Psoriasis

Aneta Szczerkowska - Dobosz

Psoriasis –epidemiology

Kanada 4,7%

USA 1,4-4,6%

Indianie Płd Am. 0%

Australia 2,6%

Aborygeni 0%

Szwecja 2,3%

Rosja 2,0%

Chiny 0,05-0,8%

Japonia 0,29%

Hiszpania 3,7%

Low incidence: West Africans, Japanese, very low: incidence or absence in North and South American Indians

males = females

Psoriasis –epidemiology

Peak incidence - 22.5 years of age

Late onset (type II) ≈ age 55

Early onset (type I) predicts a more severe and long- lasting disease, positive family history

Psoriasis - history

460-377 p.n.e – Hipokrates first description

129-99 p.n.e – Galen: term „psora” = pruritus

1841 - Ferdinand von Hebra: separated psoriasis from lepra

Psoriasis – genetic background

1963 r. Gunnar Lomhold

1972 r. – HLA: susceptibility markers

1970 - 1990 – twin studies

Genetics of psoriasis

PSORSLokalizacja

PSORS1 6q21.3

PSORS2 17q25

PSORS3 4q34

PSORS4 1q21

PSORS5 3q21

PSORS6 19p13.2

PSORS7 1p35-p34

PSORS8 16q

PSORS9 4q31

2000: susceptibility loci

Genetics of psoriasis

Nair RP. Am J Hum Gen 2006, 78, 827.

Genetics of psoriasis( GWAS, Genome wide association scans )candidate genes

James T. Elder. Genes Immun, 2009, 10, 201.

Polygenic trait

one parent has psoriasis - 8% of offspring develop psoriasis

both parents have psoriasis - 41% of children develop psoriasis

Psoriasis - complex disease

Physical trauma (Koebner phenomenon) isomorphic sign - the psoriatic papules occur in the site of the mechanical trauma within a couple of days

Infections acute streptococcal infection - guttate psoriasis Stress as high as 40% in adults and higher in children Drugs systemic glucocorticoids, oral lithium, antimalarial drugs, interferon, beta blockers (flares existing psoriasis or psoriasiform drug eruption)

Alcohol ingestion, smoking, obesity

PSORIASIS - environmental factors

Nestle F. N Engl J Med, 2009, 361, 496.

Immunopathogenesis of psoriasis – history

1980’:immunological background

1990-2000’:

psoriasis - Th1 /Th17

mediated disease

1961r. van Scott epidermal

hiperproliferation

Immunopathogenesis of psoriasis

Nestle F. N Engl J Med, 2009, 361, 496.

Innate, adaptive immunity

Keratynocytes

Macrophages

Dendytic cells Lymphocytes T

Psoriasis - immunopathogenesis

angiogenesisepidermal

neutrophiles and lymphocytes infiltrations

keratynocytes, endothelium cells

activation

Th 1

Th 17

Treg

INF-γ TNF-α

IL-17IL-22

TNF – α

↓ IL-10 TGF-β

Clinical phenotypes

A. Localised forms B. Generalised forms

Psoriasis of folds Plaque

Seborhoic psoriasis Guttata

Psoriasis capitis Generalised plaque

Psoriasis palmo-plantaris (non-pustular) Erytrodermia

Psoriasis plaque (limbs)

Psoriasis plaque (trunk)

Psoriasis – phenotype classification

International Psoriasis Council 2007

Psoriasis – sides of lesions

Auspitz sign - the appearance of bleeding spots when psoriasis scales are scraped off

The candle grease sign (the removal of the scale reveals the skin with a glossy grease-like appearance

Psoriasis – Koebner sign

Psoriasis -chronic stable type

Sharply marginated, dull-red plaques with loosely adherent, lamellar,

silvery-white scales

Plaques coalesce to form polycyclic, geographic lesions and may partially

regress, resulting in annular, serpiginous, and arciform patterns

Lamellar scaling can easily be removed, or, when the lesion is

extremely chronic, it adheres tightly to the underlying inflammatory and

infiltrated skin, resulting in hyperkeratosis

Psoriasis -chronic stable type

Finger nails and toenails frequently involved (arthritis)

pitting subungual hyperkeratosis, onycholysisyellowish-brown spots under the nail plate—the oil spot (pathognomonic)

Psoriasis – nails

One of the most common forms of the disease-occurring in 50-80% of patients, it is often the first clinical manifestation of the dermatosis. They are usually located at the border between the glabrous skin and the hairy scalp, forming the so called "psoriatic crown".

Plaques, sharply marginated, with thick adherent scales Scattered discrete or diffuse involvement of entire scalp,

Scalp psoriasis may be part of generalized psoriasis or coexist with isolated plaques, or the scalp may be only site involved.

Psoriasis – scalp

Uncommonly involved

when involved, usually associated

with a refractory type of psoriasis

Psoriasis -face

not scaly but macerated, bright red and fissured the sharp demarcation - distinction from intertrigo, candidiasis, contact dermatitis, tinea,

this form is seen rarely in clinical practice. It occurs in 3 to 6.8% of all patients with psoriasis, and if it is the only clinical presentation it may cause difficulties in getting the correct diagnosis. Scales are not found in the psoriasis of the skin folds, but maceration

and secondary infections are seen.

Chronic Psoriasis of the Perianal and Genital Regions and of the Body Folds – Inverse Psoriasis

Acute Guttate Type

• Salmon-pink papules (guttate: Latin gutta, "drop"), 2.0 mm to 1.0 cm with or without scales

• Scattered discrete lesions generally concentrated on the trunk, less on the face and scalp, usually sparing palms and soles

• Guttate lesions may resolve spontaneously within a few weeks but usually become recurrent and may evolve into chronic, stable psoriasis

Acute guttate type

Napkin psoriasis

Psoriasis palmo-plantaris

Palms and Solesmay be the only areas involved

massive silvery white or yellowish hyperkeratosis and scaling not

easily removed

there may be cracking and painful fissures and bleeding

Pustulosis palmo-plantaris (PPP)

Pustulosis palmo-plantaris (PPP)

Pustules in stages of evolution, 2–5 mm, deep-seated, yellow, develop into dusky-red macules and crusts; present in areas of erythema and scaling or normal skin Limited to palms and soles, may be only a localized patch on the sole or hand, or involve both hands and feet

Pustulosis palmo – plantaris

Psorasis ? Distinct entity?

PPP

PPP - Genetic studies

Asumalahti i inni.: J Invest Dermatol 2003, 120. Mossner R i inni.: J Invest Dermatol 2005, 124, 282-284.

PPP

Clinical observations:

Females: 90%Age onset: V-VI decade of lifeNicotine – trigger factor 95%

Generalized Acute Pustular Psoriasis (Von Zumbusch)

Fever, generalized weakness, severe malaise

Rare

The constellation of fiery-red erythema followed by formation of pustules occurs over a period of less than 1 day

Patient frightened, "toxic.„

Nikolsky phenomenon - positive

Pustules are sterile

The eruption generalized

Psoriatic erytrodermapsoriasis is one of the most

common causes of erythrodermia in adults, it can

arise anew or complicate chronic plaque psoriasis (often

if the treatment is not appropriate). Inflammation with dandruff-like scaling involving the whole skin surface, accompanied by elevated leukocyte count,

elevated ESR, and lymphadenopathy

Psoriatic arthritis

seronegative spondyloarthropathies, which include ankylosing spondylitis, enteropathic

arthritis, and reactive arthritis

Incidence is 5–8%. Rare before age 20

May be present (in 10% of individuals) without any visible psoriasis; if so, search for a family

history !

Psoriatic arthritis

Types

"Distal"—seronegative, without subcutaneous nodules, involving, asymmetrically, a few distal interphalangeal joints of the hands and feet: an asymmetric oligoarthritis.

Enthesitis—inflammation of ligament insertion into bone.

Multilating psoriatic arthritis with bone erosion and ultimately leading to osteolysis or ankylosis.

"Axial"—especially involving the sacroiliac, hip, and cervical areas with ankylosing spondylitis.

Psoriatic arthritis

Skin symptoms and signs

Swelling, redness, tenderness of involved joints or site of enthesitis (e.g., insertion of Achilles

tendon in calcaneus)

Dactylitis—sausage fingers, May or may not be associated with psoriasis elsewhere.

Often psoriatic involvement of fingertips and periungual skin. Massive nail involvement by

psoriasis is frequent

Arthritis may lead to arthritis mutilans: destruction of interphalangeal joints results in telescope fingers with mutilation of hand and

considerable functional impairment

PSORIASIS

RA, AS

Crohn disease, Colitis

ulcerosa

PSORISIS as chronic inflammatory systemic disease

CISD

I. Common ganetic background

II. Pathogenesis/efficacy of pathogenesis based treatment

III. CVD risk

I. CISD – common genetic background

Gen Chromosom Skojarzone choroby

IL-12B 5q Łuszczyca, Ch. Crohna

IL-23R 1p Łuszczyca, Ch. Crohna, ZZSK, łzs

CDKAL1 6p Łuszczyca, Ch. Crohna, cukrzyca typu 1

PTPN22 18p Łuszczyca, RZS, SLE, cukrzyca typu 2

Region genów rodziny IL-4 IL-13

5q Łuszczyca, Ch. Crohna

II. CISD -common pathogenesis Th1/Th17 mediated immunological responce

Role of TNF-α

Role of DC

Endothelium dysfunction

Oxidative stres

Inflammatory markers in circulation

Psoriasis / atheromatosis – common pathogenesis

Spach F. Br J Dermatol 2008, 159, 10. łuszczyca miażdżyca

Environmental factors associated with psoriasis

Nicotine

Alkohol

Low physical activity

Psoriasis comorbidities increasing risk of CVD

Metabolic syndrom

Associated with systemic inflammatory disease

ObestityDiabetes HiperlipidemiaHypertension

Psoriasis and obesity

Hamminga EA i inni. Med. Hypoth 2006, 67, 76.Johnson A i inni. Br J Dermatol 2008, 159, 342.

Obesity 2x increases psoriasis risk

BMI correlates with psoriasis severity

Psoriasis and diabetes

Psoriatics have diabetes more often

Role of TNF-α in insuline resistence

Significant correlation of resistine in blood with psoriasis severity

Cohen A. J Am Acad Dermatol, 2007, 56, 629.

Psoriasis and atherogenic dyslipidemia

Rocha-Pereira i inni. Clin Chim Acta 2001, 303, 33.

↑ LDL, VLDL, TG, cholesterol, ↓HDL in psoriatics

LDL correlates with psoriasis severity

Oxydative stres accelerates atherogenesis

Side effect of antipsoriatics drugs on lipide profile

Psoriasis and hipertension

Hypertension more often in psoriatics

Side effect of antipsoriatics drugs

Cohen A. J Am Acad Dermatol , 2006, 55, 829.

Psychosocial impact of psoriasis

Stygmatisation

J Am Acad Dermatol. 1999 Sep;41(3 Pt 1):401-7.

Depression: 60 %

Suicidal tendency: 7,2 %

Psychosocial impact of psoriasis

Esposito M. Dermatology, 2006, 212,123. Gupta M. Br J Dermatol 1998, 139, 846.

thickening of the epidermis (acanthosis) and thinning of epidermis over elongated dermal papillaeIncreased mitosis of keratinocytes, fibroblasts, and endothelial cellsParakeratotic hyperkeratosis (nuclei retained in the stratum corneum)Inflammatory cells in the dermis (lymphocytes and monocytes) and in the epidermis (lymphocytes and polymorphonuclear cells), forming microabscesses of Munro in the stratum corneum.

Psoriasis - laboratory examinationsdermatopathology

Psoriasis - laboratory examinations

Serology

Increased antistreptolysin titer in acute guttate psoriasis with antecedent

streptococcal infection. Sudden onset of psoriasis may be associated with HIV

infection

Culture

Throat culture for group A -hemolytic streptococcus infection.

Psoriasis treatment – factors selection of treatment

1.Age: childhood, adolescence, young adulthood, middle age, >60 years

2.Type of psoriasis: guttate, plaque, palmar and palmopustular, generalized pustular psoriasis, erythrodermic psoriasis

3.Site and extent of involvement: localized to palms and soles, scalp, anogenital area, scattered plaques but <5% involvement; generalized and >30% involvement

4.Previous treatment: ionizing radiation, systemic glucocorticoids, photochemotherapy (PUVA), cyclosporine (CS), methotrexate (MTX)

5.Associated medical disorders (e.g., HIV disease, CVD).

Psoriasis – local treatment

emolients and keratolytics anthralin vitamine D analogues topical steroids topical retinoids

Emmolients and keratolytics

• preparations containing salicylic acid (5-10%)

• urea craems

Anthralin (dithranol)usual concenrations 0.1-2%

efficacy- good in a short term

side efects: irritation

hypersensitivity, staining of nails and hair

contraindication: acute or actively inflamed psoriasis

Calcipotriene (vitamine D derivative)

benefit in mild to moderate psoriasis

combination of calcipotrene with topical steroids

provides better clearance and maintenance

may cause skin irritation

should not be used by patients with hypercalcemia or vitamine D toxicity

Topical steroidsshort period of up to 4 weeks for flexural or facial psoriasis

long-term use must be avoided - side effects:- atrophy- striae-teleangiectasia- skin fragility- dyspigmentation- systemic side effects !

Topical retinoids

Tazarotene

indicated for mild to moderate psoriasis risk: skin irritation - desquamation, pruritus, burning, stinging, dryness, discoloration

Systemic treatment

Classic

MtxCyARetinoids

Fotochemotherapy

Biologics

TNF inhibitorsIL-23/IL12 inhibitorsAnty lymphocyte

Psoriasis - treatment

oral ingestion of 8-methoxypsoralen (8-MOP) (0.6 mg 8-MOP per kilogram body weight) or, 5-MOP (1.2 mg/kg body weight) and exposure to doses of UVA that are adjusted to the sensitivity of the patient. three times a week. most patients clear after 19 to 25 treatments, and the amount of UVA needed ranges from 100 to 245 J/cm2.

Long-term side effects:

PUVA keratoses and squamous cell carcinomas

Oral PUVA Photochemotherapy

Oral retinoids in psoriasis

• Acitretin usual range 25-50mg/day very effective in inducing desquamation but only moderately effective in suppressing psoriatic plaques (an exception is pustular psoriasis

• They are highly effective when combined according to established

protocols with 311-nm UVB or PUVA (called Re-PUVA) • Contraception is mandatory during treatment and for 2 years after it is

completed • Combinations of oral retinoids and PUVA improve the efficacy of each and

permit a reduction of the dose and duration of each if refractory to treatment

Psoriasis – retinoids- side effects

• teratogenic - women of childbearing age should use contraception during and for two years after therapy!!!

• ro-dermatitis: eyes, ears, nose and throat: cheilitis, dry eyes and nose, conjunctivitis

• abnormal liver function tests, hipertriglyceridemia, hiperglycemia

• muscosceletal: arthralgia, myalgia

• central nervous system: dizziness, fatigue, headache

Psoriasis - retinoids - patient information

therapeutic effect after 2-4 week

avoid pregnancy for one month before and 2 years after treatment

avoid tetracycline

don’t donate blood one year (teratogenic effect)

avoid excessive sunlight !

Cyclosporine in psoriasis

CS treatment is highly effective at a dose of 3–5 mg/kg per day. As the patient responds, the dose is tapered to the lowest effective maintenance dose. Monitoring blood pressure and serum creatinine is mandatory because of the known nephrotoxicity of the drug. CS should be employed only in patients without risk factors.

!

Psoriasis – antibacterial interventions

antistreptococcal interventions - antibiotics and tosillectomy - guttate psoriasis

Methotrexate Therapy

Schedule of Methotrexate: the single-dose MTX once weekly (12.5-25 mg/ week)

80% improvement but total clearing only in some, and higher doses increase the risk of toxicity. Higher doses may be needed in overweight patients

CBC, Liver Function Contraindications:

anemia, thrombocytopenia or leukopenianursing mothers, pregnancy (avoid conception for 6 month after stopping men and women)gastric or duodenal ulcer

Lancet. 2002 Apr 6;359(9313):1173-7.

alkohol intake

abnormal liver parameters

liver disease in anamnesis

positive familial anamnesis into genetic liver diseases

diabetes

obesity

significant exposure into chemical substances

no folic acid suplemmentation

hiperlipidemia

Risk factors of liver damage in patients treated with mtx

Liver damage after Mtx in psoriatics

Fibrosis cirrhosis

Histological features of NAHS (non-alkoholic hepatic steatosis)

Liver toxicity in patient treated with mtx – cumulative dose

Patients with risk factors

1,5 g Mtx

Patients with no risk factors

3,5-4 g Mtx

Biologicals in psoriasis – antilymphocyte

Anty – TNF

infliksimab

adalimumab

etanercept

Anty – IL-12 IL-23

ustekinumab

Biologicals in psoriasis – antycytokines

Specifity

Short and long term efficacy

↓ organ toxicity

↓risk of drug interactions

Cardioprotective action

Biologics in psoriasis

Risk of infection

Risk of neoplasms ?

moAb antibodies

Long-term efficacy?

Costs

Biologics in psoriasis

Psoriasis - prevention

no effective preventive measures to be taken against the development of psoriasis flare-ups may be potentially reduced by modificationof risk factors – infections, stress, drugs, smoking, alkohol

interaction alert!

beta-blockers for hypertensives may cause the flare of psoriasis

Psoriasis prognosis

debilitating disease due to psychosocial impact

genaralized pustular psoriasis and erythrodermic psoriasis may be life-threatening if untreated

course of disease is chronic and may be refractory to treatment

5-8% of patients with psoriasis may develop psoriatic arthropathy

Th1 i Th17 in psoriasis pathogenesis

Psoriasis as a systemic disease decreasing QL

Severe psoriasis as a risk factor of CVD

Pathogenesis based therapy

Lichen planus

acute or chronic inflammatory dermatosis

involving skin and/or mucous membranes

Lichen planus – epidemiology

Worldwide occurrence; incidence < 1%, all racesAge of Onset: 30–60 yearsSexFemales > malesHypertrophic LP more common in blacks

LP-onset

Acute (days) or insidious (over weeks). Lesions last months to years, asymptomatic or pruritic; sometimes severe pruritus. Mucous membrane lesions are painful, especially when ulcerated

LP-etiologyIdiopathic in most cases but cell-mediated immunity plays a major role. Majority of lymphocytes in the infiltrate are CD8+ and CD45Ro+ (memory) cells. Drugs, metals (gold, mercury), or infection [hepatitis C virus (HCV)] result in alteration in cell-mediated immunity. There could be HLA-associated genetic susceptibility that would explain a predisposition in certain persons. Lichenoid lesions of chronic graft-versus-host disease (GVHD) of skin are indistinguishable from those of LP

Lichen planus - distribution: predilection for flexural aspects of arms and legs, can become generalized

LP – clinical manifestationPapules, flat-topped, 1 to 10 mm, sharply defined, shiny. Violaceous, with white lines (Wickham striae), seen best with hand lens after application of mineral oil. Polygonal or oval. Grouped, annular, or disseminated scattered discrete lesions when generalized. In dark-skinned individuals, postinflammatory hyperpigmentation is common. May present on lips and in a linear arrangement after trauma (Koebner or isomorphic phenomenon).

LP - variantsHypertrophicAtrophicFollicularIndividual keratotic-follicular papules and plaques that lead to cicatricial alopecia. Spinous follicular lesions, typical skin and mucous membrane LP, and cicatricial alopecia of the scalp are called Graham Little syndromeVesicularVesicular or bullous lesions may develop within LP patches or independent of them within normal-appearing skin. PigmentosusHyperpigmented, dark-brown macules in sun-exposed areas and flexural folds. In Latin Americans and other dark-skinned populations. Significant similarity with ashy dermatosisActinicusPapular LP lesions arise in sun-exposed sites, especially the dorsa of hands and armsUlcerativeLP may lead to therapy-resistant ulcers, particularly on the soles

LP - Mucous Membranes

Oral40–60% of individuals with LP Reticular LPReticulate (netlike) pattern of lacy white hyperkeratosis on buccal mucosa lips, tongue, gingiva; the most common pattern of oral LPErosive or Ulcerative LPSuperficial erosion with/without overlying fibrin clot; occurs on tongue and buccal mucosa); shiny red painful erosion of gingiva (desquamative gingivitis) or lips Carcinoma may very rarely develop in mouth lesions.GenitaliaPapular, annular, or erosive lesions arise on penis (especially glans), scrotum, labia majora, labia minora, vagina.

LP- nails

Destruction of nail fold and nail bed with longitudinal splintering

LP-treatment

CyclosporineOral prednisone is effective for individuals with symptomatic pruritus, painful erosions, dysphagia, or cosmetic disfigurement. A short, tapered course is preferredSystemic Retinoids (Acitretin)1 mg/kg per day is helpful as adjunctive measure in severe (oral, hypertrophic) cases, but usually additional topical treatment is required.PUVA PhotochemotherapyIn individuals with generalized LP or cases resistant to topical therapy.