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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.
In vitro experiments
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.
In vitro experiments
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.
In vitro experiments
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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