SIAAIC - Firenze 10 Ottobre 2014 Artrite reumatoide: nuove strategie biologiche Prof. Fabrizio Cantini U.O.C. di Reumatologia Azienda USL 4 - Prato
From the arrival of biologics to targeted strategic treatment in RA 2000s Many advances in RA treatment in past 15 years Early initiation of DMARDs1 • Composite measures of disease • activity2,3 Definition of disease activity states • including ACR-EULAR remission4 Today Biological agents5 • T2T Remission (or LDA) Recommendations are achievable goals 1. Lard LR, et al. Ann J Med 2001;111:446–51. 2. van der Heijde D, et al. J Rheumatol 1993;20:579–81. 3. Smolen JS, et al. F. Cantini Rheumatology 2003;42;244–57. 4. Felson DT, et al. Arthritis Rheum 2011;63:573–86. 5. Smolen JS, et al. Lancet 2007;370:1861–74.
Currently Available Biologics Drug Dose/Admin. Target Use approval Off-label Infliximab (Remicade) 3-5 mg/Kg/iv TNFα RA,AS,PsA, BD,Uveitis, UC,Crohn Dis. Adalimumab (Humira) 40 mg/eow/sc TNFα RA,AS,PsA, BD,Uveitis Crohn Dis. Etanercept (Enbrel) 50 mg/we/sc TNFα RA,AS,PsA Golimumab (Simponi) 50 mg/mo/sc TNFα RA,AS,PsA Certolizumab (Cimzia) 400 mg/we TNFα RA 0,2,4 (loading) 200mg/eow/sc Anakinra (Kineret) 100 mg/day/sc IL1 RA AOSD Rituximab (Mabthera) 2X1000/mg/iv/ CD20 RA ANCA+ every 6 mo vasculitis Tocilizumab (Roactemra) 8 mg/Kg/mo IL6 RA GCA Abatacept (Orencia) 750 mg/mo/iv CD28 RA Sjogren S.
DAS28 Remission (Primary Endpoint) and DAS Remission at Week 52 60 49.8 * 51.3 * 50 40 27.8 27.8 MTX 30 ETN +MTX 20 10 0 DAS28 Remission DAS Remission ETANERCEPT IN EARLY RA COMET STUDY *P<0.001
Recommendations for a T2T approach in RA Overarching principles for RA treatment Primary treatment goal: Long-term HRQoL – Symptom control, prevention of structural damage, • normalisation of function, social participation Abrogation of inflammation is key – T2T: Measure disease activity, adjust therapy accordingly – Shared treatment decisions : Patients and rheumatologist – Smolen JS, et al. Ann Rheum Dis 2010;69:631–37 F. Cantini
Raccomandazioni della task force T2T in ar Approccio Treat-to-target: principi Il trattamento dell’AR deve basarsi su una decisione condivisa tra paziente e reumatologo L’obiettivo primario del trattamento del paziente con AR è ottenere la migliore qualità di vita a lungo termine attraverso il controllo dei sintomi, la prevenzione del danno strutturale, la normalizzazione della funzione e della partecipazione sociale. L’eliminazione dell’infiammazione è il modo principale per raggiungere questi obiettivi. Il trattamento al target con misurazione dell’attività di malattia e aggiustamento della terapia ottimizza i risultati nell’AR. Smolen J , et al. Ann Rheum Dis 2010;69:964–75; Smolen J, et al. Ann Rheum Dis 2010;69:631–37. F. Cantini
EULAR reccomendations and T2T F. Cantini
Algorithm based 2013 EULAR recommendations on RA management: Phase II Phase II Prognostically unfavorable Prognostically unfavorable factors present factors absent Failure for lack of efficacy and/or toxicity in Phase I Such as RF / ACPA, especially at high levels; very high disease activity, early joint damage Change to a second Add a biologic agent csDMARD strategy: Achieve LEF, SSA, MTX alone or No target within TNF inhibitor, in combinationb 6 monthsa ABA, or TCZ (ideally with addition of glucocorticoids as above) Failure Phase II: Achieve target No Yes Continue go to Phase III within 6 monthsa aThe treatment target is remission according to ACR-EULAR definition or, if remission is unlikely to be achievable, at least low disease activity; bNot many data available for combinations without MTX ABA, abatacept; ACPA, anti-citrullinated protein antibody; RF, rheumatoid factor; TCZ, tocilizumab F. Cantini
clinical practice, but ACR-EULAR remission associated with 5788 patients receiving a synthetic or biologic DMARD superior outcomes Patients (%) in remission at 3 and 6 months using various measures of remission ACR/ ACR/ DAS28 SDAI a CDAI a RAPID3 ACR/ EULAR EULAR (<2.6) (≤3.3) (≤2.8) (≤1) EULARc BOOLb PRACd 3 mos 19.1 7.6 8.1 17.0 6.9 9.3 8.1 MHAQ non progr. 65.7 63.9 64.9 65.2 64.2 63.6 65.6 3-12 mos 6 mos 24.7 10.5 11.3 19.8 9.0 12.3 11.0 MHAQ non- 69.6 73.5 73.6 69.8 74.9 72.6 73.7 progr. 6-12 mos ‒ RAPID3, Routine Assessment of Patient Index Data, range 0 10. aACR/EULAR index-based remission definitions bBOOL, Boolean application tender joint count, swollen joint count, patient global assessment and CRP all must be ≤1. cACR/EULAR remission if either ACR/EULAR BOOL is satisfied or SDAI ≤3.3. dACR/EULAR PRAC, definition of ACR/EULAR BOOL for clinical practice without CRP. F. Cantini MHAQ, modified health assessment questionnaire
• The earlier, the better – Diagnosis, treatment • The earlier, the better – Achieving remission?? F. Cantini
Low probability of reaching low disease activity at 2 and 3 years if it is not attained at year 1 If DAS 28 remains 3.2–5.1 after 1 year of conventional DMARD therapy, the • likelihood of remission or a LDA state is low DAS28<2.6 DAS28<3.2 DAS28≥3.2 80 Patients with year 1 60 DAS28 (3.2–5.1) 40 20 0 Year 2 Year 3 (n=418) F. Cantini Kiely P, et al. Rheumatology 2011;50:926–931
SWEFOT: DAS28 remission achieved in 60% and 72% of MTX patients at 1 and 2 years, respectively 1 year 2 years 487 RA p. MTX 18.1 mg/week MTX 16.5 mg/week 2 years 100 80 Patients (%) High activity 60 Moderate activity 40 Low activity Remission 20 0 DAS28 SDAI CDAI DAS28 SDAI CDAI Disease activity n = 114 107 109 110 102 103 CDAI, clinical disease activity index; DAS28, 28-joint-based disease activity score; SDAI, simple disease activity index. Rezaei H, et al. Ann Rheum Dis 2012;71:186–91 F. Cantini
10 9 8 7 6 5 4 3 2 1 0 F. Cantini
Initial combo with biologics not recommended in EULAR 2013 recommendations A. 6 months of MTX for achieving LDA B. T2T approach C. Rescue with ADA+MTX to ensure optimal outcomes (Data from OPTIMA study) F. Cantini
OPTIMA F. Cantini
Study Design ARM 1 MTX ADA+MTX / MTX Yes ARM 2 ADA 40 mg eow ADA 40 mg eow + MTX + MTX * Sustained ADA+MTX DAS28<3.2 wk 22 -26 Open label ADA 40 mg eow + MTX No ARM 3 1032 RA p. ADA+MTX IR / ADA+MTX MTX Yes ARM 4 Sustained MTX MTX * DAS28<3.2 wk 22 -26 ARM 5 Open label ADA 40 mg eow + MTX No MTX IR / ADA+MTX 26 weeks 52 weeks PERIOD 1 PERIOD 2 0 26 78 F. Cantini * MTX titrated to 20 mg/wk by Wk 8
OPTIMA: targeting stable DAS28(CRP)<3.2 at wk26 ADA+MTX 100 PBO+MTX 80 % of pts 60 40 20 207/466 112/460 240/466 155/460 238/466 132/460 0 *P<0.001 vs. PBO+MTX by chi-square test, Kavanaugh A, et al. Ann Rheum Dis 2013;72:64-71 NRI analysis for completers wk26 F. Cantini
A greater proportion of pts receiving ADA+MTX achieved the primary endpoint vs. PBO+MTX 100 * 80 % of patients 60 40 20 0 D mTSS < 0.5 from bl to wk 78 * P=0.023 ADA+MTX vs. PBO+MTX Smolen J, et al. Lancet 2013 F. Cantini
Although a high % of MTX+PBO achieved a LDA or clinical remission at week 78, a significantly greater % of ADA+MTX achieved LDA and clinical remission * ** ** 100 80 * % of Patinets 60 40 20 0 _ _ *P=0.034; **P=0.002; ***P=0.019 ADA+MTX vs MTX+PBO Smolen J, et al. Lancet 2013 F. Cantini
The size of the “Opportunity Lost”due to delayed initiation of ADA ADA+MTX (Period 1) (N=508) [arm 5 MTX IR / ADA+MTX] (n=347) Mean mTSS Change from Baseline Pts identified retrospectively as MTX-IR ADA+MTX 1,50 1,30 1,20 1,20 1,00 MTX IR 0,50 0,15 0,00 0,00 0,00 0 26 52 78 Weeks Period 1 Period 2 Smolen J, et al. Lancet 2013 F. Cantini
PREMIER F. Cantini
PREMIER study Percentage of Patients Achieving DAS28(CRP) <3.2 (A), DAS28(CRP) <2.6 (B), during the Course of 10 Years of Adalimumab ± MTX Treatment For 10-year completers, patients in the adalimumab + MTX DB group achieved DAS28 LDA (92.3%) and remission (75.6%) more readily than patients who initiated treatment with adalimumab (77.8% and 61.7%, respectively) or MTX (74.0% and 56.2%, respectively) monotherapy A B Keystone E et al, J Rheumatol 2014. F. Cantini
Percentage of radiographic non- progressors over time Over the course of the 10-year study, treatment initialization with adalimumab + MTX significantly limited radiographic progression (adalimumab + MTX vs adalimumab, p = 0.01; adalimumab + MTX vs MTX, p < 0.001), joint erosion, and JSN compared to initialization with either monotherapy A B Keystone E et al, J Rheumatol 2014. F. Cantini
Percentage of patients achieving CDC and CDR during the course For 10-year completers, CDC was reported in 17.8%, 8.6%, and 9.6% of adalimumab + MTX, adalimumab, and MTX patients, respectively. Increased proportion of combination therapy of 10 years of ADA ± MTX patients achieving CDC or CDR were all statistically significant compared to either monotherapy (p ≤ 0.01). treatment A B Keystone E et al, J Rheumatol 2014. F. Cantini
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