Treatment of psoria.c arthri.s: Guidelines and beyond. Pascal RICHETTE Hôpital Lariboisière, Paris

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1 Treatment of psoria.c arthri.s: Guidelines and beyond Pascal RICHETTE Hôpital Lariboisière, Paris

2 The pa.ent: a 37 year- old man, with a history of psoriasis for 10 years Past history: - Dyslipidemia Current oral medica.on - AtorvastaBn (20mg/d) - Acetaminophen (up to 4g/d): painful joints

3 Number of tender joints (out of the 28): 6 Number of and swollen joints: 7 Erythrocyte sedimentabon rate (ESR): 45 DAS28: 5.2 acbve disease Moderate acbvity Low acbvity Remission What are the therapeubc opbons?

4 Ann Rheum Dis 2012 Aim of the treatments in PsA - To alleviate pain - To improve function - To slow down or to prevent structural damage ARD 2009

5

6 Pirmohamed BMJ 2004; 329: Drugs most commonly implicated in causing admissions (UK)

7 «Surrogate markers of subclinical atherosclerosis, arterial stiffness and cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and metabolic-related factors, were more prominent in PsA compared with controls» ARD 2013

8 Included in the study were PsA patients and psoriasis without arthritis patients Multivariate adjusted model included for age, sex, education, psoriasis duration, current smoking status, Psoriasis Area and Severity Index score, biologics, methotrexate, and nonsteroidal antiinflammatory drugs for cardiovascular disease, hypertension, and gastrointestinal disease only. This finding suggests that the additive burden of chronic inflammatory joint disease may account for the increased prevalence of hypertension seen in PsA compared with psoriasis without arthritis patients

9 NSAIDs should be used cautiously in patients with PsA +++

10

11 ARTHRITIS & RHEUMATISM Vol. 50, No. 6, June 2004, pp mg/day loading dose for 3 days followed by 20 mg/day orally, or placebo for 24 weeks.

12 Leflunomide / PsA PsARC ACR20 Répondeurs (%) * p 0,0001 * p = 0,0138 Kaltwasser JP et al. Arthri0s Rheum 2004;50:

13 Efficacy on psoriasis (ITT)

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15 Black RL, O Brien WM, Vanscott EJ, et al. Methotrexate therapy in psoriatic arthritis; double-blind study on 21 patients. JAMA 1964 ; 189 : Scarpa R, Peluso R, Atteno M, et al. The effectiveness of a traditional therapeutical approach in early psoriatic arthritis: results of a pilot randomised 6- month trial with methotrexate. Clin Rheumatol 2008 ; 27 : Willkens RF, Williams HJ, Ward JR, et al. Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 1984 ; 27 :

16 - Inclusion criteria comprised: (i) clinically apparent psoriasis (skin or nails) and active inflammatory synovitis involving at least one peripheral joint A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA - Patients were assessed at baseline, 3 and 6 months. - The primary outcome measure was the PsA response criteria (PsARC). - Global secondary outcome assessments comprised ACR 20% improvement criteria (ACR20) and DAS for 28 joints (DAS-28)

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19 BIOLOGICS Risk ratios for PsA Response Criteria (PsARC) response at weeks. Risk ratios for ACR 20 response at 12 16

20 Risk ratios for ACR 70 response at weeks Risk ratios for PASI 50 response at weeks Dramatic effect of TNF blockers In PsA

21 Étude multicentrique randomisée en double insu, contrôlée vs placebo puis extension en ouvert pendant 48 semaines. RANDOMISATION ENBREL 25 mg 2 fois par semaine ENBREL 25 mg 2 fois par semaine n=101 n=88 Placebo Placebo n=104 n=81 ENBREL 25 mg 2 fois par semaine ENBREL 25 mg 2 fois par semaine Mease PJ et al. Arthritis Rheum 2004;50: Mease PJ et al. J Rheumatol 2006;33: Patients continued to receive blind-labeled therapy in a maintenance phase until all had completed the 24-week phase then could receive open-label etanercept in a 48-week extension.

22 Efficacy: W4 60% of responders ACR20 at W12 ACR20 ACR50 ACR70 % des patients répondeurs 59%!!! P=0,009!! P<0,001 50%!! 38%!! 38%!! 37%!! 11% 15% 13% 11%! 4% 11%!! 9%! 2% 4% 0% 1% 0% 1% 4 sem. 12 sem. 24 sem. 4 sem. 12 sem. 24 sem. 4 sem. 12 sem. 24 sem. Mease PJ et al. Arthritis Rheum 2004;50: Placebo (n=104) Enbrel (n=101)

23 Enbrel prevents structural damage and radiographic progression at month Enbrel 25 mg BIW (n=101) Placebo (n=104) Change from baseline Total Sharp Score Erosion Score Joint space narrowing P< for all Bme points Data shown are 24- week results from a blind- labeled study 1. Mease P, et al. ArthriBs Rheum 2004;50:

24 Enbrel halts radiographic progression through 2 years: PsA pa.ents with mtss 1.2 Enbrel 25 mg BIW/Enbrel 25 mg BIW (n=71) Placebo/Enbrel 25 mg BIW (n=70) Change from baseline (mean ± SE) Months 86% of Enbrel pa.ents maintained structural remission at 2 years 1. Mease P, et al. J Rheumatol 2006;33;

25 PRESTA: Propor.on of pa.ents achieving PASI 75 at weeks 12 and 24 Proportion of patients p < 0,001 36% 55% ETN 50 mg x 1 / 50 mg x 1 (n=371) ETN 50 mg x 2 / 50 mg x 1 (n=377) p < 0,026 62% 70% 0 Week 12 PASI 75 Week 24 PASI 90 at 6-month: 5/10 patients responders STERRY W and al. BMJ 2010;340:c147 CSR PRESTA

26 PRESTA: Percentage of par.cipants who achieved ACR 20/50/70 responses at weeks 12 and Sterry W, et al. BMJ 2010;340:c147.

27 Global Reten.on Rate of TNFi in PsA at 5 years 76% 57% 50% The clinical improvement was maintained through the 5 years with satisfying infliximab and adalimumab survival and high etanercept survival Saougou and al. Sem Arthrit 2011

28 CONCOMITANT MTX?

29 Concomitant MTX? Very li`le data NOR- DMARD cohort: no difference for efficacy but higher treatment maintenance with concomitant MTX Patients (n = 440) Without MTX (n = 170) with MTX (n = 270) Women (%) 47,6 45,6 Age 47,0 46,1 Dis duration 5,1 5,5 SJC 2 (0-5) 3 (1-7) Δ PGA 0-6 months -26,6 ± 28,6-23,9 ± 26,9 Fagerli K et al. ACR Nov 2012

30 MEASE: Propor.on of PsARC responders with/without Methotrexate Concomitant MTX Without MTX Proportion of PsARC responders W4 W12 W24 W4 W12 W24 Mease PJ et al. ArthriBs Rheum 2004;50:

31 Ustekinumab is a fully human IgG 1κ monoclonal an0body that binds to the common p40 subunit shared by interleukins 12 and 23 In this phase 3, adults with ac.ve psoria.c arthri.s ( 5 tender and 5 swollen joints, C- reac.ve protein 3 0 mg/l) were randomly assigned to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks therealer.

32 The primary efficacy endpoint was the proporbon of pabents with at least 20% improvement in ACR response criteria (ACR20) at week 24. At week 16, propor-ons of pa-ents with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [41 8%] vs 86 of 205 [42 0%]).

33 Apremilast is an oral PDE4 inhibitor that modulates cyclic AMP metabolism and in inflammatory cells results in decreased produc0on of pro- inflammatory mediators, such as TNF, IL17, and IL23, and increased produc0on of an0inflammatory mediators, such as IL10. This phase II, mul.center, randomized, double- blind, placebo- controlled study included the following: a 12- week treatment phase, with pa.ents receiving receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day

34 The primary end point was the propor.on of pa.ents achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Most pa.ents in the treatment phase (84.3%) and treatment extension phase (68.3%) reported >1 AE. Diarrhea, headache, nausea, fa.gue, and nasopharyngi.s were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormali.es were reported.

35 IL17 Inhibitors

36 42 pabents with acbve PsA fulfilling ClASsificaBon for PsoriaBc ARthriBs (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proporbon of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one- sided p<0.1). The ACR20 response rate at week 6 was 39% (9/23) for pa0ents who received secukinumab versus 23% (3/13) for those who received placebo. Although numerically higher for secukinumab, the ACR20 response rate was not sta0s0cally different from placebo (95% CI 0.38 to 15.15, p=0.27) and the primary endpoint was not met.

37 CONCLUSIONS - Close collaboration between Dermatologists and Rheumatologists is needed - Do not neglect NSAIDs - Several DMARDs for PsA - MTX, but also - SLZ - Leflunomide - TNF blockers: dramatic efficacy, and structural effect - Alternatives in a (close) future: IL-17 inhibitors, IL12/23 inhibitors, apremilast, (tofacitinib?)