Psoriasis: A Cutaneous or Systemic Disease · • Affects 2-3% of people worldwide2 ... (4 vs 40 days) • Abnormal ... 2Camisa C, ed. Chapter 1. In: Handbook of psoriasis. 1st ed.

Psoriasis:

A Cutaneous or Systemic Disease

Ian D.R. Landells, MD, FRCPCClinical Chief Dermatology, Eastern Health

Clinical Assistant Professor

Disciplines of Medicine and Paediatrics

Faculty of Medicine

Memorial University of Newfoundland

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Overview and Epidemiology of

Psoriasis• Chronic, immune-mediated inflammatory disease of the skin1

– But really much more than the skin

• Affects 2-3% of people worldwide2

– An estimated 1 million Canadians have psoriasis3

• Nearly one quarter of psoriasis patients have moderate-to-severe

disease

1. Gudjonsson JE, Elder JT. Clin Dermatol 2007;25:535

2. NIAMS. NIH Publication No 03-5040; 2003

3. Guenther L, et al. J Cutan Med Surg 2004;8:321

4. National Psoriasis Foundation: Statistics 2003

Psoriasis Pathogenesis

• TH1/TH17 T-Cell Mediated Disease of Skin

• Hyperproliferation of keratinocytes (4 vs 40

days)

• Abnormal keratinocyte differentiation

• Infiltration of inflammatory cells

• Impaired barrier function

• Likely polygenic and multifactorial

• Genes CARD14, TNF-A, HLA-CW6 + trigger

Psoriasis in Canada

• ~ 3% (1 million) people have psoriasis

• ~150,000 people with psoriasis are being treated

– 60,000 psoriasis patients have moderate-to-severe disease

• ~40 psoriasis-related deaths each year

– Includes suicide; treatment-related complications, & other disease-related issues

– The National Psoriasis Foundation survey reported that psoriasis patients in the youngest group (18 to 34 years of age) contemplated suicide (10%), experienced depression (54%)

– * Canadian rates calculated from US rates

National Psoriasis Foundation.

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

O V E R V I E W

Nail psoriasis 3

Psoriasis is a Complex Disease

Characteristics

Inflammatory

skin disorder

Various clinical

features

Lifelong, chronic

relapsing disease

Plaque-type psoriasis

most common form

1% - 3% of Caucasian

population affected

1 Van der Kerkhof PCM, ed. Chapter 1. In: Textbook of psoriasis. 2nd ed. Blackwell Publishing; 2Camisa C, ed. Chapter 1. In:

Handbook of psoriasis. 1st ed. Blackwell Science; 1998. p.7-34. 3Griffiths CE et al. Br J Dermatol. 2007;156(2):258-62 4García-Diez A

et al. Dermatology. 2008;216(2):137-51

80%1,3

~1-2%%4

~12%4~2%4

~2-61 %

Guttate Erythrodermic

Inverse Psoriasis

Pustular

Plaque

Palmoplantar

~4%4

Scalp Psoriasis

Inverse Psoriasis

Palmoplantar Pustular Psoriasis

Guttate Psoriasis

Erythrodermic Psoriasis

Don’t Forget to Check…

Mild Plaque Psoriasis - <3% BSA

Mod-Severe Plaque Psoriasis

Proposed Model for

Immunopathology of Psoriasis

15

TNF-α

Keratino

cyte

Macroph

age

Plasmacyt

oid

DC

Natural

Killer

T Cell

Dendritic Cell

(DC)

IF

N-γ

TNF

-α

Th22

Chronic Inflammatory

Loop

Formation of

Psoriatic Plaques

Increased

Inflammation

Activated

DC

Th17

IL-22TNF-α

Th1

TNF-

α

IL-23

IL-12

Keratinocyte

Proliferation

Proinflammatory

Cytokine Production

IFN-γ

Other

Cytokines

Innate Immune

System Cells

IL-

17A/

F

Psoriasis - “The Tie that Binds”• Chronic state of systemic inflammation

• Co-morbidities now recognized

• Multi-system disease

• Multi-discipline approach

• Psychosocial burden, 1,2,3

• Reactive Depression • Higher suicidal ideation• Alcoholism

1Kimball et al. Am J Clin Dermatol 2005;6:383. 2Naldi et al. Br J Dermatol

1992;127:212. 3Mrowietz U et al. Arch Dermatol Res. 2006 Dec;298(7):309-

19.; photo from http://www.fitnessfanatic.org

Psycho-social Morbidity and Psoriasis

Mrowietz U et al. Arch Dermatol Res. 2006 Dec;298(7):309-19.

Psoriatic Arthritis

Psoriatic Arthritis 7-30%

Spondyloarthropathies

Psoriatic Arthritis

• 7-30% OF PsO PTS - Usually sero-negative

• Men and women affected equally1

• Disease onset between age 30-501

Psoriasis precedes PsA in 2/3

Usually by ~10yrs

• More than one-half of the patients with PsA may have evidence of erosions on x-rays4,5

• Up to 40% of the patients develop severe, erosive arthropathy4,5E

• Spondylitis & Enthesitis also seen

1Jiaravuthisan et al. J Am Acad Dermatol. 2007;57:1-27 2De jong et al. Dermatology. 1996;193(4):300-3033Van Laborde S, Scher RK. Dermatol Clin. 2000;18:37-46

Enthesitis

Hochberg, M., et al. Rheumatology 3rdedition

McGonagle D, et al. Arthritis Rheum 2003;48: 896-905

Nail psoriasis 40-50%

Griffiths CE et al. Br J Dermatol. 2007;156(2):258-62.

Nail Psoriasis

Incidence of Nail Psoriasis in Patients

With Psoriasis

• 15%–50% of psoriasis patients have nail

involvement1

– Fingernails > Toenails

• Only 1%–5% in patients have nail involvement

without other cutaneous findings3

• Up to 85% of patients with PsA have nail

involvement

1Jiaravuthisan et al. J Am Acad Dermatol. 2007;57:1-272De jong et al. Dermatology. 1996;193(4):300-303

3Van Laborde S, Scher RK. Dermatol Clin. 2000;18:37-46

Nail Psoriasis Linked to…

• Positively associated with longer duration

and greater extent of skin disease1

• Higher incidence in PsA patients compared

with psoriasis alone2-4

• Severe disease is correlated to enthesitis,

polyarticular disease and unremitting and

progressive arthritis4

Nail pathology may provide a mechanistic link between skin disease

and joint disease in PsA3,4

1de Jong EM, et al. Dermatology. 1996;193(4):300-303; 2Jiaravuthisan MM, et al. J Am Acad Dermatol. 2007;

57:1-27; 3Williamson L, et al. Rheumatology. 2004;43:790-794; 4Lawry M. Dermatol Ther. 2007:20;60-67.

Nail Anchored by Entheses

Extensor

tendon

Flexor

tendon

Nail

Superficial &

deep laminae

Deep

lamina

Ocular inflammation 1

(Iritis/Uveitis/Episcleritis)

Crohn‘s Disease 2

Ulcerative Colitis

1Durrani Am J Ophthalmol. 2005;139(1):106. 2 Bernstein CN et

al. Gastroenterology 2005;129:827–836.

Other Inflammatory Disorders

•The Prevalence Ratios (95% CIs) of Having IBD if a Person Has a

Diagnosis of Psoriasis

•Crohn’s disease = 1.52 (1.22–1.89)

•UC = 1.56 (1.24–1.95)

Bernstein Gastroenterology 2005;129:827–836

•Psoriasis occurs in 7-11% of the IBD population compared to 2-3%

of the general population

Tavarela et al. Aliment Pharmacol Ther. 2004;20 s4:50-3

Inflammatory Bowel Disease

•Ocular inflammation is a common feature of PsA occuring in

almost 30% PsA patients

•Conjunctivitis (20%)I

•Iritis occurring in 7% of the pts

Van de Kerkhof Textbook of Psoriasis 2nd ed. 2003 p.34

Iritis

Metabolic Syndrome:1,2,3,4

• Arterial Hypertension

• Dyslipidaemia

• Insulin resistent Diabetes

• Obesity

higher CVD risk

1Pearce DJ et al. J Dermatolog Treat. 2005;16(5-6):319-23. 2 Kimball et al. Am J Clin Dermatol

2005;6:383.. 3Mrowietz U et al. Arch Dermatol Res. 2006 Dec;298(7):309-19. 4Mallbris L et al. Curr

Rheumatol Rep. 2006;8(5):355-63; photo from http://www.weightcontroldoctor.com.au

Metabolic Syndrome

•Respective prevalence rates of risk factors in those with severe

psoriasis, mild psoriasis, and in controls follows:

•Diabetes (7.1%, 4.4%, 3.3%)

•Hypertension (20%, 14.7%, 11.9%)

•Hyperlipidemia (6%, 4.7%, 3.3%)

•Obesity (20.7%, 15.8%, 13.2%)

•Smoking (30.1%, 28%, 21.3%)

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

Metabolic Syndrome

Plaque Psoriasis and

other forms

• Psychosocial burden, 2,4,5

• Reactive Depression • Higher suicidal ideation• Alcoholism

Metabolic Syndrome:1,2,5, 8

• Arterial Hypertension

• Dyslipidaemia

• Insulin resistent Diabetes

• Obesity

higher CVD risk

Nail psoriasis 7 40-50%

Ocular inflammation 3

(Iritis/Uveitis/ Episcleritis)

Crohn‘s Disease 6

Ulcerative Colitis

1Pearce DJ et al. J Dermatolog Treat. 2005;16(5-6):319-23. 2 Kimball et al. Am J Clin Dermatol 2005;6:383. 3Durrani Am J Ophthalmol. 2005;139(1):106. 4Naldi et al. Br J Dermatol 1992;127:212. 5Mrowietz U et al. Arch Dermatol Res. 2006 Dec;298(7):309-19. 6 Bernstein CN et al. Gastroenterology

2005;129:827–836. 7Griffiths CE et al. Br J Dermatol. 2007;156(2):258-62. 8 Mallbris L et al. Curr Rheumatol Rep. 2006;8(5):355-63

Comorbidities in Psoriasis Patients

Psoriatic Arthritis 5 7-30%

Spondyloarthropathies

Co-Morbidities & Paediatric PsO

• Database of 1.3 million Germans

– 2.6% (~34,000) with psoriasis

– 0.7% <20 yrs of age

• Crohn’s - 3.7 x prevalance in PsO pts <20 yrs

• Hyperlipidemia 2.2 x “ “

• Diabetes 2.0 x “ “

• Hypertension 2.0 x “ “

• Obesity 1.7 x “ “

M.Augustin et al. Epidemiology and comorbidity of psoriasis in children.

BJD; 2009. 162:633-636

• Psoriasis is a marker of underlying

systemic disease

Psoriasis patients have increased prevalence of conditions that are:

Metabolic Inflammatory Psychosocial

Severe Psoriasis may be associated with:

Psoriatic

Arthritis

Other

Inflammatory

Conditions

Nail

DiseaseCV diseaseIncreased risk

Also…• Severe PsO associated with increased risk of

death

Patient with

Severe PsO

Patient with

Mild PsO

•50% increased risk of death

compared to patients with no PsO

•Not associated with increased risk

of death

Gelfand et al, Arch Dermatol 2007;143(12):1493-9

Psoriasis: Chronic life long disease

Christophers E. Clin Dermatol 2007;25:529

Genes

Environment

Immune Dysregulation

inflammation

Cytokines

Platelet hyperreactivity

Endothelial dysfunction

Prothrombotic activity

Obesity

Hypertension

Diabetes

Dyslipidemia

Others

Time

Psoriatic

plaques

Psoriatic

arthritis

Crohn’s

disease

Cardiovascular

diseasePustular

disorders

Psoriasis Treatment

The Rule of Tens: Defining ‘Current Severe Psoriasis’Patients who fulfill any one of the three criteria

below – Should be considered to have severe psoriasis

– Require (most likely) active intervention

✓ BSA involved > 10%

✓ PASI score > 10

✓ DLQI* >10OR

Finlay AY. Br J Dermatol. 2005;152 (5):861-7

Dubertret L et al. Br J Dermatol. 2006;155 (4) 729-36

*Patient-reported outcome assessing limitations due to impact of skin disease on: symptoms and feelings, daily activities, leisure, work/school, personal relationships,

inconvenience of treatment

1Heydendael V et al, N Engl J Med. 2003;14;349(7):658-652Courtesy of Dr. Dalakir, Denmark

PASI 9.71 PASI 17.11 PASI 312

Severe

Clinical response is measured by % reduction in PASI

Moderate

PASI: Assessing Extent

and Severity of Psoriasis

• Skin Clearance: Ultimate Goal

• Sustained response

• Long-term safety

• Improved QoL

75% improvement in PASI (PASI 75)

> PASI 75

PASI 20.0PASI 0.7

Week 0 Week 10

Treatment Goals in Psoriasis: Significant

and Rapid Improvement of the Disease

Therapeutic Options in Psoriasis

• Topical treatments– Coal tar, etc.

– Vitamin D analogues

– Topical retinoids

– Topical corticosteroids

• Phototherapy• UVB

• PUVA

• Traditional systemic treatment– Acitretin

– Methotrexate

– Cyclosporine

• Biologics

Callen JP, et al. J Am Acad Dermatol 2003;49:897

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

Lebwohl M, et al. J Am Acad Dermatol 2001;45:487

Lebwohl M, et al. J Am Acad Dermatol 2001;45:649

• Oral Agents:• Acitretin

» Hard on liver and can elevate lipids.

» Works well in about 20-40% of patients

• Methotrexate» Hard on liver and can drop blood cells. Can affect

lungs.

» Works well in about 30-50% of patients.

• Cyclosporine» Hard on kidneys and causes increase blood pressure

and lipids. Increased risk of mailgnancy

» Works well in 60-80% of patients.

• Phototherapy: (Need to be close to light unit)• Either twice per week (PUVA) for 15+ weeks.

• Three times per week (nb & bbUVb) for 10+ weeks.

• Works well in 60-80% of patients.

• Biological Agents:• Injectables from twice weekly to every 3 months.

Systemic Treatment Options to

Patient:

Non-biologic Systemic Therapies for

Moderate to Severe PsoriasisResponse by PASI 75 at primary endpoints (8-16 wks)1,2

No head to head trials%

Pati

ents

Ach

ievin

g P

AS

I 75

0

25

50

75

100

CSA4,8

3-5 mg/kg/d

Phototherapy2

3-4 times QW

MTX4

15 mg/wk

60

58-71

70-80

1Stern R. JAMA 2003;290:3133. 2Miller & Feldman. Exp Op Pharmacother 2006,7:157. 3Geiger JM. Skin Therapy Lett. 2003 ;8(4):1 4Heydendael V et al. NEJM. 2003;14;349(7):658-65 5EMEA Prod. Specific SPCs 6Katz KA et al. J Invest Dermatol. 2002;118(6):1038. 7Mrowietz & Asadullah. Trends Mol Med. 2005;11(1):43. 8Flytstrom I et al, Br J

Dermatol. 2007 Dec 7;158(1):116-121.

Acitretin3

30-40 mg/d

52

Toxicity

Cyclosporin5: Nephrotoxicity, Arterial Hypertension, Malignancy

MTX5: Hepatotoxicity, Bone marrow toxicity

Retinoids5: Teratogenicity, Hyperlipidaemia, Hepatotoxicity

PUVA6: Cutaneous malignancies

Biologic Therapies

TNF-A inhibitors

42

TNF-α

Keratino

cyte

Macroph

age

Plasmacyt

oid

DC

Natural

Killer

T Cell

Dendritic Cell

(DC)

IF

N-γTNF-α

Th22

Chronic Inflammatory

Loop

Formation of

Psoriatic Plaques

Increased

Inflammation

Activated

DC

Th17

IL-22TNF-α

Th1

TNF-

α

IL-23

IL-12

Keratinocyte

Proliferation

Proinflammatory

Cytokine Production

IFN-γ

Other

Cytokines

Innate Immune

System Cells

IL-

17A/

F

Biologic Therapies

Anti – IL12/23

43

TNF-α

Keratino

cyte

Macroph

age

Plasmacyt

oid

DC

Natural

Killer

T Cell

Dendritic Cell

(DC)

IF

N-γ

TNF

-α

Th22

Chronic Inflammatory

Loop

Formation of

Psoriatic Plaques

Increased

Inflammation

Activated

DC

Th17

IL-22TNF-α

Th1

TNF-

α

IL-23

IL-12

Keratinocyte

Proliferation

Proinflammatory

Cytokine Production

IFN-γ

Other

Cytokines

Innate Immune

System Cells

IL-

17A/

F

Biologic Therapies

Anti-IL17

44

TNF-α

Keratino

cyte

Macroph

age

Plasmacyt

oid

DC

Natural

Killer

T Cell

Dendritic Cell

(DC)

IF

N-γ

TNF

-α

Th22

Chronic Inflammatory

Loop

Formation of

Psoriatic Plaques

Increased

Inflammation

Activated

DC

Th17

IL-22TNF-α

Th1

TNF-

α

IL-23

IL-12

Keratinocyte

Proliferation

Proinflammatory

Cytokine Production

IFN-γ

Other

Cytokines

Innate Immune

System Cells

IL-

17A/

F

Biologic Therapies

Anti – IL23

45

TNF-α

Keratino

cyte

Macroph

age

Plasmacyt

oid

DC

Natural

Killer

T Cell

Dendritic Cell

(DC)

IF

N-γ

TNF

-α

Th22

Chronic Inflammatory

Loop

Formation of

Psoriatic Plaques

Increased

Inflammation

Activated

DC

Th17

IL-22TNF-α

Th1

TNF-

α

IL-23

IL-12

Keratinocyte

Proliferation

Proinflammatory

Cytokine Production

IFN-γ

Other

Cytokines

Innate Immune

System Cells

IL-

17A/

F

Proposed Model for

Immunopathology of Psoriasis

46

TNF-α

Keratino

cyte

Macroph

age

Plasmacyt

oid

DC

Natural

Killer

T Cell

Dendritic Cell

(DC)

IF

N-γ

TNF

-α

Th22

Chronic Inflammatory

Loop

Formation of

Psoriatic Plaques

Increased

Inflammation

Activated

DC

Th17

IL-22TNF-α

Th1

TNF-

α

IL-23

IL-12

Keratinocyte

Proliferation

Proinflammatory

Cytokine Production

IFN-γ

Other

Cytokines

Innate Immune

System Cells

IL-

17A/

F

Biologic Agents for Moderate to Severe Plaque

Psoriasis (no head to head trials!) – Short Term

Efficacy of Biologics at primary endpoint by PASI 75

% P

atie

nts

Ach

ievin

g P

AS

I 75

1Lebwohl M et al. N Engl J Med. 2003;349(21):2004-13.2 Gordon KB et al. JAMA. 2003;17;290(23):3073-80. 3Papp KA et al. Br J Dermatol. 2005;152(6):1304-12.

4Leonardi C et al. N Engl J Med. 2003;20;349(21):2014-22. 5Menter A et al. J Am Acad Dermatol. 2008:58:106. 6 Reich K et al. Lancet 2005; 366; 1367.

T-cells targeting

34

49

0

20

40

60

80

100

ETA

25mg

BIW

ETA

50mg

BIW

Week 123,4

1x 80mg

induction

71

0

20

40

60

80

100

Ada 40 mg EOW

Week 165

80

0

20

40

60

80

100

IFX 5 mg/kg Wk 0,2 6

TNFa inhibition

Week 106

Biologic Agents for Moderate to Severe Plaque

Psoriasis (no head to head trials!) – Short Term

Efficacy of Systemic Agents at primary endpoint by PASI 75

Efficacy of IL-17 Inhibition

Agent/Dose PASI

75

PASI

90

PASI

100

Endpoint ACR 20/Wk/Dose

Brodalumab

210mg

82 75 62 Wk 12 71 Wk 52 (140 mg)

56 Wk 52 (280 mg)

Ixekizumab

150 mg

82 71 39 Wk 12

Secukinumab

300 mg

77 54

71

24

39

Wk 12

Wk 52

54 Wk 24 (300mg)

51 Wk24 (150 mg)

Efficacy of IL-23 Inhibition

Apremilast (Otezla) PDE4 Inhibitor

• 30 mg PO BID 29% achieved PASI 75 at 16 wks

• Approved for PsO and PsA

• No lab monitoring

• Diarrhea & Depression reported

Psoriasis Conclusions

• Chronic, immune-mediated inflammatory disease

of the skin1

• Associated with numerous co-morbidities

• Initiate treatment that effectively clears the

patient’s skin and observe for co-morbidities

• Choose treatment effective against psoriasis and

co-morbidities

• Evaluate and monitor skin & co-morbidities in

concert with medical colleagues

Thank You!!