PSORIASIS THERAPY IN THE ELDERLY

Mark Lebwohl, MDSol and Clara Kest Professor

And ChairmanDepartment of Dermatology

The Mount Sinai School of Medicine

9/24/10

Mark Lebwohl, MD Psoriasis Conflict of Interest List and Statement

Relationship: C = Consultant; S = Speaker; L = Lectures, Compensation: H = Honorarium

Company Name Relationship Compensation

Abbott Laboratories C HAllostera C HAmgen/Pfizer C HAstellas C HCambridge Pharma C HCan-Fite Biopharma C HCelgene C HCentocor/Janssen/J&J C HDermaGenoma C HDermiPsor C HGlaxoSmithKline-Stiefel C HNovartis C HRanbaxy L H

Honoraria from the following entities were donated directly to charity: Actelion; Galderma Laboratories; Leo; PharmaDerm.

Members of Dr. Lebwohl’s department own patents on short-contact tazarotene, topical genistein, and use of the excimer laser for vitiligo. Members of Dr. Lebwohl's Department serve as investigators for numerous companies including: Abbott, Actavis, Amgen, Astellas, Celgene, Centocor, Galderma, Novartis, NovoNordisk, Provectus, Ranbaxy, Roche, Stiefel, VBL Pharmaceuticals, Wyeth. Dr. Lebwohl is a course director for the annual Fall and Winter Clinical Dermatology Conferences and the annual Mount Sinai Winter Symposium which receive support from numerous dermatology companies.

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80 yo ♀, psoriasis 70% BSA

• h/o multiple scc’s• h/o dm• h/o ↑BP• h/o CHF• ↑Cholesterol & TG’s

Treatment options

• UVB • PUVA• MTX• Cyclosporine• Acitretin• TNF blockers• Ustekinumab• Alefacept

PUVA: The Ideal Patient

Refractory to Topical Therapy and UVB

Psoriatic Arthritis

Palm and Sole Psoriasis

Over the Age of 65

Does not Improve with Sunlight

Cutaneous squamous-cell carcinoma in patients treated with PUVA. 3;310(18):1156-61.

Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL.

N Engl J Med. 1984 May

Malignant melanoma in patients treated for psoriasis with

methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The

PUVA Follow-Up Study.

Stern RS, Nichols KT, Vakeva LH.N Engl J Med. 1997; 336(15): 1041-5.

Treatment options

• UVB • PUVA• MTX• Cyclosporine• Acitretin• TNF blockers• Ustekinumab• Alefacept

Pancytopenia associated with low dose methotrexate therapy. A regional survey. al Awadhi A, Dale P, McKendry RJ. J Rheumatol. 1993;20(7):112 – 15.

15 cases 1981-1991

contributing fx:• ↑BUN,creatinine • ↑MCV• ↑ age • trimethoprim-sulfamethoxazole

Pancytopenia secondary to methotrexate therapy in

rheumatoid arthritis.Gutierrez-Urena S et al.

Arthritis Rheum. 1996 Feb; 39(2):272-6.

• 70 cases, 12 deaths• 1.4% in prospective trials• Risk fx: BUN, Cr; albumin; infection;

medications; age

Treatment options

• UVB • PUVA• MTX• Cyclosporine• Acitretin• TNF blockers• Ustekinumab• Alefacept

CYCLOSPORINE SIDE EFFECTS

• Nephrotoxicity• Hypertension• Hypomagnesemia, Hyperkalemia• Hyperlipidemia• Drug interactions• Hypertrichosis• Lymphoproliferative disease• “Sexual Frenzy”

Renal effects of amlodipine in normotensive renal transplant recipients.Venkat Raman G, et al.

Nephrol Dial Transplant

14(2):384-8, Feb 1999.

• Amlodipine reduced creatinine

Amlodipine (Norvasc) 2.5, 5, and 10 mg

•start with 5mg/d.• increase up to 10 mg/d.

Cutaneous malignancy related to cyclosporin A therapy.

Green C, Hawk JL. Clin Exp Dermatol. 1993;18:30-31.

Incidence and prediction of nonmelanoma skin cancer post-renal transplantation:

a prospective study in Queensland, Australia.Carroll RP et al. Am J Kidney Dis. 2003;41:676-683.

• 18.8%, <5 years• 24.8%, 5-10 years• 33.3%, 10-20 years• 47.1%, >20 years

Treatment options

• UVB • PUVA• MTX• Cyclosporine• Acitretin• TNF blockers• Ustekinumab• Alefacept

Prevention of Skin Cancer and Reduction of Keratotic Skin Lesions During Acitretin Therapy in Renal Transplant Recipients: A Double-Blind, Placebo-Controlled Study.

Bouwes Bavinck JN, Tieban LM, Van der Woude FJ, et al.

J Clin Oncol 13:1933-38,1995.

•Acitretin 30 mg/day

Multiple squamous cell carcinomas in a psoriatic patient following high-

dose photochemotherapy and cyclosporin treatment: response to

long-tern acitretin maintenance.

Van der Kerkhof PC, de Rooij MJ.

Br J Dermatol 1997 Feb;136(2):275-8.

Effects of gemfibrozil (Lopid) on hyperlipidemia in acitretin-treated patients. Results of a double-blind

cross-over study.

Vahlquist C,Olsson AG, Lindholm A,Vahlquist A.

Acta Dermato-Venereologica 1995;75(5):377-80.

Prevalence of cardiovascular risk factors in patients with psoriasis. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. J Am Acad Dermatol. 2006;55:829-35.

Prevalence of Risk Factors

diabetes

SeverePsoriasis7.1%

MildPsoriasis 4.4%

Controls

3.3%↑lipids 6% 4.7% 3.3%

obesity 20.7% 15.8% 13.2%

↑BP 20% 14.7% 11.9%

smoking 30.1% 28% 21.3%

Neimann AL et al. J Am Acad Dermatol. 2006;55:829-35.

Risk of myocardial infarction in patients with psoriasis. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. JAMA 2006;296:1735-41

age 30, severe psoriasis

HR: 3.10

0

0.5

1

1.5

2

2.5

3

3.5

age 30 age 60

control

mild psoriasis

severe psoriasis

Hazard RatioMI

3.10

1.291.361.08

Cardiovascular risk profile of patients with psoriatic arthritis compared to controls--the role of inflammation. Tam LS et al.Rheumatology (Oxford). 2008;47:718-23.

↑Myocardial infarction↑atherosclerosis↑peripheral vascular disease↑stroke

Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis.

Prodanovich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS. J Am Acad Dermatol.2005;52(2):262-7.

Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis.Jacobsson LT et al.Ann Rheum Dis. 2007;66:670-675.

• Anti-TNF: 51 deaths/3177 pt yrs• Controls: 137 deaths/3900 pt yrs

Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis.Jacobsson LT et al.J Rheumatol. 2005;32:1213-8.

First cardiac event: anti-TNF - 14.0/1000 pt yrs

controls - 35.4/1000 pt yrs

Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register.

Dixon WG, Watson KD, Lunt M, Hyrich KL; British Society for Rheumatology Biologics Register Control Centre Consortium, Silman AJ, Symmons DP; British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56(9):2905-12.

Efficacy and Safety of up to 10 years of Etanercept Therapy in North American Patients with Early and Longstanding Rheumatoid Arthritis• Open label extensions of etanercept trials• 1272 patients

Poster presented at AAD, March 6-10 2009 San Francisco

Early RA N= 558 39

Long-Standing RA N=714 53

14 33

DEATHS

observed

expected

But… RA, not Psoriasis ↓NSAIDs

Effects of etanercept on C-reactive protein levels in psoriasis and psoriatic arthritis. Strober B, Teller C, Yamauchi P, Miller JL, Hooper M, Yang YC, Dann F.Br J Dermatol. 2008;159:322-30.

Psoriasis

CRP

(mg/

L)

n = 156

n = 55

n = 15n = 56

n = 160n = 57

n = 15

n = 58

Baseline Week 12 Week 24

n = 123n = 40

n = 39

n = 114n = 33

n = 53n = 14

n = 145n = 56

n = 1091

2

3

4

5

6

7

Placebo, normal BMIEtanercept, normal BMI

Placebo, obese BMIEtanercept, obese BMI

Etanercept, overweight BMIPlacebo, overweight BMI both

panels

Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis.Zhang L et al. Arterioscler Thromb Vasc Biol. 2007;

27:1087-94.

Treatment options

• UVB • PUVA• MTX• Cyclosporine• Acitretin• TNF blockers• Ustekinumab• Alefacept

Why is congestive heart failure mentioned in the package insert

of TNF blockers?

Case reports of heart failure after therapy with a tumor necrosis factor antagonist.

Kwon HJ, et al.

Ann Intern Med. 2003;138:807-11.

FDA Medwatch• 47 pts, new (38) or worse (9) CHF• 19/38 new CHF no risk fx• 10 < age 50• 10 discontinued TNF Tx – CHF resolved in 3,

improved in 6, 1 died.

Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal

antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure:

results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial.

Chung ES, et al.

Circulation. 2003 Jul 1;107(25):3133-40.

• 10 mg infliximab group more hospitalizations or death than placebo.

1. Chung ES et al. Circulation. 2003;107:3133-40.

Placebo(n = 49)

Infliximab5 mg/kg(n = 50)

Infliximab10 mg/kg(n = 51)

Week 14 2 (4%) 2 (4%) 9 (18%)

Week 28 5 (10%) 4 (8%) 14 (27%)

ATTACH Trial

Death or Hospitalization in patients with NYHA class III - IV

CONTRAINDICATIONS REMICADE at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating REMICADE in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), REMICADE treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure (see WARNINGS and ADVERSE

REACTIONS , Patients with Heart Failure ).

Etanercept Label: CHF

PRECAUTIONS: Patients with Heart Failure

Two large clinical trials evaluating the use of ENBREL® in the treatment of heart failure were terminated early due to lack of efficacy. Results of one study suggested higher mortality in patients treated with ENBREL® compared to placebo. Results of the second study did not corroborate these observations. Analyses did not identify specific factors associated with increased risk of adverse outcomes in heart failure patients treated with ENBREL®. There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking ENBREL®. There have also been rare reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Physicians should exercise caution when using ENBREL® in patients who also have heart failure, and monitor patients carefully.

1. Coletta AP et al. Eur J Heart Failure. 2002;4:559-61.

Etanercept25 mg

once/wk

Etanercet 25 mg

twice/wk

Etanercet 25 mg three

times/wk

RECOVER 1.01 0.87RENAISSANCE 1.21 1.23RENEWAL 1.08

Hazard ratio for death/worsening of CHF at 24 weeksin more than 2000 patients with NYHA class II – IV

Results of targeted anti-tumor necrosis factor therapy with etanercept (Enbrel)

in patients with advanced heart failure.

Bozkurt B, et al. Circulation. 2001;103:1044-7.

• 5 mg, 12 mg or placebo sq biw• dose-dependent improvement in LV

ejection fraction.

Incidence of Congestive Heart Failure in Adalimumab Pivotal

StudiesPlacebo

n (%)Adalimumab

n (%)

Prior history of CHFRelapse CHF

70 (0)

180 (0)

No prior history of CHFNew onset CHF

6835 (0.7)

1,3622 (0.1)

FDA AAC March 2003.

Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy.

Wolfe F, Michaud K.

Am J Med. 2004 Mar 1;116(5):305-11.

• Heart failure ‘d in RA vs OA.• Heart failure significantly less common in anti-

TNF-treated patients.• “Rheumatoid arthritis increases the risk of

heart failure, which may be ameliorated by anti-TNF therapies.”

Treatment options

• UVB • PUVA• MTX• Cyclosporine• Acitretin• TNF blockers• Ustekinumab• Alefacept

Cardiovascular safety of ustekinumab in patients with moderate to severe psoriasis: results of integrated analyses of data from phase II and III clinical studies.

Reich K, Langley RG, Lebwohl M, Szapary P, Guzzo C, Yeilding N, Li S, Hsu MC, Griffiths CE.

Br J Dermatol. 2011;164:862-72

Major CV Events in Pooled Phase 2 & 3 trialsIn

cid

enc

e p

er

100

PY

(9

5%C

I)

0.00 (0.00, 1.69)

0.98 (0.12, 3.56)

1.47 (0.30, 4.31)

0.63 (0.25, 1.30)

0.35 (0.10, 0.90)

0.60 (0.32, 1.02) 0.31

(0.13, 0.61)

0.0

1.0

2.0

3.0

4.0

Controlled Period 1.5 Years 3 Years

Placebo Ustekinumab 45 mg Ustekinumab 90 mg Ustekinumab combined

N

Patient years

# of events

732 790 792 1582 732 1110 1156 2266 1319 1906 3117

177 203 203 407 182 1113 1138 2251 2184 2598 4782

0 2 3 5 1 7 4 11 13 8 21

1.23 (0.40, 2.87)

0.49 (0.24, 0.87)

0.44 (0.27, 0.67)

0.55 (0.01, 3.06)

*Major CV events (Cardiovascular Death, MI, Stroke)

Psoriasis Only

Frequency of major cardiovascular events compared to FHS over 3 years

Time to First Event Analysis in Psoriasis Trials for (A) Patients with MACE and (B) Patients with MI or Stroke Compared to Framingham Heart Study Expected Rate

Gordon K, et al. Poster Presentation at AAD 2011. P3305.

A) MACE (CV death, MI, or Stroke) B) MI or Stroke

Ustekinumab: Additional Clinical Studies with at least 12 weeks of completed follow up(as of Dec 31 2011)

Fully Enrolled Studies with analyzed data Population

Subjects Randomized Dose

MACE During Controlled

Period4

Japan/Phase 2/31 Psoriasis 160 45 mg, 90 mg 0

Korea & Taiwan Phase 31 Psoriasis 121 45 mg 0

TRANSIT/Phase 43 Psoriasis 491 45 mg, 90 mg 0

Phase 2b1,2 Crohn’s Disease

526IV 1 to 6 mg/kg;

SC 90 mg0

TOTALS 1298 01Studies that have completed controlled period.2 Ongoing, blinded studies with active enrollment where not all subjects have completed controlled period3 TRANSIT is not placebo-controlled & evaluates transitioning from MTX. Data displayed for first 16 weeks.4 MACE includes unadjudicated CV death, MI, CVA.

Data on file, COBI.

80 yo ♀, psoriasis 70% BSA

• h/o multiple scc’s• h/o dm• h/o ↑BP• h/o CHF• ↑Cholesterol & TG’s

Alcohol intake and risk of incident psoriasis in US women: A prospective study.Qureshi AA et al.J Invest Dermatol. 2009;129:S63.

• Non-light beer associated with psoriasis.

Presented at EADV, Sept. 2008, Paris

800-723-9166