Objective.Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib’s safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)].Methods.The “all-bari-RA” group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 (“placebo-4 mg” dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data (“2 mg-4 mg–extended”). The uncommon events description used the non-controlled all-bari-RA.Results.There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure.Conclusion.In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers:NCT01185353,NCT00902486,NCT01469013,NCT01710358,NCT01721044,NCT01721057,NCT01711359, andNCT01885078atclinicaltrials.gov.

Background Baricitinib (BARI) is an oral selective Janus kinase (JAK 1/2)1 inhibitor approved in the EU, Japan, and other countries for treatment (tx) of moderately to severely active rheumatoid arthritis (RA) in adults. RA therapies may increase risk of tuberculosis (TB).2 The use of isoniazid (INH) plays a vital role to control TB. However, INH may result in hepatic adverse events (AEs)3. Limited data exist on hepatic safety in TB patients (pts) with RA treated with JAK inhibitors and INH. Objectives To evaluate the hepatic safety in pts with RA, who were receiving INH for latent TB (LTBI) in BARI phase 3 trials. Methods This is a descriptive post-hoc analysis of three phase 3 studies: RA-BEAM, RA-BUILD, and RA-BEACON. All pts were screened for LTBI prior to randomisation. Pts with untreated LTBI and without documentation of prior completed tx, received INH at least for 4 weeks (wk) prior to randomisation and during the clinical trial period. Changes in ALT levels (≥1X,≥3X,≥5X, and ≥10X of ULN) from baseline up to 24 wk were analysed by tx groups (BARI 4 mg, BARI 2 mg, adalimumab [ADA], and placebo [PBO]). Results In total, 2516 pts were included in this analysis. Of these, 891 pts were treated with BARI 4 mg, 403 with BARI 2 mg, 330 with ADA, and 892 with PBO. Background csDMARDs, mainly methotrexate (MTX) were continued. Overall, 246 pts reported LTBI at screening across all tx groups. Of these, 169 with confirmed lab data received INH as LTBI tx. At wk 24, ALT≥1X was reported in 24 (41.4%) pts receiving BARI 4-mg+INH. None of the pts in BARI 4-mg+INH reported ALT level of ≥3X,≥5X, and ≥10X ULN. For BARI 2-mg+INH, ALT≥1X reported in 9 (33.3%) pts, ALT≥3X in 2 (7.4%), ALT≥5X in 1 (3.7%), and ALT≥10X in 1 (3.7%) of the pts. Among pts treated with ADA +INH, ALT≥1X was reported in 12 (44.4%), ALT≥3X in 2 (7.4%), ALT≥5X in 1 (3.7%), and ALT≥10X in none of pts. Among pts treated with PBO+INH, ALT≥1X was reported in 21 (36.8%), ALT≥3X and ALT≥5X levels were reported in 2 (3.5%, for both) of the pts. None of the pts reported ALT≥10X. One pt receiving INH in RA-BEAM PBO arm had temporary interruption of tx due to abnormal hepatic lab results. No study tx interruption or discontinuation was reported in INH users in BARI or ADA groups due to abnormal hepatic lab results.Abstract FRI0098 – Table 1 Changes in ALT level from baseline to week 24 in patients receiving BARI, ADA, and PBO Conclusions The percentage of pts with ≥1X ULN ALT was numerically higher in INH group vs no INH and was consistent across PBO, BARI and ADA tx groups. The data do not suggest an increased hepatic safety risk in pts treated with BARI who were receiving concomitant INH. References [1] Dougados M, et al. Ann Rheum Dis. Jan 2017;76(1):88–95. [2] Lim CH, et al. PLoS One. 2017;12(6):e0178035. [3] Vanhoof J, et al. Ann Rheum Dis. Dec 2003;62(12):1241–1242. Disclosure of Interest T.-Y. Hsieh: None declared, W.-N. Huang: None declared, H.-P. Tony Consultant for: Abbvie, AstraZeneca, Chugai, Janssen Cilag, Eli Lilly and Company, Novartis, Roche, Sandoz Hexal, A. Balsa Grant/research support from: Pfizer, AbbVie, UCB, Roche, Novartis, Consultant for: Pfizer, Novartis, AbbVie, MSD, UCB, Roche, BMS, Novartis, Celltrion, Nordic, K. Winthrop Grant/research support from: Pfizer, BMS, Consultant for: Pfizer, UCB, Abbvie, Eli Lilly and Company, Amgen, BMS, M. Harigai Grant/research support from: BristolMyers Squibb K.K., Eisai Co., Ltd., Ono Pharmaceuticals, and Takeda Pharmaceutical Co., Ltd., Consultant for: Eli Lilly and Company, C. Dickson Employee of: Eli Lilly and Company, W.-S. Wu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, I. de la Torre Employee of: Eli Lilly and Company, R. Liao Employee of: Eli Lilly and Company, L. Chen Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Kumar Employee of: Eli Lilly and Company, B. Combe Grant/research support from: Pfizer, UCB, Consultant for: Abbvie, BMS, Janssen, Lilly, MSD, Novartis, Pfizer, Roche-Chugai, UCB, Speakers bureau: BMS, Janssen, Lilly, MSD, Pfizer, Roche-Chugai, UCB

Background Rheumatoid arthritis (RA) is associated with increased neutrophil levels1 and platelet2 counts and decreased lymphocyte levels.1,3 Baricitinib (bari) is a selective and reversible Janus kinase (JAK)1/JAK2 inhibitor in development for patients (pts) with moderate to severe RA.4 Objectives To characterize changes in absolute neutrophil counts (ANC), absolute leukocyte counts (ALC), and platelet counts following once daily oral administration of bari. Methods Data were pooled from 6 placebo-controlled phase 2 and 3 studies of bari (2 and 4 mg). Changes in ANC, ALC, and platelets were evaluated for up to 52 weeks (wks) including data from a long-term extension study. Reversibility was evaluated in a subgroup of pts who discontinued treatment by wk 24. Results Mean ANC decreased within 1 month of administration of bari, followed by stabilization and an increase to baseline after treatment discontinuation (Figure 1). ANC <1000 cells/mm3 were reported in <1% of pts, and 2 bari-treated pts (0.1%) reported permanent discontinuation of study drug due to neutropenia. Incidence of neutropenia was not associated with higher risk of overall or serious infections (Table 1). Mean ALC increased within 1 month of bari administration and then decreased to baseline level in wks 12 to 24 (Figure 1). Lymphopenia appeared to be associated with slightly higher rate of overall infections (Table 1). Mean platelet counts increased to peak at wk 2, returned towards baseline, stabilized over time, and returned to baseline after treatment discontinuation (Figure 1). Permanent study drug discontinuations from thrombocytosis occurred in 2 bari-treated pts (0.1%). No clear association between platelet increase and thromboembolic events was observed. Conclusions Treatment with bari was associated with a decrease in ANC and an increase in ALC and platelets, which stabilized over time and returned to baseline with prolonged treatment (ALC) or treatment discontinuation (ANC and platelets). No associations between ANC decrease and infections or between thrombocytosis and thromboembolic events were observed. References Schulze-Koops H et al. Rheumatology. 2017;56(1):46–57. Farr M et al. Ann Rheum Dis. 1983;42(5):545–549. Symmons DP et al. J R Soc Med. 1989;82:462–463. Fridman JS et al. J Immunol. 2010;184:5298–5307. Disclosure of Interest J. Kremer Grant/research support from: Abbvie, Genentech, Eli Lilly and Company, Novartis, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, GSK, Eli Lilly and Company, Novartis, Pfizer, Employee of: Corrona, Speakers bureau: Genentech (non-promotional), T. W. J. Huizinga Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, Speakers bureau: Eli Lilly and Company, Pfizer, L. Chen Employee of: Eli Lilly and Company, C. Saifan Employee of: Eli Lilly and Company, M. Issa Employee of: Eli Lilly and Company, S. Witt Employee of: Eli Lilly and Company, C. Walls Employee of: Eli Lilly and Company, I. de la Torre Employee of: Eli Lilly and Company

Background Baricitinib (bari), a selective, transient and reversible inhibitor of Janus kinase (JAK)1 and JAK2, improved signs and symptoms of active rheumatoid arthritis (RA) in multiple phase 3 studies. Since erythropoietin (EPO) stimulates erythrocyte production via the JAK2 signaling pathway, haemoglobin (Hgb) and other haematologic parameters were thoroughly evaluated in the bari RA clinical development program. Objectives To evaluate baseline and subsequent changes in Hgb and related laboratory parameters in RA patients (pts) treated with bari (2 or 4 mg once daily), placebo (PBO), or active comparator (methotrexate [MTX] or adalimumab [ADA]). Methods Blood samples were analyzed at baseline and at each study visit for complete blood count, with more extensive phlebotomy at baseline (Wk 0) and Wks 12, 24, and 52 (Figure 1). Data were aggregated from completed Phase 2 and 3 RA studies and one ongoing long-term extension study. EPO and reticulocyte (RET) data were collected from a Phase 2 RA study in Japan. Results Hgb levels below the gender-adjusted lower limit of normal (LLN) were often observed at baseline (25%). Small declines in Hgb were observed at Wk 2 and again at Wk 14 in bari (2 and 4 mg) and PBO-treated RA pts consistent with the volume and frequency of phlebotomy (Figure 1). Initial decreases in Hgb were accompanied by declines in RET counts in bari-treated RA pts. Subsequent increases in Hgb were associated with increases in RET after Wk 8 and statistically significant dose-dependent increases vs. PBO in total iron (Fe), total iron binding capacity (TIBC) and EPO. Treatment-emergent (TE) shifts in Hgb from normal to Conclusions The proportions of RA pts with TE abnormally low Hgb did not differ significantly between bari and PBO. Reductions in Hgb, including to ≥grade 3, were generally not associated with adverse outcomes. Despite concerns about the impact of JAK2 inhibition on EPO signaling, following initial declines incident to phlebotomy, dose-dependent increases in EPO, Fe, and TIBC with return to baseline in RET and Hgb were observed with bari. This suggests that homeostatic mechanisms counterbalance the pharmacologic effect of JAK inhibition on EPO signaling and that bari treatment enhances iron utilisation markers associated with anaemia of chronic disease. Disclosure of Interest J. Kay Grant/research support from: AbbVie, Eli Lilly and Company, Pfizer, Genentech, Roche, UCB, Consultant for: Amgen, AbbVie, BMS, Eli Lilly and Company, Genentech, GlaxoSmithKline, Janssen Biotech, Merck, Novartis, Pfizer, Samsung Bioepis, Sandoz, Roche, UCB, M. Harigai Grant/research support from: BMS KK, Eisai Ltd, Ono Pharma, Takeda Ltd, Consultant for: Eli Lilly and Company, J. Rancourt Employee of: Eli Lilly and Company, C. Dickson Employee of: Eli Lilly and Company, Y. Isaka Employee of: Eli Lilly and Company, L. Chen: None declared, T. Carmack Employee of: Quintiles, D. Hyslop Employee of: Eli Lilly and Company, D. Muram Employee of: Eli Lilly and Company, W. Macias Employee of: Eli Lilly and Company, J. Bradley Employee of: Eli Lilly and Company, E. Keystone Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Hoffmann-LaRoche, Janssen, Eli Lilly and Company, Novartis, Pfizer, Sanofi-Aventis,UCB, Consultant for: Abbott, AstraZeneca, Biotest, BMS, Crescendo Biosciene, Hoffmann-LaRoche, Genentech, Janssen, Eli Lilly and Company, Merck, Pfizer, UCB, Speakers bureau: Abbott, AstraZeneca, BMS Canada, Hoffmann-laRoche, Janssen, Pfizer, UCB, Amgen

Background Temporary interruption of RA therapy is common in clinical practice; therefore, rapid clearance and low immunogenicity may be useful DMARD attributes. Baricitinib (bari) is a non-biologic Janus kinase (JAK) 1 /JAK2 selective inhibitor with a pharmacokinetic half-life in RA patients of approximately 13 hours. It has demonstrated improved clinical efficacy compared to MTX, adalimumab and placebo (pbo) with a satisfactory safety profile when administered once daily to RA patients in 4 completed Phase 3 studies. Objectives These analyses aimed to characterize temporary interruptions of study drug during these studies and explore the kinetics of RA symptoms during and following interruption. Methods During bari Phase 3 studies, investigators were required to document temporary interruptions of study drug, including timing, reason and duration, using electronic case report forms. In 2 studies, patients recorded RA symptoms (duration and severity of morning joint stiffness, worst tiredness and worst joint pain) daily for 12 weeks. Post hoc analyses investigated changes in these scores among patients randomized at least 7 days prior to interruption, having an interruption that lasted at least 3 days, and retreated. Results Across the 3 pbo-controlled studies, interruptions occurred in a larger proportion of patients with bari than pbo only in the biologic DMARD-inadequate responder (IR) study RA-BEACON. In the 2 active comparator-controlled studies, the lowest rates of interruption were in the bari monotherapy arm of the DMARD-naïve MTX-controlled RA-BEGIN study, and proportions were similar for bari and adalimumab in the MTX-IR study, RA-BEAM (Table 1). Adverse events (predominantly non-serious, mild or moderate infections, most commonly of the respiratory tract) were the most frequent reason for interruption. Few patients interrupted for the reason of abnormal laboratory results. Most interruptions lasted for 2 weeks or less; in RA-BEAM, interruptions appeared shorter in duration for bari than for adalimumab. Diary measures indicated modest symptom increases during interruption compared to the last pre-interruption value, with a return to pre-interruption values or better after resumption of study drug (Table 2). Conclusions Consistent with its pharmacologic properties, brief temporary interruptions of bari during Phase 3 studies were associated with minor increases in RA symptoms, which resolved following resumption of therapy. A small molecule with a short half-life may offer advantages over injectable biologic therapies with respect to drug interruption for clinical cause in RA patients. Disclosure of Interest P. Emery Consultant for: Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz, Eli Lilly and Company, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, Eisai, Speakers bureau: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, janssen, Eli Lilly and Company, GlaxoSmithKline, T. Cardillo Employee of: Eli Lilly and Company, D. Schlichting Employee of: Eli Lilly and Company, S. Beattie Employee of: Eli Lilly and Company, L. Chen Employee of: Eli Lilly and Company, T. Rooney Employee of: Eli Lilly and Company, J. Smolen: None declared

Background Baricitinib (BARI) is an oral Janus Kinase (JAK)1/JAK2 inhibitor in development for patients (pts) with active rheumatoid arthritis (RA). Compared to the general population, RA pts have an increased rate of serious infection events (SIE) due to disease state and concomitant therapies.1 Objectives To evaluate the incidence rate (IR) of SIE and associated risk factors in BARI-treated pts with active RA across 8 completed studies (4 Ph3, 3 Ph2, 1 Ph1) and 1 ongoing long-term extension (LTE) study. Methods The ALL BARI RA analysis set included pts exposed to any BARI dose, with exposure up to 5 years (yrs) (Phase [Ph] 1–3 and LTE studies); the comparison with placebo (PBO) was based on 6 studies (Ph 2–3) with BARI 4 mg once daily (QD) and PBO arms up to Week (Wk) 24; dose response assessment was based on 4 studies (Ph 2–3) with both BARI 2 and 4 mg QD arms up to Wk 24. An extensive list of potential risk factors for SIE was investigated in the ALL BARI RA set using Cox models; SIE risk factors among BARI-treated pts are reported (Table). Results The most frequent SIE observed in the ALL BARI RA set (N=3492; 5133 pt-yrs (PY) of exposure [PYE] were pneumonia, herpes zoster, urinary tract infection, and cellulitis (all <1%), and 2 patients with SIE died (IR=0.04/100 PY). In the ALL BARI RA set, SIE were reported in 150 pts (IR=2.9/100 PY). During 0–24 Wks, similar SIE rates were observed in BARI 4 mg (N=997; 417 PYE) and PBO (N=1070; 403 PYE) groups in the 6-study set, and between BARI 2 mg (N=479; 192 PYE) and 4 mg (N=479; 194 PYE) dose groups in the 4-study set (Figure). Prior biologic use, advancing age, region of Asia (excluding Japan), non-normal body mass index (BMI), and corticosteroid use were identified as independent factors for SIE in the ALL BARI RA set (Table). Among these SIE risk factors, none significantly differed between BARI 4 mg and PBO in the 6-study dataset (data not shown). Conclusions SIE incidence was similar between BARI- and PBO-treated RA pts. SIE risk factors include concomitant corticosteroids, prior biologics, non-normal BMI, Asian region of enrollment, and advancing age. References Listing J et al. Rheumatology. 2013;52:53–61. Disclosure of Interest K. Winthrop Grant/research support from: Pfizer, BMS, Consultant for: Pfizer, UCB, Abbvie, Eli Lilly and Company, Amgen, BMS, M. Genovese Grant/research support from: Eli Lilly and Company, Abbvie, Astellas, Galapagos, Pfizer, Vertex, Crescendo Bioscience, Consultant for: Eli Lilly and Company, Abbvie, Astellas, Galapagos, Pfizer, Vertex, Crescendo Bioscience, M. Harigai Grant/research support from: Bristol-Myers Squibb KK, Eisai Co Ltd, Ono Pharma, Takeda Pharma Ltd, Consultant for: Eli Lilly and Company, L. Chen Employee of: Eli Lilly and Company, C. Dickson Employee of: Eli Lilly and Company, D. Hyslop Employee of: Eli Lilly and Company, A. Nishikawa Employee of: Eli Lilly Japan K.K., J. Bradley Employee of: Eli Lilly and Company, M. Dougados Grant/research support from: Abbvie, Pfizer, Eli Lilly and Company, Novartis, UCB, Merck, Roche, BMS, Consultant for: Abbvie, Pfizer, Eli Lilly and Company, Novartis, UCB, Merck, Roche, BMS

While doxorubicin has been the mainstay of treatment for decades, in more recent years gemcitabine plus docetaxel has emerged as an effective treatment in metastatic STS. The platelet-derived growth factor receptor alpha (PDGFR &agr;) antibody olaratumab in combination with doxorubicin demonstrated a significant improvement of overall survival over doxorubicin alone in patients with advanced STS in a randomized phase 2 study (NCT01185964). Since some patients may not be appropriate candidates for doxorubicin-based chemotherapy, or have received prior anthracycline treatment, exploring the efficacy and safety of olaratumab with gemcitabine plus docetaxel is of considerable interest. Trial design: ANNOUNCE 2 (NCT02659020) is a multicentre Phase 1b/2 study of olaratumab in combination with gemcitabine and docetaxel in patients with advanced or metastatic STS (≥16 years; ECOG performance status ≤1; naïve to therapy with study drugs; not amenable to curative treatment with surgery or radiotherapy; ≤2 prior lines of systemic therapy for advanced or metastatic disease). The Phase 1b part of the study consists of an open-label, single-arm, dose-escalation assessment of the safety and tolerability of olaratumab administered at 15 mg/kg (Days 1 and 8) or 20 mg/kg (Days 1 and 8) with gemcitabine (900 mg/m2 [fixed dose rate: 10 mg/m2/minute] Days 1 and 8) and docetaxel (75 mg/m2 Day 8) in a 21-day cycle. The primary objective is to determine a dose of olaratumab that may be safely administered in combination with gemcitabine and docetaxel in patients with advanced or metastatic STS. Secondary objectives are to evaluate the safety and toxicity profile, pharmacokinetics, and immunogenicity of olaratumab in combination with gemcitabine and docetaxel; and to document any antitumor activity. After the optimal dose of olaratumab in combination with gemcitabine and docetaxel has been determined, the Phase 2, randomized, double-blind, placebo-controlled part of the study will open to enrolment (in approximately December 2016). The study began in March 2016; planned enrollment for the 1b phase is approximately 30 patients. Clinical trial identification: NCT02659020 Legal entity responsible for the study: Eli Lilly and Company Eli Lilly and Company

Background Baricitinib (bari; an oral JAK 1/JAK 2 inhibitor) is in development for patients (pts) with active RA. Objectives To assess the safety of bari in pts with active RA across 8 completed studies (4 Ph3, 3 Ph2, 1 Ph1b) and 1 ongoing long-term extension (LTE) study. Methods Primary safety analysis was based on 6 studies with bari 4 mg QD and placebo (PBO) arms and dose response assessments on 4 studies with bari 2 and 4 mg QD and PBO arms. In addition, the all-bari RA set included all patients exposed to any bari dose. 2 studies contained active comparators. Results 3464 pts were exposed to bari (4214 pt-yrs (PY); 2166 pts (62.5%) >1 yr; 467 (13.5%) >2 yrs). In controlled periods of the program, no increases in deaths, AEs leading to study drug discontinuation, malignancies, MACE, or serious infections were seen for bari vs PBO/active treatment. Herpes zoster was reported more frequently for bari vs PBO. In randomized, controlled periods of the program, TB was reported in 2 pts: 1 bari 4 mg, 1 adalimumab; in uncontrolled periods, 6 TB events were reported (bari 4 mg: 2 with incomplete TB screening, 3 without organism confirmed). All TB occurred in endemic areas. Two GI perforations were reported (0.05/100 PY). No confirmed opportunistic infections were reported. Bari treatment has been associated with changes in selected hematology/clinical chemistry analytes; few patients (<1%) discontinued due to abnormal lab results. There was no observed increased risk over time for the above outcome measures with longer exposure. Conclusions In the context of reported efficacy,1,2 bari had an acceptable safety profile in pts with moderate-to-severe active RA. References Dougados M. Ann Rheum Dis. 2015;74(S2):79. Taylor PC. Arthritis Rheumatol. 2015;67(suppl 10). Disclosure of Interest J. Smolen Grant/research support from: AbbVie, Janssen, Eli Lilly and Company, MSD, Pfizer, Roche, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, M. Genovese Grant/research support from: AbbVie, Astellas, Eli Lilly and Company, Galapagos, Pfizer, Vertex, Consultant for: AbbVie, Astellas, Eli Lilly and Company, Galapagos, Pfizer, T. Takeuchi Grant/research support from: Chugai Pharmaceutical Co,. Ltd, Eli Lilly and Company, Consultant for: Eli Lilly and Company, D. Hyslop Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Rooney Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, L. Chen Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, C. Dickson Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, J. Riddle Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Cardillo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, K. Winthrop Grant/research support from: BMS, Pfizer, Consultant for: BMS, Pfizer, Eli Lilly and Company, Abbvie, Galapagos

Objectives Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified 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 significant 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 significantly 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 findings and their possible clinical implications. Trial registration number NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.