988 Taylor PC, et al. Ann Rheum Dis 2018;77:988–995. doi:10.1136/annrheumdis-2017-212461 Clinical and epidemiological research EXTENDED REPORT Lipid profle and effect of statin treatment in pooled phase II and phase III baricitinib studies Peter C Taylor, 1 Joel M Kremer, 2 Paul Emery, 3 Steven H Zuckerman, 4 Giacomo Ruotolo, 4 Jinglin Zhong, 5 Lei Chen, 4 Sarah Witt, 4 Chadi Saifan, 4 Monika Kurzawa, 4 James D Otvos, 6 Margery A Connelly, 6 William L Macias, 4 Douglas E Schlichting, 4 Terence P Rooney, 4 Stephanie de Bono, 4 Iain B McInnes 7 ABSTRACT Objectives Lipid profles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modifed by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. Methods Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. Results Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no signifcant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not signifcantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. Conclusions Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these fndings and their possible clinical implications. Trial registration number NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078. INTRODUCTION Baricitinib, an oral selective inhibitor of Janus kinase (JAK) 1 and JAK 2, 1 is approved in the Euro- pean Union and Japan for the treatment of moder- ate-to-severe active rheumatoid arthritis (RA) in adults. Baricitinib improved signs and symptoms of RA in phase III, placebo and active-controlled studies in patients with active RA who were naïve to conventional synthetic disease-modifying antirheumatic drugs (csDMARD; RA-BEGIN), 2 or had an inadequate response (IR) to previous treatment with methotrexate (MTX; RA-BEAM), 3 csDMARDs (RA-BUILD) 4 and biological DMARDs (RA-BEACON). 5 In RA, the proinflammatory state in untreated patients is associated with a decrease in total choles- terol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL- C) 6 ; anti-inflammatory therapies have been shown to increase these lipid levels. 7–11 Increases in lipids persisted in a phase II study of baricitinib. 12 The increase in LDL-C was associated with an increase in large and a decrease in small LDL, without any increase in LDL particle number. The increase in HDL-C was associated with an increase in HDL particle number across all particle sizes. 12 This LDL and HDL particle profile has been associated with reduced atherogenic risk. 13 This analysis assessed the effects of baricitinib on the lipid profile, lipoprotein particle size and number, and GlycA. GlycA, a measure of glyco- sylated acute phase proteins, is an emerging inflam- matory marker that may be useful for assessing disease activity and is associated with subclinical cardiovascular disease in patients with RA. 14–19 In addition, the effect of statin therapy on these biomarkers was evaluated. The impact of lipid alteration on cardiovascular risk, changes in risk scores and association between LDL-C change and major adverse cardiovascular events (MACE) were also assessed. METHODS Study design and patients Data were included from seven randomised clinical studies: three phase II (JADA, JADC and JADN) and four phase III studies (RA-BEGIN, RA-BEAM, RA-BUILD and RA-BEACON), including data from the long-term extension (LTE) (RA-BEYOND; data through 1 January 2016). All patients completing phase III studies or JADA were eligible to enter RA-BEYOND. The designs for each study have been previously described 2–5 20–23 and are summarised in online supplementary table S1. Each study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. All patients provided written informed consent. The studies were designed by the sponsors, Eli Lilly and Company and Incyte, To cite: Taylor PC, Kremer JM, Emery P, et al. Ann Rheum Dis 2018;77:988–995. Handling editor Josef S Smolen ► Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2017-212461). For numbered affliations see end of article. Correspondence to Professor Peter C Taylor, Nuffeld Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK; peter.taylor@kennedy.ox.ac.uk This manuscript is based on work presented at the 2016 ACR/ARHP Annual Meeting: McInnes IB, Kremer J, Emery P, Zuckerman SH, Ruotolo G, Saifan C, Chen L, Thanabalasundrum S, Witt S, Macias W. Lipid profle and effect of statin treatment in pooled phase 2 and phase 3 baricitinib studies [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). Received 28 September 2017 Revised 2 February 2018 Accepted 3 February 2018 Published Online First 20 February 2018 on 20 November 2018 by guest. Protected by copyright. http://ard.bmj.com/ Ann Rheum Dis: first published as 10.1136/annrheumdis-2017-212461 on 20 February 2018. Downloaded from