Etiopathogenesis of Psoriasis

8/11/2019 Etiopathogenesis of Psoriasis

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Which is the least important in

pathogenesis of psoriasis?A. IL 12

B. IL 23

C. IL 17D. IL22


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c o ese asn een

implicated in the pathogenesis of

psoriasis?A. Staph aureus

B. Chlamydia spp.

C. Candida albicansD. Bordetella pertussis


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Which of the following is false?A. Canthelicidin levels increase in psoriatic plaques

B. TLR 1 has been implicated in pathogenesis of

psoriasisC. Frequency of psoriasis in HIV patients remains

unchanged compared to normal population

D. Vit D3 analogues act at multiple steps in

pathogenesis of psoriasis


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Presenter Dr. Gagandeep Singh

Moderator- Dr. Amit Dhawan


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Etiology

Intrinsic factors External factors

Pathogenesis


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Evidence supporting genetic

factors +ve family history- 35-90 % of patients, series dependent Lomholtsclassic epidemiological study -Faroe Islands

(1963), more than 10 000 inhabitants, incidence of psoriasis

much greater amongst first-and second degree relatives ofsufferers German survey- probability of diseased child

both parents affected 41 %single parent 14%sibling 6%

Danish Twin registry and Farther & Nall concordanceanalysis in twins monozygotic 82/141 + similar clinical featuresdizygotic 31/155

Linkage analysis family pedigrees - polygenic


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Henseler and ChristophersTYPE I TYPE II

Hereditary Sporadic

Strongly HLA associated

(particularly HLA-Cw6)

HLA

UnrelatedEarly onset Late onset

More likely to be severe Usually mild


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Haplotypes Association with certain HLA-types

HLA-Cw6

HLA-B13

HLA-B17HLA-Bw57

HLA-DR4

PSORS1 in the MHC region on chromosome 6 (6p21)associated with most cases of psoriasis.


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GENETIC LOCI LINKED TO

PSORIASIS

PSORS16p21.3

PSORS217q25

PSORS34q3235

PSORS41cenq21

PSORS53q21

PSORS619p13q13

PSORS71p35

34

PSORS816q1213

PSORS94q3134

PSORASI16q12


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Psoriasis, an inherited diseaseIf you have psoriasis, what is the risk to:

Your unrelated neighbor? About 2%Your sibling? 15-20%

Your identical twin? 65-70%

Your child? 20%- one parent75%- both parents


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InfectionStreptococcal infection is strongly

associated with guttate and chronic plaque

type of psoriasis HLA-Cw6HIV - severe psoriasis

psoriatic arthropathy

poor prognosisfrequency unchanged


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Disease exacerbation has been linked with skin and/or gutcolonization by

Staphylococcus aureus

MalasseziaCandida albicans- dendritic cells produce IL-23 when

stimulated by infection with Candida albicans, and thisevent is mediated by dectin-1, a C-type lectin receptor

Toll-like receptor (TLR) 4 signaling induced by

lipopolysaccharide from Bordetella pertussis

The role, if any, of viruses (papillomaviruses, HIV, andendogenous retroviruses) present in lesional skin is atpresent unknown


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Drugs exacerbating psoriasisDrug aggravated or drug induced

Beta blockers beta 2 mediated cAMP depletion

Lithium- IMP depletion

Antimalarials- Transglutaminase inhibition Steroid withdrawal

NSAIDS

ACE Inhibitors

Tetracyclines Interferons

Terbinafine

Benzodiazapines


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Digoxin

Clonidine

Amiodarone

Quinidine

Gold

TNF alpha inhibitors

Imiquimod

Fluoxetine

Cimetidine

Gemfibrozil


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Sunlight Generally beneficial

May provoke

40% -history of polymorphic light eruption (PLE) withpsoriasis as a secondary phenomenon

severely photosensitive psoriasis

predominantly female

distinct from PLEHLA-Cw6

family history

early age of onset


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Smoking

First study linking 1985 3 out of 4 studies have implicated increased risk

esp. in CPP More inwomen. Polymorphonuclear cells- altered by smoking. Keratinocytes possess nicotinic cholinergic

receptorswhich stimulate calcium influx andaccelerate cell differentiation. Oxidative tissue damage

Clinical and experimental derm.2005


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Alcoholism

Young & middle aged.

Increased infection and trauma.

Decreased therapeutic compliance.Metabolic & immunological effect

1. Suppression of cell-mediated immunity.

2. Enhancement of mitogen drivenlymphocyte proliferation.

3. Up-regulation of pro-inflammatory

cytokine.


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Stress and Psoriasis Psychoneuroimmunology : emotional states can

alter immune responses in body.

Onset and increased severity closely related tostress.

Psychoneural Hypothesis : stressful life events increase substance P influence inflammation

( endogenous Koebnerisation )

Decreased compliance and self care

IJD 2005


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Diet, Metabolism & PsoriasisAssociation with metabolic syndrome and

hypocalcemia Fasting periods, low energy diets and vegetarian

diets improved symptoms. Diets rich in PUFA from fish oil beneficial Influence the eicosanoid profile Patients with antigliadin antibodies improve on a

gluten-free diet.Vitamin D exhibits anti proliferative and immuno

regulatory effects.BJD 2005


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Metabolic syndrome &

psoriasis The National Health and Nutrition Examination

Survey, 2003-2006

prevalence of metabolic syndrome

40% among psoriasis cases23% among controls

2008 US census data, the projected number of patientswith psoriasis aged 20 to 59 years with the metabolic

syndrome was 2.7 million most common feature- abdominal obesity

hypertriglyceridemialow levels of HDL


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Overlapping inflammatory pathways and geneticsusceptibility

Dose-response relationships between more severepsoriasis and higher prevalence of metabolic syndromecomponents

Number of common inflammatory markers are oftenincreased in patients e.g. C-reactive protein, interleukin(IL)-6, tumour necrosis factor (TNF)-

Increased homocysteine levels Inflammation shown to be a key factor in atherogenesis Psoriasis is an inflammatory disease that is associated with

atherosclerosis, similar to the association of atherosclerosisand systemic lupus erythematosus and rheumatoidarthritis.


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Pregnancy Th-2 cytokine mediated down-regulation of the

immune response by virtue of its anti-inflammatoryand antagonizing effects on the Th-1 cytokines

improves psoriasis.

Th-1 cytokines (IL-2, IFN,TNF- alpha) are elevated in

early postpartum leading to exacerbation of thedisease activity.


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History Prior to 1980s biochemical hypothesis ; defect

presumed to be at keratinocyte level

Post cyclosporine immunopathogenesis; T cellmediated

Current hypothesis-POLYGENIC INFLAMMATORY EPITHELIAL

DISEASE Innate immune system- epidermis

Adaptive immune system- T cells


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Evidence for T cell mediation Early influx of T cells into expanding lesions

Strong association with the MHC, particularly HLA-Cw6

Ablative (albeit temporary) effect of anti-T-cell therapy

Increased antigen presentation in psoriatic plaques

Anecdotal evidence of development of psoriasis aftersyngenic bone marrow transplant

Change in phenotype to lesional psoriatic skin in non-lesional psoriatic skin transplanted on to severe combinedimmunodeficient mice and injected with autologous T cells


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? Antigen-specific response?? nature of the antigen involved

Evidence of an antigen-specific response(i) limited clonality of infiltrating T cells

(ii) persistence of T-cell clones in plaques over severalyears

(iii) identical T-cell clones in tonsils and skin of patientswith Streptococcus-associated psoriasis


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Key events

T cell activation-

accumulation of inflammatory cells, particularlyneutrophils and T lymphocytes

Epidermal hyperproliferation & loss of

differentiation

Angiogenesis-dilatation and proliferation of dermal blood vessels


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34

DERMIS

STRATUM

BASALE

STRATUMSPINOSUM

STRATUM

GRANULOSUM

STRATUM

CORNEUM

Proliferation

Immaturity

Neutrophilaccumulation

DisorganizedNO

RMA

L

PS

ORIASIS


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SENSITISATION PHASE

DCs process and present antigens, development of skininfiltrating effector memory Th17 and T1 cells .Is notaccompanied by any skin alterations.

SILENT PHASE

EFFECTOR PHASE

(i) skin infiltration of immune cells

(ii) immune cell activation in the skin and

(iii) keratinocyte response


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IL-17A

signaling activates both the nuclear factorBand mitogen-activatedprotein kinase intracellular pathways

has pleiotropic effects, but its main effect is recruitment andactivation of neutrophils

able to directly inhibit apoptosis of neutrophils in inflamed tissues

also enhances angiogenesis and mediates tissue remodeling bystimulating the production of angiogenic factors and matrixmetalloproteases

synergizes with TNF- to enhance inflammation,causing the release of IL-6, TNF-, and IL-1


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IL 22 induces keratinocyte hyperproliferation in vitro and in

vivo; this effect is mediated through Stat3 signaling

also stimulates keratinocytes to secrete antimicrobialpeptides

causes keratinocytes to produce matrixmetalloproteinase 1, which is involved in tissueremodeling


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Transcription defects in psoriasis large number of alterations of cytokine and growth factor

profiles within psoriasis - genetic aberration in psoriasis is quitebasic- proximal to the common element in the cascade ofinflammatory events that lead to a lesion of psoriasis

Defect in transcription regulatory elements associated with oneor more cytokines (or growth factors). This mutation could occur

(1) in the regulatory element itself;

(2) in the receptor, which binds both ligand and regulatoryelement;

(3) in the ligand (cytokine or growth factor); or

(4) in a gene responsible for the control of proliferation that isunder the influence of the sites mentioned in 1, 2, and 3


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Innate immunity, Vitamin D &

Psoriasis A significant component of the innate immune system is a

group of antimicrobial peptides (defensins, cathelicidins,e.g. LL-37)

Transcription factor - vitamin D receptor Recent studies have shown that clinical response of

psoriasis to 1,25-dihydroxyvitamin D3is correlatedwith the vitamin D receptor mRNA expression level

Journal of Investigative Dermatology(1999) 104 patients -A significant association between vitamin D receptorgenotypes and the mean age at onset was observed


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Effect Study type

Topical treatment with calcitriol or analogs(calcipotriol) exerts antiproliferative and

differentiation-inducing effects in epidermalkeratinocytes of lesional psoriatic skin.

Immunohisto-chemical in situ analysis ofpsoriatic skin

In dendritic cells, calcitriol suppresses expressionof MHC II molecules and of costimulatory

molecules including CD40, CD80 and CD86.Production of IL-10 is stimulated and productionof IL-12 is inhibited, leading to a suppression of T-

cell activation.

In vitro experiments

Vitamin D analogs suppress IgE-production andIgE-mediated cutaneous reactions.


Calcitriol induces the expression of the CCR-10receptor on the surface of T-cells, which leads to a

migration of these T-cells towards CCL-27-expressing epidermal keratinocytes.


Physiological concentrations of 1,25-dihydroxyvitamin D3generate in keratinocytes

apoptosis-resistance against ceramides, ultravioletradiation and tumor necrosis factor (TNF). Incontrast, pharmacological concentrations of 1,25-dihydroxyvitamin D3(10

6M) induce apoptosis.



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T helper 17 cells, produce IL-17. These Th17 cellsaccumulate in some sites of inflammation, such aspsoriasis

may contribute to LL-37 production, as well as apoptosis ofkeratinocytes in the thickening skin of psoriasis plaques

DNA is released from keratinocytes in psoriatic skin

This host DNA binds the antimicrobial peptide LL-37

The LL-37/DNA complex mimics bacterial DNA andtriggers the Toll-like receptors (TLR) on the surface ofimmune cells, dendrocytes, to activate NFkB, thetranscription factor controlling inflammation


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Caveolin-1 is a key structural and functional protein forplasmalemmal invaginations termed caveolae

loss of caveolin-1 within epidermal keratinocytes may

contribute to the development and/or progression of thepsoriatic phenotype

KC have inherent defects in intracellular signalling whichcould be usefully targeted to allow the development ofmore effective therapies

peroxisome proliferator-activated receptors, the notchreceptor and defects in calcium and other ion transportingproteins may contribute to impairment in the ability ofpsoriatic KC to differentiate


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Adipokines & psoriasis ? Missing link between psoriasis & comorbidities

Levels of adiponectin & leptin found to be increased inpsoriasis & psoriatic arthritis

Correlates with increased burden of skin & jointinflammation and with Th 17 cytokines


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Future implications ? levels of IL-22 could be used as a diagnostic &

prognostic marker for psoriasis, as these levelscorrelate with disease severity

if IL-22 was found to be the major circulating factorthat induces keratinocyte proliferation, targeting thismolecule would be a therapeutic strategy forindividuals with psoriasis

if IL-22 was the main inducer of Stat3 in psoriatickeratinocytes, this cell-signaling molecule would alsobe an attractive target for therapeutic development


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monoclonal antibodies directed against p40 have producedstriking clinical results in psoriasis patients. Thesepromising phase 2 studies have led to large-scale,ongoing

phase 3 trials in patients with moderate-to-severe psoriasis. Although these drugs were initially developed to target IL-

12, many scientists now believe that blocking the biologicactivity of IL-23 is the main mechanism for the clinical

activity of anti-p40 monoclonal antibody therapy inpsoriasis.

Is blocking IL-23 aloneby using monoclonal antibodiesdirected against p19is sufficient to improve psoriasis?


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Psoriatic arthritis10-15 % of patients with psoriasis

CD8+ T cell driven

3 main affected sites 1) Enthesis

2) Synovium of peripheral synovialjoints

3) Spine & sacroiliac joints


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Stages of pathogenesis1. Genetic predisposition

2. Triggering of T cells3. Overt joint inflammation &

injury


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HLA Associations

B27B38B39B13B57Cw6

Psors1 Inheritance may simulate incomplete

penetrance or recessive mode


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Pediatric psoriatic arthritis-

2 subsets-

11-12 years 2-4 years

predominantly female

Lower association with HLA B27 & Cw6

Positive ANA

Chronic anterior uveitis


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BIOLOGICAL MECHANISM CLINICAL STATUS

Etanercept Anti TNF alpha Approved

Infliximab Anti TNF alpha ApprovedAdalimumab Anti TNF alpha Approved

Elefacept Anti LFA3 fusion protein Approved

Efalizumab Anti CD11A Approved

Ustekinumab Anti IL12/23 Approved

Secukinumab Anti IL17 Phase III

Anti p40 Anti p40 (IL 23 subunit) Phase III

Humax CD4 Anti CD4 Phase II

CTLA4Ig Anti CD28 & CD152 Phase II

CNTO-1275 Anti IL126 Phase IIOnercept Anti TNFbp17 Phase II


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Bibliography

Rooks textbook of dermatology

Fitzpatricks dermatology in general medicine

Bologniasdermatology

Articles from IJD, IADVL, BJD

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Etiopathogenesis of Psoriasis

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