María Carmen OvejeroBenito PhD covejerosaludmadridorg Clinic Pharmacology Department Hospital Universitario de La Princesa Madrid Spain Psoriasis is a clinical heterogeneous ID: 934784
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Slide1
Polymorphism that can predict the response to anti-TNF drugs in psoriasis patients
María Carmen Ovejero-Benito,
PhD
covejero@salud.madrid.org
Clinic
Pharmacology DepartmentHospital Universitario de La PrincesaMadrid (Spain)
Slide2Psoriasis is a clinical heterogeneous skin disease Types of psoriasisPustulous: white blisters of noninfectious pus surrounded by red skinInverse: bright-red lesions that are smooth and shinyGuttata: small, pink, individual spots on the skinErythrodermic:
widespread, fiery redness of the skinPlaque psoriasis: raised, inflamed, red lesions covered by silvery white scales.
Slide3Psoriasis ranges with multiple comorbidities Arthritic psoriasisCardiovascular diseasesDepression(
Egeberg , 2016)
Slide4It affects 2-3% population world-wide altough it varies with
ethnicity and the geographic location.Psoriasis
epidemiology
Slide5Psoriasis is affected by genetic and environmental factorsGenetic predisposition
PSORS1 HLA-Cw6
Triggering factors Traumatism UV lights InfectionsEndocrine alterations Stress Alcoholism
Slide6Severity of this disease is measured by Psoriasis Area and Severity Index (PASI)
Mild psoriasis PASI<10 Moderate-to-severe psoriasis PASI>10
IndurationDescamationEritrema
Slide7LL37
Synovial fibroblast
Aberrant activation of
osteoclast
in
RA
Joint erosion
Matrix –degrading proteases
Protanoids
IL-6
IL-8
GM-CSF
IL-1B, IL23
IL-6
pDendritic cell
Intestinal fibroblasts
IL-13
TGF-
β
Fibrosis,
structure
formation
in
CD
TNF-
α
Matrix
degradation
,
epithelial
damage
,
endothelial
activation
,
vascular
disruption
in
CD
IL-1, IL-6
Osteoclast
Bone
resorption
in
PsA
.
Dendritic cell
INF-
α
CD8
Disease
associated
genes
Stressed
cells
LTh17
Environment
Stress
Microorganisms
Drugs
Trauma
Neutrophil
CXCL1
CX3
CXCL5
CXCL8
IL-1B
IL 23
IL6,
IL-6
TNF-
α
LTh1
β
d
efensin
β
d
efensin 2
S100A7
S1009
Inflammation
is
an
important
component
of psoriasis
Slide8Anti-TNF drugs are an effetive treatment for moderate-to-severe psoriasisEtanercept Human p75 Fc fusion protein Infliximab Chimeric monoclonal (IgG1)
Adalimumab Human monoclonal (IgG1)
Slide9Advantages of the use of anti-TNF drugsAdvantagesHigh efficiency. They achieve PASI75 (a decrease of 75% with respect
to basal PASI) in 3 months.SafetyDisadvantages
CostIndividual variability of drug efficacy Long term toxicity
Slide10Single nucleotide polymorphisms are small variations located in the DNA
Slide11PharmacogeneticsPharmacogenetics The main objective is to
reach personalized medicineOptimize drugs efficiency,Limite drug toxicity,
Reduce costs,Improve life quality. Disadvantages: Personalization could not reach 100% as environmental factors are also involved (infections and stress).Advantages: genotype does not vary along lifetime. It is only neccesary to determine one.
Slide12Basal
PASI
NR Responders: 58Anti-TNF drugsetanerceptinfliximabadalimumab2º Therapeutic option secukinumab ustekinumabNRR Objetive: to identify a epigenetic marker that can differentiate between R and NRDo they reach PASI75?(a decrease of 75% respect basal PASI) Non-Responders: 20
Slide13New polymorphisms associated to anti-TNF drugs in patients with moderate-to-severe plaque psoriasisrs2916205 (PGLYRP4-24)rs9304742 (ZNF816A) rs11126740 (CTNNA2)rs2546890 (IL12B)rs12191877 (HLA-C)rs96844 (MAP3K1)
Prieto-Pérez et al., 2016 New polymorphisms associated to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis. Pharmacogenomics J 2016
Slide14Experimental design
Selection
of polymorphisms (SNPs)A total of 144 have been analysed related to immunopathogenesis of psoriasis > 270 Genes seleted
Slide15Experimental design
Moderate-to-severe
psoriasis patients treated with biologic drugs (≥ 12 sem.).Informant consent3 ml EDTAMagNa Pure (Roche) ADN - 80ºC81 PATIENTS
Slide16MethodsSNP StatsThese SNPs are not in linkage disequilibrium between them. All SNPs are in Hardy-Weinberg equilibrium except rs1800896, rs848 and rs1800795.
Slide17Demographic of the population analysed Patients (N=78)
Responders (N=58)Non-responders(N=20)Age at onset psoriasis (years)
30.0 ±16.329.2 ± 15.527.53 ± 13.53Men (%)39 (50)27 (46.6)12 (60)Women (%)39 (50)31 (53.4)8 (40)Weight (Kg)76 ± 1476.1 ± 14.776.6 ± 13.7Psoriasis Type I (%)¹61 (78.2)47 (81)14 (70)Psoriasis Type II (%)²17 (21.8)11 (9)6 (30)PatientswithPsA (%)22 (28.2)8 (14.81)5 (25.00)Age at first biological agent (years)44.8 ± 16.744.0 ± 16.147.0 ± 18.3Baseline PASI22.4 ± 10.123.1 ± 10.530.0 ± 19.4Clinical response at 3 months of treatmentPASI at 3 months4.3 ± 3.92.7 ± 2.49.3 ± 8.1PASI75 (%)58 (74.4)1000
Slide18Association of PASI 75 at 3 months with the following clinical characteristics was not found gender (p=0.3)
age at onset psoriasis (p=0.85)type of psoriasis (p=0.31)presence or absence of psoriatic arthritis (p=0.71)age at prescription of the first anti-TNF drug (p=0.5)order of the treatment (p=0.1) or weight (p=0.91)
Slide1910 SNPs showed significant association with response PASI75 at 3 months
UNIVARIATE ANALYSISMULTIVARIANT ANALYSISSNP
GeneModelRisk Genotype(% Responders /% Non-responders)OR (95% CI)p-valueOR (95% CI)p-valuers2206593PTGS2DAG (13.8-0)0 (0-ND)0.0250 (0-ND)0.998rs2243188IL19C AC (36.2-65)3.01 (1.03-8.75)0.0485.34 (0.38-75.82)0.216rs1975974C17orf51AAG-GG (52.6-15)0.17 (0.04-0.62)0.00180.06 (0.01-1.26)0.070rs9304742ZNF816ARCC (6.9-25)4.50 (1.07-18.88)0.048,144.11 (13.03-5,089,337)0.006rs11126740CTNNA2RAA (5.4-25)5.89 (1.26-27.52)0.0223.18 (0.12-89.31)0.497rs842636REL-PAPOLGCAG (53.5-85)4.94 (1.02-23.87)0.0321.31 (0.15-11.22)0.807rs1008953SDC4RAA (13.8-0)0 (0-00-ND)0.0250 (0-ND)0.998rs2431697PTTG1ACT-CC (60.7-90)2.72 (1.27-5.86)0.006829.80 (1.16-765.68)0.040rs96844MAP3K1ACT-CC (56.9-30)0.33 (0.12-0.91)0.00220.011 (0.00-0.33)0.009rs13437088HLA-B/MICARTT (6.9-25)4.50 (1.07-18.88)0.041589.99 (2.71-128,614.40)0.020
Slide20The presence of arhtritic psoriasis is associated with the response to the treatment at 6 monthsA significative association was found between presence or absence of psoriatic arthritis (p=0.034), so the univariate analysis was adjusted with this covariable. No differences were found in the association with the following variables:gender (p=1)age at onset psoriasis (
p=0.66)type of psoriasis (p=0.91)age at prescription of the first anti-TNF drug (p=0.6)therapeutic option (p=0.091)weight (p=0.48)
Slide2110 SNPs showed significant association with response PASI75 at 3 monthsrs1975974 (C17orf51), rs11126740 (CTNNA2),rs13437088 (HLAB/MICA)rs2243188 (
IL19), rs96844 (MAP3K1)rs2206593 (PTGS2) rs2431697 (PTTG1)rs842636 (REL-PAPOLOG)rs1008953 (SDC4) rs9304742 (ZNF816A).
Slide228 SNPs showed significant association with response PASI75 at 6 months
UNIVARIATE ANALYSIS UNIVARIATE ANALYSIS ADJUSTED BY COMORBIDITY WITH PSA MULTIVARIANT ANALYSIS
SNPGeneModelRisk Genotype(% Responders /% Non-responders)OR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-valuers6661932IVLRTT (25.5-65)0.15 (0.02-1.27)0.0480.40 (0.15-1.03)0.0471.08 (0.191-6.090)0.933rs2206593PTGS2D AG (14.6-0)0.00 (0.00-NA)0.0220.00 (0.00-NA)0.050.00 (0.000-ND)0.999rs983332LMO4RAA (0-10)NA (0.00-NA)0.0260.00 (0.00-NA)0.0427x10-17 (0.000-ND)0.999rs928655GBP6AAG-GG (59.6-26.3)0.25 (0.08-0.78)0.00980.23 (0.07.0.74)0.00720.08 (0.012-0.523)0.008rs63115-HTR2ADCT-TT (66.7-90)4.50 (0.92-22.0)0.0364.59 (0.91-23.05)0.0383.22 (0.32-30.95)0.442rs2254441PSTP1P1AAG-AA (22.9-5)0.19 (0.02-1.50)0.0480.17 (0.02-1.41)0.040.00 (0.000-ND)0.334 rs6071980MAFBACT-CC (39.6-20)0.31 (0.09-1.03)0.0360.31 (0.09-1.03)0.0360.21 (0.21-2.01)0.174rs2546890IL12BDAG-GG (62.5-90)5.40 (1.12-26.04)0.0155.50 (1.11-27.19)0.0179.885 (0.71-138.15)0.089
Slide23ConclusionsThe polymorphisms rs2431697 (PTTG1) and rs13437088 (HLA B/MICA) are specific markers of etanercept responsers9304742 (ZNF816A) and rs96844 (MAP3K1) are biomarkers of anti-TNF drugs.rs928655
(GBP6) is a biomarker of the maintenance of the response at 6 months
Slide24Servicio de Farmacología ClínicaHospital de La PrincesaFrancisco Abad SantosTeresa CabaleiroRocío Prieto PérezMiriam Saiz RodríguezMaría TalegónUnidad de ensayos clínicos
Servicio de DermatologíaHospital de La PrincesaEsteban DaudénMar Llamas
Acknowledgements