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Psoriasis is a Systemic Disease Sharm Derma 2014 Mahira Hamdy El Sayed Professor of Dermatology and Venereology Ain Shams University

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International Federation of Pharmaceutical MAnufacturers

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IFPA International Federation of Psoriasis Association

Overview of WHO psoriasis report The psoriasis resolution was approved by the WHO Executive Board (EB) in May 2013. Prior to EB approval, a report on psoriasis was produced by the WHO Secretariat. The 4 page report deals with the following aspects of psoriasis: To add pre-formatted bullet text please use the Increase/Decrease Indent buttons found in the Top-PowerPoint menu

• Features of psoriasis: Provides a brief definition of psoriasis and its manifestations

• Prevalence of psoriasis: Provides an estimate on the global prevalence of psoriasis

• Natural history of psoriasis: Briefly discusses the onset and chronic nature of psoriasis

• Aetiology of psoriasis: Provides an overview of the understanding of what causes psoriasis

• Impact on health-related quality of life: Discusses how psoriasis affects health-related quality of life in relation to other noncommunicable diseases as well as the aspect of psychosocial distress

• Diagnosis and management of psoriasis: Discusses how psoriasis is currently diagnosed and treated

• Need for research: Makes recommendations on future areas for research • Implications for healthcare services: Makes recommendations on how management of psoriasis should be integrated into existing healthcare services

• Potential actions to strengthen services: Makes recommendations on how management of psoriasis should be integrated into existing healthcare services

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Psoriasis Cutaneous disease

Traditional

No comorbidities

Concept

(Ps Arthritis) Psoriasis

Multifaceted Systemic

New Concept

Inflammmatory Disease Comorbidities

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Psoriasis: a systemic disease

Comorbidities

Psoriasis

Inflammation

Genetic factors Environ -mental factors

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Psoriasis is a multifaceted, systemic, inflammatory disease that has an immunopathologic basis and is associated with numerous systemic comorbidities that are linked to tumour necrosis factor alpha

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What do we mean by multifaceted and systemic?  Multifaceted

“having many facets or aspects” skin, including scalp, hand-foot; nails  Systemic “of, relating to, or common to a system. as: affecting the body generally” PsA; sleep; depression; CRP; MS; CVD; CD; mortality  Co-morbid / co-morbidity “existing simultaneously with and usually independently of another medical condition”

The spectrum of psoriasis A multifaceted, systemic, inflammatory disease Scalp psoriasis

Nail psoriasis

Disease severity plaques

Psoriatic arthritis Psoriasis – A systemic inflammatory condition

Psychological co-morbidities

Low quality of life

Metabolic co-morbidities

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Why might psoriasis be a systemic inflammatory disease? • Immune abnormalities are profound • Severity is associated with greater levels of systemic inflammation (e.g. CRP, Th-1 cytokines) • Inflammation may be a common pathway to a variety of diseases including atherosclerosis, obesity, and insulin resistance

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FDG-PET/CT imaging shows inflammation in skin, liver, vasculature, joints of patients with psoriasis Psoriasis

Control

Aorta Liver

Vasculature Joints

Skin

FDG = fluorodeoxyglucose; PET/CT = Positron emission tomography/computed tomography Mehta NN, et al. Arch Dermatol. 2011;147:1031–9. 12

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Initiation Activation of (resident) immune cells

Environmental trigger

Recruitment of additional immune cells

Genetic predisposition

Inflammatory mediators

Altered tissue structure and function

Activation of dermis and epidermis

Maintenance

Once the cycle of psoriatic inflammation is underway, it is self-perpetuating

Immunopathophysiology of psoriasis

Adapted from Nestle F, et al. N Engl J Med. 2009;361:496–509

TNF-α = Tumour necrosis factor α |

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Psoriasis and its co-morbidities are thought to be TNF mediated Uveitis

Depression, fatigue, disturbed sleep, cognitive impairment CV disease (heart)

CV disease (vascular) Chronic obstructive pulmonary disease, sleep-disordered breathing Psoriatic arthritis

Metabolic syndrome (diabetes, dyslipidaemia) Crohn’s disease Psoriasis

Nijsten T, et al. J Invest Dermatol 2009;129:1601–3

Key Actions Attributed to TNFa

Increased inflammation

↑ pro-inflammatory cytokines ↑ chemokines

Increased cell infiltration

Increased angiogenesis

Increased CRP* in serum

*CRP = C-reactive protein †WBC = white blood cell

↑ metalloproteinase synthesis ↓ collagen production Synoviocytes Articular cartilage degradation

Macrophages ↑ adhesion molecules

Endothelium

↑ pro-inflammatory mediators

TNFα

Keratinocytes

↑ vascular endothelial growth factor (VEGF)

↑ WBC† recruitment to skin

↑ acute phase response

↑ ion transport ↑ permeability

Hepatocytes

Epithelium

Plaque formation

Compromised barrier function

Choy EHS, Panayi GS. N Engl J Med. 2001;344:907-916. Feldmann M. Nat Rev Immunol. 2002;2:364-371. Lipsky PE. In: Braunwald E, Fauci A. Harrison’s Principles of Internal Medicine. 15th ed. 2001:1928-1937. Paleolog EM, Arthritis Res. 2002;4(suppl 3):S81-S90. Burger D et al, Arthritis Res. 2002;4(suppl 3):S169-S176. |

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Psoriasis co-morbidities • A number of systemic co-morbid conditions have been

identified as being associated with psoriasis • Systemic inflammation due to elevated TNF-α is thought to be the etiology • Associations do not prove causality • “Dose-response” relationships have been shown for: – CV disease – Metabolic syndrome 1Gelfand JM, 2Mallbris 3Langan

et al. J Am Med Assoc 2006;296:1735–41 L, et al. Eur J Epidemiol 2004;19:225–30 SM, et al. J Invest Dermatol 2011 Nov 24. doi: 10.1038/jid.2011.365

Development of arteriosclerotic and psoriatic plaques Endothelial activation, leukocyte migration, smooth muscle cells proliferation microvessel formation Activation Inflammatory mediators: TNF-α, INF-γ, interleukins

Triggers (Genetics, environmental factors) Th1/Th17 cells

Endothelial dysfuction, intima media thickening

?

Activation and hyperproliferation of keratinocytes, leukocyte migration, proliferation, angiogenesis

INF = interferon Adapted from Flammer A, et al. Eur Heart J doi:10.1093/eurheartj/ehr425

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Co-morbidities of psoriasis ESTABLISHED

LESS EVIDENCE

• Cardiovascular (CAD, MI)

• COPD

• Gastrointestinal (Crohn's disease, ulcerative colitis)

• Cognitive impairment

• Malignancy (lymphoma) • Metabolic syndrome (hypertension, obesity, insulin resistance / diabetes, dyslipidaemia)

• Fatty liver • Osteoporosis • Sexual dysfunction • Sleep (abnormal sleep quality, sleep disordered breathing)

• Neurologic (stroke) • Ocular (uveitis, scleritis, episcleritis) • Psychiatric (depression, anxiety, fatigue) Mrowietz U, et al. Poster presentation at the 68th Annual Meeting of the American Academy of Dermatology, March 5–9, 2010, Miami Beach, FL, USA. # P3300

Features of systemic inflammation in psoriasis Psoriasis and many associated co-morbidities share multiple inflammatory processes and a number of susceptibility factors

Psoriasis lesional skin • Gene expression • Cell activation/proliferation • Pro-inflammatory cytokines Non-lesional skin • Similar abnormalities • Sub-clinical presentation

1Azfar,

• Erythema • Induration • Desquamation

• Unknown consequences

RS, and Gelfand, JM, Curr Opin Rheumatol (2008) 20:416–422 and Girolomoni, G, Semin Thrombosis Hemostasis (2009) 35:313–324 KC, and Armstrong, AW, Psoriasis:Targets and Therapy (2012) 2:1–11

2Gisondi, P, 3Pearson,

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Features of systemic inflammation in psoriasis metabolic syndrome co-morbidities Psoriasis and several associated co-morbidities share multiple inflammatory processes and a number of susceptibility factors

Processes in inflammatory co-morbidities • serum pro-inflammatory cytokines, e.g., TNF, IL-6, and others • endothelial inflammation

Metabolic syndrome

• • • • •

hypertension obesity blood glucose triglycerides HDL

Type 2 diabetes Cardiovascular disease

Myocardial infarction

atherosclerosis thrombosis

Stroke

Excess mortality

1Azfar, RS, 2Gisondi,

and Gelfand, JM, Curr Opin Rheumatol (2008) 20:416–422 P, and Girolomoni, G, Semin Thrombosis Hemostasis (2009) 35:313–324 KC, and Armstrong, AW, Psoriasis:Targets and Therapy (2012) 2:1–11

3Pearson,

How does atherosclerosis lead to fatal cardiovascular events in psoriasis patients?

Atherosclerosis • Chronic inflammatory process of the arterial wall • Enlargement of plaque can occlude artery → MI or stroke • Plaque rupture and thrombosis → acute coronary syndrome (ACS) MI or stroke

Arteriosclerosis • Progressive accumulation of cells and debris leads to stiffening of the artery

Thrombosis • Clot formation in arterial wall • Destabilisation, or atherosclerotic plaque rupture, can cause MI or stroke

Adapted from Stedman’s Medical Dictionary, 28th ed., 2006 Adapted from Weber C and Noels H. Nature Med 2011;17:1410–1422

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Excess risk of mortality in psoriasis? Selected results from 3 analyses of 1987–2002 data from GPRD (UK) database1–3 • Excess mortality risk vs controls: Patients with severe psoriasis have 50% increased risk; mild psoriasis have no overall increased risk 1

Percent of subjects

• One extra CV death per 283 PYs (adjusted for major CV risk factors) 2 Age at death by study group3 Controls • Men with severe (n=14,330) psoriasis die Psoriasis (n=3,603)

3.5 years earlier than men without psoriasis1 • Women with severe psoriasis die 4.4 years earlier than women without psoriasis1

Age (years) 1Gelfand J, 3Abuabara

et al. Arch Dermatol 2007;143:1493–1499; 2Mehta NM, et al. Eur Heart J 2010;31:1000–1006; K, et al. Br J Dermatol 2010 163:586–592

Factors influencing the association between psoriasis and systemic disease Psoriatic arthritis

HRQOL (impairment, depression) Obesity

Lifestyle changes (e.g. smoking, alcohol, exercise, diet)

Psoriasis

Biases (e.g. detection, diagnostic bias)

Inflammatory state

Therapy

Co-morbidity

HRQOL, health-related quality of life. Nijsten T, et al. J Invest Dermatol 2009;129:1601–3.

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How the march of psoriasis unfolds from gene to clinic

Genetic factors  Genetic factors drive disease specific process Griffiths &Barker (2007)lancet

Environmental factors  Triggered by environmental factors involving innate &adaptive immunity .

Expression  Leading to disease expression

Comorbidity  Comorbidity results from chronic inflammation

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The Psoriatic March Psoriasis Keratinocytes ↑proliferation ↓Differentiation

Systemic inflammation CRP↑,VEGF↑,P-Selectin↑ Resistin↑,Leptin↑

Insulin resistance Endothelial Dysfunction

Obesity

Continous Effective therapy

NO↓Endothelin↑

Atherosclerosis Adhesion molecules↑ Leucocyte extravasation↑ Coronary artery calcification

Myocardial Infarction

Boehncke et al.2011

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Comorbidities ↑ risk of cardiovascular disease (Hypertension & Heart Failure),metabolic syndrome, diabetes & obesity compared with non-psoriatic skin diseases Psoriasis is an independent risk factor for coronary artery calcification, MI & stroke . The risk associated with psoriasis is greatest in young patients with severe disease and increases with age.

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Psoriatic arthritis • PsA is a multifaceted disease, with several manifestations • The prevalence of PsA increases with increasing extent of skin psoriasis • PsA may go undiagnosed in many patients • Subclinical joint involvement in PsA is common, with the potential for structural joint damage even before clinical symptoms are evident • Patients with PsA tend to more commonly have nail psoriasis, a higher PASI and a higher DLQI

The Clinical Face of Psoriatic Arthritis

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Prevalence of PsA increases with increasing extent of skin psoriasis Degree of skin psoriasis

Prevalence of PsA

All psoriasis patients

11%

No or little psoriasis

6%

1–2 palms of psoriasis

14%

3–10 palms of psoriasis

18%

10+ palms of psoriasis

56%

Gelfand J, et al. J Am Acad Dermatol 2005;53:573–77

Psoriatic arthritis: subclinical joint involvement is common • Structural joint damage may occur before the appearance of clinical symptoms – Using MRI, approximately 2 out of 3 patients with psoriasis had at least 1 arthritic sign: • Appeared before patients experienced clinically evident joint symptoms • Joint damage was detected by x-ray imaging in 1 out of 3 patients

• Patients newly diagnosed with PsA can have joint erosions suggesting an asymptomatic course

• Multidisciplinary (dermatology and rheumatology) therapeutic approach needed to manage patients with PsA MRI = magnetic resonance imaging Offidani A, et al. Acta Derm Venereol (Stockh) 1998;78:463–65 Salvarini C, et al. Curr Opin Rheumatol 1998;10:299–305

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Impact of Psoriasis on QOL

Significant impact on QOL Negative physical impact. Negative psychological impact Stigmatized Insensitive reactions from people

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QOL

Withdrawal, anxiety and depression Very low QOL, worse than patients with stroke, COPD, heart disease & diabetes Survey by the US National Psoriasis Foundation Psoriasis has a moderate to large Impact on QOL in 75% of Psoriasis patients

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QOL Disease severity Age of onset

Factors affecting QOL

Gender Location

Underestimated by disease severity score . Weak association between PASI score and impaired QOL Lesions located on visible body parts |

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Stress-immune reactions and depression Stress Depression

ACTH

Adrenal gland NE ACh

Infection, tissue damage or destruction

TNF IL-1 IL-6

Inflammation Pro-inflammatory cytokines Chemokines Adhesion molecules Acute phase reactants

p38JNK

TLR

Adapted from Raison, et al. Trends Immunol. 2006;27:24–31

ERK

Macrophage

TLR = Toll-like receptors; ACh = Acetylcholine; NE = norepinephrine; JNK = jun amino-terminal kinase; ACTH = adrenocorticotropin; ERK = Extracellular signal-regulated kinase

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Cumulative Life Course Impairment “CLCI “ Cumulative impairment acquired by the psoriasis patient over a life time. Reflects chronic nature of the disease . Repercussions including stigmatization physical &psychological comorbidities Factors playing a moderating role making patient less vulnerable. |

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Cumulative Life Course Impairment “CLCI “ External Factors

Supportive environment

Coping strategies

Personality Style

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Cumulative Life Course Impairment “CLCI “ Patients reported psoriasis had an important influence on major life decisions Choice of work & career

Coping Strategies

Stigma

Physical Psychological comorbidities comorbidities

Personality traits

Education Marriage and having children Early retirement Personality traits

Bhatti et.al 2009,2010,2011

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Egyptian Patients

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Psoriatic arthritis in Egyptian Patients 50 patients with plaque psoriasis without a diagnosis of Ps A attending our psoriasis clinic with or without finger pain were examined by U\S and X-ray

In 80 % of patients ,U\S showed findings consistent with synovitis &or tenosynovitis in at least one finger &X-ray evaluation disclosed structural damage in 8% of patients

Connective tissue damage starts very early before bone damage so U\S is considered a golden tool to detect early psoriatic arthritis.

Study population Overall 1181 questionnaires were completed at university hospitals. SPSS was performed on all patients except those presenting single episode of psoriasis (n=97 patients) and those with missing data or inaccurate history data (n=44 patients). 181 subjects were excluded from the typology development. Some dermatologists reported erythroderma not only for total body area involvement but even for limited lesions. Thus erythroderma data were also excluded from the analysis |

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Description of medical characteristics (comorbidities) among study cases

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14.6

12 10

The table showed that HTN was the commonest co morbidity among cases (14.6%) while lipid disorder was the least frequent among cases (4%)

Lipid disorder High blood pressure Diabetes Hepatic disease

N

%

Yes

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4.0%

No

998

96.0%

Yes

152

14.6%

No

888

85.4%

Yes

96

9.2%

No

944

90.8%

Yes

62

6.0%

No

978

94.0%

Data

9.2

8 6

6

4

3.9 2 0

Comorbidities HTN

DM

Hepatic disease

Lipid Disorder |

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Age of onset

The mean age among study cases was 41.1 ± 18 ranging between 1-81 years.

20% 50% 30%

< 30 years

30 - 49 years

≥ 50 years

Pruritus

52%

Psoriatic Arthritis

27.5% |

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Extra-Cutaneous Manifestations Depression

Cerebrovascular disease

Smoking

Cardiovascular disease

Alcohol

Hypertension

Autoimmune disease

Hyperlipidemia

Psoriatic arthritis

Obesity

Chronic kidney disease

Diabetes

Inflammatory bowel disease Metabolic syndrome Melanoma and non-melanoma skin cancer

Lymphoma

Ps patients are at increased risk of death - 3 to 4 year reduction in life expectancy in patients with severe Ps Devrimci-Ozguven, H. et. al., 2000; JEADV; 14: 267-271. Prodanovich, S. et. al., 2009; Arch. Dermatol.; 145: 700-703. Schön, M. P., Boehncke, W. H., 2005; NEJM; 352: 1899-1912. Gelfand, J. M., et. al., 2007; Arch. Dermatol.; 143: 1493-1499. Gelfand, J. M., et. al., 2006; J. Invest. Dermatol.; 126: 2194-2201. Menter, A., 2010; AAD; W007. Hsu, S., et. al., 2012; Arch Dermatol; 148: 95-102. Menter, A., et. al., 2008; JAAD; 58: 826-850. Gulliver, W., 2008; BJD; 159(Suppl 2): 2-9. Menter, A., et. al., 2008; JAAD; 58: 829-830. Wan, J., et. al., 2013; BMJ; 347: f5961:1-12.

Summary • There is a high prevalence of several systemic co-morbidities in patients with psoriasis, although cause and effect has not been established • Systemic inflammation due to elevated TNF-α is thought to be the etiology of psoriasis and co-morbidities • Psoriasis has been shown to be associated with hypertension, diabetes, hyperlipidaemia, heart disease and depression • The greatest evidence of an association of psoriasis with comorbidities exists for CVD and metabolic syndrome • The interaction between psoriasis and co-morbidities is complex and several other factors may play an important role confounding this association

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