psoriasis
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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.
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