Background: Previous studies have identified several predictors of radiographic spinal progression in patients with axial spondyloarthritis (axSpA), including pre-existing structural damage (syndesmophytes) and inflammatory activity.[1] Most of these studies were conducted in patients not receiving biological disease-modifying anti-rheumatic drugs (bDMARDs) or were focusing on only one drug class. Therefore, it is uncertain whether the factors associated with the progression of structural damage are the same for patients receiving bDMARDs with different modes of action. Objectives: The aim of this post-hoc analysis was to evaluate the relationship between baseline factors and radiographic spinal progression over 2 years in the SURPASS study (NCT03259074) in patients with radiographic (r-) axSpA treated with secukinumab (SEC, an interleukin [IL]-17A inhibitor) or adalimumab biosimilar (SDZ-ADL, a tumour necrosis factor [TNF] inhibitor). Methods: SURPASS was a phase IIIb randomised controlled study in biologic-naïve patients with active r-axSpA at high risk for radiographic spinal progression (high-sensitivity C-reactive protein [hsCRP] ≥5 mg/L and/or ≥1 syndesmophyte(s) on spinal radiographs). Patients were randomised (1:1:1) to receive SEC (150 or 300 mg; dose-blinded) or SDZ-ADL (40 mg; open label) for 2 years (104 weeks). The dataset considered for this post-hoc analysis included all patients with data available for radiographs and magnetic resonance imaging (MRI) of spine at baseline and week 104. Radiographic spinal progression was assessed by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) by 3 blinded readers. A patient was considered to have a syndesmophyte if at least 2 of the 3 readers assessed mSASSS score of ≥2 for any individual vertebral corner. The proportion of patients that developed new syndesmophytes (according to majority agreement - 2 of the 3 readers) was calculated. Spinal inflammation and fat lesions as assessed by MRI were evaluated by three blinded readers. Factors associated with new syndesmophyte formation (yes/no) at week 104 were analysed using univariable logistic regression analysis. A multivariable logistic regression analysis was also conducted, incorporating sex, current smoking, presence of syndesmophytes, elevated hsCRP, non-steroidal anti-inflammatory drug score, total spine oedema score and fatty lesion score as baseline covariates, with selection of these variables informed by both univariable analyses and clinical expertise. Results: A total of 288 patients (n=99 on SEC 150 mg, n=95 on SEC 300 mg, and n=94 on SDZ-ADL) were included in the analysis based on the availability of complete sets of radiographs and MRIs. Demographic and baseline disease characteristics are provided in Table 1. At week 104, new syndesmophytes were observed in 18.2%, 15.8%, and 14.9% of the patients receiving SEC 150 mg, SEC 300 mg, and SDZ-ADL, respectively. In the univariable analysis, the presence of syndesmophytes and higher level of inflammatory activity as reflected by elevated CRP, higher Axial Spondyloarthritis Disease Activity Score, and higher spinal MRI bone marrow oedema score at baseline were associated with the development of new syndesmophytes over 2 years (Table 2). There were no relevant differences between the treatment arms regarding the factors associated with new syndesmophyte formation. The multivariable analysis confirmed the association of baseline structural damage in the spine and inflammatory activity in predicting syndesmophyte formation after 2 years (Table 2). Conclusion: Pre-existing structural damage and high inflammatory activity at baseline were associated with new syndesmophyte development in r-axSpA patients irrespective of treatment with IL-17 or TNF inhibitors over 2 years. REFERENCES: [1] Poddubnyy D, and Sieper J. Curr Rheumatol Rep. 2017;19(9):55. Acknowledgements: NIL. Disclosure of Interests: Denis Poddubnyy Speaker fees from AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, UCB, Consultation fees from AbbVie, Biocad, BMS, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Samsung Bioepis, UCB, Research grant from AbbVie, Eli Lilly, MSD, Novartis, Pfizer, Juergen Braun Received speakers bureau fees from Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Medac, MSD (Schering-Plough), Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB pharma and Eli Lilly, Consultant for Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Eli Lilly, Grant/research support from Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Eli Lilly, Pedro Machado Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, Consulting/speaker's fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, Victoria Navarro-Compán Abbvie, BMS, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, MoonLake, MSD, Novartis, Pfizer, Roche and UCB, Consulting/speaker's fees from Abbvie, BMS, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, MoonLake, MSD, Novartis, Pfizer, Roche and UCB, Lianne S Gensler Consulting fees from AbbVie, Acelyrin, Eli Lilly, Fresenius Kabi, Janssen, MoonLake, Novartis, Pfizer and UCB, Grant/research support from Novartis, UCB, and Pfizer, Kay-Geert Hermann Lecture fees from MSD, Novartis, Pfizer, Consulting fees from AbbVie, Erhard Quebe-Fehling Owns Novartis stocks, Employee of Novartis Pharma AG, Basel, Switzerland, Christelle C. Pieterse Employee of Syneos Health contracting for Novartis, Aimee Readie Owns Novartis stocks, Employee of Novartis Pharmaceuticals Corporation, Corine Gaillez Own Novartis stock, Employee of Novartis Pharma AG, Xenofon Baraliakos Speakers' bureau AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Consultant for AbbVie, BMS, Celgene, Chugai, Galapagos, Merck, Novartis, Pfizer, UCB, Grant/research support from AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB.

L'étude SURPASS, essai de phase 3b randomisé contrôlé chez des patients (pts) atteints de spondyloarthrite axiale radiographique (SA), rapporte une faible progression radiographique sur 2 ans, sans différence significative entre les pts traités par sécukinumab (SEC) et un biosimilaire de l'adalimumab (ADL-SDZ) [1]. Les altérations radiographiques (présence de syndesmophytes) et les taux élevés de protéine C-réactive (CRP) à l'inclusion (INCL) ont été identifiés comme prédicteurs de la progression radiographique dans la SA.2. L'objectif de cette analyse est d'évaluer l'effet du SEC et de l'ADL-SDZ sur la progression radiographique du rachis dans les sous-groupes de pts avec des syndesmophytes et une CRP élevée à l'INCL dans l'étude SURPASS. Les pts naïfs de biologique avec une SA active et une CRP-hs ≥ 5 mg/L et/ou ≥ 1 syndesmophyte(s) à la radiographie ont été randomisés (1:1:1) en fonction du traitement par SEC (150/300 mg, aveugle sur la dose) ou ADL-SDZ (40 mg, en ouvert). Les pts étaient répartis en sous-groupe à l'INCL : CRP-hs ≥ 5 mg/L (CRP+), CRP-hs < 5 mg/L (CRP−), présence de syndesmophyte (Synd+), absence de syndesmophyte (Synd−), et CRP+ Synd+. La proportion de pts sans progression radiographique (variation par rapport à l'INCL du mSASSS [modified Stoke AS Spinal Score] ≤ 0,5), la variation du mSASSS par rapport à l'INCL et la proportion de pts sans nouveau syndespophyte(s) dans chaque groupe à 104 semaines (sem) a été rapportée (données observées). Parmi les 859 pts, 653 (76 %) étaient CRP+, 627 (73 %) étaient Synd+ et 466 (54 %) étaient CRP+ Synd+ à l'INCL. Les caractéristiques démographiques et de la maladie à l'INCL étaient équilibrées entre les sous-groupes et les bras de traitements, sauf pour le groupe Synd− qui présentaient un âge moyen, une proportion d'hommes et un délai de diagnostic inférieur aux autres sous-groupes. Tous les paramètres radiographiques à 104 sem étaient similaires entre les groupes de traitement ; pour autant, des différences étaient rapportées entre les sous-groupes indépendamment des traitements. Les sous-groupes Synd- et CRP- montraient la progression radiographique la plus faible pour tous les bras de traitement reflétée par une proportion plus élevée de pts sans progression radiographique et sans nouveau syndesmophyte ainsi que les variations de mSASSS par rapport à l'INCL les plus faibles. Le sous-groupe CRP + Synd+ ainsi que les sous-groupes Synd+ et CRP+ présentaient une progression radiographique plus élevée comparativement aux sous-groupes Synd− et CRP−. La progression radiographique est faible sur 2 ans, sans différence notable entre les bras SEC et ADL-SDZ, quelle que soit la présence ou l'absence de facteurs prédictifs spécifiques de progression (syndesmophytes/CRP élevée). Les patients des sous-groupes sans facteurs prédictifs (particulièrement Synd− et CRP−) présentaient les taux de progression radiographique les plus faibles.

Background SURPASS, a phase IIIb randomised controlled study in patients (pts) with radiographic axial spondyloarthritis (r-axSpA), found low spinal radiographic progression over 2 years with no significant difference between the secukinumab (SEC) and adalimumab biosimilar (SDZ-ADL) arms.[1,2] Baseline (BSL) radiographic damage (presence of syndesmophytes) and elevated C-reactive protein (CRP) levels have been identified as predictors of radiographic progression in r-axSpA.[3] Objectives To evaluate the effect of SEC and SDZ-ADL on spinal radiographic progression in subgroups of pts based on the presence of syndesmophytes and elevated high-sensitivity CRP (hsCRP) levels at BSL, from the SURPASS study. Methods Biologic-naïve pts with active r-axSpA and with hsCRP ≥5 mg/L and/or ≥1 syndesmophyte(s) on spinal radiographs were randomised (1:1:1) to SEC (150 or 300 mg; dose-blinded) or SDZ-ADL (40 mg; open label). Pts were categorised into the following subgroups at BSL: hsCRP ≥5 mg/L (CRP+), hsCRP <5 mg/L (CRP−), presence of syndesmophyte(s) (Synd+), absence of syndesmophyte(s) (Synd−), and CRP+Synd+. The proportion of pts with no radiographic progression (change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS] ≤0.5), mean change from BSL in mSASSS, and proportion of pts with no new syndesmophytes(s) in each subgroup at week 104 (all as observed) are reported. Results Of the 859 pts, 653 (76%) were CRP+, 627 (73%) were Synd+, and 466 (54%) were CRP+Synd+ at BSL. Demographic and BSL disease characteristics were largely balanced across subgroups and treatment arms, except for the Synd− group in which mean age, proportion of male pts, and mean time since diagnosis were lower than in other subgroups (Table 1). All radiographic outcomes at week 104 were similar across treatment arms; however, differences were observed between subgroups irrespective of the treatment arm. The Synd− subgroup followed by the CRP− subgroup showed the least progression in all radiographic outcomes (as indicated by the higher proportion of pts with no radiographic progression and no new syndesmophytes, and lower mean change from BSL in mSASSS), across treatment arms (Figure 1). The CRP+Synd+ subgroup followed by the Synd+ subgroup and the CRP+ subgroup had higher radiographic progression compared with the Synd− and CRP− subgroups (Figure 1). Conclusion Spinal radiographic progression over 2 years was low with no notable difference between SEC and SDZ-ADL arms regardless of the presence or absence of specific predictive factors for progression (syndesmophytes/elevated CRP). Expectedly, pts from subgroups without predictive factors (especially Synd−, followed by CRP−) had lower rates of radiographic progression. References [1]Baraliakos X et al. Clin Drug Investig. 2020;40(3):269-78 [2]Baraliakos X et al. Arthritis Rheumatol. 2022;74 (suppl 9) [3]Poddubnyy D et al. Arthritis Rheum. 2012;64(5):1388-98 Acknowledgements: NIL. Disclosure of Interests Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Celgene, Chugai, MSD, Novartis, Pfizer, UCB, Consultant of: AbbVie, BMS, Celgene, Chugai, Galapagos, MSD, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, BMS, Celgene, Chugai, MSD, Novartis, Pfizer, UCB, Désirée van der Heijde Consultant of: Personal fees from Novartis, AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Pfizer, UCB Pharma, Pedro Machado Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, Victoria Navarro-Compán Speakers bureau: Abbvie, BMS, Eli Lilly, Galapagos, Janssen, MoonLake, MSD, Novartis, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Eli Lilly, Galapagos, Janssen, MoonLake, MSD, Novartis, Pfizer, Roche and UCB, Grant/research support from: AbbVie, Novartis, Lianne S. Gensler Consultant of: AbbVie, Acelyrin, Gilead, Eli Lilly, Fresenius Kabi, Janssen, MoonLake, Novartis, Pfizer and UCB, Grant/research support from: Novartis, UCB, Patricia Pertel Shareholder of: Novartis, Employee of: Novartis, Erhard Quebe-Fehling Shareholder of: Novartis, Employee of: Novartis, Aimee Readie Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis, Employee of: Novartis, Denis Poddubnyy Speakers bureau: AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, UCB, Consultant of: AbbVie, Biocad, BMS, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Samsung Bioepis, UCB, Grant/research support from: AbbVie, Eli Lilly, MSD, Novartis, Pfizer.

Peu de données sont disponibles concernant l’efficacité des traitements biologiques sur la progression radiographique dans les spondyloarthrites axiales radiographiques (SA). Les données à 2 ans de l’études MEASURE 1 ont montré une progression radiographique ralentie avec le sécukinumab (SEC) [1]. L’étude SURPASS est la 1re étude visant à comparer l’effet du SEC versus un biosimilaire de l’adalimumab (ADL-SDZ) sur la progression radiographique [2]. Il s’agit d’un essai de phase 3b mené chez des patients (pts) atteints de SA active, naïfs de traitement biologique avec un BASDAI ≥ 4, une douleur rachidienne ≥ 4 et soit une CRP-hs ≥ 5 mg/L et/ou ≥ 1 syndesmophyte(s) à la radiographie (Rx). Les patients étaient randomisés en 3 groupes (1:1:1) en fonction du traitement par SEC (150/300 mg) ou ADL-SDZ. L’analyse de Rx et des IRM était centralisée et réalisée par 3 relecteurs indépendants et en aveugle pour le traitement et la chronologie des images. Le critère principal était la proportion de pts sans progression radiographique (variation par rapport à l’inclusion du mSASSS [modified Stoke AS Spinal Score] ≤ 0,5) pour SEC versus ADL-SDZ à 104 semaines (sem). Les critères secondaires incluaient la variation par rapport à l’inclusion à 104 sem, du mSASSS et des scores d’inflammation des articulations sacro-iliaques (SI ; score de Berlin) et du rachis (score ASspiMRI-a [AS Spine MRI-activity]), la proportion de pts avec ≥ 1 syndesmophyte(s) à l’inclusion sans nouveau syndespophyte(s) et la tolérance. Les 859 pts randomisés ont reçu SEC 150 mg (n = 287), SEC 300 mg (n = 286) ou ADL-SDZ (n = 286). Cette population présentait un risque important de progression radiographique puisque constituée de 78,5 % d’hommes d’âge moyen de 42,1 ans avec un mSASSS moyen de 16,6 ; un BASDAI moyen de 7,1 ; une CRP-hs de 20,4 mg/L et 73 % de pts avec ≥ 1 syndesmophyte(s). À 104 sem, la distribution cumulée des pts sans progression radiographique par rapport à l’inclusion était similaire entre les 3 bras. La proportion de pts sans progression radiographique était de 66,1 % ; 66,9 % et 65,6 % (p = ns) et la variation moyenne du mSASSS par rapport à l’inclusion était de 0,54 ; 0,55 et 0,72 avec SEC 150 mg, 300 mg et ADL-SDZ, respectivement. Parmi les pts avec ≥ 1 syndesmophyte(s) à l’inclusion, 56,9 % ; 53,8 % et 53,3 % des pts SEC 150 mg, 300 mg et ADL-SDZ, respectivement, ne présentaient pas de nouveau syndespophyte(s). Parmi les pts avec une IRM (n = 418), les scores des SI étaient, à l’inclusion puis à 16 sem, de 2,54 et 0,98 (SEC 150 mg) ; 1,96 et 0,92 (SEC 300 mg) et 1,59 et 0,38 (ADL-SDZ). Les scores correspondants pour le rachis étaient de 3,50 et 1,79 ; 2,56 et 1,25 ; 3,00 et 0,71. La progression radiographique est faible sur 2 ans, sans différence significative entre les bras SEC et ADL-SDZ. Aucun nouveau signal de tolérance n’a été rapporté.

Background:Magnetic resonance imaging (MRI) offers a non-invasive and objective method of early diagnosis and classification, monitoring disease burden and treatment response for patients (pts) with axial spondyloarthritis (axSpA) including ankylosing spondylitis (AS).1Numerous scoring schemes such as the AS Spine MRI Activity (ASspiMRIa) score are available for the quantitative assessment of MRI, but are subject to intra- and inter-rater variability, labor intensive and costly. Nevertheless, quantification of MRI changes has become an important tool to demonstrate treatment success of biologic drugs in axSpA.Objectives:To evaluate the performance of machine learning (ML) based software for automated Berlin grading of spinal MRI bone marrow oedema in pts with AS and compare with expert scoring.Methods:Fully automated ML software (Figure) was developed to detect and label 23 vertebrae, define vertebral units (VU) as per the Berlin modification of the ASspiMRIa score, and score each VU as either 0 (score of 0) or 1 (score of 1, 2 or 3). The ML algorithm was based on the previously developed SpineNet software.2Analysis included 108 pts from the secukinumab MEASURE 1 study3, in which imaging was done using T1 and STIR sagittal MRI at baseline and Weeks 16, 52, 104, 156 and 208. Two expert readers, blinded to treatment and visit, evaluated all images by ASspiMRIa score. The scores from Reader 2 (R2) were binned into two groups: 0 vs 1, 2, or 3. As a result of multiple pt time points and expert reading sessions, the complete dataset comprised of 10,988 VU. Ten-way cross-validation at per-VU was used to train and validate the ML software. The dataset was split into 10 randomly selected subsets, ensuring that each pt appears in only one subset, after which 8 subsets were used for training the ML software, 1 was used to check for correct training and 1 was used for validation. The process was repeated ten times such that all 10 subsets were used for validation. Accuracy weighted for the frequency of each category, sensitivity and specificity were calculated using scores from R2 as reference. Intra-reader accuracy was also calculated.Results:Accuracy of the software in relation to expert reader scores was 67% with a sensitivity of 0.63 and specificity of 0.70. The intra-reader accuracy was 71% and 77% for R1 and R2, respectively. Individual VU scoring of the Software vs. R2 are presented in the Table as a confusion matrix.Conclusion:Automated scoring of MR images in AS pts provided moderate agreement to that of expert reader-based assessments. ML software has potential to provide an automated guided-reading approach to scoring MR images, which may enable further clinical insights.References:[1]Lukas C, et al. J Rheumatol. 2007;34:862-70.[2]Jamaludin A, et al. Eur Spine J. 2017;26:1374-83.[3]Baeten D, et al. N Engl J Med. 2015;373,2534-48.Figure.Processing pipeline of automated Berlin scoring softwareTable.Confusion matrix between the software and R2SoftwareScore = 0SoftwareScore = 1, 2 or 3Total VU scoredR2 Score = 07199 (70%)3068 (30%)10,267R2 Score = 1, 2 or 3251 (35%)475 (65%)7267,4503,54310,993Percentages calculated as a fraction over the total in each row. Overall accuracy is the average of the highlighted percentages.Disclosure of Interests:Amir Jamaludin: None declared, Rhydian Windsor: None declared, Sarim Ather: None declared, Timor Kadir: None declared, Andrew Zisserman: None declared, Juergen Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD (Schering Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis, and UCB Pharma, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Lianne S. Gensler Grant/research support from: Pfizer, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, GSK, Novartis, UCB, Pedro Machado Consultant of: Abbvie, Celgene, Janssen, Lilly, MSD, BMS, Novartis, Pfizer, Roche and UCB, Speakers bureau: AbbVie, Centocor, Eli Lilly, Janssen, MSD, Novartis, Pfizer and UCB Pharma, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Thibaud Coroller Shareholder of: Novartis, Employee of: Novartis, Brian Porter Shareholder of: Novartis, Employee of: Novartis, Shephard Mpofu Shareholder of: Novartis, Employee of: Novartis, Aimee Readie Shareholder of: Novartis, Employee of: Novartis

The aim of this study was to compare radiographic progression in patients with ankylosing spondylitis (AS) treated for up to 2 years with secukinumab (MEASURE 1) with a historical cohort of biologic-naïve patients treated with NSAIDs (ENRADAS). Baseline and 2-year lateral cervical and lumbar spine radiographs were independently evaluated using mSASSS by two readers, who were blinded to the chronology and cohort of the radiographs. The primary endpoint was the proportion of patients with no radiographic progression (mSASSS change ≤ 0 from baseline to year 2). The Primary Analysis Set included patients with baseline (≤ day 30) and post-baseline day 31–743 radiographs. Sensitivity analyses were performed to assess the robustness of the comparison between the two cohorts, as follows: Sensitivity Analysis Set 1 included all patients with baseline (≤ day 30) and year 2 (days 640–819) radiographs; Sensitivity Analysis Set 2 included all patients with baseline and post-baseline (> day 30) radiographs. A total of 168 patients (84%) from the MEASURE 1 cohort and 69 (57%) from the ENRADAS cohort qualified for the Primary Analysis Set. Over 2 years, the LS (SE) mean change from baseline in mSASSS for the primary analysis was 0.55 (0.139) for MEASURE 1 vs 0.89 (0.216) for ENRADAS (p = 0.1852). Mean changes from baseline in mSASSS were lower in MEASURE 1 vs ENRADAS for the primary and sensitivity analyses. The proportion of patients with no radiographic progression was consistently higher in the MEASURE 1 vs ENRADAS cohort across all cutoffs for no radiographic progression (change in mSASSS from baseline to year 2 of ≤ 0, ≤ 0.5, ≤ 1, and ≤ 2), but the differences were not statistically significant. Secukinumab-treated patients demonstrated a numerical, but statistically non-significant, higher proportion of non-progressors and lower change in mSASSS over 2 years versus a cohort of biologic-naïve patients treated with NSAIDs.

Background Secukinumab, a fully human interleukin 17A (IL-17A) inhibitor, improved signs and symptoms of ankylosing spondylitis (AS) in patients (pts) in the MEASURE 1 core trial at 2 years and through 4 years in the extension study.1,2 A low radiographic progression rate was reported for the modified Stoke Ankylosing Spondylitis Spinal Score (Δ mSASSS at Yr 2=0.3).1 Comparison of anti-TNF agents with historical NSAID-treated cohorts have not shown a significant benefit at 2 years in reducing radiographic progression.3,4 Objectives This retrospective analysis compared spinal radiographic progression over 2 years in the MEASURE 1 cohort of secukinumab-treated AS patients (C1; NCT01358175) vs a historical cohort of biologic-naïve AS pts (ENRADAS [C2; NCT00715091]).5 Methods Baseline (BL) and 2 year X-ray data from the 2 cohorts were compared. Only data from pts with X-rays at BL and Yr 2 (data capture window for Yr 2 X-rays: 31–744 days) were included (n=168 [C1], n=69 [C2]). X-rays were independently re-evaluated using the mSASSS by 2 reviewers and an adjudicator blinded to the timing and cohorts; averaged values were analysed. Cases with the highest difference in Δ mSASSS between readers (top 10%) were adjudicated. The primary outcome was to compare the% pts with no radiographic progression (Δ mSASSS at Year 2≤0) in C1 vs C2. The difference between C1 and C2 was analysed using a logistic regression with cohort as a factor and BL mSASSS as a covariate. Results BL demographics were comparable across cohorts, with mean age 40.9 vs 42.6 years, and gender 72.8% vs 66.7% male in C1 vs C2, respectively. Over 2 years, least squares (LS) mean Δ mSASSS was 0.55 for C1 vs 0.89 for C2 (p=0.185) and% pts with no radiographic progression (Δ mSASSS at Year 2≤0) was slightly higher in C1 vs C2 (table 1). Conclusions Over 2 years, a numerically lower rate of progression was seen in secukinumab-treated pts vs a control cohort of biologic-naïve AS pts. Further research is needed to understand the impact of IL-17A inhibition with secukinumab on spinal disease progression in AS pts; SURPASS (NCT03259074), an ongoing H2H study powered to compare differences in spinal radiographic progression with secukinumab vs biosimilar adalimumab, will help answer these questions. References [1] Braun J, et al. Ann Rheum Dis Ann Rheum Dis2017;76:1070–77. [2] Braun J, et al. Arthritis Rheumatol2017;69(10). [3] van der Heijde D, et al. Arthritis Rheum2008;58:1324–31. [4] van der Heijde D, et al. Arthritis Res Ther2009;11:R127. [5] Sieper J, et al. Ann Rheum Dis2016;75:1438–43. Disclosure of Interest J. Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Consultant for: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis and UCB, H. Haibel: None declared, M. de Hooge Employee of: MdH Research, R. Landewé Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB and Wyeth, Consultant for: Abbott/AbbVie, Ablynx, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB and Wyeth, Employee of: Rheumatology Consultancy BV, Speakers bureau: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB and Wyeth, M. Rudwaleit Speakers bureau: Abbvie, BMS, Celgene, Chugai, Janssen, MSD, Novartis, Pfizer, UCB, T. Fox Shareholder of: Novartis, Employee of: Novartis Pharma AG, A. Readie Shareholder of: Novartis, Employee of: Novartis Pharmaceuticals Corporation, H. Richards Shareholder of: Novartis, Employee of: Novartis Pharma AG, B. Porter Shareholder of: Novartis, Employee of: Novartis Pharmaceuticals Corporation, R. Martin Shareholder of: Novartis, Employee of: Novartis Pharmaceuticals Corporation, D. Poddubny Grant/research support from: Abbvie, Janssen, MSD, Novartis and Pfizer, Consultant for: AbbVie, Bristol-Myers Squibb, MSD, Novartis, Pfizer and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer, Roche and UCB, J. Sieper Grant/research support from: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Merck, Lilly, Pfizer, and UCB, Consultant for: AbbVie, Janssen, Novartis, Merck, Lilly, Pfizer, Sun and UCB, Speakers bureau: AbbVie, Janssen, Novartis, Merck, Pfizer, Roche and UCB, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boeringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB, Employee of: Imaging Rheumatology BV

BACKGROUND: Fixed combinations are commonplace in dermatology, providing significant efficacy and tolerability benefits. In some cases, two active ingredients complement each other providing a cumulative or additive effect. In rarer cases, a synergistic effect may be seen where the sum of the two active ingredients combined action is greater than the sum of the efficacy of the constituent parts. Being able to demonstrate synergy is important in situations where the two active ingredients may be used individually to provide layering. OBJECTIVE: To determine whether a novel halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic effect in the treatment of moderate-to-severe plaque psoriasis. MATERIALS/METHODS: Post hoc analysis of 212 patients with moderate-to-severe plaque psoriasis randomized (2:2:2:1) to HP/TAZ lotion, HP, TAZ or vehicle once-daily for 8 weeks, with a 4-week posttreatment follow-up. Treatment success was evaluated based on two outcomes: percent of patients achieving at least a 2-grade improvement in Investigator Global Assessment (IGA) and IGA score equating to ‘clear’ or ‘almost clear’; and percent change from baseline in the IGA multiplied by Body Surface Area (BSA) composite score, a simple validated alternative to assessing response to therapy that correlates well with the Psoriasis Area Severity Index (PASI). Synergy was calculated by summing up the contribution of the individual active ingredients (HP and TAZ) to overall efficacy and comparing to the efficacy achieved with HP/ TAZ lotion relative to vehicle. RESULTS: At Week 8, treatment success with HP/TAZ lotion, relative to vehicle was 42.8% compared with 23.6% and 9.0% for HP and TAZ. Percent change from baseline in IGAxBSA score, relative to vehicle was 51.6% compared with 37.3% and 3.3% for HP and TAZ. In both cases the synergy ratios were 1.3. At Week 12, treatment success with HP/TAZ lotion, relative to vehicle was 31.3% compared with 14.1% and 5.9% for HP and TAZ. Percent change from baseline in IGAxBSA score, relative to vehicle was 47.3% compared with 25.7% and 8.6% for HP and TAZ. Synergy ratios were 1.6 and 1.4 respectively. CONCLUSIONS: Halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic effect in the treatment of moderate-to-severe plaque psoriasis. In addition, by combining two agents into one once-daily formulation, this novel formulation reduces the number of product applications and may help patient adherence. CORRESPONDENCE: brian.bulley@btinternet.com DISCLOSURES: Tina Lin, is an employee of Bausch Health; Leon Kircik: has been a consultant and investigator for Valeant Pharmaceuticals.

Background Psoriatic arthritis (PsA) is associated with joint inflammation, characterised by synovitis, presence of erosions, joint space narrowing (JSN) and new bone formation leading to structural damage, increased disability and reduced quality of life. Secukinumab (SEC) provided significant and rapid clinical efficacy, and inhibition of radiographic progression in PsA patients (pts) in the FUTURE 5 study.1 Objectives To assess the effect of subcutaneous (sc) SEC on radiographic progression by prior anti–TNF therapy or concomitant methotrexate (MTX) use in the FUTURE 5 study. Methods Adults (n=996) with active PsA, stratified by prior anti–TNF therapy (naïve and inadequate response/intolerance [IR]) were randomised 2:2:2:3 to sc SEC 300 mg with loading dose (LD), 150 mg LD, 150 mg no LD, or placebo (PBO) at baseline (BL), Wks 1, 2, 3, 4, and every 4 wks thereafter.1 At Wk 16, PBO non-responders were switched to SEC 300 or 150 mg. Concomitant MTX (≤25 mg/week) was allowed. Radiographic progression (mean change in van der Heijde-modified total Sharp score for PsA [vdH-mTSS] and its components: erosion and joint space narrowing [JSN] scores from BL to Wk 24) was based on hand/wrist/foot X-rays obtained at BL, Wks 16 (non-responders) assessed by two blinded readers (plus an adjudicator if required). Average scores were used. Statistical analyses used linear extrapolation at Wk 24 for all PBO non-responders and for all other pts with missing Wk 24 X-rays. Results At BL, 30% pts were anti–TNF-IR and 50% were on concomitant MTX. Radiographic progression was significantly inhibited at Wk 24 in the overall population with SEC vs PBO; mean change from BL in vdH-mTSS was 0.08 (300mg; p<0.01), 0.17 (150mg; p<0.05),–0.09 (150mg no LD; P<0.01) vs 0.50 (PBO). Lower radiographic progression (vdH-mTSS, erosion and JSN scores) was observed with SEC vs PBO regardless of prior anti–TNF therapy or concomitant MTX use (table 1). Conclusions Subcutaneous secukinumab 300 mg with loading dose, and 150 mg with and without loading dose, inhibited radiographic progression in patients with active PsA. Low rates of radiographic progression were observed regardless of previous anti-TNF therapy or concomitant MTX use. Reference [[1] ] ] Mease PJ, et al. Arthritis Rheumatol2017;69(suppl 10). Disclosure of Interest D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB, Employee of: Director of Imaging Rheumatology, P. Mease Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, SUN, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Covagen, Crescendo, Janssen, LEO, Lilly, Merck, Novartis, Pfizer, SUN, and UCB; speakers’ bureau for AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Pfizer, and UCB, R. Landewé Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB, Wyeth, Employee of: Director of Rheumatology Consultancy BV, Speakers bureau: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB, Wyeth, S. Mpofu Shareholder of: Novartis, Employee of: Novartis, P. Rahman Consultant for: Abbott, AbbVie, Amgen, BMS, Celgene, Janssen, Novartis, Pfizer and Roche, pharmaceutical companies dealing with biologic agents in Rheumatology, H. Tahir Grant/research support from: Novartis, Pfizer, Consultant for: Abbvie, Novartis, Pfizer, UCB, Eli-Lilly, Janssen, A. Singhal Grant/research support from: AbbVie, Gilead, Sanofi, Regeneron, Amgen, Roche, BMS, Janssen, Lilly, Novartis, Pfizer, UCB, Astra Zeneca, MedImmune, FujiFilm, Nichi-Iko, Mallinckrodt, Speakers bureau: AbbVie, E. Boettcher Consultant for: Amgen, Roche, Eli Lilly, Pfizer, MSD, Novartis, Speakers bureau: Amgen, Roche, Eli Lilly, Pfizer, MSD, Novartis, S. Navarra Consultant for: Pfizer, Novartis, Astra-Zeneca, Janssen, Astellas, Roche, Speakers bureau: Pfizer, Novartis, Astra-Zeneca, Janssen, Astellas, Roche, X. Zhu Employee of: Novartis, A. Readie Shareholder of: Novartis stock, Employee of: Novartis, L. Pricop Shareholder of: Novartis stock, Employee of: Novartis, K. Abrams Shareholder of: Novartis stock, Employee of: Novartis

OBJECTIVE:Secukinumab improved the signs and symptoms of ankylosing spondylitis (AS) over 52 weeks in the phase III MEASURE 2 study. Here, we report longer-term (104 weeks) efficacy and safety results.METHODS:Patients with active AS were randomized to subcutaneous secukinumab 150 mg, 75 mg, or placebo at baseline; weeks 1, 2, and 3; and every 4 weeks from week 4. The primary end point was the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) response rate at week 16. Other end points included ASAS40, high-sensitivity C-reactive protein, ASAS5/6, Bath Ankylosing Spondylitis Disease Activity Index, Short Form 36 health survey physical component summary, ASAS partial remission, EuroQol 5-domain measure, and Functional Assessment of Chronic Illness Therapy fatigue subscale. End points were assessed through week 104, with multiple imputation for binary variables and a mixed-effects model repeated measures for continuous variables.RESULTS:Of 219 randomized patients, 60 of 72 (83.3%) and 57 of 73 (78.1%) patients completed 104 weeks of treatment with secukinumab 150 mg and 75 mg, respectively; ASAS20/ASAS40 response rates at week 104 were 71.5% and 47.5% with both secukinumab doses, respectively. Clinical improvements with secukinumab were sustained through week 104 across all secondary end points. Across the entire treatment period (mean secukinumab exposure 735.6 days), exposure-adjusted incidence rates for serious infections and infestations, Crohn's disease, malignant or unspecified tumors, and major adverse cardiac events with secukinumab were 1.2, 0.7, 0.5, and 0.7 per 100 patient-years, respectively. No cases of tuberculosis reactivation, opportunistic infections, or suicidal ideation were reported.CONCLUSION:Secukinumab provided sustained improvement through 2 years in the signs and symptoms of AS, with a safety profile consistent with previous reports.

Background Secukinumab, an anti–interleukin-17A monoclonal antibody, improved the signs and symptoms of ankylosing spondylitis (AS) over 52 weeks (wks) in the randomised, double-blind, placebo (PBO)-controlled, Phase 3 MEASURE 2 study (NCT01649375).1 Objectives To evaluate the long-term (104 wks) efficacy and safety of secukinumab in MEASURE 2 study. Methods 219 subjects with active AS, classified by modified New York criteria, despite therapy with NSAIDs, were randomised to subcutaneous (s.c.) secukinumab 150 or 75 mg or PBO at baseline (BL), Wks 1, 2 and 3, and every 4 wks (q4w) from Wk 4. At Wk 16, PBO-treated subjects were re-randomised to secukinumab 150 or 75 mg s.c. q4w. At BL, 39% of subjects had an inadequate response/intolerance to prior anti-TNF therapy (anti–TNF-IR). Primary endpoint was ASAS20 response rates at Wk 16. Secondary endpoints included ASAS40, hsCRP, ASAS5/6, BASDAI, SF-36 PCS and ASAS partial remission. Endpoints were assessed through Wk 104, with multiple imputation for binary variables and a mixed-model repeated measures for continuous variables. Analyses stratified by anti-TNF history were pre-specified and are reported as observed. Results 60/72 (83.3%), 57/73 (78.1%) and 57/74 (77%) subjects completed 104 wks of treatment with secukinumab 150 mg, 75 mg and PBO, respectively. As reported previously, secukinumab 150 mg significantly improved all pre-specified endpoints at Wk 16 vs. PBO, except ASAS partial remission; the 75 mg dose did not reach statistical significance at Wk 16 based on hierarchical testing.1 ASAS20/40 response rates at Wk 104 were 71.5/47.5% with both secukinumab doses. Clinical improvements with secukinumab were sustained through Wk 104 across all secondary endpoints (Table). In the subgroup of anti–TNF-naïve subjects, ASAS20/40 response rates at Wk 104 (observed data) were 76.9/56.4% and 80.0/60.0% with secukinumab 150 mg and 75 mg, respectively; corresponding rates in anti–TNF-IR subjects were 85.0/50.0% and 68.8/43.8%. Across the treatment period (mean secukinumab exposure: 735.6 days), exposure-adjusted incidence rates for serious infections/infestations, IBD, malignant/unspecified tumours and MACE with secukinumab were 1.2, 1.4, 0.5 and 0.7 per 100 subject-years, respectively. No cases of TB, opportunistic infections or suicidality-related AEs were reported. Conclusions Secukinumab provided sustained improvement through 2 years in the signs and symptoms of AS with improved physical function, regardless of anti-TNF status. Safety was consistent with previous reports. References Baeten D et al. N Engl J Med 2015;373:2534–48 Disclosure of Interest H. Marzo-Ortega Grant/research support from: Janssen and Pfizer, Consultant for: Abbvie, Celgene, Janssen, Novartis and UCB, Speakers bureau: Abbvie, Celgene, Janssen and UCB, C. Legerton Grant/research support from: AbbVie, Ablynx, Acerta, Amgen, AstraZeneca, Celgene, GSK, Janssen, E. Lilly, BMS, Pfizer, Novartis, Sandoz, UCB, Daiichi Sankyo, ChemoCentryx, Boehringer Ingelheim, Speakers bureau: Celgene and Amgen, J. Sieper Grant/research support from: AbbVie, Pfizer and Merck, Consultant for: AbbVie, Pfizer, Merck, UCB and Novartis, Speakers bureau: AbbVie, Pfizer, Merck and UCB, A. Kivitz Consultant for: AbbVie, Pfizer, Genentech, UCB and Celgene, Speakers bureau: Celgene, Pfizer, and Genentech, R. Blanco: None declared, M. Cohen Consultant for: Abbvie, Amgen, BMS, Celgene, Hospira, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi and UCB, Speakers bureau: Abbvie, Amgen, BMS, Celgene, Hospira, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi and UCB, J. Zuazo Employee of: Novartis, A. Readie Shareholder of: Novartis, Employee of: Novartis, B. Porter Shareholder of: Novartis, Employee of: Novartis, H. Richards Employee of: Novartis

Background MEASURE 1 (NCT01358175) is a randomized, double-blind, placebo (PBO)-controlled trial that has demonstrated the efficacy and safety of secukinumab, a human anti–interleukin-17A monoclonal antibody, in subjects with active ankylosing spondylitis (AS).1 Objectives To investigate the effect of secukinumab on objective signs of inflammation in the sacroiliac (SI) joints and spine at Weeks (Wks) 16 and 52 using magnetic resonance imaging (MRI) in the MEASURE 1 study. Methods 371 adults with active AS were randomized to secukinumab or PBO: i.v. secukinumab 10 mg/kg (Wks 0, 2, 4) followed by s.c. secukinumab 75 mg every 4 wks (10 IV → 75 SC); s.c. secukinumab 150 mg every 4 wks (10 IV → 150 SC); or PBO on the same i.v. and s.c. schedules. MRI of the SI joints and spine were performed on a subset of 105 subjects with no prior exposure to therapies targeting tumor necrosis factor (anti–TNF-naïve). Assessments were completed at baseline, Wks 16 and 52. MRI variables were assessed by the Berlin SI joint total edema score, MRI score for spinal activity (ASspi-MRI-a), and the Berlin spine score (derived from the ASspi-MRI-a results). Two experienced readers, blinded to treatment and visit, evaluated all MRIs and their mean scores were used for the final analyses. Results Mean baseline ASspi-MRI-a and Berlin spine scores were lower in the secukinumab 10 IV → 150 SC group than in the 10 IV → 75 SC and PBO groups (Table). At Wk 16, improvements were shown in Berlin SI joint total edema score with secukinumab vs PBO (mean change from baseline: –1.30 and –1.05 vs –0.17 in secukinumab 10 IV → 150 SC and 10 IV → 75 SC vs PBO groups, respectively; P <0.01) (Table). Both secukinumab doses also resulted in greater mean percentage improvements from baseline in ASspi-MRI-a and Berlin spine scores vs PBO (Table). Improvements in all MRI measures with secukinumab were sustained through Wk 52. Conclusions MRI measures demonstrate that secukinumab provides early reductions in spinal inflammation in subjects with active AS, and that these improvements are sustained through 52 wks of therapy. References Baeten D, et al. Arthritis Rheumatol. 2014;66(Suppl):S360 Acknowledgements Medical writing support was provided by Jessica Breen at Seren Communications (Tytherington, UK), and was funded by Novartis. Disclosure of Interest X. Baraliakos Grant/research support from: AbbVie, Merck, Pfizer, UCB, Novartis, and Chugai, Consultant for: AbbVie, Merck, Pfizer, UCB, Novartis, and Chugai, Speakers bureau: AbbVie, Merck, Pfizer, UCB, Novartis, and Chugai, J. Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer-Ingelheim, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB, Consultant for: Abbvie (Abbott), Amgen, BMS, Boehringer-Ingelheim, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer-Ingelheim, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB, J. Sieper Grant/research support from: AbbVie, Pfizer, and Merck, Consultant for: AbbVie, Pfizer, Merck, UCB, and Novartis, Speakers bureau: AbbVie, Pfizer, Merck, and UCB, D. Baeten Grant/research support from: Boehringer-Ingelheim, Janssen, MSD, Novartis, and Pfizer, Consultant for: AbbVie, Boehringer-Ingelheim, BMS, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, A. Readie Shareholder of: Novartis, Employee of: Novartis, G. Ligozio Shareholder of: Novartis, Employee of: Novartis, H. Richards Employee of: Novartis