ARTROPATIA PSORIAZICA

SpA este un termen “umbrela” care acopera un grup de boli

musculo-scheletice inflamatoare, ce includ:
SA (manif axiale) & APs (manif periferice)

Undifferentiated
Reactive arthritis
peripheral SpA

Ankylosing Psoriatic
spondylitis arthritis

Peripheral
manifestations

Axial
manifestations
SpA with associated IBD/
enteropathic arthritis
Adapted with permission from:
AS, ankylosing spondylitis; IBD, inflammatory bowel disease; Proft F, Poddubnyy D. Ther Adv Musculoskelet Dis 2018;10:129–39;
PsA, psoriatic arthritis; SpA, spondyloarthritis Duba AS, Matthew SD. Prim Care 2018;45(2):271–87
 APs este o boala inflamatorie sistemica
asociata cu psoriazisul
• Artropatia psoriazica (AP) face parte din familia spondiloartritelor1
- caracterizata prin inflamatia articulatiilor, entezelor si a coloanei vertebrale si de obicei
seronegativa pentru factorul reumatoid1

• Psoriazisul in placi este fenotipul cutanat cel mai frecvent intalnit la pacientii cu AP
- psoriazisul afecteaza aproximativ 2% din populatia generala
- pana la 30-40% dintre pacientii cu psoriazis dezvolta AP 2-5

• In general, susceptibilitatea de aparitie si progresie spre forme severe de artrita

este direct proportionala cu severitatea afectarii cutanate5
• NU prezinta predominanta in functie de sex
• varsta cea mai frecventa la debut: 20-40 ani
• prezinta agregare familiala

1. Fitzgerald O. In: Kelley's Textbook of Rheumatology 8th Ed. 2009;10:1201–1216; 2. Gottlieb A, et al. J Dermatol Treat 2008;19:5–21; 3. Mease
P. Curr Rheumatol Ther 2006;8:348–354; 4. Gladman D. Dermatol Ther 2004;17:350–363; 5. Winchester R. In: Freedberg IM, et al (eds).
Fitzpatrick‘s Dermatology in General Medicine 2003;1:427–436.

De regula, psoriazisul in placi precede

aparitia simptomelor articulare

• Simptomele cutanate apar de regula inaintea celor articulare1

• In medie, simptomele cutanate le preced cu 10 ani pe cele articulare

1. Helliwell PS, et al. In: Klippel JH, Dieppe PA (eds), Rheumatology 2nd ed. 1998;108–115; 2. Stern RS. J
Rheumatol 1985;12:315–320; 3. Winchester R, et al. Arthritis Rheum 2012;64(4):1134–1144.
 APs este frecvent subdiagnosticata
Intr-un studiu efectuat in 34 centre de dermatologie 30% din
pacientii cu psoriazis au fost identificati de reumatolog ca avand
si Aps; din acestia 41% au fost dg pt prima data

100 100
Patients with psoriasis,

80 80

Patients with PsA, %

60 60
%

40 40
PsA 1st time
diagnosis by
20 20
PsA, 30% rheumatologist
in this study, 41%
0 0
(N=949) (N=285)
PsO patients PsO patients given PsO patients given the
without PsA the diagnosis of PsA when diagnosis of PsA for the first time
assessed by a rheumatologist

1. Mease PJ et al. J Am Acad Dermatol 2013;69:729–735.

Psoriasis Epidemiology Screening Tool

(PEST)
• Have you ever had a swollen joint In the drawing below,
(or joints)? please tick the joints that have
caused you discomfort
• Has a doctor ever told you that you have
(i.e. stiff, swollen or painful joints)
arthritis?
• Do your finger nails or toe nails have holes
or pits?
• Have you had pain in your heel?
• Have you ever had a finger or toe that was
completely swollen and painful for no
apparent reason?

Adapted from: Ibrahim G, et al. Clin Exp Rheumatol. 2009;27:469–74.

 Prevalenta APs creste proportional cu durata de
evolutie a psoriazisului

Adapted from Christophers E, et al. J Eur Acad Dermatol Venerol 2010;24:548–555.

© 2009 Wyeth Pharmaceutical. Journal compilation © 2009 European Academy of Dermatology and Venereology
 Predictorii clinici semnificativi ai APs la pacientii
cu psoriazis
Susceptibilitatea de aparitie a APs este determinata de fenotipul psoriazic

Wilson FC, et al. Arth Care Res 2009;61:233–239.

 Diagnosticul APs
 Diagnosticul poate fi dificil
 Manifestari din cadrul spondilartritelor
 Simptome:
 durere lombara de tip inflamator
 artrita

 entezita

 uveita anterioara acuta

Clinica artropatiei psoriazice

heterogeneitate remarcabila !
◼ afectare articulara: oligoartrita asimetrica
◼ afectarea frecventa a IFD
◼ dactilita
◼ entezopatie
◼ afectare axiala, inclusiv de sacroiliace
◼ manifestari cutanate / tegumentare
◼ afectare sistemica
 APs este o boala heterogena
Scalp psoriasis

APs are 6 tipuri principale de manifestare

Psoriatic skin
nu toate apar la toti pacientii, iar manifestarile pot varia lesions
in timp, functie de evolutia bolii Tender/swollen
sacroiliac pain

Enthesitis of
superior/inferior patella or
GRAPPA identifica 6 domenii ale bolii lateral epicondyle

Artrita periferica Dactilita Psoriatic nail

lesions

Dactylitis
Afectarea axiala Afectarea cutanata
Inflammatory
Entezita Afectarea unghiala arthritis involving
PIP/DIP joint
distribution Plantar fasciitis/
Achilles' tendon pain

Activitatea bolii DIP, distal interphalangeal; GRAPPA, Group for Research and Assessment of Psoriasis
1. Gottlieb AB, Merola JF. J Dermatolog Treat 2020;31(7):662-79; and Psoriatic Arthritis; PIP, proximal interphalangeal; PsA, psoriatic arthritis.
2. Giannelli A. Rheumatol Ther 2019;6(1):5-21.

Existenta subgrupurilor complica procesul

de diagnostic al APs
 Diagnosticul AP este complicat de existenta mai multor sub-grupuri1
 Clasificarea traditionala realizata de Moll si Wright in 1973 continua sa fie utilizata
pe scara larga (nu include toate formele de manifestare, respectiv posibilitatea
evolutiei de la o forma la alta in decursul timpului)

• In prezent, exista criterii mai specifice si mai sensibile, cum sunt criteriile CASPAR3
1. Helliwell PS, et al. Ann Rheum Dis 2005;64(Suppl 2):ii3–8; 2. Mease P, et al. J Am Acad Dermatol 2005;52:1–19; 3. Fitzgerald O. In: Kelley's Textbook of Rheumatology 8th Ed.
2009;10:1201–1216.
Reprinted from J Am Acad Dermatol, vol 52 no. 1, Phillip Mease and Bernard Goffe, Diagnosis and treatment of psoriatic arthritis, p3, 2005, with permission from Elsevier.
 Forme de prezentare a Artritei Psoriazice :
5 Pattern-uri clinice care se suprapun

Poliartrita
simetrica Oligoartrita
~12–70% asimetrica
~37–70%

Boala axiala
Afectarea periferica
poate fi prezenta sau nu
la acesti pacienti
~5–70% Arthritis mutilans
~5%
Afectare IFD
~5%

In practica clinica sunt recunoscute trei

forme clinice de APs

Artrita Afectarea coloanei Combinatie intre

vertebrale acestea doua
periferica

 Prin contrast cu clasificarile traditionale ale Moll si Wright, artrita

mutilanta nu este considerata o forma clinica separata, deoarece
poate aparea in toate celelalte forme clinice
 Dactilita si entezita sunt in prezent recunoscute mai degraba ca
trasaturi clinice importante ale AP, decat ca subgrupuri distincte

Gladman D, et al. Curr Rheumatol Rep 2011;13:346–352 .

 Criteriile CASPAR de clasificare ale APs
Taylor W et al. Arthritis Rheum. 2006;54:2665-73
*current psoriasis counts as 2

Diagnosticul diferential al APs

poate fi dificil
• APs poate fi dificil de diferentiat de AR sau SA
- daca exista afectarea coloanei vertebrale, AP poate fi imposibil de
diferentiat de SA
• Afectarea coloanei vertebrale este adesea asimptomatica
in APs
- in plus, durerea si rigidizarea coloanei vertebrale sunt simptome frecvent
intalnite, a caror prezenta nu poate indica in mod cert prezenta spondilitei2

1. Helliwell PS, et al. Ann Rheum Dis 2005 Mar;64 Suppl 2:ii3–8; 2. Heliwell PS. J Rheumatol

Suppl 2009;83:21–23 .
 Diferentierea APs de PR este dificila
dar importanta pentru gestionarea bolii
• Nu exista un test de diagnostic al AP Caracteristici clinice de
• Majoritatea pacientilor indeplinesc criteriile diferentiere optima intre
de definire a AP si anume artrita activa
concomitenta cu manifestarile de psoriazis
si seronegativa pentru FR

• Pe de alta parte:
- aceasta forma de artrita poate avea implicare
predominant vertebrala
- poate fi localizata exclusiv periarticular
- poate aparea inainte de leziunile cutanate
- FR poate fi detectat in titruri scazute
• Fitzgerald O. In: Kelley's Textbook of Rheumatology 8th Ed. 2009;10:1201–1216.

Spectru larg de comorbidități în artrita psoriazică

Urogenitale/
Digestive¹ Oculare¹ CV¹⁻³ Metabolice⁴ Altele¹⁻⁴⁻⁵
renale¹
boala Crohn uveita HTA diabet uretrite fibroza pulmonară
colita ulcerativa conjunctivita boala coronariană obezitate prostatite apicală
alte boli insuf aortică sd.metabolic balanite depresie
inflamatorii tulb. de conducere osteoporoza vaginite anxietate
intestinale tromboze,flebite cervicite guta
nespecifice amiloidoza fibromialgie
nefropatia IgA NASH

16% 16% 14% NR 13% 16%

NASH: non-alcoholic steatohepatitis

1.Peluso R,et al. Clin Rheumatol 2015, 34:745-753;2. Charlton R, et al.Rheumatology 2018,sept 6, doi:10.10903;3.Eder L. et al, Ann Rheum Disease, 2015,74:1830-1835;4.Coates LC et al Arthritis rheum
2016;68:1060-1071.5..Mease PJ et al. Curr Opin Rheumatol 2017;29:304-310
 Evoluția artritei psoriazice poate fi impredictibilă

debut: artrita durere de spate

psoriazică severă, Artrita mutilans
inflamatorie,
cu afectare afectare axială
unghială
Severitatea bolii

Debut: oligoartrită
forma ușoară,
non-progresivă

Forma ușoară de
artrită periferică

Timp
Images from www.rheumatology.org/Learning-Center/Educational-Activities/Rheumatology-Image-Library
Helliwell PS,et al. Rheum Dis Clin North Am.2015;41:581-591

Prognosticul APs
 Progresie variabila: aprox 20% din pacienti au boala sever evolutiva
 Severitatea bolii are mai multe aspecte:
 clinic
 radiologic
 impactul pe calitatea vietii
 predictori de severitate radiografica:
 activitatea bolii: numaratori articulare1
 reactanti de faza acuta2
 prezenta leziunilor Rx la baseline3
 posibil: afectare functionala, utilizare de glucocorticoizi, dactilita4

1. McHugh N. et al., Rheumatology 2003, 42, 776-83

2. Kane D. et al., Rheumatology 2003, 42, 1469-76
3. Khraishi M. et al., Ann Rheum Dis 2012, 71 (S3), 692
 Evolutie
 nu este o boala benigna: distructiv – progresiva, severa in cel putin 20%
 poliartrita in 40% din cazuri
 limitare functionala severa la 11% din indivizii afectati

1 3
5

Evaluarea artropatiei psoriazice

 Criteriu de raspuns ACR: 20%, 50%, 70% (validat in AR, nu APs)
 Criteriu de raspuns in artrita psoriazica (PsARC)
 Disease Activity Score (DAS)
 Scorul entezitic
 Scorul dactilitei
 Scoruri functionale / QOL / indici de deficit functional (HAQ, SF-36)
 Evaluare radiografica ( Sharp modificat)
 Evaluare cutanata (PASI: Psoriasis Area Severity Index)
 Scoruri compozite specifice pt APs
CPDAI PASDAS DAPSA
(Clinical Psoriatic Disease Activity Index) (Psoriatic Arthritis Disease Activity (Disease Activity Index for
Score) Psoriatic Arthritis)
Nr articulare 66/68 Nr articulare 66/68 Nr articulare 66/68
Af cutanata (PASI) entezita VAS eval globala medic
entesita (LEI) dactilita VAS eval globala pacient

dactilita (numaratori) VAS eval globala medic CRP

HAQ VAS eval globala pacient
DLQI SF-36
(Dermatology Life Quality Index)

Forme axiale: BASDAI, ASQOL CRP

(Ankylosing Spondylitis Quality of Life)

Activitatea minima a bolii (MDA)

5 din urmatoarele 7 criterii:1-3
 artic dureroase ≤ 1 † Are valoare predictiva pt reducerea
 artic tumefiate ≤ 1 degradarii structurale:
 enteze dureroase ≤ 1 • Cohorta observationala: 34% au
 PASI ≤ 1 sau suprafata corporala ≤ 3 avut MDA pt cel putin 1 an: acestia
%†
 VAS durere pacient ≤ 15
au progresat Rx mai putin decat cei
 VAS eval globala pacient ≤ 20 care nu au atins MDA4
 HAQ ≤ 0.5 • in RCTs: atingerea MDA se asociaza
cu mai putine leziuni structurale,
† criteriile cele mai limitative ameliorarea functiei si a calitatii
1. Coates L. et al., Arthritis Care Res 2010, 62. 970-6
2.
3.
Coates L. et al., Ann Rheum Dis 2010, 68, 48-53
Mease P. et al., J Rheum 2013, 40, 647-52
vietii5-6
4. Coates L. et al, Arthritis Care Res 2010, 62. 965-9
5. Kavanaugh A. et al., Arthritis Care Res 2015 online
 Activitate foarte joasa a bolii
7 din urmatoarele 7 criterii:1
 artic dureroase ≤ 1
 artic tumefiate ≤ 1
 enteze dureroase ≤ 1
 PASI ≤ 1 sau suprafata corporala ≤ 3 %
 VAS durere pacient ≤ 15
 VAS eval globala pacient ≤ 20
 HAQ ≤ 0.5

1. Coates L. et al, J Rheumatol 2016, 43, 371-75

Tratamentul artritei psoriazice

◼ AINS (antiinflamatoare nonsteroidiene)
◼ steroizi intra-articulari
◼ terapii remisive conventionale sintetice
⚫ methotrexat
⚫ leflunomid
⚫ ciclosporina A
⚫ sulfasalazina
⚫ hidroxiclorochina ?
◼ terapii sintetice tintite: apremilast, tofacitinib
◼ terapii biologice
⚫ anti-TNF: etanercept, infliximab, adalimumab, golimumab, certolizumab
⚫ non-TNF: secukinumab, ixekizumab si ustekinumab
 O abordare terapeutica in trepte
AINS
Cortico-steroizi local (IA)
Remisive sintetice
conventionale
Biologice

Remisive
sintetice
tintite
Gossec L. et al., Ann Rheum Dis 2016, 75,
499-510
Coates L.C. et al., Arthritis Rheum 2016 epub

Remisive sintetice conventionale in Aps: MTX

 Metotrexat - doze de 20-30mg / sapt

 datele observationale:
 arata utilizarea larga a MTX in cohortele din registre
 persistenta mare pe tratament: 65% la 3 ani (similar cu AR)
 date de eficacitate in TICOPA (ACR20 40%, MDA 22%)

Lie E. et al., Ann Rheum Dis 2010, 69, 671-6

Gladman D.D. et al., Arthritis Res Ther 2010, 12, R113 Gladman D.D. et al., Ann Rheum Dis 2011, 70, 12, 2152-54
Cresswell L. et al., Ann Rheum Dis 2011, 70, 305-8 Ash Z. et al., Ann Rheum Dis 2012, 71, 319-326
Simon P. et al., Clin Exp Rheumatol 2012, 30, 45-50 Kingsley G.H. et al., Rheumatology 2012, 51, 1368-77
Coates L.C. et al., J Rheumatol 2016, 43, 356-61
Asocierea cu MTX amelioreaza rezultatele tratamentului biologic

 datele pt asocierea cu MTX raman

limitate: nu exista un raspuns clar
din studii
 datele din practica clinica:
 registrele suedeze si NOR-DMARD:
◼ 440 si 261 pacienti, 66% pe terapie
combinata
◼ fara diferente de eficacitate
◼ supravietuire mai mare pe tratament in
asociere cu MTX
Fagerli K. et al., Ann Rheum Dis 2013, 72, 1840-4
Ramiro S. et al., Ann Rheum Dis 2016, 75, 490-6
Mease P. et al., RMD Open 2015

Remisive sintetice conventionale in Aps:

leflunomida
Studiul TOPAS:
criteriul de raspuns la tratament in artrita psoriazica (PsARC)
80 Leflunomid (n = 96)
70 *
59.0 Placebo (n = 92)
60
*p  0.0001 vs placebo
Repsonders (%)

50
40
29.7
30
20
10
0
Kaltwasser et al. Arthritis and Rheumatism 2004
Aps: modificari cutanate dupa
tratamentul cu leflunomid

inainte de tratament dupa 24 sapt de trat cu leflunomid

Nash P, Thaçi D. J EADV 2004; 18:78 PS172

O abordare terapeutica in trepte

AINS
Cortico-steroizi local (IA)
Remisive sintetice
conventionale
Biologice

Remisive
sintetice
tintite
Gossec L. et al., Ann Rheum Dis 2016, 75, 499-510
Coates L.C. et al., Arthritis Rheum 2016 epub
 Terapii biologice in APs

Inhibitori IL-12/IL-23
Inhibitori TNF-α Inhibitori IL-17RA

Inhibitori IL-17A

TNF-α Cel Th17

IL-17A/F IL-17
responsive cell

Nestle FO, et al. N Engl J Med. 2009;361:496–509; Kopf M, et al. Nat Rev Drug Discov. 2010;9:703–18; Garber K. Nat Biotechnol. 2011;29:563–6

Blocanti TNF in APs

Eficacitate certa a blocantilor TNF pe:
 tegumente
 manif scheletice:
◼ articulatii
◼ enteze
◼ dactilita
◼ simpt axiale
◼ leziunile structurale articulare
 manifestari sistemice Ash Z. et al., Ann Rheum Dis 2012, 71, 319-326
Ramiro S. et al., Ann Rheum Dis 2016, 75, 490-6
 Aproximativ 60% din pacientii cu Aps
tratati cu blocanti TNF ating un raspuns
ACR 20 la sapt 12 - 14

TNFi: eficacitate structurala in APs

 Blocanti TNF in APs:
oprirea progresiei leziunilor structurale

Sapt 0 12 luni
IFX: PsA MCP / PIP
de trat

Alte tinte terapeutice in SpA & APs - citokine noi: familia IL-17

Secukinumab &
Ixekizumab Ac
monoclonal
indreptat
impotriva IL-
17A, rezultate
bune in SA si
APs
 FUTURE 1
Secukinumab: raspuns ACR20 rapid instalat si sustinut pe termen lung
- pacienti anti-TNF naivi si pacienti cu raspuns inadecvat la anti-TNF -
100 Anti-TNF- Anti-TNF-IR
100
naïve

Percentage of responders
Percentage of responders

81.0%
80 80
61.5%
60 67.3% 60
55.6%
40 40
20 20
0 0
24 52 104 0 24 52 104 156
0 156
n =120 119 116 111 116 n = 41 39 39 35 39
n =110 108 108 100 107 n = 37 36 36 30 36
Weeks Weeks

Secukinumab 10 mg/kg i.v.  150 mg s.c. (N = 120) Secukinumab 10 mg/kg i.v.  150 mg s.c. (N = 41)
Secukinumab 10 mg/kg i.v.  75 mg s.c. (N = 110) Secukinumab 10 mg/kg i.v.  75 mg s.c. (N = 37)

Mease PJ, et al. RMD Open 2018;4:e000723. doi:10.1136/rmdopen-2018-000723

Rezolutia semnificativa a dactilitei si entezitei cu secukinumab vs.

placebo la sapt 24 - 52

90.0 Dactylitis 90.0 Enthesitis

79.9 78.0
80.0 76.1 74.3 80.0
71.5
70.0 65.9 65.1 70.0 61.8
56.5 55.1 58.8
60.0 60.0 54.3
Percentage
Percentage

50.0 50.0
40.0 40.0
30.0 30.0
20.0 20.0
10.0 10.0
0.0 0.0
Week 24 Week 52 Week 104 Week 24 Week 52 Week 104

Resolution of dactylitis and enthesitis evaluated amongst those

patients with these symptoms at baseline (overall population)
Data were analysed using multiple imputation through Week 104. N, number of randomised patients McInnes et al, OP0222, EULAR 2017
 Secukinumab: inhibitie semnificativa a progresiei radiografice (mTSS)
vs. placebo la sapt 24
0.6 0.57

0.5
Mean change from baseline

0.4 0.35

0.3
0.23
0.2
‡0.13
0.10
0.1 ‡ 0.08 + 0.06
0.08
‡
0.02 +
0.04 + 0.02
0.0 N=185 N=366 N=179 N=18 N=182 N=367 N=179 N=185 + N=179
N=181 5
N=181 N=366
-0.1 -0.06
mTSS Erosion score Joint spacing narrowing
score

Secukinumb 10 mg/kg i.v. → 150 mg s.c.Secukinumb 10 mg/kg i.v. → 75 mg s.c.

Secukinumab pooled doses Placebo
‡P < 0.05 vs. placebo (P-values at Week 24 adjusted for multiplicity of testing); +P < 0.05 vs. placebo.

for missing values at Week 24. In the FUTURE 1

mTSS, modified total Sharp score. Data presented are full analysis set using non-parametric ANCOVA (analysis of covariance) with linear extrapolation
study, patients received an intravenous (i.v.) loading dose of secukinumab (10 mg/kg) followed by subcutaneous (s.c.) maintenance dosing (75 mg or 150 mg) van der Heijde D, et al Arthritis Rheum. 2016;68:1914–21

IXEKIZUMAB: raspuns ACR 20/50/70 la sapt 24

100
100
Response Rate (%)

80
Response Rate (%)

80
62
60 57 58
* 60
* * 53
47
39 40 48
40 30
* * 34
40 * * *
263523 33*
PBO (N=106)
20 15 * * * * 22
1
20 9 6 ADA *(N=101)
12 *
5.
0 1 0 *
ACR20 0 ACR50 ACR70 *p≤.001 vs. PBO.
ACR20 ACR50 ACR70
Significantly more patients, biologic-naïve and TNF-IR, treated with IXE achieved ACR 20/50/70 Response

Note: ADA represents an active control; the study was not powered to test equivalence or non-inferiority IXE Q4W:80mg of Ixekizumab Every 4 Weeks; NRI:Nonresponder Imputation; PBO:Placebo;
of active treatment groups to each other, including IXE vs. ADA. TNF-IR:Tumor Necrosis Factor Inhibitor Inadequate Responder.
ACR 20/50/70:American College of Rheumatology 20%/50%/70% response rate; ADA:Adalimumab; 1. Mease PJ, et al. Ann Rheum Dis. 2017;76:79-87; 2. Nash P, et al. Lancet. 2017;389:2317-2327.
ITT:Intent-to-Treat; IXE:Ixekizumab; IXE Q2W:80mg of Ixekizumab Every 2 Weeks;
 IXEKIZUMAB: modificarea scorului mTSS at Week 24, Spirit 1
0.49
0.5 (0.09)
Worsening (Erosion)

in mTSS (LSM [SE]a)

Mean Change From

0.4

0.3
Baseline

0.17
0.2 (0.08)
0.10
(0.09) † 0.08
0.1 (0.08) PBO (N=106)
*
*
0
Week 24 *p≤.001 vs. PBO; †p≤.01 vs. PBO.

IXE significantly inhibited the progression of joint damage

Note: ADA represents an active control; the study was not powered to test equivalence or non-inferiority
of active treatment groups to each other, including IXE vs. ADA.
aHigher mTSS scores indicate more articular damage. The mean change from baseline at Week 24 was
assessed with a statistical significance threshold of p<0.025 in a hierarchical analysis; all other endpoints
were assessed with
a statistical significance threshold of p<0.05.
ADA:Adalimumab; ITT:Intent-to-Treat; IXE:Ixekizumab; IXE Q2W;80 mg of Ixekizumab Every 2 Weeks;
IXE Q4W:80 mg of Ixekizumab Every 4 Weeks; LSM:Least Squares Mean; MMRM;Mixed-Model Repeated
Measures; mTSS:modified Total Sharp Score; PBO;Placebo; SE:Standard Error.
1. Mease PJ, et al. Ann Rheum Dis. 2017;76:79-87.

Alte tinte terapeutice in SpA & APs - citokine noi:

familia IL-12/23
# blocarea IL12/23:
- Ustekinumab: Ac monoclonal
indreptat impotriva subunitatii p40
comuna pt IL12 si IL23, cu rezultate
bune in PsO si APs ( FARA eficacitate
in SA)

# blocarea IL23 (p19):

- Guselkumab: Ac monoclonal
indreptat impotriva subunitatii p19 a
IL23, cu rezultate bune in PsO si Aps
 Ustekinumab in PsA: raspuns ACR si PASI la sapt 52

100 PSUMMIT 2

80
64.4
Patients (%)

60 55.8 56.1 56.5

46.8 48.4 49.3

40 36.8 37.7
28.6 27.7 26.3

20 15.6 12.8 17.9

0
ACR20 ACR50 ACR70 PASI75 PASI90
Placebo → UST 45 mg (N=77) Ustekinumab 45 mg (N=94)
PSUMMIT 2 patients could have had previous anti-TNF experience.

Summary of observed efficacy data at Week 52 among randomized patients; patients in the placebo group who Ritchlin C, et al. Ann Rheum Dis. 2014;73:990–9
did not crossover to ustekinumab 45 mg were excluded.

Methods: PsABio is a prospective,

observational cohort study of patients with
psoriatic arthritis (PsA) at 92 sites in eight
European countries, who received first-line
to third-line ustekinumab or a TNFi.

Conclusion: Treatment
targets were reached
similarly after 6 months of
treatment with
ustekinumab and TNFi.
 Guselkumab (Tremfya): a monoclonal Ab against IL-23

BIMEKIZUMAB (Bimzelx): neutralizeaza si IL-17F suplimentar fata de IL-17A

heterodimer Bimekizumab
IL-17A–IL-17A IL-17F–IL-17F
IL-17A and IL-17F share ~50% structural homology and have
homodimer homodimer
similar proinflammatory functions1,2,3

Both IL-17A and IL-17F are expressed at sites of

inflammation4,5 and independently cooperate with other
cytokines to mediate inflammation in humans5

Preclinical5 and early clinical5,6,7,8 data support neutralization IL-17RA IL-17RC

of IL-17F together with IL-17A as a
novel targeting approach in PSO, PsA and AS Immune-mediated inflammatory diseases

Dual targeting hypothesis

Bimekizumab is a mAb that potently and Partial blockade: IL-17A neutralization only
selectively neutralizes both IL-17A and IL-17F
Complete blockade: IL-17A and IL-17F neutralization

1Yang XO et al. J Exp Med 2008;1063–1075; 2Hymowitz SG et al. EMBO 2001;20:5332–5341; 3Chu CQ. Targeting the IL-17 Pathway in Inflammatory Disorders ADIS 2017; 4Van Baarsen LGM et al. Arthritis Res & Ther 2014;16:426; 5Glatt S et al. Ann Rheum Dis 2018;77:523–532;
6Glattet al. Br J Clin Pharmacol 2017;83:991–1001; 7Papp et al. J Am Acad Dermatol 2018:79:279–286; 8van der Heijde et al. Ann Rheum Dis 2018;77:A70. 9UCB DOF (Ritchlin et al. ACR2018 L17 oral presentation) AS, ankylosing spondylitis; IL, interleukin; mAb, monoclonal
antibody; PsA, psoriatic arthritis; PSO, psoriasis
 Study designs of NCT02969525A – A Multicenter, Phase 2B, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group, Dose-Ranging Study to Evaluate the Efficacy and Safety of Bimekizumab in Active PsA
Screening* Double-blind period Dose-blind period

n=42 Bimekizumab 160 mg Q4W

Placebo Q4W
Bimekizumab 320 mg Q4W
Key inclusion criteria Extension study to
n=41 Bimekizumab 160 mg Q4W evaluate response to
• Active PsA Bimekizumab 16 mg Q4W treatment and long-
Bimekizumab 320 mg Q4W
o TJC ≥3 out of 78 term safety

o SJC ≥3 out of 76 n=41

Bimekizumab 160 mg Q4W Bimekizumab 160 mg Q4W
o CASPAR ≥3 Safety follow up visit
20 weeks after last
• Patients with or without prior n=41 Bimekizumab 160 mg Q4W dose for patients not
exposure to one anti-TNF therapy Bimekizumab 160 mg Q4W
(320 mg LD at baseline) enrolling in
were permitted extension study
n=41
Bimekizumab 320 mg Q4W Bimekizumab 320 mg Q4W
Weeks 16, 24 and 36:
Dosing evaluation for eligibility
for rescue therapy†

2–4 weeks
Baseline 4 8 12 16 20 24 28 32 36 40 48
Week Week
Primary endpoint Efficacy and
ACR50 response safety at Week 48
Bimekizumab was supplied as a clear to opalescent, colorless to slightly brown, sterile, preservative free solution. Each single-use dose vial contained 160 mg/mL bimekizumab in 55 mM sodium acetate, 220 mM glycine and 0.04% (w/v)
polysorbate 80 at pH 5.0. Placebo was supplied as a 0.9% sodium chloride aqueous solution.

*Enrolled set. After Week 12, patients receiving placebo or bimekizumab 16 mg were re-randomized (1:1) to receive bimekizumab 160 mg or 320 mg; all other patients continued on their previous dose; †Patients with <10% improvement from baseline in
TJC and SJC are eligible for rescue therapy. CASPAR, Classification Criteria for Psoriatic Arthritis; LD, loading dose; Q4W, every four weeks; SJC, swollen joint count; TJC, tender joint count; TNF, tumor necrosis factor

Ritchlin et al. ACR2018 L17 oral presentation

Key Results:
Durable efficacy outcomes at 1-year of OLE Week 60 (Week 108 total BKZ treatment):

100 Treatment groups at end of PA0008

(Week 48):
83.3 82.6
78.6 BKZ 160 mg (N=82)
77.9
80 75.4 75.6
Efficacy at 108 weeks (%)

70.5 BKZ 320 mg (N=41)

67.6 66.7
66.1 65.6 65.9
BKZ total (N=123)
60.9 59.3
60 57.1

TEAEs reported for Safety Set

40

20 ▪ Serious TEAEs in 9.3%

patients
▪ No deaths or major adverse
cardiac events
0
ACR50 BSA 0%* MDA** Dactylitis Enthesitis ▪ Oral candidiasis in 7.8%
patients (no serious cases)
Resolution Resolution**

Conclusion: BKZ leads to long-term efficacy for skin/joint manifestations of PsA, with >50% patients achieving high thresholds of disease control (ACR50, BSA 0%, MDA) after 108 weeks’
treatment. The safety profile reflects previous observations.1

Data for Dactylitis and Enthesitis Resolution were measured using non-responder imputation. All other data reported in figure was observed cases. *Patients with BSA ≥3% at baseline. **Data from OLE Week 72 (Week 120 total). 1. Ritchlin CT et al. Ann Rheum Dis
2019;78:127–8. ACR: American College of Rheumatology; BKZ: bimekizumab; BSA: body surface area; FAS: full analysis set; MDA: Minimal Disease Activity; OLE: open label extension; PsA: psoriatic arthritis;
TEAE: treatment-emergent adverse event
McInnes I et al. Ann Rheum Dis 2020;79(suppl 1):1149-1150. Abstract Number: SAT0403.
 O abordare terapeutica in trepte
AINS
Cortico-steroizi local (IA)
Remisive sintetice
conventionale
Biologice

Remisive
sintetice
tintite
Gossec L. et al., Ann Rheum Dis 2016, 75, 499-510
Coates L.C. et al., Arthritis Rheum 2016 epub

JAK inhibitors being evaluated for the treatment of

SpA include TOFA, FILGO, and UPA
TOFA UPA
• TOFA & UPA: approved for
csDMARD-IR OPAL Broaden1 SELECT-PsA 18 PsA
PsA • UPA is currently the only
JAKi approved for AS by
bDMARD-IR OPAL Beyond2 SELECT-PsA 29 EMA
• TOFA are currently under
investigation for AS
TOFA SELECT-AXIS 1b,10
AS NSAID-IR
AS studya,3 SELECT-AXIS 211

Filgotinib: stopped studies due to testicular toxicity concerns

1. Mease P, et al. N Engl J Med 2017;377:1537–50;

2. Gladman D, et al. N Engl J Med 2017;377:1525–36; 3. van der Heijde D, et al. Ann Rheum Dis 2017;76:1340–7;
aPhase 2. bPhase 2/3 4. Mease P, et al. Lancet 2018;392:2367–77; 5. Clinicaltrials.gov. NCT04115748;
6. Clinicaltrials.gov. NCT04115839; 7. van der Heijde D, et al. Lancet 2018;392:2378–87;
8. McInnes IB, et al. EULAR 2020 Abstract LB0001; 9. Genovese MC, et al. EULAR 2020 Abstract OP0223;
UPA Upadacitinib, TOFA Tofacitinib 10. van der Heijde D, et al. Lancet 2019;394:2108–17; 11. Clinicaltrials.gov. NCT04169373;
NSAID, non-steroidal anti-inflammatory drug
 A greater proportion of patients with PsA achieved ACR
responses with TOFA than PBO at Month 3

csDMARD-IR (OPAL Broaden)1 TNFi-IR (OPAL Beyond)2

100 100

80 † 80

Patients (%)
Patients (%)

***
† 61 †
†
60 **
50 52 † 60 ***
50 ***47
***
† 40
40 33 *** 33 40 30 **28
**
28 † † 24
**
17 14 * 19 15 17 14
20 10 20 10
5
0 0
ACR20 ACR50 ACR70 ACR20 ACR50 ACR70
(Coprimary endpoint) (Coprimary endpoint)
PBO (n=105) TOFA 5 mg (n=107) PBO (n=131) TOFA 5 mg (n=131)

• Both TOFA doses significantly increased ACR20 at Month 3 vs PBO & significantly increased ACR70
in patients with csDMARD-IR, but not in patients with TNFi-IR
• TOFA was associated with numerically similar ACR responses vs ADA in patients with csDMARD-IR
Comparisons unadjusted for multiplicity: Nominal *p≤0.05, **p≤0.01, ***p<0.001 vs PBO, †p≤0.05 according to
the prespecified stepdown testing procedure for global type I error control 1. Mease P, et al. N Engl J Med 2017;377:1537–50;
ACR20/50/70, 20%/50%/70% improvement in American College of Rheumatology criteria; PBO, placebo 2. Gladman D, et al. N Engl J Med 2017;377:1525–36
UPA is currently the only JAK inhibitor approved for AS by EMA, but it is not approved locally by any regulatory authority, FILGO & TOFA are currently under investigation for AS, TOFA is approved for PsA

A greater proportion of patients with PsA achieved ACR

responses with UPA than PBO at Week 12
Non-bDMARD-IR (SELECT-PsA 1)1 bDMARD-IR (SELECT-PsA 2)2
†
100 [###] 100
† [***]
[***] 79
80 71 80 [****]
65 ###
64
Patients (%)
Patients (%)

[****]
***
52 57
60 60
*** ****
36 38 38 ### 38
40 *** 40 32
****

25 24 ****
13 16
***
14 17
20 20 ****
9
2 5 1
0 0
ACR20
(Primary endpoint)
ACR50 ACR70 ACR20
(Primary endpoint)
ACR50 ACR70
PBO (n=423) UPA 15 mg (n=429) PBO (n=212) UPA 15 mg (n=211)

• Significantly greater proportions of patients achieved ACR50 and ACR70 with UPA vs PBO in both patient populations
• Both UPA doses achieved non-inferiority vs ADA in terms of ACR20 at Week 12, with UPA 30 mg achieving superiority
(ACR20) and greater response rates (ACR50/70) vs ADA, in patients with csDMARD-IR

Comparisons adjusted for multiplicity: [***]p<0.001, [****]p<0.0001 vs PBO; [###]p<0.001 vs ADA (superiority); †p<0.001 vs ADA
(non-inferiority). Comparisons unadjusted for multiplicity: Nominal ***p<0.001, ****p<0.0001 vs PBO; nominal ###p<0.001 vs ADA 1. McInnes IB, et al. EULAR 2020 Abstract LB0001;
(superiority) 2. Genovese MC, et al. EULAR 2020 Abstract OP0223
UPA is currently the only JAK inhibitor approved for AS by EMA, but it is not approved locally by any regulatory authority, FILGO & TOFA are currently under investigation for AS, TOFA is approved for PsA
 UPA inhibited radiographic progression vs PBO at Week 24 in
patients with non-biologic DMARD-IR PsA

Mean change from baseline in mTSS at Week 24

(non-bDMARD-IR; SELECT-PsA 1)
0.3
0.25 PBO (n=423)
UPA 15 mg (n=429)
0.2 UPA 30 mg (n=423)
∆ mTSS

0.1
[***]
0.03
0.01
0

-0.04
[***]
-0.1

UPA significantly inhibited radiographic progression vs PBO at Week 24

Comparisons adjusted for multiplicity: [***]p<0.001 vs PBO. Comparisons unadjusted for multiplicity: Nominal #p<0.05 vs ADA
aIn patients with LEI>0

LEI, Leeds Enthesitis Index; mTSS, modified Total Sharp Score McInnes IB, et al. EULAR 2020 Abstract LB0001
UPA is currently the only JAK inhibitor approved for AS by EMA, but it is not approved locally by any regulatory authority, FILGO & TOFA are currently under investigation for AS, TOFA is approved for PsA

Alte tsDMARDs: Apremilast

 inhibitor oral selectiv al enzimei fosfodiesteraza 4
 aprobat in APs & PsO
 Eficacitate buna pe toate componentele bolii
 Profil bun de tolerabilitate

Cutolo M et al, J Rheumatol 2016, 43; 1724-34

 Principiile terapiei APs
Controlul
Prevenirea Mentinerea
semnelor & Prevenirea
distructiei functiei
simptomelor comorbiditatilor
structurale articulare
bolii

Pastrarea
calitatii vietii

T2T in APs

Adaptarea Urmarind o tinta

tratamentului terapeutica

• TINTA:
remisiune sau MDA?
• Primul studiu T2T in
APs: TICOPA
Evaluari regulate
Recomandari pt T2T in APs
 Recomandari EULAR1: tratamentul va urmari atingerea
remisiunii sau alternativ a activitatii minimale/joase a
bolii, prin monitorizare regulata si ajustarea
corespunzatoare a terapiei

 Recomandari T2T2:
 remisiune: absenta oricarui semn clinic si de laborator de
activitate inflamatorie evidenta a bolii
 Alternativ activitate joasa/minimala a bolii

1. Gossec L. et al, Ann Rheum Dis 2016, 75, 499-510

2. Smolen J.S. et al., Ann Rheum Dis 2014, 73, 6-16

Recomandarile EULAR 2020

Gossec L, et al. Ann Rheum Dis 2020;79:700–712. doi:10.1136/annrheumdis-2020-217159

 Recomandarile EULAR 2020

Gossec L, et al. Ann Rheum Dis 2020;79:700–712. doi:10.1136/annrheumdis-2020-217159

Recomandarile GRAPPA 2021 pentru tratamentul APs

Consider which domains are involved, patient preference and previous/concomitant therapies;
choice of therapy should address as many domains as possible

Peripheral arthritis Axial disease Enthesitis Dactylitis Skin Nails

csDMARDs NSAIDs NSAIDs NSAIDs Topicals (keratolytics, Topical therapies,

Corticosteroid injections as indicated
NSAIDs and IAI corticosteroids as indicated

Physiotherapy and NSAIDs

steroids, vitamin D pulsed dye laser,

analogues, emollients, csDMARDs,
Physiotherapy

Topicals and phototx as indicated

Biologics (TNFi, MTX, TNFi, MTX, TNFi, calcineurin inhibitors) acitretin, JAKi
IL-12/23i, IL-17i, TNFi, IL-17i or IL-12/23i, IL-17i, IL-12/23i, IL-17i,
IL-23i) or JAKi, JAKi IL-23i, JAKi, IL-23i or JAKi,
PDE4i PDE4i PDE4i
Phototx or
csDMARDs, TNFi, IL-12/23i,
TNFi, IL-12/23i, IL-17i, IL-23i or
Switch biologics Switch biologics IL-17i, IL-23i, PDE4i
Switch biologic JAKi, PDE4i
(TNFi, IL-12/23i, (TNFi, IL-12/23i, Switch biologics
(TNFi, IL-17i) or
or IL-17i, IL-23i) IL-17i, IL-23i) or (TNFi, IL-12/23i,
JAKi
or JAKi, PDE4i JAKi, PDE4i IL-17i, IL-23i) or
JAKi, PDE4i
Switch biologic Switch biologic
Corticosteroid injections: TNFi, IL-12/23i, TNFi, IL-12/23i,
Limited direct evidence for
consider on an individual IL-17i, IL-23i, IL-17i, IL-23i, or
therapies in axial PsA;
basis due to potential for JAKi, PDE4i PDE4i
recommendations based on
serious side effects; no clear
axial SpA literature
evidence for efficacy

Black text = Strong recommendation Comorbidities and associated conditions may impact
Grey text = Conditional
Treat, periodically re-evaluate treatment
recommendation choice of therapy and/or guide monitoring goals and modify therapy as required
= Standard therapeutic route
= Expedited therapeutic route

csDMARD=conventional synthetic disease-modifying antirheumatic drug; GRAPPA=Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; IL-12/23i=interleukin 12/23 inhibitor; IL-17i=interleukin 17 inhibitor; IL-23i=interleukin 23 inhibitor; JAKi=Janus
kinase inhibitor; MTX=methotrexate; NSAID=nonsteroidal anti-inflammatory drug; PDE4i=phosphodiesterase 4 inhibitor; phototx=phototherapy; PsA=psoriatic arthritis; SpA=spondyloarthritis; TNFi=tumour necrosis factor inhibitor.
Coates LC, The Group For Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations 2021. EULAR 2021. Abstract OP0229. Reference available on request. Adapted from Coates L, et al. 2021
 APs: solutii potentiale
 diagnosticul precoce al bolii
 evaluarea corecta a ambelor fatete clinice: cutanata / articulara
 initierea imediata a tratamentului remisiv: clasic / biologic la non-
responsivi
 orientarea tratamentului catre tinte specifice: tegumente,
articulatii, dactilita, entezita, etc
 conlucrare: dermatolog & reumatolog