Abstract Background/Aims Baricitinib (BARI) is an oral, reversible, selective JAK1/2 inhibitor. Treatment with once-daily oral BARI resulted in low rates of radiographic progression for up to 2 years in patients with rheumatoid arthritis (RA). Here, we evaluate the radiographic progression of structural joint damage in patients with RA over 5 years of treatment with BARI. Methods This included patients who completed three Phase 3 trials, RA-BEGIN (DMARD-naive), RA-BUILD (csDMARD-IR), or RA-BEAM (MTX-IR), and enrolled in long-term extension study, RA-BEYOND. Patients receiving blinded BARI at the conclusion of Phase 3 trials remained on that dose (2mg/4mg, once daily) in RA-BEYOND. At 52 weeks, DMARD-naive patients receiving methotrexate(MTX) or combination therapy(BARI 4mg+MTX) were switched to BARI 4mg monotherapy; MTX-IR patients receiving adalimumab(ADA) were switched to BARI 4mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo(PBO) were switched to BARI 4mg on background csDMARD. Analysis population included patients who had baseline and at least one radiograph collected after 2 years. Radiographic progression of structural joint damage (Years 3-5) was determined by changes from baseline in van der Heijdemodified Total Sharp Score(ΔmTSS), erosion score, and joint space narrowing. Proportion of patients showing no progression was assessed based on change from baseline mTSS(ΔmTSS) from originating study, using thresholds of 0.5 or smallest detectable change(SDC). Mixedmodel repeatedmeasures and logistic regression models were used to analyze continuous variables and categorical variables, respectively; linear extrapolation was used for imputation of missing data(maximum of 1 year). Results 82.6% (2125/2573) of patients entered long-term extension study. Among DMARD-naive patients, those on initial BARI monotherapy or in combination with MTX had significantly slower radiographic progression(ΔmTSS) versus those on initial MTX at Years 3, 4, 5 (p ≤ 0.05). They had significantly fewer erosions at these time points (p ≤ 0.05). A greater proportion of patients who received initial BARI therapy and BARI+MTX had no radiographic progression versus initial MTX monotherapy using thresholds of 0.5 (p ≤ 0.05). Among MTX-IR patients, those on initial BARI treatment had slower radiographic progression compared to PBO and results were comparable to those on initial ADA treatment at Years 3, 4, 5. A greater proportion of patients who received initial BARI therapy had no radiographic progression versus initial PBO using thresholds of SDC (p ≤ 0.05). Among csDMARD-IR patients, although differences between groups were small, patients on initial BARI 4mg had slowest radiographic progression compared to initial PBO and initial BARI 2mg. At least 74% of the structure data used in the analyses are based on observed data. Conclusion Treatment with once-daily oral BARI maintained low rates of radiographic progression for up to 5 years in different patient populations with RA. Disclosure D.M.F.M. van der Heijde: Consultancies; AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma. C.E. Kartman: Shareholder/stock ownership; Eli Lilly and Company. L. Xie: Shareholder/stock ownership; Eli Lilly and Company. S. Beattie: Shareholder/stock ownership; Eli Lilly and Company. D.E. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. P. Durez: Member of speakers’ bureau; Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, and Sanofi. Y. Tanaka: Member of speakers’ bureau; AbbVie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Takeda, UCB, and YL Biologics. Grants/research support; AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, and Taisho-Toyama and Takeda. R. Fleischmann: Consultancies; AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB.

Abstract Background/Aims Baricitinib (BARI) is an oral selective inhibitor of Janus kinase (JAK)1/2, approved for treatment of moderate-to-severe- rheumatoid arthritis (RA) in adults. Here, we update the drug’s safety profile with data up to 8.4 years of treatment. Methods Long-term safety of BARI was assessed from 9 completed randomized trials(5 Ph3, 3 Ph2, 1 Ph 1b) and 1 ongoing long-term extension(LTE) study. Incidence rates(IRs) per 100 patient-years (PY) were calculated for all RA patients treated with ≥1 dose of BARI through 1-Sep-2019(All-BARI-RA set). IRs for deep vein thrombosis(DVT), pulmonary embolism(PE), and DVT and/or PE(DVT/PE) were also calculated for groups of patients while receiving BARI 2mg/4mg within All-BARI-RA. Major adverse cardiovascular events(MACE) were adjudicated in 5 Ph3 studies and the LTE. Results 3770 pts received BARI for 13,148 PY, with median and maximum exposure: 4.2 and 8.4 years, respectively. Overall IRs per 100 PY were: for any treatment-emergent adverse event (AE)(25.8); serious AE (including death)(7.2); temporary interruption due to AE (9.5); permanent discontinuation due to AE (4.8); death (0.52); serious infection (2.7); opportunistic infection (0.46)(excluding tuberculosis [TB], including multidermatomal herpes zoster [HZ]); TB (0.15); HZ (3.0); MACE (0.50); DVT (0.31); PE (0.24); DVT/PE (0.46); malignancies excluding non-melanoma skin cancer (NMSC)(0.91); NMSC (0.33); lymphoma (0.07); and gastrointestinal perforation (0.04). (IRs)[95% confidence intervals] for patients while receiving BARI 2mg (N = 1077) and BARI 4mg (N = 3400) were DVT 2mg (0.38)[0.18, 0.73] and 4mg (0.30)[0.21, 0.43]; PE 2mg (0.26)[0.09, 0.56] and 4mg (0.25)[0.16, 0.36]; and DVT/PE 2mg (0.47)[0.23, 0.84] and 4mg (0.46)[0.34, 0.61]. IRs for death tended to increase in later time intervals (beyond 192 weeks). No particular cause of death contributed to this increase. For all other safety topics of interest, across 48-week treatment intervals, IRs remained stable over time. Across safety topics, IRs were consistent with previous analyses. Conclusion In this update, with 3021 additional PY of exposure, BARI maintained a safety profile similar to that previously reported, with no increase of IRs across safety topics through exposures up to 8.4 years. Disclosure K.L. Winthrop: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Pfizer, and UCB Pharma. Grants/research support; Bristol Myers Squibb and Pfizer. T. Takeuchi: Consultancies; AbbVie, Asahi Kasei Medical, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi Tanabe Pharma, Nippon Kayaku, Novartis, Pfizer Japan, Taiho Pharmaceutical, Taiho Toyama Pharmaceutical, Takeda, and UCB Japan. G. Burmester: Consultancies; Eli Lilly and Company, Janssen, Novartis, and Pfizer. Grants/research support; Eli Lilly and Company. W. Deberdt: Shareholder/stock ownership; Eli Lilly and Company. D. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. D. Mo: Shareholder/stock ownership; Eli Lilly and Company. C. Walls: Shareholder/stock ownership; Eli Lilly and Company. J.S. Smolen: Consultancies; AbbVie, Amgen, AstraZeneca, Astro Pharma, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Eli Lilly and Company, Gilead Sciences, ILTOO Pharma, Janssen, MedImmune, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB Pharma. Grants/research support; AbbVie, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche.

Objective To evaluate the effect of baricitinib on inhibiting radiographic progression of structural joint damage over 5 years in patients with active rheumatoid arthritis (RA). Methods Patients completed 1 of 3 phase III baricitinib trials (ClinicalTrials.gov: NCT01711359, NCT01710358, or NCT01721057) and entered the long-term extension RA-BEYOND (NCT01885078), in which patients received once-daily 4 mg or 2 mg baricitinib. Across these trials, patients initially receiving methotrexate (MTX) or adalimumab (ADA) switched to baricitinib 4 mg at Week 52. Patients initially receiving placebo (PBO) switched to baricitinib 4 mg at Week 24. Radiographs were scored at baseline and Years 2, 3, 4, and 5. Change from baseline in van der Heijde modified total Sharp score (ΔmTSS) was computed. Results Overall, 2125 of 2573 (82.6%) randomized patients entered RA-BEYOND; 1837 of 2125 (86.4%) entered this analysis. From Years 3 to 5, higher proportions of disease-modifying antirheumatic drug (DMARD)-naïve patients on initial baricitinib (monotherapy or with MTX) had no progression vs initial MTX (ΔmTSS ≤ 0 at Year 5: 59.6% baricitinib 4 mg; 66.2% baricitinib 4 mg + MTX; 40.7% MTX). Higher proportions of patients with inadequate response (IR) to MTX on initial baricitinib or ADA vs PBO had no progression (ΔmTSS ≤ 0 at Year 5: 54.8% baricitinib 4 mg; 55.0% ADA; 50.3% PBO). Higher proportions of patients with conventional synthetic DMARD-IR on initial baricitinib 4 mg had less progression vs initial PBO or baricitinib 2 mg (ΔmTSS ≤ 0 at Year 5: 66.7% baricitinib 4 mg; 58.2% baricitinib 2 mg; 60.0% PBO). Conclusion Oral baricitinib maintained lower levels of radiographic progression than initial conventional synthetic DMARD or PBO through 5 years in patients with active RA.

OBJECTIVE:Pain reduction with baricitinib was assessed in patients with rheumatoid arthritis (RA) who either used opioids or did not use opioids during three randomized, double-blind phase 3 trials.METHODS:Analysis populations were as follows: i) baricitinib 4 mg once daily versus placebo groups integrated from RA-BEAM (NCT01710358) for patients with inadequate response (IR) to methotrexate, RA-BUILD (NCT01721057) with IR to conventional disease-modifying antirheumatic drugs, and RA-BEACON (NCT01721044) with IR to at least one tumor necrosis factor inhibitors; ii) baricitinib 2 mg versus placebo from RA-BUILD and RA-BEACON; and iii) adalimumab 40 mg every other week versus placebo from RA-BEAM. Pain was measured by the Patient Assessment of Pain Visual Analog Scale. Analysis of covariance modeling assessed differences in pain reduction between treatments at each time point through Week 24, with an interaction term to test heterogeneous treatment effects across opioid users and nonusers.RESULTS:Baricitinib 4 mg had greater pain reduction versus placebo in opioid users and nonusers (P < 0.05) at all time points starting from Week 1; the pain reduction was similar between opioid users and nonusers. Baricitinib 2 mg had greater pain reduction versus placebo in opioid users and nonusers starting at Week 4. A significant difference in pain reduction was not observed for adalimumab versus placebo in the opioid users but was observed in nonusers at all time points.CONCLUSION:Pain reduction was observed and was similar between opioid users and nonusers with baricitinib 2 mg and 4 mg but not adalimumab in this post hoc analysis.

Purpose: To evaluate a novel quantitative methodology to assess inflammatory changes in magnetic resonance imaging (MRI) data from patients with rheumatoid arthritis (RA) and the impact of image quality on imaging outcomes compared to the RA Magnetic Resonance Imaging Score (RAMRIS). Methods: Three-dimensional, T1-weighted, fat-suppressed MRI sequences of the hand/wrist before and after intravenous Gadolinium contrast from patients with RA in a placebo-controlled clinical trial (NCT01185353) were re-evaluated post hoc. The methodology was integrated into proprietary software (DYNAMIKA (R)) and assessed inflammation through pixelated measurements of the contrast-enhancing (inflammatory) volume. A semi-automatic approach outlined contrast-enhancing synovial tissue in the wrist and second to fifth metacarpophalangeal joints with a rough region of interest (ROI); quantitative imaging biomarkers were generated by means of quantitative total volume of inflammation and quantitative degree of inflammation relative to the signal in a 1 cm in diameter ROI in the center of the thenar or lumbrical muscle for internal reference. The time from Gadolinium injection to finalization of the post-contrast images was calculated from the images' Digital Imaging and Communications in Medicine header. An experienced reader graded image quality as poor, acceptable, or good. Results: Results from this quantitative methodology, especially when excluding images with poor quality scores (14-32%), provided a more pronounced and monotonically increasing dose-response than the original RAMRIS results on synovitis and osteitis. Conclusions: This computer-aided quantitative scoring method provided continuous measures of inflammatory changes relative to muscle and may be more sensitive and interpretable concerning dose/response separation between RA treatment groups.

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and the most common systemic disorder associated with uveitis in childhood. Uveitis is more common in JIA patients who are antinuclear antibody (ANA)-positive, have an early-onset disease, and have oligoarticular arthritis. JIA-associated uveitis (JIA-uveitis) is typically anterior, chronic, bilateral, nongranulomatous, and asymptomatic. Visual outcomes in JIA-uveitis have improved with current screening and treatment options; however, many patients fail to respond or do not achieve long-lasting remission. Baricitinib, an oral selective Janus kinase (JAK)1 and 2 inhibitor, may impact key cytokines implicated in the pathogenesis of JIA-uveitis or ANA-positive uveitis, representing a potential novel treatment option for disease management. The multicenter, phase 3 trial will be conducted using an open-label Bayesian design. The study will enroll at least 20 and up to 40 patients aged 2 to <18 years with active JIA-uveitis or chronic ANA-positive uveitis without systemic features. At least 20 patients who have had an inadequate response or intolerance to methotrexate (MTX-IR), but not biologic disease-modifying antirheumatic drugs (bDMARDs), will be randomized (1:1) to open-label baricitinib or adalimumab. Approximately 20 additional patients who are MTX-IR or bDMARD inadequate responders will receive baricitinib treatment. Patients will be treated with once daily oral baricitinib at a fixed dose by age group (4 mg for patients aged ≥6 to <18 years and 2 mg for patients <6 years) or adalimumab (20 mg for patients weighing <30 kg and 40 mg for patients ≥30 kg) as a subcutaneous injection every 2 weeks. Treatment with stable background conventional synthetic DMARDs, low-dose corticosteroids, and/or nonsteroidal anti-inflammatory drugs is allowed. The primary endpoint is the proportion of patients with response at week 24. Patients may continue treatment for up to 5 years. This is the first pediatric clinical trial to assess the clinical effectiveness and safety of a JAK inhibitor in JIA-uveitis or chronic ANA-positive uveitis. A novel Bayesian design is used to assess the efficacy of baricitinib, including an adalimumab reference arm, in this small patient population with unmet medical need. EudraCT 2019-000119-10 . Registered on January 4, 2019; NCT04088409 . Registered on September 12, 2019

Background and aims: There is an unmet need for alternative treatments for patients with primary biliary cholangitis (PBC) who do not respond to treatment with ursodeoxycholic acid (UDCA). A proof-of-concept study of baricitinib, an orally administered Janus kinase 1 and 2 inhibitor, was initiated to evaluate its use in PBC patients. Approach and results: Patients with PBC showing inadequate response or intolerance to UDCA were eligible. This was a randomized, double-blinded placebo-controlled trial. Enrollees were assigned 1:1 to baricitinib (2 mg/day) or placebo. Endpoints included change in alkaline phosphatase (ALP), itch Numeric Rating Score (NRS), and fatigue NRS at 12 weeks post-baseline; exploratory markers included high sensitivity C-reactive protein (hs-CRP) and Enhanced Liver Fibrosis (ELF) score. Due to low enrollment, the study was terminated early. Two patients were enrolled and completed the trial; 1 was randomized to receive baricitinib and 1 to placebo. Over the treatment period, the baricitinib-treated patient demonstrated a 30% decrease in ALP and a 7-point improvement in the itch NRS, but a 2-point increase in the Fatigue NRS. Markers of inflammation and liver fibrosis (hs-CRP and ELF score) also improved over the study period. In contrast, the placebo-treated patient showed no improvement in primary or secondary endpoints. A single non-serious treatment-emergent adverse event of moderate sinusitis was reported by the baricitinibtreated patient at day 47. Conclusions: In a 12-week trial, a patient with PBC showing inadequate response to treatment with UDCA demonstrated a dramatic response to treatment with baricitinib.

Background:Baricitinib (bari) is an oral selective inhibitor of Janus kinase (JAK) 1 and 2, approved for the treatment of moderately to severely active rheumatoid arthritis (RA) in adults.Objectives:Here we update the drug’s safety profile with data up to 8.4 years of treatment.Methods:Long-term safety of bari was assessed from 9 completed randomized trials (5 Ph3, 3 Ph2, 1 Ph 1b) and 1 ongoing long-term extension (LTE) study. Incidence rates (IR) per 100 patient-years (PY) were calculated for all patients with RA treated with ≥1 dose of bari through 1-Sep-2019 (All-Bari-RA analysis set). IRs for deep vein thrombosis (DVT), pulmonary embolism (PE), and DVT and/or PE (DVT/PE) were also calculated for groups of patients while receiving bari 2mg or bari 4mg within All-Bari-RA. Major adverse cardiovascular events (MACE) were adjudicated in 5 phase 3 studies and the LTE.Results:3770 pts received bari for 13,148 PY, with a median and maximum exposure of 4.2 and 8.4 years, respectively. Overall IRs per 100 PY were: for any treatment-emergent adverse event (AE)(25.8); serious AE (including death)(7.2); temporary interruption due to AE (9.5); permanent discontinuation due to AE (4.8); death (0.52); serious infection (2.7); opportunistic infection (0.44) (excluding tuberculosis [TB], including multidermatomal herpes zoster [HZ]); TB (0.15); HZ (3.0); MACE (0.50); DVT (0.31); PE (0.24); DVT/PE (0.45); malignancies excluding non-melanoma skin cancer (NMSC) (0.90); NMSC (0.33); lymphoma (0.06); and gastrointestinal perforation (0.04). Incidence rates (IR)[95% confidence intervals] for patients while receiving bari 2mg (N=1077) and bari 4mg (N=3400) were DVT 2mg (0.38) [0.18, 0.73] and 4mg (0.30) [0.21, 0.43]; PE 2mg (0.26) [0.09, 0.56] and 4mg (0.25) [0.16, 0.36]; and DVT/PE 2mg (0.47) [0.23, 0.84] and 4mg (0.46) [0.34, 0.61]. IRs for death tended to increase in later time intervals (beyond 192 weeks). No particular cause of death contributed to this increase. For all other safety topics of interest, across 48-week treatment intervals, IRs remained stable over time. Across safety topics, IRs were consistent with previous analyses1,2.Conclusion:In this update with 3,021 additional PY of exposure, bari maintained a safety profile similar to that previously reported,1,2with no increase of IRs across safety topics through exposures up to 8.4 years.References:[1]Smolen JS et al. J Rheumatol. 2019 Jan;46(1):7-18[2]Genovese MC et al. Ann Rheum Dis. 2019 78(supp. 2):A308Table.n/NARIRTreatment emergent AE3391/377025.8Serious AE (including death)940/37707.2Temporary d/c due to AE1241/36479.5Permanent d/c due to AE644/37704.8Death69/37700.52Serious infection344/37702.7Opportunistic infection (excluding tuberculosis, including multidermatomal herpes zoster)59/37700.44Herpes zoster384/37703.0Tuberculosis20/37700.15Major adverse cardiovascular events*63/32510.50DVT41/37700.31PE32/37700.24DVT and/or PE60/37700.45Malignancies excluding NMSC120/37700.90NMSC44/37700.33Lymphoma8/37700.06Gastrointestinal perforation6/37700.04*studies with positive adjudication. AE=adverse event; D/C= discontinuation; DVT=deep vein thrombosis; IR=incidence rate; NAR=number of patients at risk; NMSC=non-melanoma skin cancer; PE=pulmonary embolismDisclosure of Interests:Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., 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, Walter Deberdt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Douglas Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Hongsuk Song Employee of: Syneos Health under contract to Eli Lilly and Company, Daojun Mo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chad Walls Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB

Background: Magnetic resonance imaging (MRI) was used to confirm dose selection in a phase IIb clinical trial of baricitinib in patients with active rheumatoid arthritis (RA) on background methotrexate therapy ( NCT01185353 ).[1] MRI data were retrospectively assessed for consistency, timing of post-contrast sequences following intravenous (IV) Gadolinium (Gd), and readability. Data were re-analyzed using a novel quantitative computer-aided methodology to extract the continuous volume of inflammatory changes.[2] Objectives: The objective was to examine how image quality and timing of the post-contrast MRI sequence can impact MRI-based exploratory endpoints in RA clinical trials when using novel computer-aided analysis tools. Methods: A total of 154 patients with definitive radiographic erosion had an MRI of the hand and wrist at baseline and at weeks 12 and 24. Three-dimensional T1-w fat-suppressed MRI sequences before and after IV Gd contrast were performed with dedicated coils. Due to the limited field of view, the coils were re-positioned during the image acquisition between the metacarpophalangeal (MCP) and finger joints and the wrist, following IV Gd injection, which introduced a time delay of the post-contrast sequences in the two anatomies in all patients. Digital Imaging and Communications in Medicine (DICOM) headers of the MRIs were automatically assessed; the distribution of the time delay in minutes from Gd injection to post-contrast scan acquisition was calculated and the image quality and suitability for reading were evaluated (Figure 1). The time delays across MRI acquisitions at baseline and weeks 12 and 24 were also compared. Quality scores were assigned for each image using visual image quality assessment by an experienced reader blinded to treatment regimen, patient visits, and time after Gd. The images were categorized by quality based on total score. The reader used a proprietary software, to pre-define regions of interest (ROI) around the wrist and MCP joints (MCP-2 to MCP-5) in all three timepoints as a batch, avoiding adjacent blood vessels and possible artifacts. From these ROIs, the normalized volume of inflammation (NormI) was calculated in each joint relative to a standardized ROI in the thenar muscle. Quantitative Total Volume of Inflammation (QVI) was extracted automatically from all ROIs by counting the pixels that were enhanced two standard deviations above the intensity level of the normal muscle, allowing differentiation of areas with low-to-high inflammation. Results: The timing of post-contrast images from Gd injection was closely linked to image quality. In up to 10% of MRI data, the delay from Gd injection to scan acquisition caused significant variation in signal intensities. This led to a perceived increase in enhanced synovial volume due to the known effusion effects of the contrast media over time, which did not correspond to real size of the underlying synovial volume and pathology (Figure 2). Conclusion: The acquisition of MRIs in RA trials should be done in a methodical and systematic manner, where the quality of MRI scans and the correct timing of post-contrast sequences are optimized. The incorporation of unacceptable quality data will impact the interpretation of RA clinical trial data, especially when novel computer-assisted quantitative analysis methods for post-processing are used. Incorrect timing and inconsistency in image quality can be prevented by using coils covering the whole hand and/or a dynamic contrast-enhance (DCE)-MRI sequence immediately following IV Gd injection to ensure correct timing of the post-contrast MRI sequence. References: [1]Peterfy C, et al. J Rheumatol. 2019 46: 887–895. [2]Tripathi D, et al. IJRCI. 2014 2(S1):SR2. DOI: 10.15305/ijrci/v2iS1/89. Disclosure of Interests: Mikael Boesen Consultant of: AbbVie, AstraZeneca, Eli Lilly, Esaote, Glenmark, Novartis, Pfizer, UCB, Paid instructor for: IAG, Image Analysis Group, AbbVie, Eli Lilly, AstraZeneca, esaote, Glenmark, Novartis, Pfizer, UCB (scientific advisor)., Speakers bureau: Eli Lilly, Esaote, Novartis, Pfizer, UCB, Mark Hinton: None declared, Javier Gonzalez-Zabaleta: None declared, Scott Beattie Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Douglas Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Terence Rooney Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Olga Kubassova Shareholder of: IAG, Image Analysis Group, Consultant of: Novartis, Takeda, Lilly, Employee of: IAG, Image Analysis Group

Background: Reducing structural damage is an important treatment goal for rheumatoid arthritis (RA). Demonstrating a clinically meaningful, statistically significant difference in radiographic progression (assessed by van der Heijde modified total Sharp score, mTSS) is a common objective in trials for RA treatments. Complete collection of radiographic data is challenging, especially in long term follow-up and pediatric studies. Therefore, scores for individual joints or entire patients are regularly missing. A frequently used analysis method for mTSS is the analysis of covariance model, in which missing data are imputed using linear extrapolation (ANCOVA+LE). However, other ways to deal with missing information have also been proposed. Objectives: To evaluate robust analysis methods for mTSS data. Methods: Simulated data were used to compare a random coefficient model (RC) without imputation, ANCOVA+LE and ANCOVA with last observation carry forward imputation (LOCF). A log-normal distribution was used to generate baseline patient level data to simulate a 2-arm clinical trial using baseline mTSS and rate of change in mTSS from recently completed trials. Changes in mTSS (12, 28 and 44 week timepoints) were generated under linear, concave quadratic (fast progression then slow progression), and convex quadratic (slow progression then fast progression) assumptions, with the proportion of change forced to be 0 (a proportion of simulated patients do not have progression). A monotone missing pattern was assumed to generate a data set with missing data (the ‘observed’ dataset). ANCOVA analyses were performed using baseline and treatment as predictors. The RC model was applied using baseline, treatment, time, and time-by-treatment interactions as fixed effect and time as a random effect. Bias (difference between average of simulation sample mean and true value, the smaller the better), root mean square error (RMSE, a measure of variation among simulation samples, the smaller the better), power and type I error rate were compared between methods. Results: The random coefficient model provided better or at least similar results in bias, RMSE, power and type I error rate as ANCOVA+LE under evaluated scenarios (Table 1). Progression assumption Simulation parameters (Number of simulations = 500; common sample size=300, baseline mTSS=~11.7) Model Bias Power RMSE Linear p pbo = 0.6, r pbo = 0.065 p trt = 0.68 r pbo = 0.046 Δ wk44 = −0.49 ANCOVA + Full 0.002 0.924 0.140 ANCOVA + LE 0.003 0.866 0.155 ANCOVA+LOCF 0.154 0.844 0.190 RC + FULL 0.001 0.92 0.139 RC + OBS −0.002 0.872 0.156 Concave p pbo = 0.6, r pbo = −0.0009, q pbo = 0.11 p trt = 0.68, r trt = −0.0011, q trt = 0.093 Δ wk44 = −0.611 ANCOVA + Full 0.002 0.982 0.141 ANCOVA + LE −0.002 0.926 0.180 ANCOVA+LOCF 0.188 0.94 0.222 RC + FULL 0.002 0.978 0.141 RC + OBS −0.005 0.924 0.174 Convex p pbo =0.6, r pbo = 0.0037, q pbo =−0.09 p trt = 0.68, r trt = 0.003, q trt = −0.1 Δ wk44 = −0.83 ANCOVA + Full 0.003 1 0.139 ANCOVA + LE 0.343 0.948 0.368 ANCOVA+LOCF 0.391 0.974 0.405 RC + FULL −0.004 1 0.140 RC + OBS 0.199 0.988 0.249 Abbreviations: FULL = complete dataset with no missing values trt = active treatment, OBS = the ‘observed’ dataset, pbo = placebo, p= proportion of patients with no progression, r = linear progression rate (mTSS units per week), q = quadratic term coefficient. Δ = active treatment progression – placebo r Conclusion: RC is a robust analysis method for mTSS. We recommend its use in primary analyses, especially for long-term extension and pediatric studies with a higher likelihood of missing data. This method can also provide reference for time points when no data are collected via estimated slope. ANCOVA+LE can be used for sensitivity analysis. References: None. Disclosure of Interests: Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Luna Sun Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Yun-Fei Chen Shareholder of: Own shares in Eli Lilly and Company., Employee of: Employee of Eli Lilly and Company, Douglas Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, 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

Objective To evaluate the long-term efficacy and safety of maintaining baricitinib monotherapy in patients with active rheumatoid arthritis (RA) originally treated with baricitinib monotherapy or switched from methotrexate (MTX) or the combination of baricitinib plusMTXto baricitinib monotherapy. Methods This is a post hoc analysis of patients from theRA-BEGINstudy who entered a long-term extension,RA-BEYOND, and were assessed for up to 24 weeks. InRA-BEGIN,MTX-naive patients with early activeRAwere randomized toMTXmonotherapy, baricitinib 4 mg monotherapy, or baricitinib 4 mg plusMTX. At week 52, all patients enteringRA-BEYONDreceived baricitinib 4 mg monotherapy.MTXcould be prescribed duringRA-BEYONDat the investigator's discretion. Results Patients inRA-BEYONDwho were not rescued inRA-BEGIN(n = 423) were evaluated. Of these, 47% continued baricitinib monotherapy and 53% addedMTX, with similar proportions from the 3 original arms. Patients with lower disease activity at theRA-BEYONDbaseline generally continued to do well with baricitinib monotherapy as assessed by the Simplified Disease Activity Index, the Clinical Disease Activity Index, and the Health Assessment Questionnaire disability index scores. Patients prescribedMTXhad higher disease activity at theRA-BEYONDbaseline and had improved disease activity after the addition ofMTX. Safety outcomes were similar across treatment groups. Conclusion Many patients responded well to continued baricitinib monotherapy or to switching to baricitinib monotherapy fromMTXmonotherapy or baricitinib plusMTX, showing sustained or improved disease control. The groups of patients who had less disease control on their original therapies showed sustained or improved disease control with the addition ofMTXto baricitinib.

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful forCOVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated thein vitropharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated inCOVID-19 infection. We validated theAI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities forAAK1,BIKE, andGAK. Inhibition ofNAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateralCOVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline inSARS-CoV-2 viral load, inflammatory markers, andIL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalizedCOVID-19 patients.

Baricitinib, un inhibiteur oral sélectif des Janus Kinases (JAK)1/JAK2, indiqué dans le traitement de patients adultes atteints de polyarthrite rhumatoïde (PR) active modérée à sévère. Ce travail a eu comme objectif de décrire le profil de tolérance de ce médicament à partir de données allant jusqu'à 8,4 ans d'exposition au traitement. Le profil de tolérance à long terme de baricitinib a été évalué à partir de 9 essais randomisés terminés (5 de phase 3, 3 de phase 2, 1 de phase 1b) et d'une étude d'extension à long terme en cours. Les taux d'incidence pour 100 patients–années ont été calculés pour tous les patients atteints de polyarthrite rhumatoïde traités avec ≥ 1 dose de baricitinib jusqu'au 1er septembre 2019 (ensemble d'analyse « bari-PR-toute-dose »). Les taux d'incidence pour la thrombose veineuse profonde, l'embolie pulmonaire et la combinaison thrombose veineuse profonde et/ou embolie pulmonaire ont également été calculés pour des groupes de patients recevant 2 mg ou 4 mg de baricitinib dans la population d'analyse « bari-PR-toute-dose ». Les événements cardiovasculaires majeurs (MACE) ont été adjudiqués dans les 5 études de phase 3 et l'étude d'extension à long terme. Dans le cadre de cette analyse, 3770 patients ont reçu baricitinib, représentant une exposition totale de 13 148 patients–années avec une durée d'exposition médiane et maximale de 4,2 et 8,4 ans, respectivement. Les taux d'incidence globaux pour 100 patients–années étaient : pour les événements indésirables apparus sous traitement (25,8) ; événements indésirables graves (y compris les décès) (7,2) ; interruption temporaire due à un évènement indésirable (9,5) ; arrêt permanent du traitement à l'étude en lien avec un événement indésirable (4,8) ; décès (0,52) ; infection grave (2,7) ; infection opportuniste (excluant la tuberculose, mais incluant le zona multimétamérique) (0,46) ; tuberculose (0,15) ; zona (3,0) ; événements cardiovasculaires majeurs (MACE) (0,50) ; thrombose veineuse profonde (0,31) ; embolie pulmonaire (0,24) ; thrombose veineuse profonde/embolie pulmonaire (0,46) ; cancers (hors cancers cutanés non mélanome) (0,91) ; cancers cutanés non mélanome (0,33) ; lymphome (0,07) ; et perforation gastro-intestinale (0,04). Pour les groupes de patients recevant baricitinib 2 mg (1077) et baricitinib 4 mg (3400), les taux d'incidences [intervalles de confiance à 95 %] étaient respectivement de (0,38) [0,18 ; 0,73] et de (0,30) [0,21 ; 0,43] pour la thrombose veineuse profonde, de (0,26) [0,09 ; 0,56] et de (0,25) [0,16 ; 0,36] pour l'embolie pulmonaire, et de (0,47) [0,23 ; 0,84] et de (0,46) [0,34 ; 0,61] pour la thrombose veineuse profonde/embolie pulmonaire. Le taux d'incidence des décès a eu tendance à augmenter au cours des derniers intervalles de temps (au-delà de 192 semaines). Aucune cause particulière de décès n'a contribué à cette augmentation. Pour tous les autres évènements indésirables d'intérêt, sur des intervalles de traitement de 48 semaines, les taux d'incidence sont restés stables dans le temps. Pour tous les évènements indésirables, les taux d'incidence sont restés cohérents avec les analyses rapportées précédemment [1], [2]. Dans cette mise à jour de l'analyse intégrée de la tolérance avec une exposition additionnelle de 3021 patients–années, le profil de tolérance de baricitinib était similaire à celui rapporté précédemment [1], [2], sans augmentation des taux d'incidence des évènements indésirables pour une durée d'exposition maximale au traitement allant jusqu'à 8,4 ans.

An amendment to this paper has been published and can be accessed via the original article.

Numerous cytokines have been implicated in the pathogenesis of inflammatory diseases, and their dysregulation is a main feature of rheumatoid arthritis (RA). Cytokines stimulate signal transduction through several intracellular pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to changes in cell activation, proliferation and survival. Consequently, agents that selectively target elements of the JAK/STAT pathways have received significant attention in recent years as potential new treatments for the disease. Baricitinib, an oral selective inhibitor of JAK1 and JAK2, offers an effective treatment for RA in a wide range of patients. The in vitro selectivity of different JAK inhibitors is an important consideration given that key cytokines, growth factors and hormone receptors involved in the pathogenesis of RA signal through specific JAKs. However, it is complex and far from understood how the in vitro effects of JAK inhibitors extrapolate into in vivo and clinical effects in individual patients. This narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.

The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient's assessment on a 0-100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments.

Objective. RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety. Methods. RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) <= 10. An interaction P-value <= 0.10 was considered significant, with significance at both weeks 12 and 24 given more weight. Results. The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24:ACR20 by region (larger effect Europe) and CDAI <= 10 by disease duration (larger effect >= 10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use. Conclusion. Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use. Trial registration:ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044

The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.