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Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk, and progression, of diabetic kidney disease. We hypothesized that sodium-glucose cotransporter 2 inhibitors could similarly improve the microvascular complication of neuropathy. Methods: The CREDENCE trial randomized participants with type 2 diabetes and albuminuria to canagliflozin or placebo. Neuropathy events were defined as any reported adverse event with a Medical Dictionary for Regulatory Activities (MedDRA) term consistent with peripheral or autonomic neuropathy. The effect of canagliflozin on neuropathy events was calculated by Cox regression. In secondary analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, or non-autonomic neuropathy events, and subgroups were analysed. P-values adjusted for multiplicity using the Holm-Bonferroni correction were derived for the subgroup analyses. Results: Half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, p=0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, p=0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, p=0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, p=0.77). The lack of effect on neuropathy events was consistent in subgroup analyses. Conclusions: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial despite clear benefits for nephropathy, cardiovascular disease and glycemic control. Disclosure J. Liao: None. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. H. Zhang: None. D. C. Wheeler: Advisory Panel; Self; Merck Sharp & Dohme Corp., Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Janssen Global Services, LLC., Mundipharma International, Tricida, Inc., Speaker’s Bureau; Self; Amgen Astellas BioPharma, Astellas Pharma Inc., Napp Pharmaceuticals, Vifor Pharma Management Ltd. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. V. Perkovic: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Baxter, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Bristol-Myers Squibb Company, Eli Lilly Japan K. K., Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Retrophin, Inc., Roche Pharma, Sanofi, Servier Laboratories. M. J. Jardine: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Intern

Background: Canagliflozin reduces the incidence of kidney and cardiovascular events in people with type 2 diabetes and chronic kidney disease (CKD). We assessed the effects of canagliflozin according to age and sex in a randomized, placebo-controlled trial. Methods: The CREDENCE study randomized participants with type 2 diabetes and albuminuric CKD. The effects of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of the serum creatinine level, or death from kidney or cardiovascular causes), and secondary outcomes were evaluated by age at baseline ( Results: Of the 4401 participants, 33.5%, 42.1%, and 24.4% were Conclusion: Canagliflozin reduces the risk of kidney and cardiovascular events in people with type 2 diabetes and CKD with consistent effects and no differences in safety outcomes across subgroups defined by age and sex. Disclosure T. Yi: None. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. D. C. Wheeler: Advisory Panel; Self; Merck Sharp & Dohme Corp., Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Janssen Global Services, LLC., Mundipharma International, Tricida, Inc., Speaker’s Bureau; Self; Amgen Astellas BioPharma, Astellas Pharma Inc., Napp Pharmaceuticals, Vifor Pharma Management Ltd. H. Zhang: None. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & C

KidneyIntelX is a composite risk score incorporating biomarkers and clinical variables for predicting progression of prevalent diabetic kidney disease (DKD). The change of this score over time in response to SGLT2 inhibitors and how these changes associate with future kidney outcomes is unknown. We measured soluble Tumor Necrosis Factor Receptor 1 (sTNFR-1), soluble Tumor Necrosis Factor Receptor 2 (sTNFR-2), and Kidney Injury Molecule (KIM-1) on banked samples from CANVAS trial participants with baseline DKD (eGFR In conclusion, CANA treatment reduced KidneyIntelX risk scores. Changes in the KidneyIntelX score from baseline to 1 year predict future risk of DKD progression whether they resulted from kidney protection afforded by SGLT2i therapy, or decline in kidney function caused by disease progression. Disclosure D. W. Lam: None. G. N. Nadkarni: Advisory Panel; Self; Renalytix AI plc., Consultant; Self; AstraZeneca, Renalytix AI plc., Variant Bio, Research Support; Self; Renalytix AI plc., Stock/Shareholder; Self; Renalytix AI plc. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. N. Rosenthal: Employee; Self; Janssen Research & Development, LLC. M. K. Hansen: Employee; Self; Janssen Pharmaceuticals, Inc. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. S. Coca: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer AG, Boehringer Ingelheim International GmbH, Consultant; Self; CHF Solutions, Relypsa Inc., Renalytix AI plc., Takeda Pharmaceutical Co., Research Support; Self; inRegen, XORTX Therapeutics Inc., Stock/Shareholder; Self; Renalytix AI plc.

Background: The sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of first hospitalization for heart failure (HHF) in the CREDENCE trial. The prevention of recurrent events is important to patients, clinicians and payers. In this post-hoc analysis, we evaluated the effect of canagliflozin on total HHF events. Methods: The CREDENCE trial compared canagliflozin or matching placebo and followed patients for a median of 2.6 years. The study included 4401 participants with type 2 diabetes, substantial albuminuria and estimated glomerular filtration rate (eGFR) 30 to

We tested whether circulating metabolites reflecting cytosolic (lactate/pyruvate) or mitochondrial (β-hydroxybutyrate/acetoacetate [AcAc]) redox balance are associated with major clinical outcomes in patients with type 2 diabetes. The CANVAS study randomized participants to placebo (Plb) or canagliflozin (100mg or 300mg) (Tx) and followed them for up to 6 years. Metabolic markers were measured at baseline (2,373 in Tx [dose combined] and 1,185 in Plb), at year 1 (2,022 in Tx and 949 in Plb) and year 2 (1,793 in Tx and 834 in Plb). By linear mixed model analysis, plasma free fatty acids, AcAc, and β-hydroxybutyrate increased with Tx vs. Plb, whereas plasma pyruvate decreased with Tx while glycerol and lactate did not change significantly. Of note, these changes were independent of the background antihyperglycemic medication (metformin, sulfonylureas, insulin, or combinations thereof). The incidence of hospitalized heart failure or cardiovascular death (HHF/CVD) was 10.2%, the incidence of the renal composite endpoint (CombR; i.e., 40% reduction in eGFR or renal replacement/death) was 3.9%. In Cox models adjusting for sex, age, BMI, HbA1c, baseline systolic blood pressure, diabetes duration, smoking, baseline use of diuretics or statins, history of heart failure, prior CV disease, and Tx, baseline AcAc was a negative predictor of HHF/CVD (HR=0.83 [95%CI 0.75-0.94]), while baseline lactate was a positive predictor (HR=1.42 [95%CI 1.20-1.68]). Adding baseline ACR and eGFR to the same multivariate model for CombR as the outcome, AcAc was still a negative (HR=0.84 [95%CI 0.75-0.94]) and lactate still a positive predictor (HR=1.42 [95%CI 1.20-1.67]). For CV and renal outcomes, higher baseline plasma lactate is an independent positive risk marker potentially reflecting a reducing cytosolic redox shift, but higher baseline plasma AcAc is a protective factor, which may be related to efficient mitochondrial supply/usage of reducing equivalents. Further analysis is needed to test these hypotheses. Disclosure E. Ferrannini: Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Oramed Pharmaceuticals. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. S. Baldi: None. T. Scozzaro: None. F. Tesfaye: Employee; Self; Janssen Research & Development, LLC. W. Shaw: Employee; Self; Janssen Pharmaceuticals, Inc. N. Rosenthal: None. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. V. Perkovic: Other Relationship; Self; See Other Relationship field. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. Funding Janssen Research & Development, LLC

Background: Canagliflozin (CANA) slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its association with long-term eGFR trajectories and safety outcomes are unknown. Methods: This post-hoc study of the CREDENCE trial included 4289 patients with type 2 diabetes and CKD who had eGFR measured at both baseline and week 3. Participants were categorized by percentage decline in eGFR at week 3: >10%, ≤10% to >0%, and ≤0%. Baseline characteristics associated with acute eGFR declines >10% were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use. Results: More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO; p10%, respectively (both p for interaction 0.05). Results were consistent when other decline thresholds (>20%) were used and in subgroup analysis by baseline eGFR (30- Conclusions: Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with placebo was observed regardless of the acute eGFR decline and safety profiles were similar. Disclosure M. Oshima: Research Support; Self; Japan Society for the Promotion of Science Program for Fostering Globally Talented Researchers. M.J. Jardine: Other Relationship; Self; See Other Relationship field. R. Agarwal: Other Relationship; Self; AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. C. Cannon: None. D.M. Charytan: Advisory Panel; Self; Allena Pharmaceuticals, AstraZeneca, Merck & Co., Inc., PLC Medical. Employee; Self; BAIM Institute. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. R. Edwards: Employee; Self; Janssen. T. Greene: Other Relationship; Self; Janssen, Durect, and Pfizer. A. Levin: Consultant; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support; Self; Diabetes Australia. Speaker’s Bureau; Self; AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship; Self; Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.C. Wheeler: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant; Self; AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. H. Zhang: Employee; Self; Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. V. Perkovic: Other Relationship; Self; See Other Relationship field. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC

The benefits of CANA for HF in people with T2D at CV risk appeared to be statistically mediated by erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio (UACR) in the CANVAS Program. CANA reduced the risk of HF in patients with T2D and CKD in CREDENCE. We explored potential mediators of CANA's effects on the composite of hospitalized HF (HHF) and CV death. Mediation analyses are hypothesis-generating observational analyses that calculate the effect of selected biomarkers on the overall treatment effect using time-varying Cox regression. We compared hazard ratios for the effect of randomized treatment from an unadjusted model versus a model adjusted for the average post-randomization level of the biomarker of interest. 62 routine clinical biomarkers and vital sign indicators were collected on all participants and tested as potential mediators. When multiple potential mediators represented a single pathway, those with the strongest univariable mediation were tested in multivariable models. 12 biomarkers, including 3 markers of volume/erythropoiesis (hematocrit [24%], hemoglobin [32%], erythrocytes [27%]), 2 markers of kidney function (UACR [28%], eGFR from wk 3 [7.4%]), and serum albumin (39%), serum protein (24%), lactate dehydrogenase (13%), systolic BP (10%), urine pH (8%), serum urate (7%) and gamma glutamyltransferase (4%), mediated the effect of CANA on HHF/CV death in univariable models. In the multivariable model, hemoglobin, UACR, serum urate and systolic BP maximized cumulative mediation (74%). A diverse set of potential mediators of CANA's effect on HHF/CV death were identified with serum albumin, hemoglobin (or its analogues) and UACR being the most important. The extent to which these mediators reflect underlying inflammatory, nutritional, volume-related or cardiorenal pathways is unclear and underscores the need for further research into the mechanisms of benefit of SGLT2 inhibitors. Disclosure: J. Li: Employee;Self;George Institute. B. Neal: Research Support;Self;Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship;Self;Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. H.L. Heerspink: Consultant;Self;AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. C. Arnott: Employee;Self;George Institute for Global Health. C. Cannon: None. R. Agarwal: Other Relationship;Self;AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant;Self;Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship;Self;Bayer AG, Novo Nordisk Inc., Vascular Dynamics. D.M. Charytan: Advisory Panel;Self;Allena Pharmaceuticals, AstraZeneca, Merck & Co., Inc., PLC Medical. Employee;Self;BAIM Institute. Research Support;Self;Janssen Pharmaceuticals, Inc. Other Relationship;Self;Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel;Self;AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. T. Greene: Other Relationship;Self;Janssen, Durect, and Pfizer. A. Levin: Consultant;Self;Janssen Pharmaceuticals, Inc. Research Support;Self;AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. R. Oh: Employee;Self;Janssen Pharmaceuticals, Inc. C.A. Pollock: Advisory Panel;Self;AstraZeneca, Boehringer Ingelheim Pharma euticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support;Self;Diabetes Australia. Speaker's Bureau;Self;AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship;Self;Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. D.C. Wheeler: Advisory Panel;Self;Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant;Self;AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker's Bureau;Self;Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. Y. Yavin: Employee;Self;Janssen Research & Development, LLC. H. Zhang: Employee;Self;Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel;Self;Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. G. Di Tanna: Employee;Self;George Institute for Global Health. V. Perkovic: Other Relationship;Self;See Other Relationship field. K.W. Mahaffey: Consultant;Self;Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support;Self;Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. M. Jardine: Other Relationship;Self;See Other Relationship field. Funding: Janssen Research & Development, LLC [ABSTRACT FROM AUTHOR] Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Growth differentiation factor 15 (GDF-15) is a marker of inflammation and cellular injury. Small clinical studies have suggested that SGLT2 inhibitors exert anti-inflammatory effects. We examined the association of baseline GDF-15 with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) participating in the CANagliflozin cardioVascular Assessment Study (CANVAS) study. We also assessed the effect of the SGLT2 inhibitor canagliflozin (CANA) on GDF-15. Methods: The CANVAS trial randomized 4330 people with T2DM at high cardiovascular risk to CANA or placebo. Plasma GDF-15 concentration was measured with GDF-15 Roche Elecsys assay at baseline and follow-up. The association between GDF-15 and the primary kidney outcome (40% eGFR decline, end-stage kidney disease, or renal death) was assessed using multivariable adjusted Cox regression. Linear mixed effects models were used to assess the effect of CANA versus placebo on GDF-15 levels. Results: We included 3557 CANVAS participants with available plasma samples (mean age 62.8 years, 33.1% female, mean eGFR 76.9 ml/min/1.73 m2, median uACR 11.6 mg/g, median GDF-15 1776.0 pg/ml). During a mean follow-up of 5.7 years, 137 kidney outcomes occurred. Higher GDF-15 levels were independently associated with higher risk of kidney events (HR 1.98 [95% CI 1.40 to 2.81] per log increment GDF-15). Treatment with CANA modestly lowered GDF-15 compared to placebo (-2% [95% CI -5 to 0; p=0.046]). The effect of CANA on the kidney outcome (HR 0.56, 95% CI 0.40-0.79) was consistent regardless of baseline GDF-15 levels (p-interaction=0.75). GDF-15 did however not mediate the renal protective effect of CANA (percent mediation 3.9% [95% CI -3.6 to 14.0]). Conclusion: CANA modestly lowers GDF-15, which is independently associated with a higher risk of kidney disease progression in patients with T2DM at high cardiovascular risk. The modest reduction in GDF-15 with CANA did not mediate the renal protective effect of CANA. Disclosure J. Li: Employee; Self; George Institute. T. Sen: None. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research & Development, LLC. V. Perkovic: Other Relationship; Self; See Other Relationship field. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. Y. Yavin: Employee; Self; Janssen Research & Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC

Introduction: Canagliflozin (CANA) slows progression of kidney disease, which may be at least partly mediated by improvements in tubular function. To test this hypothesis, we assessed effects of CANA on markers of tubular function and injury in the CANVAS trial. Methods: Urine biomarkers of tubule function (β2-microglobulin [B2M], cystatin C, and uromodulin), tubular injury (interleukin-18 [IL-18], kidney injury molecule-1 [KIM-1], neutrophil gelatinase associated lipocalin [NGAL], and osteopontin), and inflammation (monocyte chemotactic protein-1 [MCP-1]) were measured at baseline and after 12 months. Biomarker concentrations were standardized for urine creatinine concentration. Differences between CANA and placebo treatment were assessed using ANCOVA models. Results: We included 3723 CANVAS participants with available urine samples (eGFR 77.1 ml/min/1.73 m2 and median UACR 11.7 mg/g). Clinical characteristics and biomarker levels were well balanced between treatment groups at baseline. CANA compared to placebo significantly reduced urinary KIM-1, uromodulin, cystatin C, and osteopontin. It did not change NGAL or MCP-1 and increased IL-18 and B2M. Results were consistent in subgroups by baseline UACR except MCP-1, which decreased in patients with UACR ≥30 mg/g (Table). Conclusion: CANA had variable effects on markers of tubule cell injury and function, decreasing 4, while 2 remained stable and 2 increased. Disclosure T. Sen: None. J. Li: Employee; Self; George Institute. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research & Development, LLC. M.J. Jardine: Other Relationship; Self; See Other Relationship field. J. Ix: Research Support; Self; Baxter. M.G. Shlipak: Advisory Panel; Self; Cricket Health, Tai Diagnostics. V. Perkovic: Other Relationship; Self; See Other Relationshipfield. Y. Yavin: Employee; Self; Janssen Research & Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC

Background:Axial spondyloarthritis (axSpA) spectrum covers radiographic axSpA and non-radiographic axSpA (nr-axSpA). PREVENT (NCT02696031) is the first phase III, placebo (PBO) controlled study evaluating secukinumab (SEC) 150 mg with (LD) or without loading (NL) dose, in patients (pts) with nr-axSpA.1The study had 2 independent analysis plans as per EU (Wk 16) and US (Wk 52) regulatory requirements.Objectives:To report efficacy through Wk 52 and safety up to two years for the PREVENT study.Methods:555 pts fulfilling ASAS criteria for axSpA plus abnormal CRP and/or MRI, without evidence of radiographic changes in sacroiliac (SI) joints according to modified New York Criteria for AS were enrolled. All images were assessed centrally before inclusion. Pts were randomised (1:1:1) to SEC 150 mg with LD, NL, or PBO at baseline (BL). LD pts received SEC 150 mg at Wks 1, 2, 3, and 4, and then every 4 wks (q4wk) starting at Wk 4. NL pts received SEC 150 mg at BL and PBO at Wks 1, 2, and 3, and then 150 mg q4wk. Switch to open-label (OL) SEC 150 mg or standard of care (SoC) was permitted after Wk 20. Primary endpoint was ASAS40 at Wk 16 (LD) and at Wk 52 (NL) in anti-TNF-naïve pts. Secondary endpoints (overall population) included ASAS40, BASDAI50, SI joint bone marrow edema (BME) score by MRI at Wks 16 and 52 and ASDAS-CRP inactive disease (ID) at Wk 52. Endpoints were analysed according to statistical hierarchy. Analysis used non responder imputation through Wk 52. Safety analyses included all pts who received ≥1 dose of study treatment.Results:Overall, 481 pts completed 52 wks with no major differences in retention across groups: 84.3% (156/185; LD), 89.7% (165/184; NL) and 86.0% (160/186; PBO). BL characteristics were similar across groups; 90% pts were anti-TNF-naïve, 56-58% pts had elevated CRP, 71-75% pts had evidence of SI joint inflammation by MRI. Proportion of pts who switched to OL or SoC between Wks 20 and 48 was 52.1% (LD), 49.2% (NL), and 67.4% (PBO). Primary endpoints at Wk 16 and Wk 52 were met (Table). SEC 150 mg LD or NL significantly improved secondary endpoints at Wk 16 and 52 vs PBO (Table). SEC significantly reduced SI joint MRI BME score vs PBO at Wk 16 (-1.68 and -1.03 vs -0.39;P= 0.0197 and 0.026, LD and NL respectively). No unexpected safety signals were reported.Conclusion:SEC 150 mg provided significant and sustained improvement in signs and symptoms of pts with nr-axSpA through Wk 52. MRI BME scores were reduced accordingly. There was no major difference between LD and NL. Safety of SEC was consistent with previous reports.2References:[1]Deodhar A, et al.Arthritis Rheumatol. 2019;71(suppl 10).[2]Deodhar A, et al. Arth Res Ther. 2019;21:111.TableEndpoints, % respondersWkSEC150 mg LD(N = 185)SEC150 mg NL(N = 184)PBO(N = 186)PrimaryASAS40 in anti-TNF-naïve pts1641.5‡42.2‡29.25235.4‡39.8‡19.9SecondaryASAS401640.0‡40.8‡28.05233.5‡38.0‡19.4BASDAI501637.3‡37.5‡21.05230.8‡35.3‡19.9ASDAS-CRP ID1620.5†21.7†8.15215.723.9‡10.2†P< 0.001;‡P< 0.05 vs PBO (Pvalues are adjusted for multiplicity of testing at Wks 16 and 52. UnadjustedPvalue for ASDAS-CRP ID at Wk 16). Missing values were imputed as non-response.N, number of randomised ptsDisclosure of Interests: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, Ricardo Blanco Grant/research support from: AbbVie, MSD, Roche, Consultant of: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma and MSD, Speakers bureau: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma. MSD, Eva Dokoupilova Grant/research support from: Eli Lilly, AbbVie, Novartis, Lianne S. Gensler Grant/research support from: Pfizer, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, GSK, Novartis, UCB, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Stephen Hall Grant/research support from: Abbvie, UCB, Janssen, Merck, Hideto Kameda Grant/research support from: Abbvie, Asahi-Kasei, Chugai, Eisai, Mitsubishi-Tanabe and Novartis, Consultant of: Abbvie, Boehringer, Celgene, Eli Lilly, Janssen, Novartis, Sanofi, UCB, Speakers bureau: Abbvie, Asahi-Kasei, BMS, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Novartis and Pfizer, 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, Marleen van de Sande Grant/research support from: Novartis, Eli Lilly, Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Novartis, Eli Lilly, Speakers bureau: Novartis, MSD, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Anna Wiksten Shareholder of: Novartis, Employee of: Novartis, Brian Porter Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis, Employee of: Novartis, Sibylle Haemmerle Shareholder of: Novartis, Employee of: Novartis, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB

Background:Axial spondyloarthritis (axSpA) is a chronic disease characterised by inflammation in the sacroiliac joints and spine, causing severe back pain and stiffness. Emerging evidence suggests chronic spinal inflammation may be associated with osteoproliferation leading to syndesmophyte formation and spinal ankylosis, with subsequent worsening of patient mobility and function.1Fatty lesions (FLs) on magnetic resonance imaging (MRI) T1 sequences are considered to be post-inflammatory precursors to these changes. Certolizumab pegol (CZP), an Fc-free, PEGylated tumour necrosis factor inhibitor (TNFi), has proven efficacy in treating the signs and symptoms of axSpA.2,3CZP has also been shown to decrease spinal and sacroiliac joint MRI inflammation, and limit radiographic progression of the spine over 4 years of treatment.4Objectives:To report the effect of early post-baseline (BL) inflammatory changes on fatty lesion prevalence over 4 years in a broad axSpA patient population treated with CZP.Methods:RAPID-axSpA (NCT01087762) was a phase 3 trial which was double-blind and placebo (PBO)-controlled to Week (Wk) 24, dose-blind to Wk 48 and open-label to Wk 204. CZP-randomised axSpA patients (Wk 0 CZP: 200 mg every 2 wks [Q2W] or 400 mg Q4W) continued their assigned dose throughout; PBO-randomised axSpA patients (Wk 0 PBO) received CZP from Wk 24, or if non-responders, from Wk 16 onwards. Blinded spinal MRI scans at Wks 0, 12, 48, 96 and 204 were assessed by 2 central readers to evaluate FL and inflammatory lesions in vertebral edges (VEs). Changes in FL prevalence are reported as odds ratios (OR; FL+/FL-) between time points or inflammation states, with nominal 95% confidence intervals (CI), for Wk 0 CZP. ORs were estimated from a logistic regression model for VE level data with random effects for patient and VE (within patient). The fixed model effects included time point, inflammatory status of VEs at BL and Wk 12, FL status at BL, and interactions if appropriate.Results:Of 325 axSpA patients, 89 and 47 initially randomised to CZP or PBO, respectively, had a BL and ≥1 post-BL MRI and therefore were eligible for these analyses. In these patients, a total of 3,127 of VEs were assessed at BL; inflammation was observed in 21.6% and FL in 29.3% of VEs, equating to mean counts of 5.0 and 6.7 per patient; 10.5% of VEs had both inflammation and FL at BL. At BL, FLs were relatively more often observed in inflamed VEs vs non-inflamed VEs: OR (95% CI) of 3.30 (1.94, 5.61). This difference increased over time, as the OR of FL at Wk 204 vs BL was 2.82 (1.70, 4.66) in VEs that were inflamed at BL compared with 1.08 (0.79, 1.48) in VEs that were not inflamed at BL (Figure 1A). Resolution of inflammation by Wk 12 appeared to lower the risk of FL prevalence over 4 years. When adjusted for BL VE status with respect to inflammation and FL, if inflammation prevailed at Wk 12, the OR of FL vs no FL was 1.80 (0.93, 3.49) at Wk 48, 2.54 (1.32, 4.91) at Wk 96 and 3.91 (1.87, 8.15) at Wk 204 (Figure 1B).Conclusion:This is the first report from a clinical interventional PBO-controlled study in a broad axSpA population showing that inflammation that prevailed after the start of TNFi treatment was associated with increased FL prevalence over 4 years. Reduction of inflammation by Wk 12 mitigated the risk of FL over the long-term, indicating the importance of early, effective and long-term treatment targeting inflammation. Similarly, a complete and persistent reduction of inflammation appears to be critical in these patients.References:[1]Maksymowych WP. Ann Rheum Dis 2013;72:23–8;2.Van der Heijde D. Rheumatology (Oxford) 2017;56:1498–509;3.Deodhar A. Arthritis Rheumatol 2019;71:1101–11;4.Van der Heijde D. Ann Rheum Dis 2018;77:699–705.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Sebastian Kruse: None declared, Simone Auteri Shareholder of: UCB Pharma, Employee of: UCB Pharma, Natasha de Peyrecave Employee of: UCB Pharma, Tommi Nurminen Employee of: UCB Pharma, Thomas Kumke Employee of: UCB Pharma, Bengt Hoepken Employee of: UCB Pharma, 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

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

Background:Rheumatoid arthritis (RA) is a chronic inflammatory joint disease potentially leading to disability, impaired functioning, and premature death. Most treatment strategies include the early use of disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) which is considered as an established ‘anchor’ therapy. Since it takes some weeks until MTX shows clinical efficacy, glucocorticoids (GC) are widely used for bridging.Objectives:The aim of the study “Comparison of the efficacy and safety of two starting dosages of prednisolone in early active RA” (CORRA) is to compare the efficacy and safety of two standard GC bridging schedules vs. placebo in addition to MTX, following a treat-to-target regimen, in early RA.Methods:CORRA is an investigator-initiated, randomised, multi-center, double-blind, placebo-controlled trial. Adult RA patients who were eligible for inclusion in the trial if they had a disease duration of less than 3 years and moderate or high disease activity were recruited in one hospital and 18 rheumatology practices in Germany. Patients were randomised (1:1:1) to receive 60 mg or 10 mg prednisolone (Pred) orally once daily (tapered down to 5 mg Pred within 8 weeks) or placebo. The duration of the intervention was 12 weeks, followed by an open observational phase for another 40 weeks. All patients were also treated with MTX (usually starting with 15mg/week followed by a treat-to target scheme). The primary efficacy endpoint was the progression of the radiographic joint damage after one year compared to baseline as determined by the van der Heijde modification of the Sharp score (SHS). Patients, physicians and readers of radiographs were unaware of the treatment assignments. For the comparison of the two GC groups, a non-inferiority margin of 1.3 points of the SHS was set. This trial was registered at ClinicalTrials.gov, numberNCT02000336.Results:Between February 2014 and February 2017, 395 patients were included in the trial, 381 of which had sufficient data also of follow-up visits. A total of 129 patients were assigned to the 60 mg Pred group, 124 to 10 mg Pred and 128 to the placebo group. At baseline, mean age was 58 years, 58% were female, 55% were rheumatoid factor and 52% ACPA positive. The mean number of swollen joints was 12.8 out of 28, mean ESR was 33.6 mm/h, mean CRP 2.2 mg/dL, mean DAS 28 6.0. Radiographic damage was 4.9 as measured by the SHS. In the 60 mg, 10 mg Pred group and in the placebo group, the DAS 28 was 2.6, 3.1, 4.5 at week 4 (pConclusion:The bridging schedule starting with 60 mg Pred reduced disease activity better than the 10 mg schedule or placebo only for a short time. The primary outcome structural damage was non-inferior in the 10 mg Pred and the placebo group in comparison to the 60 mg Pred group. Initial advantages of the higher dose may have been compromised by the long follow-up with the possible escalation of therapy due to the treat-to-target regimen.Disclosure of Interests:Dietmar Krause Grant/research support from: Pfizer and AbbVie (Abbott), Anna Mai: None declared, Nina Timmesfeld: None declared, Ulrike Trampisch: None declared, Renate Klaassen-Mielke: None declared, Henrik Rudolf: None declared, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Elmar Schmitz: None declared, Claas Fendler: None declared, Claudia Klink: None declared, Stephanie Boeddeker: None declared, Ertan Saracbasi: None declared, Jochen Christoph: None declared, Manfred Igelmann: None declared, Hans Juergen Menne: None declared, Albert Schmid: None declared, Hans J Trampisch: 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

Background:Ixekizumab has demonstrated efficacy in treating signs and symptoms of patients with non-radiographic axial spondyloarthritis (nr-axSpA).1The Assessment of SpondyloArthritis International Society Health Index (ASAS HI) is a composite measure consisting of 17 dichotomous items to assess overall functioning and health in patients with spondyloarthritis.2Objectives:To assess health outcomes using ASAS HI in patients with nr-axSpA treated with ixekizumab (IXE) for 52 weeks.Methods:COAST-X (NCT02757352) was a 52-week, randomized, double-blind, placebo (PBO)-controlled study enrolling adults with an established diagnosis of axSpA (ASAS classification criteria, but not modified New York criteria for sacroiliitis), had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥4, back pain score ≥4, inflammation (sacroiliitis on magnetic resonance imaging [MRI] per ASAS criteria) or an elevated C-reactive protein [CRP] level >5 mg/L), and inadequate response or intolerance to nonsteroidal anti-inflammatory drugs. Patients were randomized 1:1:1 to receive PBO or 80 mg IXE every 4 weeks (Q4W) or every 2 weeks (Q2W). Changing background medications or switching to open-label IXE Q2W, or both, was allowed after week 16 at investigator discretion. Change from baseline in ASAS HI (score 0-17 with higher score indicating worse health) was analyzed using logistic regression analysis at Weeks 0, 4, 8, 16, 36, and 52. For the ASAS HI, the smallest detectable change was calculated as 3.0. Patients having an ASAS HI score ≤5 were defined as being in a good health state.3Comparisons between IXE treatments and PBO were made using logistic regression analysis. Non-responder imputation was used for missing data. Patients who switched to open label IXEQ2W were considered non-responders after they switched.Results:At baseline, ASAS HI scores were similar between the three groups (PBO 9.0 ± 3.7; IXE Q4W 8.6 ± 3.4; IXE Q2W 9.6 ± 3.4). Significantly more patients receiving IXE Q4W versus PBO achieved ASAS HI score ≤5 at Week 16 (pFigure.Improvement in ASAS HI scores through Week 52.A: Proportion of patients who achieved an ASAS HI score ≤5 in patients with baseline ASAS HI score >5. B: Proportion of patients who achieved ≥3-point improvement in ASAS HI in patients with baseline ASAS HI score ≥3. ***pConclusion:Ixekizumab improves overall functioning and health in patients with nr-axSpA as assessed by ASAS HI, with significantly more patients achieving good health status.References:[1]Deodhar A, van der Heijde D, Gensler LS, et al.Lancet. 2020; 395(10217):53-64.[2]Kiltz U, van der Heijde D, Boonen A, et al.Ann Rheum Dis. 2015;74(5):830-5.[3]Kiltz U, van der Heijde D, Boonen A, et al.Ann Rheum Dis. 2018;77(9):1311-7.Disclosure of Interests:Uta Kiltz Grant/research support from: AbbVie, Amgen, Biogen, Novartis, Pfizer, Consultant of: AbbVie, Biocad, Eli Lilly and Company, Grünenthal, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Novartis, Pfizer, Roche, UCB, Jessica A. Walsh Grant/research support from: AbbVie, Pfizer, Janssen, Consultant of: AbbVie, Novartis, Eli Lilly and Company, UCB, Ruben Burgos Vargas: None declared, Theresa Hunter Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Rebecca Bolce Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ann Leung: None declared, Xiaoqi Li Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Emily Blue Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, 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

Background:The clinical efficacy of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA) is well established but its effect on new bone formation is still unclear (1). Positron emission tomography (PET) using bone-seeking18F-Fluoride [18F]F in combination with magnetic resonance imaging ([18F]F /MRI) has been shown to depict not only bone marrow edema (BME) but also shows the quantity of tracer uptake in the late phase of perfusion suggestive of remodeling and osteoblastic activity, not only in radiographic axSpA (r-axSpA) (2).Objectives:Assess the effect of TNFi on bone remodeling processes in the axial skeleton of r-axSpA patients using [18F]F/MRI prior (baseline, BL) and 4 months after (follow-up, FU) treatment.Methods:Patients (11 male, 5 female, mean age 38.6±12.0 years) with clinically active r-axSpA (BASDAI>4, failure of NSAIDs, no previous biologics) prospectively underwent 3-Tesla and [18F]F PET/MRI (40 minutes after injection of a mean activity of 157 MBq [18F]F). Images of the SIJ (n=16 patients) and the whole spine (n=10 patients) were performed at BL and FU. Three readers (1 for [18F]F/MRI and 2 for conventional MRI) evaluated all images independently and blinded to timepoint allocation. Only lesions on which all readers agreed on were used for further analyses. Inflammation (bone marrow edema, BME), structural lesions (fat deposition (FD), sclerosis, erosions and ankylosis) and focal [18F]F uptake were recorded on the level of SIJ (SIJ-Q) and vertebral quadrants (V-Q), with each SIJ or vertebral body consisting of 4 VQs (superior and inferior sacral and iliac for the SIJ, and superior and inferior, anterior and posterior for the vertebral bodies).Results:A total of 128 SIJ-Q and 920 VQs were analyzed at both BL and FU. In the SIJs, 75 (58.6%), 120 (93.8%), 69 (53.9%), 99 (77.3%) and 16 (12.5%) SIJ-Q showed BME, FD, sclerosis, erosions and ankylosis, while 111 (86.7%) SIJ-Q showed focal [18F]F-uptake at BL. Association with increased [18F]F-uptake was found most frequently in SIJ-Q with BME (70/75 SIJ-Q, 93.3%), sclerosis (65/69 SIJ-Q, 94.2%) and FD (105/120 SIJ-Q, 87.5%). At FU, 37 SIJ-Q still showed BME (improvement by 50.7%), while almost no changes were observed in chronic lesions. In comparison, improvement of focal [18F]F-uptake was found in all lesion combinations, with improvement of focal [18F]F-lesions associated with BME by 62.9%, with sclerosis by 33.8% and with FD by 22.9% of SIJ-Q.In the spine, only 41 (4.5%), 61 (6.6%), 14 (1.5%) V-Q showed BME, FD and sclerosis, respectively, while 77 V-Q (8.4%) showed focal [18F]F-uptake. An association to increased [18F]F-uptake was found most frequently with sclerosis (7/14 V-Q, 50%) and FD (25/61 V-Q, 41%). At FU, 12 V-Q still showed BME (improvement by 70.7%), while, similar to SIJ, almost no changes were observed in the chronic lesions. The largest improvement was found in focal [18F]F-lesions associated with BME 81.8% and with FD by 22.9% of V-Q.Conclusion:In this first prospective study on whole spine and SIJ [18F]F/MRI in patients with r-axSpA, a significant decrease of osteoblastic activity was observed over 4 months of continuous anti-TNF treatment. The effect of treatment was observed not only at sites with inflammatory lesions (BME) but also at sites with pre-existing chronic structural lesions, while some osteoblastic activity remained visible at 4 months. These data support a short-term effect of anti-TNF treatment on osteoblastic activity, while the long-term effects need to be further studied.References:[1]Van der Heijde D et al, Ann Rheum Dis 2017[2]Buchbender C et al, J Rheumatol 2015This work was supported by an unrestricted Grant by MSD GmbH, GermanyDisclosure of Interests:Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Styliani Tsiami: None declared, Christoph Rischpler: None declared, Nils-Martin Bruckmann: None declared, Wolfgang Fendler: None declared, Julian Kirchner: None declared, Ken Hermann: None declared, Lino Sawicki: 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

Background:Early diagnosis and treatment are important for the management of inflammatory rheumatic diseases (RMD). However, the availability of rheumatologists is limited in most European countries and selection strategies lack sensitivity and/or specificity.Objectives:To evaluate a triage strategy that offers the possibility to see patients within 4 weeks for short term appointments in order to check the probability of an inflammatory RMD and the necessity to further evaluate the patients in due time.Methods:Physician’s and patient’s information who called our tertiary rheumatology department´s outpatient clinic for a date in the triage system were included in this analysis. The time to first appointment as assessed by a nurse (Step 1), the short evaluation by a rheumatologist in the triage (Step 2) and the patient´s complaints and the diagnoses after an extensive diagnostic evaluation (Step 3) were documented.Results:In a period of 9 months in 2018, a total of 982 patients presented. A total of 62 patients (6.3%) were considered urgent (appointment within 3 days), while 240 (24.4%) were appointed within 4 weeks at Step 2. Of the former 46 (19.2%), and of the latter 151 patients (62.9%) were diagnosed with inflammatory RMD at Step 3.In total, 334 patients (34.0%) were diagnosed with inflammatory RMD at Step 3, including 126 with RA (37.7%), 71 with axSpA/PsA (21.3%), 95 with connective tissue disease/vasculitis (28.4%) and 20 with gout (6.0%). The diagnosis suspected in Step 2 was confirmed in Step 3 in 77.9% of cases. In 217 patients, the diagnosis suspected in Step 2 was not confirmed in Step 3. Of them, 34 (15.7%) had unclear findings at Step 2 but an inflammatory RMD was found at Step 3, while 148 (68.2%) had a suspected inflammatory RMD at Step 2 but this was not confirmed at Step 3.The most frequent musculoskeletal complaint at the time point of referral was pain in small peripheral joints (hands and/or feet) in 858 patients (87.4%), in large peripheral joints (knees, shoulders and/or hips) in 780 patients (79.4%) and back pain in 682 patients (69.5%). Fever, night sweats and unclear weight loss was reported by 50 patients (5.1%), while 210 patients (24.5%) presented with findings suspicious of inflammatory RMD such as elevated CRP of unclear origin, and 43 patients (4.8%) because of a threat of organ damage such as unclear elevation of creatinine, as reported by the referring physician. In addition, 167 patients (17.0%) had received glucocorticoids prior to referral, 87 (52.1%) of which finally did not receive the diagnosis of inflammatory RMD at Step 3, while 737 patients (75.1%) were receiving NSAIDs prior to referral.Conclusion:In this prospective evaluation of a triage system where all patients were pre-screened by a nurse and were seen within 4 weeks by a rheumatologist, clinical differentiation could be performed timely due to a successfully structured triage system. The initially suspected diagnosis was finally confirmed in ≥75% of cases, while ≥1/3 of patients had a definite inflammatory RMD.This work was supported by an unrestricted Grant from AbbvieDisclosure of Interests:Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Imke Redeker: None declared, Maria Zacharopoulou: None declared, Styliani Tsiami: None declared, Konstantia Tsiaousi: None declared, Doris Morzeck: 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

Background:Axial spondyloarthritis (axSpA) is a potentially severe chronic inflammatory disease with impact on function and quality of life. About 20-30% of axSpA patients show symptoms of depression or are diagnosed with depression [1]. Depression may influence outcome, especially patient reported outcomes.Objectives:To assess differences in baseline characteristics and outcome parameters between patients with and without symptoms of depression using WHO-5 score.Methods:RABBIT-SpA is a prospective longitudinal cohort study including axSpA patients enrolled at start of a new conventional treatment (including NSAID) or bDMARD. WHO-5 score was used to identify depressive symptoms categorised into 3 groups using validated cut-offs: moderate to severe depressive symptoms 50. Baseline values of patients categorised as having moderate to severe depressive symptoms were compared with the rest of the patients using t-test. Spearman correlation coefficient was calculated to analyse the relationship between WHO-5 score and other outcome parameters.Results:A total of 848 axSpA patients were included in this analysis (table 1). Moderate to severe depressive symptoms were found in 221 patients (30%), 226 (31%) had mild depressive symptoms and 285 (39%) reported a good well-being. Percentages of patients with inflammatory back pain, peripheral arthritis or enthesitis as well as the number of affected joints (44 JC) and entheseal sites (using SPARCC) were higher in the group of patients with moderate to severe depressive symptoms.Table 1.ParameterWHO-5 (Moderate severeN=221WHO-5 (29-50/>50)Mild/well-beingN=511Age, mean43.844.1Female, n (%)100 (45.2)229 (44.8)Disease duration, years, mean6.86.5Inflammatory back pain, n (%)195 (88.6)416 (81.6)Enthesitis, n (%)49 (22.3)78 (15.4)Peripheral arthritis (44 JC), n (%)64 (29.1)134 (26.3)Uveitis, n (%)45 (20.4)76 (15)IBD, n (%)13 (5.9)31 (6.1)Psoriasis, n (%)35 (15.8)58 (11.4)CRP positive (≥5mg/l), n (%)115 (59)243 (55.1)HLA-B27, n (%)151 (72.6)354 (74.2)BMI≥30, n (%)66 (30)117 (23.6)Comorbidities ≥3, n (%)50 (22.6)89 (17.4)Current smoking, n (%)102 (47.2)185 (36.7)All analysed outcome parameters (e.g. ASDAS, ASAS-HI, BASDAI, BASFI, patient global, physician global, pain, sleep) were significantly worse in the group of patients with moderate to severe depressive symptoms versus the other patients (table 2). This includes physician-reported, patient-reported and composite scores.Table 2.ParameterWHO-5 (Moderate severeN=221WHO-5 (29-50/>50)Mild/well-beingN=511p-valuePhysGA (NRS 0-10)6.2 (1.6)5.4 (1.9)0.0001ASDAS6.1 (1.6)4.2 (1.8)0.0001BASDAI (NRS 0-10)3.5 (0.8)2.9 (0.9)0.0001BASFI (NRS 0-10)5.5 (2.2)3.2 (2.2)0.0001ASAS-HI (0-17)9.8 (3.1)5.8 (3.1)0.0001PatGA (NRS 0-10)7 (1.8)5.4 (2.3)0.0001PatPain (NRS 0-10)6.9 (1.9)5.2 (2.3)0.0001PatSleep (NRS 0-10)7.2 (2.4)4.6 (2.9)0.0001Results are presented as mean ± SD.WHO-5 was highly correlated with all outcome parameters regardless of gender. Figure 1 shows the correlation of BASDAI and WHO-5 stratified for gender.Figure 1.Conclusion:Almost one third (30%) of axSpA patients in this analysis reported scores indicative of depressive symptoms and depression. The strong correlation of WHO-5 scores with patient and physician reported outcomes may be relevant for the management of patients with axSpA.References:[1]Redeker I, et al. Ann Rheum Dis 2018;0:1–8. doi:10.1136Acknowledgments:RABBIT-SpA is supported by a joint, unconditional grant from AbbVie, Amgen, Janssen-Cilag, Lilly, MSD, Mylan, Novartis, Pfizer, and UCB.Disclosure of Interests:Anne Regierer Speakers bureau: Novartis, Celgene, Janssen-Cilag, Anja Weiß: None declared, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, 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, Ilka Schwarze: 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, Joachim Sieper Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Speakers bureau: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Angela Zink Speakers bureau: AbbVie, Amgen, BMS, Gilead, Hexal, Janssen, Lilly, MSD, Pfizer, Roche, Sanofi Aventis, UCB, Anja Strangfeld Speakers bureau: AbbVie, BMS, Pfizer, Roche, Sanofi-Aventis

Background:Assessment and monitoring of disease activity and functioning is of major importance for the course of axial spondyloarthritis (axSpA). This is equally important for patient monitoring in daily routine as also for tight control strategies. Even though there is evidence that a closer monitoring of patients is better than routine care, more intensive treatment schedules are often not realized in daily practice for several reasons including shortage of time and personal resources. Using application software devices (apps) in clinical routine for the recording of disease-specific patient reported outcomes (PRO) may facilitate monitoring and improve clinical decision processes but there is a lack of data on the use of apps.Objectives:To investigate the use of such App technology in respect to usability, feasibility and equivalence of data in daily care of patients with axSpA. In more detail, it will be first determined how many patients are capable and ready to use the technology in a routine setting. Furthermore, the usage and behavior of patients using the app will be studied, the usability of the app and the equivalence of the collected parameters as well as the adherence to the documentation of disease activity over time.Methods:Patients diagnosed with axSpA were consecutively included in this ongoing monocentric prospective cohort study. In addition to patient and disease characteristics, information on previous experience with digital health apps was collected. Patients were asked to submit BASDAI and BASFI scores regularly every 2 weeks. The free to use AxSpA Live App is available for Android and iOS as a Class I certified medical device.Results:Out of 103 axSpA patients asked, 69 patients with axSpA (mean age 41.5 ± 11.3, 58% male, 76.8% use of bDMARDs, BASDAI 4.3 ± 2.0, BASFI 3.8 ± 2.5) out of 103 patients (67%) agreed to use participate, while 5 did not have a smartphone, 1 was unable to download the app for technical reasons, 28 reported other personal reasons). Of the 69, 62 patients (89.9%) reported using electronic media frequently and had used digital health apps (mean apps used 1.0 ± 1.3) in everyday life before. There were no systematic differences between pain levels documented on paper or by app at baseline (ICC 0.9 (95%CI 0.82 – 0.93). Out of 55 patients who completed week 2, only 33 patients (60%) used the App regularly to transmit their BASDAI/BASFI responses within the first two weeks (60%). Patients who started a new drug treatment because of high disease activity, reported BASDAI values more often than patients without a treatment change within a follow-up period of 5.5± 2.4 weeks (Table).Conclusion:The majority of patients with axSpA were able to use the AxSpA Live App. Most patients report scores regularly. The current disease activity seems to influence the adherence to reporting.Patients without change in their medication (n=53)Patients with change in their medication (n=16)Age, years42.0 (11.9)39.8 (9.3)Sex, male (%)62.343.8BASDAI, baseline4.1 (2.1)4.9 (1.7)BASFI, baseline3.8 (2.6)3.8 (2.3)Time of follow-up, in weeks5.4 (2.4)5.6 (2.5)Number of transmitted BASDAI values at week 222 (41%)11 (69%)Median number of transmitted BASDAI values during follow up1.0(3.6)1.5 (1.4)This work was supported by an unrestricted Grant by Novartis Pharma GmbH, GermanyAcknowledgments:n/aDisclosure of Interests:Uta Kiltz Grant/research support from: AbbVie, Amgen, Biogen, Novartis, Pfizer, Consultant of: AbbVie, Biocad, Eli Lilly and Company, Grünenthal, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Novartis, Pfizer, Roche, UCB, Robin Kempin: None declared, Anna Schlegel: None declared, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Styliani Tsiami: None declared, Bjoern Buehring Grant/research support from: GE/Lunar, Kinemed, Consultant of: Gilead, Abbvie, Lilly, GE/Lunar, Janssen, Amgen, Speakers bureau: UCB, David Kiefer Grant/research support from: Novartis, 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

Background:Taking advantage of a large population-based study we have recently reported that the frequency of bone marrow edema (BME) and fatty lesions (FL) in the sacroiliac joints (SIJ) and the spine of individuals Objectives:To identify and compare factors associated with the extension of MRI lesions in the spine and the SIJ in the general population.Methods:All available spinal- (sagittal T1/T2 sequences) and SIJ- (semicoronal STIR sequences) MRIs were evaluated by two trained readers blinded to clinical data. BME (SIJ and spine) suggestive of axSpA were recorded. The extension of BME was quantified using the Berlin MRI score. Discrepancies were resolved by consensus. Degenerative lesions of the Modic type were excluded. The association of age (increase per decade), sex, HLA-B27 and hsCRP positivity, smoking (ever smoker vs. no smoker), spinal pain (yes vs. no in last 3 months), body mass index (BMI) categories (WHO definition), physically demanding job, and giving birth within the last 12 month with the severity of BME were examined. Associations between clinical factors and the Berlin MRI score were analyzed by negative binomial regression models resulting in incidence rate ratios (IRRs).Results:MRIs of 793 volunteers from the general population, mean age 37.3±6.3 years, 49.4% male, 8.9% HLA B27+, 7% CRP-positive, 56.9% with back pain in the last 3 months (28.8% with back pain NRS ≥4/10), 35.7% reported physically heavy work, 55% with BMI > 25 kg/m2, 16.2% current smokers, and 5% of females with pregnancy in the last year before MRI examination, were evaluated.For BME on SIJ-MRIs, significant associations (IRR, 95% confidence level) were found for pregnancy in the last year (3.82, 1.17-14.24), HLA-B27+ (2.42, 1.33-4.55), BMI (25-30 vs. For BME on spinal MRIs, significant associations were found for age per decade increase (1.45, 1.10-1.91) and physically demanding work (1.45, 1.04-2.00), while HLA-B27+ (1.32, 0.79-2.24), BMI (>30: 0.84, 0.53-1.32 (Conclusion:In this population-based study, individuals aged Acknowledgments:n/aDisclosure of Interests:Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Adrian Richter: None declared, Daniel Feldmann: None declared, Anne Ott: None declared, Robin Buelow: None declared, Carsten Schmidt: 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

Background:Inflammatory involvement of the axial skeleton (sacroiliac joints and / or spine) is one of the relatively frequent musculoskeletal manifestations associated with psoriasis / psoriatic arthritis (PsA). There is an urgent need for an evidence-based definition for axial involvement in PsA that would identify a subgroup of patients within the heterogeneous PsA population to conduct observational, interventional and translational studies. ASAS and GRAPPA embarked on a collaborative initiative to develop a definition of axial involvement in PsA.Objectives:To perform a survey to identify variables relevant in the identification of the presence of axial involvement in PsA among members of ASAS and GRAPPA.Methods:The online survey utilized thePAPRIKAmethodology (PotentiallyAllPairwiseRanKings of all possibleAlternatives) that determines decision-makers’ part-worth utilities representing the relative importance of the attributes. Participants were exposed to number of clinical scenarios and were prompted to decide which of the scenarios is more compatible with axial involvement in PsA unless they are equal (Figure). The constant stem of each scenario was “a patient diagnosed with psoriatic arthritis fulfilling the CASPAR criteria”; the variable part included 13 common spondyloarthritis variables (Table). Variables were ranked according to their relative importance.Results:The survey was completed by 186 ASAS/GRAPPA members (63 ASAS only, 80 GRAPPA only, and 43 both societies). The ranking of the variables is presented inTable. The highest ranked parameters indicative of axial involvement in a patient with PsA were presence of typical radiographic or MRI changes in the sacroiliac joints and/or spine followed by the presence of chronic back pain and then inflammatory back pain. A separate analysis of ASAS and GRAPPA members provided the similar results concerning the relevance of the variables.Conclusion:Objective signs of inflammatory involvement of the axial skeleton are the most important indicators of axial disease in PsA in the opinion of the experts. A prospective cohort study is currently being planned to address the value of these and other variables in defining axial involvement in PsA.Table.Ranking of the parameters relevant to deciding on the presence of axial involvement in a PsA patient in the opinion of ASAS and GRAPPA members (n=186).NParametersMedian rankMean rank1Presence of structural damage on an X-ray of SIJ22.82Presence of structural damage on an X-ray of spine3.54.13Presence of subchondral BME / osteitis on MRI of SIJ compatible with SpA44.54Presence of BME / osteitis on MRI of spine compatible with SpA455History or current presence of back pain5.55.86History of or current presence of inflammatory back pain5.567Good response of back pain to non-steroidal anti-inflammatory drugs87.88HLA-B2788.19Family history for SpA9.5910Elevated C-reactive protein109.311Presence of peripheral arthritis and/or enthesitis and/or dactylitis109.412Presence of anterior uveitis109.513Presence of inflammatory bowel disease109.6BME=bone marrow edema, MRI=magnetic resonance imaging, SIJ=sacroiliac joints, SpA=spondyloarthritisDisclosure of Interests: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, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Filip van den Bosch Consultant of: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, 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, Alice Gottlieb Grant/research support from: Boehringer Ingelheim, Incyte, Janssen, Novartis, UCB, Xbiotech, Consultant of: AbbVie, Allergan, Avotres Therapeutics, Beiersdorf, Boehringer Ingelheim, BMS, Celgene, Dermira, Incyte, Eli Lilly, Janssen, LEO Pharma, Novartis, Reddy Labs, Sun Pharmaceutical Industries, UCB, Valeant, Xbiotech, Laura C Coates: None declared, Vinod Chandran Grant/research support from: Abbvie, Celgene, Consultant of: Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lily, Janssen, Novartis, Pfizer, UCB, Employee of: Spouse employed by Eli Lily, Philip Helliwell: None declared, Deepak Jadon: None declared, Joachim Sieper Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Speakers bureau: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant

Background:The risk of herpes zoster (HZ) is higher in patients with rheumatoid arthritis (RA) than in the general population. This risk is further increased with biologic disease-modifying anti-rheumatic drugs (bDMARDs) such as tumour necrosis factor inhibitors (TNFi) and targeted synthetic (ts)DMARDs such as Janus kinase inhibitors (JAKi) compared to patients taking conventional synthetic (cs)DMARDs such as methotrexate (MTX).Objectives:To compare incidence rates of HZ in RA patients under treatment with bDMARDs, tsDMARDs and csDMARDs with different modes of action and to find potential risk factors.Methods:Data of patients enrolled in the German biologics register RABBIT from 2007 onwards with the start of a bDMARD, tsDMARD or a change in csDMARD treatment were analysed. Patients were included when at least one follow-up documentation was available. All HZ events reported until 30 April 2019 were identified and assigned to treatments administered within the 3 month period prior to the HZ event. Crude incidence rates (IR) of HZ were calculated per 1,000 patient years (py). Cox regression was applied to investigate risk factors for the occurrence of HZ with and without inverse probability weights (IPW) to adjust for confounding by indication.Results:Data of 12,470 patients (53,218 py of observation) were included in the analysis. A total of 452 HZ cases in 433 patients were reported, of which 52 events were serious. The crude IRs per 1,000 py are illustrated by Figure. Adjusted for age, sex, and glucocorticoid use, a significantly increased risk was observed for treatment with monoclonal TNF antibodies (hazard ratio [HR], 1.55 [95% CI, 1.21-2.00]), B-cell targeted therapies (HR, 1.45 [95% CI, 1.07-1.97]), and tsDMARDs (HR, 3.55 [95% CI, 2.33-5.41]). Treatment with soluble TNF receptors, T-cell co-stimulation modulator, and IL-6 inhibitors were not significantly associated (Table). Adjustment with IPW amplified the effect and treatment with T-cell co-stimulation modulator and IL-6 inhibitors were also significantly associated with a higher risk compared to csDMARD treatment (Table).Conclusion:This is the first analysis in a European prospective cohort study comparing the incidence rates and risk of HZ in RA patients under treatment with six different modes of action within one cohort to csDMARD treatment. We found a significant association between HZ and treatment with JAKi. Our results also confirm a higher risk for monoclonal TNF antibodies and show a similar result for the T-cell co-stimulation modulator and B-cell targeted therapies. This study clearly supports systematic HZ vaccination of RA patients.Table.Risk of herpes zoster: Results of adjusted regression analyses with and without inverse probability weightsMultivariate Analysiswithout IPWMultivariate Analysiswith IPWAdjusted HR (95% CI)P ValueAdjusted HR (95% CI)P ValueFemale sex1.42 (1.12-1.82)0.00421.21 (0.96-1.53)0.1095Age per 10 years1.23 (1.13-1.33)1.31 (1.2-1.43)Glucocorticoids, 5-10 vs 0 mg/d1.16 (0.95-1.41)0.15771.23 (1-1.52)0.0501Glucocorticoids, >10 vs 0 mg/d1.58 (1.02-2.46)0.04171.92 (1.27-2.92)0.0022csDMARD treatmentReferenceReferenceMonoclonal TNFi antibodies1.55 (1.20-2.00)0.00091.63 (1.25-2.12)0.0003Soluble TNF receptors1.32 (0.98-1.77)0.06831.34 (0.98-1.83)0.0631T-cell co-stimulation modulator1.41 (0.97-2.05)0.07461.69 (1.17-2.45)0.0048B-cell targeted therapies1.45 (1.07-1.97)0.01561.66 (1.19-2.3)0.0026IL-6 inhibitors1.31 (0.97-1.77)0.07371.55 (1.15-2.09)0.0045JAK inhibitors3.55 (2.33-5.41)5.01 (3.45-7.28)Acknowledgments:RABBIT is supported by a joint, unconditional grant from AbbVie, Amgen, BMS, Fresenius Kabi, Hexal, Lilly, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis and UCBDisclosure of Interests:Anja Strangfeld Speakers bureau: AbbVie, BMS, Pfizer, Roche, Sanofi-Aventis, Imke Redeker: None declared, Jörn Kekow Speakers bureau: BMS, MSD, Pfizer, Roche, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, 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, Angela Zink Speakers bureau: AbbVie, Amgen, BMS, Gilead, Hexal, Janssen, Lilly, MSD, Pfizer, Roche, Sanofi Aventis, UCB

SGLT2 inhibitors are approved for glucose lowering in type 2 diabetes (T2DM) and have proven CV benefits, but are not approved for people with significantly reduced kidney function as glycemic efficacy is dependent on glomerular filtration. This analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program assessed effects of canagliflozin on CV outcomes in T2DM according to kidney function (estimated glomerular filtration rate [eGFR] Disclosure B.L. Neuen: Employee; Self; The George Institute for Global Health. T. Ohkuma: None. B. Neal: Research Support; Self; Australian National Health and Medical Research Council Principal Research Fellowship. Other Relationship; Self; Janssen Scientific Affairs, LLC., Roche Pharma, Servier. Research Support; Self; Merck Schering Plough. Advisory Panel; Self; Abbott, Novartis Pharmaceuticals Corporation, Pfizer Inc. D.R. Matthews: Other Relationship; Self; Janssen Scientific Affairs, LLC., Novo Nordisk Inc., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Sanofi-Aventis, Servier, Aché Laboratories. D. de Zeeuw: Other Relationship; Self; AbbVie Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Fresenius SE & Co. KGaA, Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Bayer AG, Mitsubishi Tanabe Pharma Corporation. K.W. Mahaffey: Research Support; Self; Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Janssen, Medtronic, Merck, Novartis, Sanofi, and St. Jude. Consultant; Self; Ablynx, AstraZeneca, BAROnova, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson, GlaxoSmithKline, Janssen, Merck, Mt. Sinai, Radiometer, Springer Publishing, The Medicines Company, Theravance, Vindico, and WebMD. Stock/Shareholder; Self; BioPrint Fitness. G. Fulcher: Other Relationship; Self; Novo Nordisk Inc., Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp. M. Desai: Employee; Self; Janssen Research&Development. Q. Li: Employee; Self; George Institute for Global Health. H. Deng: Employee; Self; Janssen Research&Development. N. Rosenthal: Employee; Self; Janssen Research & Development. M. Jardine: Other Relationship; Self; Fellowships. Research Support; Self; Gambro, Baxter, CSL Behring, Amgen Inc., Eli Lilly and Company, Merck & Co., Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Baxter, Amgen Inc., Roche Pharma. G. Bakris: Other Relationship; Self; Forest Labs, Takeda, Medtronic (15%), Relypsa (15%). Consultant; Self; Takeda, Abbott, CVRx, Johnson&Johnson, Eli Lilly, Food and Drug Administration. Board Member; Self; National Kidney Foundation, American Society of Hypertension. Other Relationship; Self; Editor-Am J Nephrology, HTN ed. UpToDate, Assoc. Ed.- Diabetes Care, Nephrology Dialysis and Transpl. V. Perkovic: Research Support; Self; Australian National Health and Medical Research Council (Senior Research Fellowship and Program Grant). Other Relationship; Self; AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, and Pfizer. Advisory Panel; Self; AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relyps.

Summary Major depressive disorder is a common diagnosis associated with a high burden of disease that has proven to be highly heterogeneous and unreliable. Treatments currently available demonstrate limited efficacy and effectiveness. New drug development is urgently required but is likely to be hindered by diagnostic limitations. Declarations of interest D.J.C. has received grants and personal fees from Eli Lilly, Janssen-Cilag, Roche, Allergen, Bristol-Myers Squibb, Pfizer, Lundbeck, AstraZeneca, Hospira, Organon, Sanofi-Aventis, and Wyeth during the writing of this review. C.P. has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, and received honoraria for consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, Schering Plough, and Lundbeck. Over the past 2 years he has participated on advisory boards for Janssen-Cilag and Lundbeck, and received honoraria for talks presented at educational meetings organised by AstraZeneca, Janssen-Cilag and Lundbeck. M.H. has received personal fees or grants from Lundbeck, AstraZeneca and Servier during the writing of this review. A.H.Y. reports personal fees from Lundbeck, Sunovion, AstraZeneca and Janssen outside the submitted work. I.P.E. has received personal fees or grants from Lundbeck, AstraZeneca, and Abbvie during the writing of this review. Copyright and usage © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Summary The appeal of ketamine – in promptly ameliorating depressive symptoms even in those with non-response – has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine’s potential as an option for treating depression and provide a synthesis of perspectives – derived from evidence and clinical experience – and to consider strategies for future investigations. Declaration of interests G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker’s Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; ‘paid-for’ ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse’s employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998–2013. Copyright and usage © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

The International Society of Nurses in Cancer Care (ISNCC) has, as part of its mission, the goal of fostering the growth of oncology nursing in parts of the world where cancer nursing is not perceived as a specialty. The idea of “twinning” high-resource countries with middle/low-resource countries was proposed, as a potential strategy to the ISNCC Board for achieving this goal. The Odette Cancer Centre Nursing Division from Sunnybrook Health Sciences Centre stepped forward and indicated it would be a “test case” for this new twinning or partnership program. Based on several conversations between M. Fitch when she was President of ISNCC and D. Makumi, Aga Khan University Hospital in Nairobi, Kenya, an agreement was reached to work together. A proposal was then developed for submission to the International Union Against Cancer (UICC) to hold an oncology nursing workshop on chemotherapy administration in Nairobi. This was a first step in our twinning experience. This article describes the experiences of the four nurses from Odette Cancer Centre (who prepared and offered the program) and the nurses in Kenya (who helped to plan and participated in the program) in working collaboratively as “twins.”

The availability and use of medicines to control infestations of sea lice on Atlantic salmon, Salmosalar L., farms in Scotland has changed considerably in the last decade (Lees, Gettinby & Revie 2008b). Whereas hydrogen peroxide and organophosphate compounds were used widely throughout the 1990s and in the early 2000s, only two therapeutants have remained in common use since 2005: topical cypermethrin (Excis; Novartis Animal Health, Camberley, UK) and an oral formulation of emamectin benzoate (SLICE; Schering Plough Animal Health, Uxbridge, UK).

r. Friedewald has received honoraria from Novartis, E anover, New Jersey. Dr. Kastrati has received honor rom Astra-Zeneca, Wilmington, Delaware; Bristol-Mye quibb, Plainsboro, New Jersey; Cordis, Miami Lak lorida; and Eli Lilly, Indianapolis, Indianapolis. Dr. R rts has received honoraria from Merck, Whitehouse ion, New Jersey; Schering Plough, Kenilworth, New ey; Pfizer, New York, New York; AstraZeneca; ovartis. Dr. Vetrovec is a member of the speaker’s bu f Pfizer; CV Therapeutics, Palo Alto, California; Eli L ordis; and Stereotaxis, St. Louis, Missouri. Dr. Vetro as received education or research grants from Cordis; illy; and The Medicines Company, Parsippany, New ey. Dr. Vetrovec has received end point committee racts from Merck; Pfizer; Boston Scientific, Natick, M achusetts; and Abbott Laboratories, Abbott Park, Illin r. Vetrovec has received consulting fees from Cordis he United States Food and Drug Administration, Rockv aryland. Dr. Vetrovec owns stock in Merck; Pfi edtronic, Minneapolis, Minnesota; Boston Scientific; a ohnson & Johnson, Piscataway, New Jersey. Dr. W cker has received honoraria from Biotronik, Berlin, G any; Boston Scientific; Biosensors, Victoria, Austral ordis; Medtronic; and Abbott Laboratories.

Robert E. Chapin, Jane Adams, Kim Boekelheide, L. Earl Gray Jr, Simon W. Hayward, Peter S.J. Lees, Barry S. McIntyre, Kenneth M. Portier, Teresa M. Schnorr, Sherry G. Selevan, John G. Vandenbergh, and Susan R. Woskie Pfizer, Inc., Groton, CT University of Massachusetts, Boston, MA Brown University, Providence, RI U.S. Environmental Protection Agency, Research Triangle Park, NC Vanderbilt University Medical Center, Nashville, TN Johns Hopkins University, Baltimore, MD Schering Plough Research Institute, Summit, NJ American Cancer Society, Atlanta, GA National Institute for Occupational Safety and Health, Cincinnati, OH U.S. Public Health Service (Ret), Silver Spring, MD North Carolina State University, Raleigh, NC University of Massachusetts, Lowell, MA

Ezetimibe lowers the intestinal absorption of cholesterol, being complementary to the effects of statin. To check its efficacy in lowering the carotid intima-media thickness, in 2002 a multicenter international trial called ENHANCE was started, in order to assess by ultrasound the regression of atherosclerotic plaques. The protocol tested the use of simvastatin 80 mg + placebo versus simvastatin 80 mg + ezetimibe 10 mg in 720 randomized patients. Both drugs were well tolerated. Combination therapy was associated with a larger reduction in LDL cholesterol, but there were no differences in the intima-media thickness measured at three sites in the carotid arteries, nor differences in cardiovascular events between the two groups in the trial. These results provoked disappointment of sponsors (Merck, Schering Plough) who, although the results of the trial were available since march 2007, delayed official communication of about 18 months. This led to speculations and rumors among media, American Government, cardiologic scientific associations, and consequences in the Ezetimibe market and at Wall Street. In particular, the American College of Cardiology didn’t accept the communication of ENHANCE results to the Late Breaking Trial Session of the Chicago congress, diverting it to another secondary forum. In conclusion, the experience of the ENHANCE trial suggests to pharmaceutical companies, researchers, clinicians, scientific companies and media a deep meditation in order to avoid in the future similar problems in the management of results of medical research.

Contains fulltext : 171486.pdf (Publisher’s version ) (Closed access) STUDY QUESTION: Do BRCA1/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Mullerian hormone (AMH) levels? SUMMARY ANSWER: BRCA1/2 mutation carriers do not show a lower serum AMH level in comparison to proven non-carriers, after adjustment for potential confounders. WHAT IS KNOWN ALREADY: It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum AMH levels and BRCA mutation status. Hence, it is yet unclear whether BRCA1/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 BRCA1/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in AMH levels of 0.40 microg/l (SD +/- 0.12 microg/l, two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHOD: Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive BRCA1/2 testing because of a familial BRCA1/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum AMH levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum AMH levels. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 BRCA1/2 mutation carriers and 131 proven non-carriers. The median [range] AMH level in carriers was 1.90 microg/l [0.11-19.00] compared to 1.80 microg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in AMH level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76). LIMITATIONS, REASONS FOR CAUTION: Participants were relatively young. Power was insufficient to analyze BRCA1 and BRCA2 mutation carriers separately. AMH levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis. WIDER IMPLICATIONS OF THE FINDINGS: Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent AMH measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care. STUDY FUNDING/COMPETING INTERESTS: This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe & Dome, Organon, and Schering Plough, outside the submitted work. Frank J.M. Broekmans is a member of the external advisory board for Merck Serono (The Netherlands), outside the submitted work. TRIAL REGISTRATION NUMBER: NTR no. 4324.

r. Roberts has received honoraria for speaking from erck, Whitehouse Station, New Jersey; Schering Plough, enilworth, New Jersey; Pfizer, New York, New York; straZeneca, Wilmington, Delaware; and Novartis, Annanale, New Jersey. Dr. Black has received honoraria for peaking and consulting from Pfizer, Novartis, Bristol-Myrs Squibb, New York, New York; Sanofi-Aventis, Bridgeater, New Jersey; Forest, New York, New York; Boehrnger-Ingelheim, Ridgefield, Connecticut; Merck, Gilead, oster City, California; Myogen, and Intercure, Fort Lee, ew Jersey. Dr. Bakris has received honoraria for speaking nd consulting from AstraZeneca, Abbott, Abbott Park, llinois; Bristol-Myers Squibb/Sanofi-Aventis, GlaxoSmithline, Research Triange Park, North Carolina; Merck, Noartis, Lilly, Indianapolis, Indiana; Walgreens, and Myoen. He has received grants from the National Institutes of ealth, Abbott, Boehringer-Ingelheim, GlaxoSmithline, Novartis, and Myogen. Dr. Mason has received inestigator-initiated research grants and honoraria for speakng or consulting from sanofi-aventis, Bristol-Myers quibb, Pfizer, and Forest Laboratories. Dr. Giles has reeived honoraria for speaking and consulting from Boehrnger-Ingelheim, Bristol-Myers Squibb, Sanofi-Aventis, ovartis, Forest Laboratories, and Pfizer. He has received rant funding from Novartis and AstraZeneca. All other ndividuals in a position to control content disclosed no elevant financial relationships.

The use of isotopically labelled compounds at Schering-Plough (S-P) has substantially increased over the past 30 years. Since the formation of the S-P Radiochemistry section in the early 1970s, the group has expanded its role from supplying 14C- and 3H-labelled compounds for ADME studies for compounds in development, to providing 3H-labelled compounds for drug discovery and also to provide stable isotope-labelled compounds that are used as LC/MS internal standards. Other isotopes used by the group have included 125I and 35S, which have been used to label both small molecules and proteins. Copyright © 2007 John Wiley & Sons, Ltd.

Porcine Respiratory Disease Complex (PRDC) is one of the most common and costly clinical conditions encountered in veterinary medicine in commercially kept pigs. In this introductory article (sponsored by Intervet/Schering Plough AH), the clinical presentation in both the individual pig and groups will be described, along with the pathological lesions encountered. The multiple aetiological factors involved in the syndrome, ranging from primary and secondary infectious agents to environmental and managemental factors will be explored. Diagnostic and monitoring methods are also discussed. Subsequent articles will look in detail at specific elements of the syndrome.

FONDATION RENE TOURAINE POUR LA RECHERCHE EN DERMATOLOGIE SCIENTIFIC MEETING 2001 Thursday 15th November 2001, Paris, France Ministere de la Recherche et de la Technologie Amphitheâtre Poincare, 1, rue Descartes, F-75005 Paris *** NEUROPHYSIOLOGY OF THE SKIN 9h30–10h30 E. DUPIN Embryogenesis of neuro-epithelial interactions 10h30–11h15 D. METZE Functional anatomy of the skin nervous system 11h15–12h00 T. LUGER Neuroimmunology 12h00 Winners of fellowships 12h30 Cocktail and Lunch 14h30–15h00 H. O. HANDWERKER Neuromediators, pruritus and pain 15h00–15h30 J. ANSEL Neuromediators and inflammation 15h30–16h00 Z. ABDEL-MALEK Neuromediators and pigmentation Break 16h30–17h00 R. PAUS Stress and skin 17h00–17h30 N. W. BUNNETT Pharmacological modulation of skin neuromediators (PAR II) La Fondation Rene Touraine est une Fondation reconnue d’utilite publique. Les Membres Fondateurs sont: les Laboratoires BAILLEUL, BERGADERM, BOOTS-LUTSIA, CHANEL, PIERRE FABRE, FONDATION LEO, GALDERMA, LABORATOIRES SEROBIOLOGIQUES, LA ROCHE POSAY, L’OREAL, L.V.M.H., ROCHE, SCHERING PLOUGH. Inscription : Fondation Rene Touraine, Hopital Saint-Louis, Pavillon Bazin, 1, Avenue Claude Vellefaux – 75475 – Paris – France. Tel : ++33 1 53 72 20 60 – Fax : ++33 1 53 72 20 61 – e-mail: fond.r.touraine@chu-stlouis.fr

I would like to thank Bob Coffman, Thierry von der Weid, Nancy Hosken, Amy Beebe, Steve Hurst, and Douglas Robinson for useful suggestions and discussion and Lewis Lanier for critical reviewing of the mansucript. I also thank Maribel Andonian for excellent help with graphics. DNAX Research Institute is funded by Schering Plough Research Institute, New Jersey.

B RIEF R EPORT Whipple’s Disease Masquerades as Dementia With Lewy Bodies Kyle Hurth, MD, PhD,* Rawan Tarawneh, MD, wz Nupur Ghoshal, MD, PhD, wz Tammie L.S. Benzinger, MD, PhD, wzy David B. Clifford, MD, y Michael Geschwind, MD, PhD,8 John C. Morris, MD, wz James E. Galvin, MD, z Robert E. Schmidt, MD, PhD,* and Nigel J. Cairns, PhD, FRCPath* wz (Alzheimer Dis Assoc Disord 2015;29:85–89) Key Words: Whipple’s disease, bacterial infection, dementia with Lewy bodies Received for publication March 25, 2013; accepted July 1, 2013. From the *Department of Pathology and Immunology, Division of Neuropathology; wCharles F. and Joanne Knight Alzheimer’s Disease Research Center; zDepartment of Neurology; yMallinck- rodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO; 8Department of Neurology, University of California, San Francisco, CA; and zComprehensive Center on Brain Aging, New York University Langone School of Medicine, New York, NY. K.H., R.T., and N.G. contributed equally. Supported by grants from the National Institute on Aging of the National Institutes of Health (P50-AG05681, P01-AG03991), the Hope Center for Neurological Disorders, the Buchanan Fund, the Charles F. & Joanne Knight Alzheimer’s Disease Research Center, and the Barnes- Jewish Hospital Foundation. A summary of these data were presented at the 2012 Annual Meeting of the American Association of Neuropathologists. N.G. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Elan/Janssen, Eli Lilly and Company, Wyeth, Pfizer, Novartis, and Bristol-Myers Squibb. T.L.S.B. declares an interest as a consultant for Biomedical Sys- tems, ICON Medical Imaging, Eli Lilly Advisory Board, and Avid Radiopharmaceuticals. D.B.C. serves on Data Safety Boards for Amgen, Biogen, GlaxoSmithKline, Millennium, Genzyme, Genentech, and Pfizer. He has been a consultant to Brinker, Biddle, Reath [Progressive Multifocal Leukoencephalopathy (PML) Consortium], Genentech, Genzyme, Bristol-Myers Squibb, Millen- nium, Biogen Idec, and Pfizer. He has received research support from the Alzheimer’s Association, Biogen Idec, Eli Lilly, Roche and Pfizer. He has received speaking fees from Biogen, University of Kentucky, ECTRIMS, and CMSC/ACTRIMS. J.C.M. declares an interest as a consultant for: Eisai, Elan/Janssen Alzheimer Immu- notherapy Program, GlaxoSmithKline, Novartis, Otsuka Pharma- ceuticals, Pfizer/Wyeth, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, and Schering Plough; support form NIH/NIA; speaking fees: Dickinson address at Ohio Wesleyan, ABA Soriano Lectureship, Morrell Lecture (Chicago), Eisai (South Korea), Bial Neurology Forum (Portugal); royalties from: Black- well Medical, Taylor and Francis. J.E.G. serves on a scientific advisory board for the American Federation for Aging Research and on the Board of Directors and the Scientific Advisory Council for the Lewy Body Dementia Association; he serves on speakers’ bureaus for Pfizer Inc., Eisai Inc., Novartis, and Forest Labo- ratories Inc.; has served as a consultant for Novartis, Forest Lab- oratories Inc., Pfizer Inc., Eisai Inc., Janssen, and Medivation Inc.; he has received license fee payments for AD8 dementia screening test (copyrighted): license agreements between Washington Uni- versity and Pfizer Inc., Eisai Inc., and Novartis; and receives research support from Novartis, Eli Lilly and Company, Elan Corporation, Wyeth, Bristol-Myers Squibb, the NIH/NIA, and the Alzheimer Association. The remaining authors declare no conflicts of interest. Reprints: Nigel J. Cairns, PhD, FRCPath, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110 (e-mail: cairns@wustl.edu). Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. Alzheimer Dis Assoc Disord CASE HISTORY Dr George Whipple first described the disease which bears his name in 1907. 1 He described a 36-year-old male physician who presented with a 5- to 6-year history of insidious symptoms including cough, recurrent attacks of arthritis, gradual weight loss, and asthenia. By the end of his life, skin changes, diarrhea, abdominal swelling, and mesenteric adenopathy were prominent. Pathologic examination showed macrophages and fat vacuoles in the small bowel and inflammation and macrophages within pleura, peritoneum, and the aortic valve. Silver staining demonstrated rod- shaped structures. Electron microscopy has revealed that these aggregates consist of networks of membranous structures and bacillary bodies of the bacterium Tropheryma whipplei. 2,3 Bacterial DNA sequencing and antibodies to T. whipplei may now be used to confirm the diagnosis. We report a 49-year-old white man with a 4-year history of progressive cognitive and behavioral impairment, parkinsonism, cognitive fluctuation, altered sleep-wake cycles, myoclonus, visual hallucinations, and subsequent death. His past medical history included hypertension, chronic obstructive pulmonary disease, smoking, alcohol use, and cadaveric growth hormone replacement for delayed puberty as a child. There was no family history of dementia or movement disorder. He worked as a painter and was frequently exposed to solvents. He was in his usual state of health until approximately 2 years before initial evaluation. At that time, behavioral disturbances were noted by the family from whom he was estranged. He was described as depressed and severely withdrawn. Approximately 12 to 16 months into his course, he became forgetful of recent events and conversations and repeated himself. He had increasingly odd behavior including sleeping during the day and being awake at night, wandering outside inappropriately dressed, and confabulating. His cognition fluctuated from staring spells to deep sleep from which he was difficult to arouse. At other times he was alert and fully oriented without recollection of prior events. He began to have well-formed visual hallucinations that he described as “brightly-colored pets” or “small people” and occur- red during periods of lucidity. Eighteen months after onset, he was evaluated at an outside hospital for pneumonia, confusion, and agitation. He had notable parkinsonism and myoclonus of the left upper extremity. Imaging and diagnostic studies were unrevealing. Valproic acid partially improved his myoclonic movements. He was also treated with intravenous thiamine given his prior alcohol use and presentation concerning for Wernicke-Korsakoff syndrome. Small doses of risperidone and olanzapine produced generalized rigidity and drowsiness. He had one unexplained syncopal episode during his admission. Between episodes, he was alert and fully oriented and was discharged to a skilled nursing facility. Sporadic Creutzfeldt-Jakob disease was considered because of the rapid cognitive decline and a history of treatment with cadaveric growth hormone extract led to the suspicion of iatrogenic Creutzfeldt-Jakob disease. However, the absence of periodic sharp wave complexes in the context of mildly left predominant Volume 29, Number 1, January–March 2015 www.alzheimerjournal.com

Study question Is routine screening by oral glucose tolerance test (OGTT) needed for all women with polycystic ovary syndrome (PCOS)? Summary answer Screening for glucose metabolism abnormalities of PCOS patients by an OGTT could potentially be limited to patients who present with a fasting glucose concentration between 6.1 and 7.0 mmol/l only. What is known already Women with PCOS are at increased risk of developing diabetes. This study proposes a stepwise screening strategy for (pre)diabetes for PCOS patients based on risk stratification by fasting plasma glucose. Study design, size, duration A cross-sectional study of 226 women diagnosed with anovulatory PCOS. Participants and setting A consecutive series of 226 patients, diagnosed with PCOS at the University Medical Centre Utrecht, the Netherlands, were screened for glucose metabolism abnormalities by OGTT (75 g glucose load). Main results and role of chance The majority of the 226 women (mean age: 29.6 ± 4.3 years; BMI: 27.3 ± 6.7 kg/m(2); 81% Caucasian) presented with a normal OGTT (169 women (75%)). Of the 57 (25%) women presenting with mild to moderate glucose abnormalities, 53 (93%) could be identified by fasting glucose concentrations only. Diabetes was diagnosed in a total of eight women (3.5%). In six women, the diagnosis was based on fasting glucose >7.0 mmol/l. The other two cases of diabetes initially presented with fasting glucose between 6.1 and 7.0 mmol/l and were diagnosed by OGTT assessment. No women diagnosed with diabetes presented with fasting glucose levels below 6.1 mmol/l. We therefore conclude that all diabetes patients could potentially be found by initial fasting glucose assessment followed by OGTT only in patients with fasting glucose between 6.1 and 7.0 mmol/l. Limitations, reasons for caution Before general implementation can be advised, this screening algorithm should be validated in a prospective study of a similar or greater number of PCOS women. Wider implications of the findings Our study comprised of a mostly Caucasian (81%) population, therefore generalization to other ethnic populations should be done with caution. Study funding/competing interest(s) No external finance was involved in this study. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. A.J.G. has received fees from Abbott, Bayer Schering and IBSA. T.W.H. has received fees from Merck, Sharpe & Dohme, GlaxoSmithKline, NovoNordisk and Eli Lilly. The authors declare complete independence from funders. Clinical trial registration number NCT00821379.

study question: what is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? Summary answer: early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. What is known already: during ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. Study design, size, duration: this open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. Participants/materials, setting, methods: recombinant FSH (150–225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. Main results and the role of chance: there were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). Limitations, reasons for caution: the study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. Wider implications of the findings: the present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. Study funding/competing interests: this study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono

This essay comprises personal recollections, ideas, and insights, gleaned from many decades of drug discovery research and development, identifying important trends in medicinal chemistry and the pharmaceutical industry. Drawing examples from the Schering–Plough Research Institute in the latter half of the twentieth century, a panoply of techniques and a host of scientists are presented addressing the challenges of creating chemical compounds to combat disease. Drug classes considered include anti-inflammatories, antihistamines, antibiotics, antifungals, antivirals, as well as anticholesterol, anticancer, and anticlotting agents.

This chapter describes the career in drug discovery of Malcolm MacCoss, from his early studies as a graduate student in the UK and as a postdoctoral fellow in Canada, through his work at Argonne National Laboratory and on to his career at Merck Research Laboratories in Rahway, NJ and eventually to Schering-Plough in Kenilworth, NJ. The particular discoveries of EMEND® and JANUVIA® are discussed.

Introduction Intensive induction chemotherapy for acute myeloid leukemia (AML) in patients aged 60 years or older has lower remission rates with increased induction mortality compared with younger patients. CPX-351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio. Previously reported results from a phase III, randomized, open-label study of CPX-351 versus 7+3 (cytarabine and daunorubicin) in newly diagnosed older patients with secondary AML suggested superior survival in those randomized to CPX-351. We conducted an exploratory analysis of patients who received allogeneic hematopoietic cell transplantation (HCT) after induction treatment, to determine the effect of HCT on outcome by arm, as few patients in this age range can be cured with chemotherapy alone. Methods This phase III trial was a randomized, open-label, parallel-arm, standard therapy-controlled study. Eligible patients were aged 60 to 75 years with newly diagnosed secondary AML defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) (± prior treatment with hypomethylating agents), or AML with World Health Organization-defined MDS-related cytogenetic abnormalities. Patients were randomized 1:1 to CPX-351 induction (100 units/m2 [100 mg/m2 cytarabine + 44 mg daunorubicin mg/m2] on days 1, 3, and 5 [first induction only]) or 7+3 induction (cytarabine 100 mg/m2/day x 7 days plus daunorubicin 60 mg/m2 on days 1, 2, and 3 [first induction] or x 5 days [reinduction/consolidation] plus daunorubicin 60 mg/m2 on days 1 and 2). The distribution of overall survival (OS) after HCT in each treatment arm was estimated using the Kaplan-Meier method, and Cox regression hazard ratio and OS rates, along with corresponding confidence intervals, are reported. Results Three hundred and nine (309) patients were enrolled from December 2012 to November 2014 at 39 US and Canadian sites, with 153 patients randomized to the CPX-351 arm and 156 to the 7+3 arm. Patients in either arm responding to induction with a complete response (CR) or a CR with incomplete platelet or neutrophil recovery (n=125) were considered for allogeneic HCT when possible. In total, 91 patients were transplanted: 52 (34%) from the CPX-351 arm and 39 (25%) from the 7+3 arm. Patient and AML characteristics were similar according to randomized arm, including percentage of patients in each arm that underwent transplant in CR/CRi status (Table); however, the CPX-351 arm contained a higher percentage of older patients (age ≥ 70) who were transplanted (CPX-351, 31%; 7+3, 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% in the 7+3 arm patients. Causes of death Conclusions An exploratory analysis from this phase III study demonstrated that CPX-351, compared with standard cytarabine and daunorubicin, resulted in better outcomes after allogeneic HCT in older patients with high-risk AML, including 53% fewer deaths within 100 days of transplant. These results suggest that CPX-351 may provide an effective bridge to successful transplant for a very poor-risk subgroup of AML patients. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. Disclosures Uy: Boehringer Ingelheim: Consultancy; Glycomimetics: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Ritchie:Astellas Pharma: Research Funding; Ariad: Speakers Bureau; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; NS Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding. Stuart:Celator: Research Funding; Incyte: Research Funding; Astellas: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Bayer: Research Funding. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Hogge:Sanofi: Consultancy; Roche: Other: Travel, Accomodations, Expenses. Stone:Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy; Agios: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celator: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. Kolitz:Gliead Sciences: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy. Schiller:Celator: Research Funding. Ryan:AbbVie: Equity Ownership; U of Rochester: Patents & Royalties. Chiarella:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Medeiros:MEI Pharma: Research Funding; Merck/Schering Plough: Research Funding; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; ARIAD: Consultancy; Celator: Other: Travel, Accomodations, Expenses, Research Funding; Roche/Genentech: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Amgen: Consultancy.

Introduction CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio, has shown enhanced efficacy compared with standard induction in older adults with high-risk AML in phase II clinical trials. Presented here are pre-specified secondary subgroup results from a phase III randomized, open-label study of CPX-351 versus 7+3 (cytarabine plus daunorubicin) in newly diagnosed patients with high-risk features, focusing on efficacy results stratified by age group. Methods Eligible patients were aged 60 to 75 years and had secondary AML, either therapy-related or an antecedent myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, or AML with World Health Organization-defined MDS-related cytogenetic abnormalities. Patients were randomized 1:1 to receive CPX-351 induction (100 units/m2 [100 mg/m2 cytarabine + 44 mg daunorubicin mg/m2] on days 1, 3, and 5 [first induction only]) or 7+3 induction (cytarabine 100 mg/m2/day x 7 days plus daunorubicin 60 mg/m2 on days 1, 2, and 3 [first induction] or x 5 days [reinduction/consolidation] plus daunorubicin 60 mg/m2 on days 1 and 2). A dynamic allocation procedure was performed to stratify patients by age group (60-69 or 70-75 years) for each arm of the study. The distribution of overall survival (OS) by treatment arm was estimated using the method of Kaplan-Meier. Efficacy for each age group was reported in terms of median OS in months and percentage of patients with a morphologic complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) according to International Working Group criteria. Results Three hundred and nine patients were enrolled from December 2012 to November 2014 at 39 US and Canadian sites, with 153 patients randomized to the CPX-351 arm and 156 to the 7+3 arm. Among patients aged 60-69 years, there were 96 patients in the CPX-351 arm and 102 in the 7+3 arm; for patients aged 70-75 years, there were 57 and 54 patients in each arm, respectively. Demographic data for these age subgroups were similar between the CPX-351 and 7+3 arms of the study. The CR+CRi rates for patients aged 60-69 years were 50.0% for patients in the CPX-351 arm and 36.3% in the 7+3 arm, with an odds ratio (OR) of 1.76 (95% confidence interval [CI], 1.00-3.10); for patients aged 70-75 years, the rates of CR+CRi were 43.9% and 27.8%, respectively, with an OR of 2.03 (95% CI, 0.92-4.49). Kaplan-Meier curves for OS by age group are shown in the Figure. Median OS in months for patients aged 60-69 years was 9.63 in the CPX-351 arm and 6.87 in the 7+3 arm, with a hazard ratio of 0.68 (95% CI, 0.49-0.95); for patients aged 70-75 years these were 8.87 for the CPX-351 arm and 5.62 for the 7+3 arm, with a hazard ratio of 0.55 (95% CI, 0.36-0.84). The allogeneic hematopoietic cell transplant (HCT) rate in patients aged 60-69 years was 37.5% in the CPX-351 arm and 32.4% in the 7+3 arm, with an OR of 1.25 (95% CI, 0.70-2.25). For patients aged 70-75 years, the allogeneic HCT rates were 28.1% and 11.1%, respectively, with an OR of 3.12 (95% CI, 1.12-8.72). Incidence of grade 3-5 adverse events were virtually equal (92% vs 91%) and were similar in frequency and severity in both arms. The most common grade 3-5 nonhematologic adverse events (>10% overall) were febrile neutropenia (CPX-351: 68%; 7+3: 71%), pneumonia (CPX-351: 20%; 7+3: 15%), and hypoxia (CPX-351: 13%; 7+3: 15%). Conclusions This subgroup analysis of patients aged 60-69 and 70-75 years with untreated secondary AML demonstrated that CPX-351 treatment had substantially greater median OS and higher CR+CRi rates than standard 7+3 (cytarabine and daunorubicin) in both age groups. In addition, somewhat more patients in each age group in the CPX-351 arm received allogeneic HCT compared with the 7+3 arm, with the greatest difference in the older age group. Future studies with larger patient groups are warranted. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. Disclosures Medeiros: Agios: Consultancy, Research Funding; Amgen: Consultancy; ARIAD: Consultancy; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy, Research Funding; Celator: Other: Travel, Accomodations, Expenses, Research Funding; MEI Pharma: Research Funding; Merck/Schering Plough: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Quantum First: Consultancy; Kalo Bios: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; ERYtech: Consultancy; Biopath Holdings: Consultancy; Karyopharm: Consultancy; Boehringer-Ingelheim: Consultancy; Seattle Genetics: Consultancy; Baxalta: Consultancy; Amgen: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Stuart:Astellas: Research Funding; Incyte: Research Funding; Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Research Funding; Celator: Research Funding. Strickland:Sunesis Pharmaceuticals: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Alexion Pharmaceuticals: Consultancy; Sanofi: Research Funding; CTI Biopharma: Consultancy; Karyopharm Therapeutica: Research Funding; Baxalta: Consultancy; Daiichi Sankyo: Consultancy; Ambit: Consultancy; Abbvie: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding. Hogge:Sanofi: Consultancy; Roche: Other: Travel, Accomodations, Expenses. Stone:ONO: Consultancy; Xenetic Biosciences: Consultancy; Seattle Genetics: Consultancy; Amgen: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Juno Therapeutics: Consultancy; Celator: Consultancy; Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Jansen: Consultancy. Kolitz:Gliead Sciences: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Schiller:Celator: Research Funding. Ryan:AbbVie: Equity Ownership; U of Rochester: Patents & Royalties. Chiarella:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Uy:Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy.

Background RA leads to high burden on patient (pt) work, functioning and quality of life. Certolizumab pegol (CZP)+MTX improves physical function,1 and workplace and household productivity,2,3 in established and early active RA. Here we report impact of maintaining, reducing frequency or stopping CZP from Week (Wk) 52 to 104 in pts who achieved sustained low disease activity (sLDA) following 1 year (yr) of CZP+optimized MTX. Objectives To assess effect of 2 dosing frequencies of CZP+MTX vs stopping CZP on physical function and workplace/household productivity in Period 2 of C-EARLY, a phase 3 study in early RA pts with severe progressive disease. Methods CZP+MTX-treated pts achieving sLDA (DAS28[ESR]≤3.2 at Wks40 and 52) in C-EARLY Period 1 (NCT01519791)4 entered Period 2 (NCT01521923), a randomized, double-blind study. Pts were randomized 2:3:2 to CZP standard dose (200mg Q2W+MTX), CZP reduced-frequency dose (200mg Q4W+MTX) or CZP stopped (PBO+MTX). Physical function (HAQ-DI) and %pts achieving normative physical function (HAQ-DI≤0.5) from Wk52 to 104 are reported (ANCOVA model with factors treatment, region, time since diagnosis at BL [≤4 vs >4 months], and BL/Wk52 values as covariate and logistic regression models [treatment, region and time since diagnosis at BL as factors] respectively; CZP stopped as comparator; LOCF). Workplace/household productivity (Work Productivity Survey, WPS)5 at Wk52 and 104 are reported (LOCF); non-parametric bootstrap-t method (CZP stopped as comparator). Results In Period 2, 289 pts were included in the full analysis set: CZP Q2W+MTX (n=84), CZP Q4W+MTX (n=126) or PBO+MTX (n=79). Improvements in physical function were maintained from Wk52 to 104 in CZP Q2W+MTX (HAQ-DI mean [SD] 0.32 [0.42] to 0.37 [0.48], respectively) and CZP Q4W+MTX (0.33 [0.49] to 0.41 [0.57]), whereas deterioration was seen in PBO+MTX (0.33 [0.47] to 0.57 [0.65]). %pts with normative function was generally maintained between Wk52 to 104 in CZP Q2W+MTX (80.7% to 71.4%) and CZP Q4W+MTX (80.2% to 70.6%), but decreased in PBO+MTX pts (75.9% to 57.0%). At Wk104, employed CZP Q2W+MTX and CZP Q4W+MTX pts maintained on average the improvements in workplace productivity, whereas worsening was seen in pts stopping CZP (Table). Similar trends were observed in household productivity and need for regular assistance (Table). Conclusions Pts continuing CZP treatment (both dose frequencies) after 1yr further maintained improvements at 2yrs in physical function and workplace/household productivity, compared with pts who stopped CZP. References Strand V. Arthritis Res Ther 2009;11:R170; Kavanaugh A. Arthritis Care Res 2009;61(11);1592–1600; Emery P. Ann Rheum Dis 2015;74(S2);712; Weinblatt M. Arthritis Rheumatol. 2015;67(S10); Osterhaus J. Arthritis Res Ther 2009;11:R73 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest C. Bingham Consultant for: UCB Pharma, P. Emery Consultant for: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, X. Mariette Grant/research support from: Pfizer, GlaxoSmithKline and Roche. Consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma and Sanofi-Aventis, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, O. Purcaru Employee of: UCB Pharma, V. Bykerk: None declared

Background C-EARLY (NCT01519791) assessed the efficacy and safety of certolizumab pegol (CZP)+optimized MTX vs placebo (PBO)+optimized MTX in inducing and maintaining a sustained clinical response, and inhibiting radiographic damage, in DMARD-naive patients (pts) with active, severe, progressive RA. 1 Here, we examine the association between an inadequate response to PBO+MTX or CZP+MTX treatments at Week (Wk) 12 (lack of improvement from baseline [BL] in DAS28[ESR], DAS28[CRP] or CDAI) and corresponding response at Wk 52. Objectives To examine the association between Wk12 response and Wk52 clinical response (remission [REM]/low disease activity [LDA]) in recently diagnosed DMARD-naive pts with active, severe, progressive RA, treated with CZP+optimized MTX vs PBO+optimized MTX. Methods This multicenter, double-blind, randomized controlled trial enrolled pts who were DMARD-naive with active, severe, progressive RA ( Results The NPV of Wk12 responses were high (Table): PBO+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥0.6 had 94% probability of not being in REM or LDA at Wk52. CZP+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥1.2 had 93% probability of not being in REM at Wk52. NPV of changes in DAS28(CRP) and CDAI at Wk12 were less informative for predicting remission at 1yr (Table). Conclusions In early RA pts treated with optimized-dose MTX, failure to achieve a ≥0.6 DAS28(ESR) reduction from BL at Wk12 was associated with a low probability (6%) of DAS28(ESR) REM/LDA at Wk52, supporting treatment step-up at 3 months. For pts with active, severe RA with poor prognostic factors where CZP has been initiated as first-line treatment, failure to achieve a rapid decrease of 1.2 points was associated with a reduced likelihood of achieving REM (7%). These findings in DMARD-naive pts are consistent with the negative predictability outcomes for CZP in established RA. 2 References Weinblatt M. Arthritis Rheumatol 2015;67(S10); van der Heijde D. J Rheumatol 2012;39:1326–33 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest X. Mariette Grant/research support from: Pfizer and GlaxoSmithKline., Consultant for: Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, UCB Pharma and Sanofi-Aventis, C. Bingham Consultant for: UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, V. Bykerk: None declared, P. Emery Consultant for: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Employee of: Director of Imaging at Rheumatology BV, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, C. Arendt Employee of: UCB Pharma, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma