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ARTRITE PSORIASICA STRATEGIE
TERAPEUTICHETRA PRESENTE E FUTURO
Mauro GaleazziUniversitagrave di Siena
Le Spondiloartriti
Psoriatic Arthritis (PsA)Definition
Psoriatic arthritis is a manifestation of psoriatic disease
characterized by inflammatory involvement of
entheses joints and bone which may affect both peripheral and axial
articular compartment
PsA extrarticular manifestations (EAM)
EAM Prevalence () Uveitisiridocyclitis 30-40IBD 20-35Subclinical IBD 20-80Cutaneous involvement 70-80
Nail involvement 80
Crohn diseaseUveitis Psoriasis Psoriatic onychopathy
PsA ndash Comorbidities 1 CVDHypertension2 Obesity3 Diabetes4 DyslipidemiaHyperuricemia5 Metabolic Syndrome6 Non-alcoholic fatty liver disease
(NAFLD)7 Fibromyalgia8 Neurological manifestations9 AnxietyDepression
EAM and Comorbidities must be investigated and treated with
multidisciplinary approach
Patients with psoriatic arthritis are at
greater risk of death compared to the
general populationWong K et al Arthritis Rheum 1997401868ndash72
How to identify ePsA in the psoriatic population
The importance of Dermatologistto early Referral to
Rheumatologist
CASPAR Classification criteria for PsASensibilitagrave 098 specificitagrave 097
Taylor et sl Arthritis Rheum 2006 Aug54(8)2665-73
1 Inflammatory articular disease (joint spine enthesial) plus ge 1 of the following findings
Scorecurrent (2) history (1) or family history (1)
(1)
(1)
current or history of (1)
juxta-articular new bone formation other than osteophytes (1)
Tab CIassification criteria for Psoriasic ARthritis (CASPAR)5
Findings2 Psoriasis
3 Nail dystrophy
4 Negative rheumatoid factor
5 Dactylitis
6 Radiographic changes (hand and foot)
PSA = 1 + gt 3 scores of the categories 2-6
bullSensitivity 99 either at 1 or at 7 years of diseasebullTheir use in practice for the diagnosis of ePsA is not yet validated
EARP questionnaire to detect early PsA
The EARP questionnaire is simple and fast to administer and proved robust for the identification of PsA in the
dermatological setting Dermatologists should consider the EARP for patients
Treat-to-target in PsA
bull Targetndash the best possible disease clinical control in that patient (ideally
remission or at least minimal disease activity)ndash no anatomical damage
ndash good quality of life Comprehensive Disease Control
bull Definition of clinical remissionndash biological definition no inflammationndash surrogates of biological remission eg PASDAS lt32
bull Methods to achieve the target as early as possiblendash early diagnosis (window of opportunity)ndash tight controlndash proper treatment individualized therapy
DMARDs for PsA
bull TNF-α inhibitorsndash infliximabndash etanerceptndash adalimumabndash golimumabndash certolizumab pegol
bull Biosimilarsndash bs-infliximabndash bs-etanercept
bull csDMARDsndash methotrexatendash sulphasalazinendash leflunomidendash cyclosporin A
bull Anti-IL17 pathwayndash ustekinumab (anti-IL23IL12)ndash guselkumab and tildrakizumabndash brodalumabndash secukinumabndash ixekizumab
bull tsDMARDsndash apremilastndash tofacitinib
bull Others bDMARDsndash abatacept
bull Investigational drugsndash many others
1 Gately MK et al Annu Rev Immunol 199816495-521 2 Wilson NJ et al Nat Immunol 20078(9)950-7 3 Nickoloff BJ Nestle FO J Clin Invest 2004113(12)1664-75 4 Nestle FO et al J Invest Dermatol 2004 123xiv-xxv
TNF-αIFN-γ
TNF-αIL-17IL-22
T cell
Differentiation and clonal expansionof Th1 and Th17
subsets is prevented
Antibody binds to the p40 subunit of IL-12 and
IL-23 preventing binding to their cell surface
receptors
Th1
Th17
Down-regulationof inflammatory
cytokines
Proposed mechanism of action for ustekinumab
USTEKINUMABSTELARA
La posologia Con o senza MTX dose iniziale di 45 mg somministrata per via sottocutanea seguita da una dose di 45 mg dopo 4 settimane e successivamente ogni 12 settimane In pazienti con un peso superiore a 100 kg la dose egrave di 90 mg
Interruzione del trattamento Non risposta al trattamento di 28 settimane
Ustekinumab in PsAPSUMMIT-II
438
554
356
202
286
19
0
10
20
30
40
50
60
tutti no anti-TNF anti-TNF
UstekinumabPlacebo
Week 24
Combined UST dose 45-90 mg Placebo 104UST 45 103UST 90 105
Ritchlin C et al Ann Rheum Dis 201473990
ACR20 response
ResultsAlla settimana 24 la risposta egrave stata raggiunta indipendentemente dal concomitante uso di MTX
dagger per i pazienti qualificati allrsquoearly escape i dati alla settimana 16 sono stati portati avanti fino alla settimana 24 successivamente sono stati utilizzati i dati osservati
Ritchlin et al PSUMMIT2 ARD 2014
Ustekinumab in PsAPSUMMIT-II
Patients who did not receive UST are excluded
Mea
n C
hang
e fr
om B
asel
ine
Radiographic progression
Ritchlin C et al Ann Rheum Dis 201473990
Dactylitis responseMedian percent change from baseline
0
-1000 -1000
(n=90)(n=84)
Med
ian
chan
ge (
)
-40
-80
-100
-20
-60
0
-1000-950
(n=44)(n=24)
-40
-80
-100
-20
-60
Med
ian
chan
ge (
)
(n=86)
-909-1000
(n=38)
PSUMMIT 11 ndash Week 100 PSUMMIT 22 ndash Week 52
1 Kavanaugh A et al Arthritis Care Res (Hoboken) 2015 doi 101002acr22645 [Epub ahead of print] 2 Ritchlin CT et al Ann Rheum Dis 201473990ndash9 supplementary appendix
Placeborarrustekinumab 45 mg Ustekinumab 90 mgUstekinumab 45 mg
PSUMMIT I - III
18
n=118
n=119 n=130 n=249
Kavanaugh A et al Arthritis Care amp Research 2015 67 1739ndash1749
PSUMMIT 1
Enthesitis responseMedian Percent Change from Baseline in Entheses Score
Ritchlin C et al Ann Rheum Dis 2014 73 990ndash999
PSUMMIT 2
Patients who discontinued for efficacy reasons or who initiated protocol prohibited medications were included in all analyses as non-responders Patients with missing Wk 12 data were considered Wk 12 non-responder Patients randomized to UST 45mg or 90mg at Wk0 are included beginning at Wk0 Patients randomized to Placebo at Wk0 and crossed-over to UST at Wk 12 are included beginning at Wk 24
Ustekinumab in pts with moderate-to-severe psoriasis PHOENIX 1 study (5 years)
Perc
enta
ge o
f Pat
ient
s (
)
45 mg n =
90 mg n =
Week568566
517515
508507
504503
494485
548542
538538
533531
524522
550551
512507
555558
538534
527524
499499
553552
580577
409411
591
594409411
589
587
584
585
Clinical Response Through Week 244 Overall Population
789
714
459
551 555
765
786
500
Kimball AB et al J Eur Acad Dermatol Venereol 2013 271535
Improvement in Nail Psoriasis Severity Index (NAPSI) score
NAPSI
Miglioramento delle caratteristiche piugrave comuni della psoriasi delle unghie (pitting onicolisi e ipercheratosi) alla settimana 52
P Rich et alBritish Journal of Dermatology 2014 Feb170(2)398-407
Phoenix I
Cumulative incidence rates of serious infections per 100 patient-years overall population
(PSOLAR)
21Kalb R et al G2C 2014 P1643
Rat
es p
er 1
00 P
Y (9
5 C
I)
UST(N=49)
IFX(N=56)
ETA(N=55)
ADA(N=102)
MTXNon-
biologic(N=16)
Non-MTXNon-
biologic(N=40)
All(N=323)
249 147 197083 128 105 145
Age and gender adjusted cumulative rates of malignancies (excluding NMSC) per 100 patient-years (PY)
Fiorentino D et al AAD 2015 P1631
Cum
ulat
ive
Rat
es p
er 1
00 P
Y (9
5 C
I)
Ustekinumab(6012472 PY)
Infliximab(415176 PY)
Other Biologics
(11615991 PY)
Non-biologic
(576749 PY)
All(27440388 PY)
081 073 075 068051
Cumulative rates of malignancies
This group Includes (n=36) patients exposed to golimumab only957 (n=4067) are adalimumab ampor etanercept patients with the remainder exposed to other biologicsAdjustment used all population as reference
When to use USTEKINUMABbull in early phase of PsA to reduce radiological
progressionbull in dactilytisenthesitis subsetsbull High NAPSI levelbull in monotherapy (DMARDs controindications
or adverse event)bull complianceadherence to therapy (every 12
weeks)
Secukinumab
IL-17A
Delayed-type hypersensitivity
and cellular immunity
Tissue inflammation and pathogen
defense
Tissue inflammation
IFN-γIL-2
IL-17FIL-21IL-22
IL-17A
Selective inhibition of IL-17A may preserve normal components of the host immune response
Neutralization of IL-17A rapidly inhibits downstream inflammatory
cytokine and chemokine networks and thus may be useful for the treatment of
several immune-mediated diseases
IL-17A neutralized by Secukinumab
IL-12
Th17
Mast cells
Other leukocytes
Th1
IL-23
TNF
Dendritic cells
Secukinumab binds with high affinity and selectivity to human IL 17A
Secukinumab
secukinumab(Cosenty)
la dose con o senza MTXEgrave di 150 mg per iniezione sottocutanea con dosaggio iniziale alle settimane 0 1 2 e 3 seguito da un dosaggio di mantenimento mensile a partire dalla settimana 4 Per i pazienti con AP e con concomitante psoriasi a placche da moderata a severa o che non hanno risposto in modo adeguato alla terapia con anti-TNFalfa la dose raccomandata del secukinumab egrave 300 mg
60
ACR20
40
0
Res
pond
er (
)
20
ACR50 ACR70
Dagger
Dagger
Secukinumab in PsA ACR responseFUTURE 2
80
ACR20
60
40
0
Res
pond
er (
)
20
ACR50 ACR70
Dagger
Dagger
Dagger
Dagger
DaggerDaggerDaggerDagger
n = 67 n = 63 n = 65 n = 63 n = 67 n = 63 n = 65 n = 63 n = 67 n = 63 n = 65
n = 33 n = 37 n = 34 n = 35 n = 33 n = 37 n = 34 n = 35 n = 33 n = 37 n = 34
Anti-TNF naiumlve
Anti‒TNF non-responnder
Secukinumab 300 mg sc Secukinumab 75 mg sc PlaceboSecukinumab 150 mg sc
McInnes IB et al Lancet 2015 386 1137