H. Nüßlein

Real-world effectiveness of abatacept for rheumatoid arthritis treatment in European and Canadian populations: a 6-month interim analysis of the 2-year, observational, prospective ACTION study

BackgroundDiscontinuation of rheumatoid arthritis (RA) treatment for lack or loss of initial response, tolerability issues, or development of antibodies against the therapeutic agent remains a challenge in clinical practice. Here we present a 6-month interim analysis of a 2-year prospective observational trial in Europe and Canada aiming to assess the real-world effectiveness, safety, and tolerability of intravenous abatacept for the treatment of moderate-to-severe RA.MethodsACTION (AbataCepT In rOutiNe clinical practice) is a prospective, observational study assessing effectiveness, safety, and tolerability of abatacept in patients with RA enrolled in Europe and Canada between May 2008 and January 2011. The patient population was divided into two groups: biologic naïve (‘first-line’) patients and patients who had previously failed treatment with at least one biologic agent (‘second-line’). Retention rates were calculated using Kaplan–Meier curve estimates. Effectiveness was measured using European League Against Rheumatism (EULAR) response criteria, the 28-item Disease Activity Score, the Clinical Disease Activity Index (CDAI), and physical function, as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Serious adverse events (SAEs) were reported for all enrolled patients.ResultsOf 1138 consecutively enrolled patients, 1114 and 1079 patients were evaluable for retention and effectiveness, respectively. Overall, retention rates were 88.6% (95% confidence interval [CI]: 86.4, 90.4); 67.4% of patients achieved good/moderate EULAR response; 32.8% had a CDAI Low Disease Activity State (LDAS); and 44.7% a HAQ-DI response. Retention rates among first- and second-line patients were 93.0% (95% CI: 85.9, 96.6) and 88.1% (95% CI: 85.7, 90.0), respectively. The percentage of patients achieving CDAI LDAS was 40.0% (95% CI: 26.4, 53.6) for first- and 32.2% (95% CI: 28.4, 36.0) for second-line patients and the proportion achieving a HAQ-DI response was 60.3% (95% CI: 47.8, 72.9) versus 43.1% (95% CI: 39.0, 47.2), respectively. The incidence of SAEs was 4.7%.ConclusionsEvidence from this 6-month interim analysis suggests that abatacept offers an effective and well-tolerated treatment option for patients with RA, including those who have previously failed anti-tumor necrosis factor treatment. In addition, higher retention rates and effectiveness outcomes were observed when abatacept treatment was initiated earlier in the course of the disease.

German guidelines for the sequential medical treatment of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs

The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease-modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice.

IGM-containing immune complexes and antiphospholipid antibodies in patients with Sneddon's syndrome

SummaryWe report three patients with a Sneddon syndrome in whom predominantly small (500–900 kD) IgM-containing serum immune complexes were detectable. Furthermore, antiphospholipid antibodies and increased von Willebrand factor antigen were found in the sera of two cases. Especially the data demonstrating small circulating immune complex as suggest that Sneddons syndrome, a rare vasculitis disorder, might immunologically be characterized by circulating IgM-containing immune complexes which, in addition, could play a role in the pathogenesis of this disease entity. The elevated antiphospholipid antibodies as well as the increased von Willebrand factor antigen in the sera of the investigated patients have to be considered as nonspecific vasculitis-associated phenomena.

The effect of body mass index on clinical response to abatacept as a first-line biologic for rheumatoid arthritis: 6-month results from the 2-year, observational, prospective ACTION study

OBJECTIVE To assess the impact of baseline body mass index (BMI) on the efficacy and retention of intravenous abatacept at 6 months in biologic-naïve patients with rheumatoid arthritis (RA). METHODS This was a 6-month analysis of a 2-year, non-interventional, international, prospective study. Baseline characteristics, clinical response and retention rates were compared by BMI subgroup: underweight/normal, overweight and obese (<25, 25 to <30 and ≥30kg/m2, respectively). RESULTS BMI was reported in 643/672 (96%) patients: 264 (41%) were underweight/normal, 224 (35%) overweight and 155 (24%) obese. At baseline, the obese group had more active disease (mean [95% confidence intervals] 28-joint Disease Activity Score [C-reactive protein; derived] 4.6 [4.5, 4.7], 4.8 [4.7, 5.0] and 5.1 [4.9, 5.2] for underweight/normal, overweight and obese groups, respectively), a higher prevalence of metabolic disorders, a greater proportion of women and a lower proportion of patients with rheumatoid factor positivity. There were no significant differences in the percentages of patients achieving a good/moderate European League Against Rheumatism response by BMI group (80.7, 86.1 and 77.0% for underweight/normal, overweight and obese groups, respectively; P=0.178). Overall retention rates at 6 months did not differ across groups (89, 92 and 89% for underweight/normal, overweight and obese groups, respectively; log-rank P=0.382). After adjustment for baseline characteristics, BMI was not significantly associated with risk of discontinuation (reference BMI<25kg/m2; hazard ratio [95% confidence intervals] 0.46 [0.22, 0.99] and 0.69 [0.34, 1.41] for overweight and obese patients, respectively). CONCLUSION BMI does not impact abatacept clinical response or retention in biologic-naïve patients with RA.

Decreased use of glucocorticoids in biological-experienced patients with rheumatoid arthritis who initiated intravenous abatacept: results from the 2-year ACTION study

Introduction Prolonged glucocorticoid use may increase the risk of adverse safety outcomes, including cardiovascular events. The European League Against Rheumatism and the Canadian Rheumatology Association advise tapering glucocorticoid dose as rapidly as clinically feasible. There is a paucity of published data on RA that adequately describe concomitant treatment patterns. Methods ACTION (AbataCepT In rOutiNe clinical practice) is a non-interventional cohort study of patients from Europe and Canada that investigated the long-term retention of intravenous abatacept in clinical practice. We assessed concomitant glucocorticoids in patients with established RA who had participated in ACTION and received ≥1 biological agent prior to abatacept initiation. Results The analysis included 1009 patients. Glucocorticoids were prescribed at abatacept initiation in 734 (72.7%) patients at a median 7.5 mg/day dose (n=692). Of the patients who remained on abatacept at 24 months, 40.7% were able to decrease their dose of glucocorticoids, including 26.9% who decreased their dose from >5 mg/day to ≤5 mg/day. Conclusion Reduction and/or cessation of glucocorticoid therapy is possible with intravenous abatacept in clinical practice.

Baseline autoantibodies preferentially impact abatacept efficacy in patients with rheumatoid arthritis who are biologic naïve: 6-month results from a real-world, international, prospective study.

Objectives To determine the impact of baseline rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) status on the clinical efficacy of intravenous abatacept in biologic-naïve patients with rheumatoid arthritis (RA) enrolled in the real-world ACTION study. Methods Clinical outcomes (European League Against Rheumatism (EULAR) response, mean Clinical Disease Activity Index (CDAI) and Boolean remission) at 6 months were compared by baseline RF and anti-CCP status. Results Of 672 biologic-naïve patients, RF status was reported in 577 (86%) (412 (71%) positive) and anti-CCP status in 552 (82%) (364 (66%) positive); of 511 patients for whom data were available, 308/511 (60%) were double positive and 127/511 (25%) were double negative. Clinical outcomes were improved with RF-positive or anti-CCP-positive versus RF-negative/anti-CCP-negative status—good or moderate EULAR response: RF: 84.6 vs 72.9%, p=0.012; anti-CCP: 85.2 vs 74.2%, p=0.015; mean CDAI (calculated): RF: 10.8 vs 15.3, p<0.001; anti-CCP: 10.9 vs 14.3, p=0.002; and Boolean remission: RF: 13.3 vs 4.0%, p=0.008; anti-CCP: 12.5 vs 6.3%, p=0.096. Clinical outcomes were also improved with single or double RF-positive/anti-CCP-positive versus double-negative status. Conclusions In biologic-naïve patients with RA, RF-positive and/or anti-CCP-positive status is associated with greater efficacy of intravenous abatacept than seronegative status. Trial registration number NCT02109666.

Real-world predictors of 12–month intravenous abatacept retention in patients with rheumatoid arthritis in the ACTION observational study

Introduction An understanding of real-world predictors of abatacept retention is limited. We analysed retention rates and predictors of abatacept retention in biologic-naïve and biologic-failure patients in a 12-month interim analysis of the 2-yearAbataCepTIn rOutiNe clinical practice (ACTION) study. Methods ACTION was an international, observational study of patients with moderate-to-severe rheumatoid arthritis (RA) who initiated intravenous abatacept. In this 12-month interim analysis, crude abatacept retention rates, predictors of retention and European League Against Rheumatism (EULAR) response were evaluated in both biologic-naïve and biologic-failure patients. Retention by rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) status was also assessed, in patients with or without baseline radiographic erosions, and by body mass index (BMI). Results Overall, 2350/2364 enrolled patients were evaluable (674 biologic naїve; 1676 biologic failure). Baseline characteristics were largely similar in biologic-naïve and biologic-failure groups. Crude retention rates (95% CI) at 12 months were significantly higher in biologic-naїve (78.1%(74.7% to 81.2%)) versus biologic-failure patients (69.9%(67.6% to 72.1%); P<0.001). RF/anti-CCP double positivity predicted higher retention in both patient groups, and remained associated with higher retention in patients with erosive disease. BMI did not impact abatacept retention in either patient group, irrespective of RF/anti-CCP serostatus. Good/moderate EULAR response rate at 12 months was numerically higher in biologic-naїve (83.8%) versus biologic-failure (73.3%) patients. There were no new safety signals. Conclusion High levels of intravenous abatacept retention in clinical practice were confirmed, particularly in biologic-naïve patients, including in those with poor RA prognostic factors. Retention was unaffected by BMI, regardless of RF/anti-CCP serostatus. Trial registration number NCT02109666; retrospectively registered 8 April 2014.

FRI0245 Abatacept retention rates and prognostic factors of retention in patients with rheumatoid arthritis: 2-year results from the real-world action study

Background The ACTION (NCT02109666) study was designed to provide prospective, real-world data on abatacept (ABA) retention in patients (pts) with RA. Objectives To assess the retention rate and to identify prognostic factors of ABA retention in the overall ACTION population and by treatment line over 2 yrs. Methods ACTION is a 2-yr, international, observational study of pts with RA who initiated IV ABA as first- or as second-/further-line biologic therapy in routine clinical practice. Biologic-naïve and biologic-failure pts were enrolled during three periods between May 2008 and December 2013. The primary endpoint was crude ABA retention rate over 2 yrs (Kaplan–Meier plot). Prognostic factors (p≤0.2) from univariate analyses with no colinearity, clinically relevant variables and known risk factors were entered into a multivariate model; factors with p≤0.1 were retained by backward selection. EULAR response was compared by Fishers exact test. Results In the ACTION cohort, 2350/2364 enrolled pts were evaluable for analysis; 673 (28.6%) were biologic naïve and 1677 (71.4%) had failed biologic treatment. Most biologic-failure pts (56.6%) had previously received ≥2 biologics. Some expected differences in baseline characteristics were observed between groups; mean (SD) RA duration was shorter (7.2 [8.2] vs 12.1 [9.1] yrs; p<0.001), more pts had RA for ≤2 yrs (35.7 vs 9.0%; p<0.001) and fewer pts had radiographic erosions (58.2 vs 71.5%; p<0.001) for biologic-naïve vs biologic-failure pts. At Yr 2, the overall retention rate was 47.9% (95% CI 45.7, 50.0). The retention rate was higher in biologic-naïve vs biologic-failure pts (54.5 vs 45.2%; p<0.001) and in pts with 1 vs ≥2 previous biologics (Fig). Reasons for discontinuation were comparable between groups; main reasons were lack of efficacy (61.4 vs 67.7%) and safety (21.3 vs 21.2%). RF and anti-citrullinated protein antibody (ACPA) seropositivity were prognostic factors for higher retention in biologic-naïve (p=0.030) and biologic-failure pts (p=0.028); other positively impacting factors were diabetes mellitus (p=0.044; biologic naïve); geographic location (p<0.001; biologic naïve) and ABA combination therapy (p<0.001; biologic failure). Only Pt Global Assessment (p=0.009; biologic failure) predicted lower retention. Among pts continuing ABA, a greater proportion of biologic-naïve vs biologic-failure pts had a good/moderate EULAR response (90.7 vs 81.6%; p=0.005) and RF/ACPA seropositivity was associated with a better response (p=0.002). There were no new safety signals. Conclusions In this first prospective, international, non-interventional research evaluating the long-term IV abatacept retention, RF and ACPA seropositivity were predictors of 2-yr higher retention and better outcomes. Higher retention rates may be achievable with earlier vs later initiation of abatacept treatment, consistent with prior findings from a pooled analysis of EU and Canadian registries.1 References Iannone F et al. Clin Rheumatol (2016): doi:10.1007/s10067–016–3505–5. Disclosure of Interest R. Alten Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, H.-M. Lorenz Consultant for: AbbVie, Bristol-Myers Squibb, Roche-Chugai, UCB, MSD, GSK, SOBI, Medac, Novartis, Janssen-Cilag, AstraZeneca, Pfizer, Actelion, X. Mariette Grant/research support from: Biogen, Pfizer, UCB, Consultant for: Bristol-Myers Squibb, LFB, Pfizer, GSK, UCB, H. Nüßlein Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, M. Galeazzi: None declared, F. Navarro Grant/research support from: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, Roche, Consultant for: Pfizer, MSD, Roche, UCB, AbbVie, Bristol-Myers Squibb, Jansen, Lilly, Speakers bureau: Pfizer, MSD, Roche, UCB, AbbVie, Bristol-Myers Squibb, M. Chartier Employee of: Bristol-Myers Squibb, Y. Elbez: None declared, C. Rauch Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Le Bars Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

AB0412 Less than 5% of real-life patients who switch from iv to sc abatacept in real-world clinical practice subsequently switch back to the iv formulation

Background Patients (pts) with RA may be able to switch from IV to SC abatacept with no loss of efficacy or safety concerns, but data are inconclusive.1–4 In the ACTION (AbataCepT In rOutiNe clinical practice; NCT02109666) study, a 1-year interim analysis showed that switching had no adverse clinical effect.5 Objectives To examine treatment patterns and explore abatacept formulation switching over 2 years in ACTION. Methods ACTION is a 2-year, prospective, observational study of pts with moderate-to-severe RA who initiated IV abatacept in Europe and Canada between May 2008 and December 2013. Assessments in biologic-naïve and biologic-failure pts were: baseline characteristics, rates of and reasons for switching (IV to SC), and re-switching to IV over 2 years. Descriptive data were generated: mean (SD) for continuous variables and n (%) for categorical variables. Rates of switching were estimated by Kaplan–Meier analysis. Cohorts were pooled to analyse further pts who switched owing to low numbers. Results In the ACTION cohort, 2350/2364 pts (99.4%) were evaluable for this analysis (673 [28.6%] biologic naïve, 1677 [71.4%] biologic failure). A total of 729 (43.4%) biologic-failure pts had received 1, and 948 (56.6%) had received ≥2 previous biologics. Baseline characteristics in biologic-naïve and biologic-failure pts, respectively, were: mean (SD) age 59.9 (12.7) and 56.9 (12.5) years; RA duration 7.2 (8.22) and 12.1 (9.13) years; 496 (73.7%) and 1379 (82.2%) were women; 621 (92.3%) and 1552 (92.5%) had received prior MTX; and 533 (79.2%) and 1386 (82.6%) had received corticosteroids. Over 2 years, 195 pts switched from IV to SC abatacept (57 biologic naïve, 138 biologic failure; Fig.). Reasons for switching were available for 172 pts (51 biologic naïve, 121 biologic failure; some had >1 reason); biologic naïve/biologic failure: pt wish 54.9%/62.0%, physician choice 31.4%/19.8%, safety 5.9%/9.9%, remission/major improvement 3.9%/5.0%, poor compliance 0%/4.1%, lack of efficacy 2.0%/3.3%, surgery 2.0%/0.8%, weight adjustment 2.0%/0%, other 49.0%/36.4%. Only eight pts (2.6%) re-switched to IV abatacept (2 biologic naïve, 6 biologic failure). Reasons for re-switching were: pt wish (n=4), lack of efficacy (n=4), safety issue (n=1) and other (n=2). Conclusions Less than 5% of pts who switched formulation from IV to SC abatacept in real-world clinical practice re-switched to the IV formulation, suggesting that switching has no adverse clinical impact. A change in formulation was mainly due to pt wish, reflecting their involvement in decision-making. References Keystone EC, et al. Ann Rheum Dis 2012;71:857–61. Mueller R, et al. Arthritis Rheumatol 2015;67(Suppl. 10):651–52. Reggia R, et al. J Rheumatol 2015;42:193–5. Monti S, et al. J Rheumatol 2015;42:1993–4. Alten R, et al. Ann Rheum Dis 2016;75(Suppl. 2):202. Disclosure of Interest R. Alten Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, H.-M. Lorenz Consultant for: AbbVie, Bristol-Myers Squibb, Roche-Chugai, UCB, MSD, GSK, SOBI, Medac, Novartis, Janssen-Cilag, Astra-Zeneca, Pfizer, Actelion, X. Mariette Grant/research support from: Biogen, Pfizer, UCB, Consultant for: Bristol-Myers Squibb, LFB, Pfizer, GSK, UCB, H. Nüßlein Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, M. Galeazzi: None declared, F. Navarro Grant/research support from: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, Roche, Consultant for: Pfizer, MSD, Roche, UCB, AbbVie, Bristol-Myers Squibb, Jansen, Lilly, Speakers bureau: Pfizer, MSD, Roche, UCB, AbbVie, Bristol-Myers Squibb, M. Chartier Employee of: Bristol-Myers Squibb, J. Heitzmann: None declared, C. Rauch Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Le Bars Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

AB0267 Treatment paradigms in real-world practice: biologic agent use prior to and after discontinuation of abatacept in the action study

Background ACTION is a 2-year, observational study of patients (pts) with moderate-to-severe RA who initiated IV abatacept (ABA) in Canada and Europe (NCT02109666). Objectives To determine pt biologic (b)DMARD use prior to initiation and after discontinuation of ABA overall and by treatment line in ACTION. Methods Pts with RA initiated IV ABA as first- or second-/further-line therapy. Biologic-naïve and biologic-failure pts were enrolled during three periods between May 2008 and December 2013. Pts could switch administration routes (IV to SC) during treatment. Crude retention rates (Kaplan–Meier) were compared by log-rank test. Results Of the 2364 pts enrolled, 2350 were evaluable for analysis: 673 (28.6%) were biologic naïve and 1677 (71.4%) biologic failures. Baseline characteristics differed: biologic-failure pts had longer RA duration, higher CRP levels and prevalence of radiographic erosions, and lower rates of chronic obstructive pulmonary disease and neoplasms vs biologic-naïve pts. Most biologic-failure pts (96.7%) had previously received ≥1 TNF inhibitor (TNFi): 48.7% had received 1 and 48.0% ≥2 TNFi; 56.6% had received ≥2 bDMARDs. The overall 2-year retention rate was 47.9% and was higher for biologic-naïve vs biologic-failure pts (54.5 vs 45.2%; p<0.001); the most common reasons for ABA discontinuation were inefficacy (61.4 vs 67.7%) and safety (21.3 vs 21.2%). In pts who discontinued ABA, 83.0% started a bDMARD ≤6 months after discontinuation (Table), most commonly ABA IV. Mean (SD) days from stopping ABA to starting a bDMARD was similar for biologic-naïve (93.4 [51.3]) and biologic-failure pts (93.6 [48.0]). Among pts who restarted ABA, 62 (80.5%) biologic-naïve and 158 (85.0%) biologic-failure pts were considered to have discontinued as the time from last dose was >84 (IV) or >28 (SC) days, and thus were no longer temporary discontinuations, as predefined in the protocol. Three pts discontinued for bad compliance, 3 for lack of efficacy, 3 for remission/major improvement, 12 for safety and 15 for surgery. A good/moderate EULAR response was achieved by 76.7% of pts at the last follow-up before ABA discontinuation and 58.3% at ABA restart; mean (SD) DAS28 (CRP) was 3.2 (1.1) and 3.8 (1.4), respectively. bDMARD ≤6 months after ABA discontinuation bDMARD prior to initial ABA treatment in pts who restarted ABA Biologic naïve Biologic failure Biologic failure n=186 n=526 n=186 None 35 (18.8) 86 (16.3) Abatacept 77 (41.4) 186 (35.4) – IV 71 (38.2) 170 (32.3) SC 6 (3.2) 16 (3.0) TNFi 41 (22.0) 74 (14.1) 181 (97.3) Adalimumab 10 (5.4) 12 (2.3) 108 (58.1) Etanercept 13 (7.0) 21 (4.0) 125 (67.2) Infliximab 7 (3.8) 13 (2.5) 55 (29.6) Certolizumab 7 (3.8) 17 (3.2) 5 (2.7) Golimumab 4 (2.2) 11 (2.1) 2 (1.1) Other bDMARD 33 (17.7) 180 (34.2) 51 (27.4) Anakinra 1 (0.5) 4 (0.8) 5 (2.7) Rituximab 6 (3.2) 58 (11.0) 30 (16.1) Tocilizumab 26 (14.0) 118 (22.4) 21 (11.3) Data are n (%) Conclusions Prior to abatacept treatment, over half of biologic-failure pts had received ≥2 bDMARDs and most had received a TNFi. After initial discontinuation (protocol defined), over one-third of pts restarted abatacept. Disclosure of Interest R. Alten Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, H.-M. Lorenz Consultant for: AbbVie, Bristol-Myers Squibb, Roche-Chugai, UCB, MSD, GSK, SOBI, Medac, Novartis, Janssen-Cilag, AstraZeneca, Pfizer, Actelion, Speakers bureau: AbbVie, Bristol-Myers Squibb, Roche-Chugai, UCB, MSD, GSK, SOBI, Medac, Novartis, Janssen-Cilag, AstraZeneca, Pfizer, Actelion, X. Mariette Grant/research support from: Biogen, Pfizer, UCB, Consultant for: Bristol-Myers Squibb, LFB, Pfizer, GSK, UCB, H. Nüßlein Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, M. Galeazzi: None declared, F. Navarro Grant/research support from: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, Roche, Consultant for: Pfizer, MSD, Roche, UCB, AbbVie, Bristol-Myers Squibb, Jansen, Lilly, Speakers bureau: Pfizer, MSD, Roche, UCB, AbbVie, Bristol-Myers Squibb, M. Chartier Employee of: Bristol-Myers Squibb, Y. Elbez: None declared, C. Rauch Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Le Bars Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb