 2007

Disaster waiting to happen!Disaster waiting to happen!

METABOLIC SYNDROMEMETABOLIC SYNDROME

Co-Morbid Conditions in Psoriatics

Arch Dermatol Res 298: 321, 2006; Br J Dermatol 157:68, 2007 and Jul 15, 2008 epub; J Am Acad Dermatol 57:347, 2007

ConditionCondition OROR 95% CI95% CI

Metabolic SyndromeMetabolic Syndrome 5.925.92 2.78 2.78 –– 12.812.8

DM Type IIDM Type II 2.482.48 1.70 1.70 –– 3.613.61

HypertensionHypertension 3.273.27 2.41 2.41 –– 4.434.43

DyslipidemiaDyslipidemia 2.092.09 1.23 1.23 –– 3.543.54

Coronary artery Coronary artery diseasedisease 1.771.77 1.07 1.07 –– 2.932.93

COPDCOPD 1.631.63 1.47 1.47 -- 1.831.83

Alcohol (heavy)Alcohol (heavy) 3.613.61 1.85 1.85 –– 7.077.07

TobaccoTobacco 2.962.96 2.27 2.27 –– 3.843.84

KEY POINT

•• Psoriasis may be a sign Psoriasis may be a sign of serious coof serious co--morbiditiesmorbidities

Overview/Epidemiology PsA•• Between 10% and 30% of Between 10% and 30% of PsOPsO patients develop patients develop

psoriatic arthritispsoriatic arthritis(6(6--42% are actual reported extremes)42% are actual reported extremes)

•• Onset typically occurs between 30Onset typically occurs between 30––50 years of 50 years of age (younger than RA)age (younger than RA)

•• Psoriasis usually precedes onset of Psoriasis usually precedes onset of PsAPsA by an by an average of 10 years in about 70% of patientsaverage of 10 years in about 70% of patients

•• PsAPsA can precede the development of psoriasis or can precede the development of psoriasis or have simultaneous onset with psoriasis in 11have simultaneous onset with psoriasis in 11––21% of patients21% of patients

•• Increased mortality has been observed in a Increased mortality has been observed in a large ongoing case registrylarge ongoing case registry

Arthritis Rheum. 41:1103Arthritis Rheum. 41:1103––1110, 19981110, 1998J Am J Am AcadAcad DermatolDermatol. 52:1. 52:1––19, 200519, 2005 J Am Acad Dermatol 52:1, 2005

Psoriatic Arthritis Differential Diagnosis•• Differential diagnosis includes:Differential diagnosis includes:

–– Reactive arthritis (ReiterReactive arthritis (Reiter’’s disease)s disease)

–– OsteoarthritisOsteoarthritis

–– AnkylosingAnkylosing spondylitisspondylitis

–– Rheumatoid arthritisRheumatoid arthritis

–– Septic arthritisSeptic arthritis

–– Gouty arthritisGouty arthritis

–– Arthritis inflammatory bowel diseaseArthritis inflammatory bowel disease

Dis Managed Health Outcomes. 1998;4:315–324Ann Intern Med. 2002;136:896-907

J Am Acad Dermatol. 2005;52:1–19

CASPAR: CASPAR: Diagnostic AlgorithmDiagnostic Algorithm

•• Inflammatory Inflammatory articulararticular diseasedisease

PLUS ANY THREE OF THESE:PLUS ANY THREE OF THESE:

•• Active psoriasis OR Active psoriasis OR FHxFHx of Psoriasisof Psoriasis

•• Psoriatic nail dystrophy Psoriatic nail dystrophy

•• DactylitisDactylitis OR Personal OR Personal HxHx of of dactylitisdactylitis

•• Negative RF statusNegative RF status

•• Radiologic changes Radiologic changes c/wc/w PsAPsA (X(X--rayray--MRI)MRI)

•• Specificity 98.7% and Sensitivity 91.4%Specificity 98.7% and Sensitivity 91.4%

Ann Rheum Dis 64(Suppl 2):3-8, 2005; Arthritis Rheum 54:2665, 2006

Peripheral Erosion Central Erosion and Periostitis

Pencil-in-cup deformity

Psoriatic ArthritisPsoriatic Arthritis

66% have difficulty using hands 63% have difficulty standing 43% leave workforce due to PsA

Arch Arch DermatolDermatol 137:280137:280––284, 2001284, 2001J Am J Am AcadAcad DermatolDermatol 36:38836:388––394, 1997394, 1997

46 yoNSAIDs

Radiologic ProgressionProgression of PsA Inhibited Inhibited by anti-TNF Rx

Drug mTSS

Placebo mTSS

Etanercept -0.03 (48 wk) -0.48 (96 wk)

+1.00

Adalimumab -0.20 (24 wk) +0.10 (48 wk)

+0.90

Infliximab -0.70 (24 wk) +0.05 (96 wk) +0.80-1.23

mTSS = Mean Total Sharp ScoresPosters at: AAD 2005, New Orleans; ECR 2005, Vienna; EADV 2005, Posters at: AAD 2005, New Orleans; ECR 2005, Vienna; EADV 2005, London London

J Rheum 33:712, 2006, J Rheum 33:712, 2006, ArthArth Rheum 56:476, 2007, Ann Rheum Rheum 56:476, 2007, Ann Rheum DisDis Aug 6, 2008, J Rheum 35:869, 2008Aug 6, 2008, J Rheum 35:869, 2008

5750 54

39 37 41

23

9

27

0

20

40

60

80

100ACR20 ACR50 ACR70

TNF Antagonists for Psoriatic Arthritis:ACR 20/50/70 Responses at 24 Weeks

40 mg eow(N=151)†

Adalimumab

25 mg biw(N=101)†

Etanercept Infliximab

5 mg/kg*(N=100)†

Sources: Sources: MeaseMease P, et al. Presented at: ACR; October 14P, et al. Presented at: ACR; October 14--19, 2004; San Antonio, Tex. (Abstract 19, 2004; San Antonio, Tex. (Abstract L6L6--521) 521) EnbrelEnbrel package insert. Amgen. package insert. Amgen. AntoniAntoni C, et al. C, et al. Ann Rheum Dis.Ann Rheum Dis. Published Online Published Online First January 27, 2005. First January 27, 2005. doidoi: 10.1136/ard.2004.032268.: 10.1136/ard.2004.032268.

Per

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*Infliximab was given at weeks 0, 2, 6, 14, 22. †Non-responder imputation

KEY POINT

•• Psoriasis may be associated with Psoriasis may be associated with inflammatory inflammatory arthropathyarthropathy

•• Psoriatic arthritis can be disablingPsoriatic arthritis can be disabling

•• Newer treatment modalities prevent Newer treatment modalities prevent progression of disease, not just progression of disease, not just improve improve SxSx

Pathogenesis

And how it influences RxAnd how it influences Rx

KEY CONCEPT•• Psoriasis is like an automotive assembly Psoriasis is like an automotive assembly

lineline•• A sequence of steps results in the A sequence of steps results in the

complete productcomplete product•• The assembly can be disrupted at more The assembly can be disrupted at more

than one stepthan one step•• The plant foreman is, so far, invincible, The plant foreman is, so far, invincible,

but progress is being made to dethrone but progress is being made to dethrone himhim……. (genetics). (genetics)

450BC to

500AD

Sulfur Sulfur baths baths TarTar

500AD to

1000AD

PrayerPrayer

1000 1000 to 1500to 1500

TortureTorture

1500 1500 to 1800to 1800

S, Hg S, Hg Tar Tar ArsenicArsenic

1876 1876 to 1914to 1914

AnthrallinAnthrallin(Arsenic (Arsenic continued)continued)

1925

UVBUVB

1948-1974

PUVAPUVA

1950s 1960s

Steroids Ingram

MTXMTX

1980s1980s

CycCyc--AA

19851985

VitVit D3D3

1997 to 1997 to 2009+2009+

BiologicsBiologics

RetinoidsRetinoids

1997

Middle Ages Middle Ages (ca 1000(ca 1000--1400AD)1400AD)

•• Medieval times: SuperstitionMedieval times: Superstition

•• Psoriasis sufferers were treated as if they Psoriasis sufferers were treated as if they were true leperswere true lepers

•• Forbidden to touch others or eat with Forbidden to touch others or eat with anyone except lepersanyone except lepers

•• Cause = Conspiring w/ DevilCause = Conspiring w/ Devil

•• Rx = Ordered Rx = Ordered psoriaticspsoriatics burned burned at the stake for witchcraft! at the stake for witchcraft! (1313AD)(1313AD)

•• Arch Arch DermDerm 33:327, 193633:327, 1936

Phillip the Fair 1263-1314AD

Therapeutic Options•• Topical agentsTopical agents

•• PUVAPUVA

•• UVB, NBUVB, NB--UVBUVB

•• AcitretinAcitretin

•• MethotrexateMethotrexate

•• CyclosporineCyclosporine

•• HydroxyureaHydroxyurea

•• 66--ThioguanineThioguanine

•• AdalimumabAdalimumab

•• AlefaceptAlefacept

•• EfalizumabEfalizumab

•• EtanerceptEtanercept

•• InfliximabInfliximab

•• UstekinumabUstekinumab


•• PUVAPUVA


•• AcitretinAcitretin










•• UstekinumabUstekinumabEfalizumab withdrawn from marketplace June 9, 2009

Efalizumab Associated with PML• Rapidly advancing, typically fatal CNS disease• Polyomavirus JC: attacks cell that make

myelin (unlike MS which attacks myelin)• JC latency in ~85-92% population; re- activates

with various forms of immunosuppression• Signs/Sx similar to Multiple Sclerosis

Confusion, Coordination, Weakness, Visual disturbance

• No pre-disease test useful; MRI & spinal fluid PCR (Sensitivity = 72-92% Specificity = 92-100%) establish diagnosis (as does brain biopsy)

• No therapy uniformly beneficial (IL-2, IFN-g, acyclovir cidofovir, amantadine, cytarbine, vidarabine, topotecan)

• AIDS, hematologic malignancy and organ transplants

Neurol Clin 26:833-54, 2008

Proportion of Psoriasis Patients Receiving Treatment

Moderate(3-10% BSA)

Severe(>10% BSA)

Any BSA

% r

es

po

nd

en

ts

Data from National Psoriasis Foundation patient survey (2003-2005)

J Am J Am AcadAcad DermatolDermatol. 2007;57:957. 2007;57:957––962962.

37 39 39

63 61 61

0

10

20

30

40

50

60

70

No Treatment (n=654) Any Current Treatment (n=1003)

Psoriasis Patients Treatment Severity Level and Type of Therapy

9 1511

227

6

7357

0

20

40

60

80

100

Biologic therapy Traditional systemic therapy

Phototherapy Topical therapy only

Moderate(3-10% BSA)

Severe(>10% BSA)

% r

es

po

nd

en

ts

Reflects real world data from National Psoriasis Foundation patient survey (2003-2005); may not reflect approved uses for all products

J Am J Am AcadAcad DermatolDermatol. 2007;57:957. 2007;57:957––962962.

PrePre--Biologic Treatment ParadigmBiologic Treatment Paradigm

OTC ProductsOTC Products•• EmollientsEmollients•• OtherOther

Rx Topical AgentsRx Topical Agents•• Topical steroidsTopical steroids•• Vitamin D analogsVitamin D analogs•• Topical Topical retinoidsretinoids•• Other Rx Other Rx topicalstopicals

egeg SalicyclicSalicyclic acidacid

PhototherapyPhototherapy•• UVB broadbandUVB broadband•• UVB narrowbandUVB narrowband•• PUVAPUVA•• LaserLaser

Process: Process:

•• Psoriasis therapy followed Psoriasis therapy followed stepwisestepwise progressionprogression

•• Patients must fail the Patients must fail the previous previous ““stepstep”” of therapy of therapy before initiating a more before initiating a more ““aggressiveaggressive”” therapytherapy

Order of Treatment Progression

Incr

easi

ng

Ris

k

Systemic TherapySystemic Therapy•• CyclosporineCyclosporine•• MethotrexateMethotrexate•• AcitretinAcitretin•• Systemic steroidSystemic steroid

Modern Treatment Paradigm

Biologic Agents• Adalimumab• Alefacept• Efalizumab• Etanercept• Infliximab• Ustekinumab

Phototherapy• UVB• PUVA

Traditional Systemic Drugs• Methotrexate• Cyclosporine• Soriatane• Fumarates• Other immunosuppressants

Key Points• Psoriasis treatment is not stepwise, sequential or ladder-like• Choice of therapy depends on individual patient characteristics• AAD, BAD, CDA all agree in their various consensus statements

AppropriateFor

TopicalTherapy






80% Appropriate

ForTopicalTherapy

Koo, J: Cutis. 2007;79(1 Suppl 2):11-7






Failure

AppropriateFor

TopicalTherapy

InappropriateFor

TopicalTherapy

Initiate

Algorithm for Systemic Treatment in Psoriasis

J Am Acad Dermatol. 54:101‐107, 2005

No to allPsoriasis affects 5% BSA?Patient disabled by the psoriasis?

QOL issues?

Phototherapy issues?Does the patient have psoriatic arthritis?

Yes to any of the above

The patient is acandidate for

systemic treatment

Yes to any of the above

No to allThe patient is a

candidate for systemic therapy or phototherapy

The patient is not acandidate for systemic therapy or phototherapy

Traditional systemic therapy Biological drug therapy


•• PUVAPUVA


•• AcetretinAcetretin










•• UstekinumabUstekinumab

Topical Agents

•• Steroids Steroids (various)(various)

•• VitaminVitamin--D Derivative D Derivative ((CalcipotrieneCalcipotriene, , CalcitriolCalcitriol))

•• Retinoid Retinoid ((TazaroteneTazarotene))

•• Tar derivatives Tar derivatives ((AnthralinAnthralin))

Topical Agents: Pointers•• Steroids Steroids (Efficacy rates = 58(Efficacy rates = 58--92%)92%)

-- Start high potency, work down to lowStart high potency, work down to low-- Maintain w/ lowest potency possible Maintain w/ lowest potency possible --Site determines vehicle Site determines vehicle --Foams often preferred by patient Foams often preferred by patient DesonideDesonide

((VerdesoVerdeso®®) ) BetamethasoneBetamethasone ((LuxiqLuxiq®®) ) ClobetasolClobetasol ((OluxOlux®®))

-- Combine with ANYTHING for spot RxCombine with ANYTHING for spot Rx

•• Vitamin D Derivative Vitamin D Derivative ((EfficayEfficay rate = ~70%)rate = ~70%)-- Available as scalp, cream Available as scalp, cream ((DovonexDovonex®® VecticalVectical®®))

-- Steroid combo (Steroid combo (TaclonexTaclonex®®))

•• Retinoid Retinoid ((TazoracTazorac®®) ) (Efficacy rate = 50(Efficacy rate = 50--63%)63%)-- Available Cream/Gel and 0.05Available Cream/Gel and 0.05--0.1% 0.1% -- Irritating; Best to THIN scales; then D/C Irritating; Best to THIN scales; then D/C

•• AnthralinAnthralin ((DrithocremeDrithocreme®®, , MicanolMicanol®®, , AnthradermAnthraderm®®))

-- Messy, smelly, staining, irritatingMessy, smelly, staining, irritating

Coal Tar Foam (New: 2009)•• 2% Crude coal tar (OTC)2% Crude coal tar (OTC)

•• Applied 1Applied 1--4x daily4x daily

•• Smells bad for about 30 min, and Smells bad for about 30 min, and then no smellthen no smell

•• Foam well tolerated and Foam well tolerated and covers large areacovers large area

•• Can be combined with Can be combined with other therapiesother therapies

•• Good Good maintenancemaintenance drugdrug

•• $36 per 100g canister$36 per 100g canister

Phototherapy•• Heliotherapy: Heliotherapy: India, Egypt, Greece, RomeIndia, Egypt, Greece, Rome

•• Ultraviolet light in sunlight 1801Ultraviolet light in sunlight 1801

•• Filtered sunlight (lupus Filtered sunlight (lupus vulgarisvulgaris) 1893) 1893

•Carbon arc 1901 and Quartz Lamp 1906

•La Cure Du Soleil (Rollier) 1914

UVA and UVB Phototherapy

Phototherapy (UVB, nb-UVB, PUVA)

•• AdvantagesAdvantages

•• High responseHigh response

•• Long remissionLong remission

•• Can be used with other Can be used with other Rx Rx --Oral retinoid Oral retinoid -- Topical RxTopical Rx

•• Treats high BSA of Treats high BSA of involvement involvement

•• DisadvantagesDisadvantages

•• Availability limitedAvailability limited

•• InconvenientInconvenient

•• ? Insurance approval? Insurance approval

•• Premature agingPremature aging

•• BCE, SCCA, ? MelanomaBCE, SCCA, ? Melanoma

•• Nausea, itching (PUVA)Nausea, itching (PUVA)

•• Cataracts (PUVA)Cataracts (PUVA)

Retinoids: Advantages

•• NonNon--immunosuppressiveimmunosuppressive

•• ?Prophylaxis ?Prophylaxis vrsvrs NMSCNMSC

•• Easy to combine with other RxEasy to combine with other Rx

•• In fact, In fact, retinoidsretinoids work BEST in work BEST in combination Rx regimenscombination Rx regimens

•• Combine with steroids, UVA, UVBCombine with steroids, UVA, UVB• Am J Clin Derm 6:255, 2005

• Am J Clin Derm 4:197, 2003

Retinoids: Disadvantages•• AcitretinAcitretin: SLOW : SLOW

•• CheilitisCheilitis (100%)(100%) XerosisXerosis(70%)(70%)

•• Hair lossHair loss

•• Triglycerides Triglycerides (66%)(66%)

•• Cholesterol Cholesterol (33%)(33%)

•• LFTsLFTs (33%)(33%)

•• PseudotumorPseudotumor cerebricerebri

•• PancreatitisPancreatitis

•• Poor healingPoor healing

•• TeratogenicTeratogenic (Class X)(Class X)

Expert Opin Pharmacother 6:1725, 2005

Methotrexate

•• AdvantagesAdvantages•• Easy (oral)Easy (oral)•• Can be used with Can be used with

other Rxother Rx•• Treat high BSA of Treat high BSA of

involvementinvolvement•• Reasonable Reasonable

response rateresponse rate•• PsOPsO and and PsAPsA

concurrent Rxconcurrent Rx

•• DisadvantagesDisadvantages•• NauseaNausea•• StomatitisStomatitis•• AlopeciaAlopecia•• Marrow toxicityMarrow toxicity•• PneumonitisPneumonitis•• DrugDrug--Drug Drug rxnrxn•• HepatotoxicityHepatotoxicity•• Liver biopsy Liver biopsy QQ1.5g1.5g

Callis K, et al. SID Annual Meeting 2002; Poster 220.

PASI Response to Methotrexate15-30mg/week at Week 24

Percentage of Patients (N=25)

PASI 75 PASI 75 ResponseResponse

(26%)(26%)

<PASI 50 Response

(37%)

PASI 50 PASI 50 Response Response

(37%)(37%)

• Appropriate Use

• Fetal Death/Congenital Abnormalities

• Impaired Drug Elimination

• Concomitant NSAID Use

• Hepatotoxicity

• Pulmonary Toxicity

• GI Toxicity

• Malignant Lymphoma

• Tumor Lysis Syndrome

• Skin Rxns

• Opportunistic Infections

• Concomitant Radiotherapy

Methotrexate Black Box Warnings

Cyc-A

•• AdvantagesAdvantages

•• Easy (oral)Easy (oral)

•• Can be used with Can be used with other Rxother Rx

•• Treat high BSA of Treat high BSA of involvementinvolvement

•• Rapid response Rapid response (Most rapid)(Most rapid)

•• Most Most surefilresurefilre

•• DisadvantagesDisadvantages

•• Nausea/vomitingNausea/vomiting

•• HypertensionHypertension

•• HypertrichosisHypertrichosis•• Magnesium, PotassiumMagnesium, Potassium

•• Dose/time limitsDose/time limits

•• NephrotoxicityNephrotoxicity

•• Increased risk of Increased risk of lymphoma lymphoma (?10x)(?10x)

AlefaceptAlefacept AmeviveAmevive®®

EfalizumabEfalizumab RaptivaRaptiva®®

EtanerceptEtanercept EnbrelEnbrel®®

InfliximabInfliximab RemicadeRemicade®®

AdalimumabAdalimumab HumiraHumira®®

UstekinumabUstekinumab StelaraStelara®®

T-cell Blockers

Anti-TNF-alfa

Anti-IL12/23

AlefaceptAlefacept AmeviveAmevive®® IM, weeklyIM, weekly BiogenBiogen//AstellasAstellas Approved Approved PsoPso

UstekinumabUstekinumab StelaraStelara®® SQ, Q12W SQ, Q12W CentocorCentocor, Inc, Inc Approved Approved PsoPso

EtanerceptEtanercept** EnbrelEnbrel®® Amgen, IncAmgen, Inc Approved forApproved forSQ, weeklySQ, weekly psoriatic arthritispsoriatic arthritis

and psoriasisand psoriasis

InfliximabInfliximab** RemicadeRemicade®® IV, Q8W IV, Q8W CentocorCentocor, Inc, Inc PsOPsO and and PsAPsA

AdalimumabAdalimumab** HumiraHumira®® SQ, Q8WSQ, Q8W Abbott Labs, IncAbbott Labs, Inc PsOPsO and and PsAPsA

GenericGenericNameName

BrandBrandNameName Given CompanyCompany StatusStatus

*Drug is FDA approved for an indication other than psoriasis.

FDA Approved Biologic Therapies for Psoriasis

58

Baseline

Week 12

Week 52

Typical Biologic Drug Result

PASI Score = 43.9

PASI Score = 0.4

PASI Score = 1.2

Biologics in Psoriasis and Biologics in Psoriasis and PsAPsA

COST

How much is getting your life back worth?BE PREPARED TO BECOME YOUR

PATIENTS’ ADVOCATE

KEY POINT

•• Treatment of psoriasis (with TNFTreatment of psoriasis (with TNF--alfaalfa blocking blocking biologics) biologics) maymay reduce the negative impact of serious reduce the negative impact of serious coco--morbiditiesmorbidities

Summary: Spah F: Br J Dermatol. 2008;159 Suppl 2:10-7

Typical Biologic Dosing RegimensTypical Biologic Dosing Regimens•• AdalimumabAdalimumab——40 mg every other week, administered 40 mg every other week, administered

subcutaneously; 80 mg starting dosesubcutaneously; 80 mg starting dose

•• AlefaceptAlefacept——course of 12 weekly 15course of 12 weekly 15--mg IM injections; mg IM injections; 12 week 12 week hiatus between courses hiatus between courses

•• UstekinumabUstekinumab——initial dose (45 or 90mg) at weeks 0 and 4; initial dose (45 or 90mg) at weeks 0 and 4; administered subcutaneously; repeated every 12 weeks afterwardadministered subcutaneously; repeated every 12 weeks afterward

•• EtanerceptEtanercept–– Psoriasis: 50 mg once weekly, after an initial 3 months of Psoriasis: 50 mg once weekly, after an initial 3 months of

50 mg twice weekly50 mg twice weekly

–– PsAPsA: 50 mg once weekly: 50 mg once weekly

•• InfliximabInfliximab——5 mg/kg IV infusion at baseline, week 2, and week 6, 5 mg/kg IV infusion at baseline, week 2, and week 6, and every 8 weeks thereafter; more frequent dosing and higher and every 8 weeks thereafter; more frequent dosing and higher doses may be necessarydoses may be necessary

Graves JE, et al. J Am Acad Dermatol. 2007;56:55-79.

Biologicals Differentiated•• TNFTNF--αα agents treat joint AND skin Tagents treat joint AND skin T--cell cell

blockers treat skin ONLYblockers treat skin ONLY•• UstekinumabUstekinumab has short track recordhas short track record•• AmeviveAmevive is slow; IM inconvenientis slow; IM inconvenient•• RemicadeRemicade most rapid, but most dangerous most rapid, but most dangerous

and inconvenient (IV)and inconvenient (IV)•• HumiraHumira MOA similar to MOA similar to RemicadeRemicade. Suggests . Suggests

we should worry about AEwe should worry about AE•• EnbrelEnbrel better for joints than skin; slower in better for joints than skin; slower in

onset than other onset than other TNFsTNFs but likely the safestbut likely the safest

PASI-75 Achieved at 12 Months

0

20

40

60

80

100

0 12 24 36 48 60

Etanercept 50 --> 253

Adalimumab 40 qeow*

Raptiva 1mg/kg/w

Infliximab 5mg/kg

Etanercept 25 BIW2

Weeks of Therapy

Per

cen

t o

f P

atie

nts

Ac

hie

vin

g P

AS

I-75

Alefacept 15mg QWKey Actions of IL-12 & IL-23 in PsO

J Am Acad Dermatol. 2007;57:1059-106 Expert Opin Ther Targets. 2008;12:1085-1096.

Skin Plaques

keratinocytehyperproliferation

IL-12

IL-23

TH1 celldifferentiation

TNF-

IFN-

keratinocytehyperproliferation

TH17 celldifferentiation

IL-17

IL-22

TNF-

Skin Plaques

Increasedinflammation

pro-inflammatory factors

Ustekinumab is not known to bind to any other cytokines

p40 p35

p40p19

Ustekinumab

64

Ustekinumab

Increasedinflammation

Ustekinumab: Phase III Clinical TrialsPASI-75 Response at Weeks 12 and 28

* P<0.001 vs placebo. Intent-to-treat: nonresponder imputation.1. J Am Acad Dermatol. 2008;58:AB122 (P2621); 2. Lancet. 2008;371:1665

Pa

tie

nts

(%

)

Phoenix 22

(N=1230)Phoenix 11

(N=766)

*

***

Week 12 Week 28

3

67 6671

79

0

20

40

60

80

100

Placebo 45 mg 90 mg

4

67

7670

79

0

20

40

60

80

100

Placebo 45 mg 90 mg

Pa

tie

nts

(%

)

Ustekinumab: Phase III Clinical TrialPASI-75 Response at Weeks 12 and 28 and 72

J Am Acad Dermatol. 2008;58 (2Suppl 2):AB4 P2620

Pa

tie

nts

(%

)

Phoenix 1(N=766)

**

Week 12 Week 28

3

67 6671

79

0

20

40

60

80

100

Placebo 45 mg 90 mg

8287

0

20

40

60

80

100

45 mg 90 mg

Pa

tie

nts

(%

)

Phoenix 11

(N=766)

Week 72

Biologicals: Safety Issues

•• Hypersensitivity: Local, SystemicHypersensitivity: Local, Systemic

•• Infection: New or Reactivation (TB)Infection: New or Reactivation (TB)

•• Malignancy: Visceral, LymphomaMalignancy: Visceral, Lymphoma

•• Other endOther end--organ concerns Cardiovascular organ concerns Cardiovascular (CHF: (CHF: TNFsTNFs)) Hematological Hematological ((CytopeniaCytopenia: T: T--cell)cell) Hepatic Hepatic (Toxicity: All; low risk)(Toxicity: All; low risk)Neurological Neurological (MS: (MS: TNFsTNFs))

•• Pregnancy: Largely nonPregnancy: Largely non--issueissue

•• Psoriasis: Psoriasis: Paradoxical EffectsParadoxical Effects

Pregnancy Systemic psoriasis Rx in women of

child bearing potential

•• AlefaceptAlefacept BB

•• CyclosporineCyclosporine CC

•• EtanerceptEtanercept BB

•• AdalimumabAdalimumab BB

•• MethotrexateMethotrexate XX

•• PUVAPUVA DD

•• InfliximabInfliximab BB

•• UstekinumabUstekinumab BB

•• AcitretinAcitretin XX

•• Paradoxical responsesParadoxical responses•• Psoriasis following antiPsoriasis following anti--TNF Rx for IBD TNF Rx for IBD

J Dermatol 34:468, 2007

Inflamm Bowel Dis 13:1059, 2007

•• IBD following antiIBD following anti--TNF Rx for Psoriasis TNF Rx for Psoriasis J Rheum 32:752, 2005

Br J Derm 157:396, 2007

All 127 cases in literature PsO during anti-TNF, through 2007 Infliximab 55% Etanercept 28% Adalimumab 17% Female 58% Male 42% Average duration of therapy = 10 months Only 15% resolve by changing anti-TNF agent Systemic therapy resolves 65% Ko JM, et al. J Dermatol Treat 2008;16:1-8

Potential Biologic Rx Patients•• CBC with platelet countCBC with platelet count

•• LFTsLFTs

•• PPD; PPD; (maybe)(maybe) Chest xChest x--rayray

•• HBsAgHBsAg

•• HIV screening (ELISA)HIV screening (ELISA)

•• OBESE (BMI > 30) OBESE (BMI > 30)

•• Lipid profile Lipid profile (TG, (TG, CholChol, HDL, LDL), HDL, LDL)

•• Fasting glucose; HbA1C Fasting glucose; HbA1C

•• CRP CRP (> 3mg/L high risk CVD) (> 3mg/L high risk CVD)

What Is Lack of Response?

Maintained Response

Initial Improvement

What Is Lack of Response?

Maintained Response

Initial Improvement

Primary Non-response

Primary Inadequate Response

T-cell >> Anti-TNF>>IL12/23

Secondary Efficacy LossSecondary Efficacy LossSecondary Efficacy Loss

Anti-TNF >> T-cell>>IL12/23

Inadequate Biologic Response What to do?

•• Wait and seeWait and see……..•• Increase dose? If feasibleIncrease dose? If feasible……•• Add adjunct therapy? Add adjunct therapy?

Phototherapy, Retinoid, MTX, Phototherapy, Retinoid, MTX, CsACsA•• Add second biologic? Add second biologic?

Disconnect between Disconnect between PsOPsO and and PsAPsAresponsesresponses

•• Change therapy? (Overlap) Change therapy? (Overlap) TNFTNF--alfaalfa blocker blocker ““switchingswitching””TNFTNF--alfaalfa blocker to Tblocker to T--cell inhibitor cell inhibitor TT--cell inhibitor to TNFcell inhibitor to TNF--alfaalfa blocker blocker

Studies indicate that treatment response

is consistentacross BMI groups

Dosing of Systemic Psoriasis Agents

AgentAgentRecommended Recommended Psoriasis DosePsoriasis Dose

Dosing Dosing RegimenRegimen

UstekinumabUstekinumab 45 45 oror 90 mg Q3mo90 mg Q3mo Weight basedWeight based

InfliximabInfliximab 3 or 5 mg/kg3 or 5 mg/kg Weight basedWeight based

CyclosporineCyclosporine 2.52.5--5.0 mg/kg/day5.0 mg/kg/day Weight basedWeight based

EtanerceptEtanercept50 mg 250 mg 2××/wk for 3 /wk for 3 mo, then 50 mg/wkmo, then 50 mg/wk

FixedFixed

AdalimumabAdalimumab80mg, 40mg, then 80mg, 40mg, then

40 mg EOW40 mg EOWFixedFixed

AlefaceptAlefacept 15 mg/wk15 mg/wk FixedFixed

MethotrexateMethotrexate 1010--25 mg/wk25 mg/wk FixedFixed

AcitretinAcitretin 1010--50 mg/day50 mg/day FixedFixed

Studies indicate thattreatment response

may show variationacross BMI groups

CNTO 1275 = Ustekinumab•• Human monoclonal antibodyHuman monoclonal antibody

•• Directed against p40 subunit common to Directed against p40 subunit common to ILIL--12 and IL12 and IL--23 (interference w/ TH23 (interference w/ TH--17 17 cells)cells)

•• Subcutaneous injection Q3 mo!!!!Subcutaneous injection Q3 mo!!!!

•• PsOPsO, , PsAPsA, , CrohnCrohn’’ss DiseaseDisease

•• CentocorCentocor ((MedarexMedarex developed antibody)developed antibody)

•• Abbott: ABTAbbott: ABT--874 comparable drug874 comparable drug

Lancet 371:1665 and 1675, 2008

Potential new products….•• AntiAnti--TNF TNF mononclonalmononclonal FAB only FAB only (SQ)(SQ)

CertolizumabCertolizumab UCB UCB (approved (approved CrohnCrohn’’ss) ) 7575--83% 83% PASI 75 @12 weeks; dosePASI 75 @12 weeks; dose--related related Expert Expert OpinOpin TherTher Targets12:1085,2008 Targets12:1085,2008

•• New oral New oral calcineurincalcineurin inhibitor ISA 247 inhibitor ISA 247 IsotechnikaIsotechnika, Alberta, CA , Alberta, CA 2525--47% PASI 75 47% PASI 75 @12 weeks; dose@12 weeks; dose--relatedrelated Lancet 371:1337, 2008Lancet 371:1337, 2008

•• Small molecule antiSmall molecule anti--inflammatory CCinflammatory CC--10004 10004 CelegeneCelegene, USA , USA 24.4% 24.4% PASI75 @12 weeks; 20mg BID PASI75 @12 weeks; 20mg BID CurrCurr Med Res Med Res OpinOpin 24:1529, 200824:1529, 2008

ConclusionConclusion

•• Lots of material presented!Lots of material presented!•• Hopefully, you found something Hopefully, you found something

interesting and maybe of interesting and maybe of pragmatic value in the talkpragmatic value in the talk……....

overview/epidemiologysma.org/.../2010/05/rosen_psoriasismanagement.pdf · social impact of...

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