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BackgroundThe preferential Janus kinase-1 inhibitor FIL significantly improved signs and symptoms of RA in Phase 2 and 3 trials.1–5 FIL is approved for treatment of moderate to severe active RA in Europe and Japan. Integrated safety analysis of FIL with patient data through 2019 was presented at the 2020 ACR virtual meeting.6ObjectivesTo report updated, as-treated data from the FIL integrated safety analysis with increased study drug exposure.MethodsData were integrated from 2 Phase 2 (NCT01668641, NCT01894516), 3 Phase 3 (NCT02889796, NCT02873936, NCT02886728), and 2 long-term extension (LTE) (NCT02065700, NCT03025308) trials. Phase 2 and 3 LTE data were through Nov 2020 and Jan 2021, respectively. The as-treated analysis set included all available data for pts receiving ≥1 dose FIL 200 (FIL200) or 100 mg (FIL100), including those rerandomized to FIL for LTE. Exposure-adjusted incidence rates (EAIR)/100 patient-y exposure (PYE) of treatment-emergent adverse events (TEAEs; onset after first dose and no later than 30 days after last dose or new drug first dose date −1 day) and TEAEs of special interest (AESIs) are presented.Results3691 pts received FIL200 or FIL100 for 8085.1 PYE (median 2.2, maximum 6.8 y). In the as-treated set, 61% of FIL200 and 45% of FIL100 pts received FIL for ≥2 y, 19% and 5% for ≥3 y, and 11% and 0.5% for ≥4.5 y, respectively. EAIR for TEAEs was higher with FIL100 than FIL200; EAIRs for deaths were 0.5 and 0.3 for FIL200 and FIL100 (Figure 1). Incidences of infections and serious infections were numerically greater for FIL100 vs FIL200, while EAIRs for other AESIs were comparable between doses (Table 1). EAIRs for AESIs tended to decrease since the previous update, except for venous thromboembolism (total FIL 0.1 to 0.2) and malignancies excluding NMSC (total FIL 0.5 to 0.6).Table 1.TEAEs of special interest, as-treated setTEAE, n (%) and EAIR per 100 PYE (95% CI)FIL 200 mgn=2267PYE=5302.5FIL 100 mgn=1647PYE=2782.6Total FILN=3691PYE=8085.1Infectious AEs1206 (53.2)747 (45.4)1927 (52.2)EAIR21.1 (19.7, 22.5)30.2 (26.8, 34.0)21.0 (19.9, 22.3)Serious infectious AEs80 (3.5)57 (3.5)137 (3.7)EAIR1.5 (1.1, 1.9)2.7 (1.9, 3.9)1.6 (1.3, 2.0)Opportunistic infections5 (0.2)4 (0.2)9 (0.2)EAIR0.1 (0, 0.2)*0.1 (0.1, 0.4)*0.1 (0.1, 0.2)*Active tuberculosis03 (0.2)3 (EAIR00.1 (0, 0.3)*0 (0, 0.1)*Herpes zoster84 (3.7)30 (1.8)114 (3.1)EAIR1.6 (1.2, 2.0)1.1 (0.8, 1.5)*1.4 (1.1, 1.7)Major adverse cardiovascular eventsa19 (0.8)14 (0.9)33 (0.9)EAIR0.3 (0.2, 0.5)0.5 (0.3, 0.8)*0.4 (0.2, 0.6)Venous thromboembolismb11 (0.5)4 (0.2)15 (0.4)EAIR0.2 (0.1, 0.4)*0.1 (0.1, 0.4)*0.2 (0.1, 0.3)*Atrial systemic thrombotic eventsa1 (1 (2 (EAIR0 (0, 0.1)0 (0, 0.3)0 (0, 0.1)Malignancy excluding NMSC32 (1.4)17 (1.0)49 (1.3)EAIR0.6 (0.4, 0.9)0.6 (0.4, 1.0)*0.6 (0.4, 0.8)NMSC15 (0.7)5 (0.3)20 (0.5)EAIR0.3 (0.2, 0.5)*0.2 (0.1, 0.4)*0.2 (0.2, 0.4)*Gastrointestinal perforations3 (0.1)1 (4 (0.1)EAIR0.1 (0, 0.2)*0 (0, 0.3)*0 (0, 0.1)**Except when any study had 0 event within the treatment, the Poisson model was not adjusted by study. PYE was defined as (last dose date − first dose date + 1)/365.25.aPositively adjudicated.bAdjudicated as deep vein thrombosis or pulmonary embolism.NMSC, nonmelanoma skin cancerConclusionWith 1 additional year of exposure since the 2020 report, FIL continues to be well tolerated with no new safety concerns emerging. EAIRs of TEAEs, including deaths, and AESIs remained stable or decreased since the 2020 report, except for slight increases in rates of NMSC and malignancies excluding NMSC. In the context of demonstrated efficacy, both FIL doses had an acceptable risk/benefit profile.References[1]Westhovens R et al. Ann Rheum Dis 2017;76:998–1008.[2]Kavanaugh A et al. Ann Rheum Dis 2017;76:1009–19.[3]Combe B et al. Ann Rheum Dis 2021;80:848–58.[4]Genovese MC et al. JAMA 2019;322:315–25.[5]Westhovens R et al. Ann Rheum Dis 2021;80:727–38.[6]Winthrop K et al. Arthritis Rheumatol 2020;72(suppl 10); abstract 0229.AcknowledgementsFunding for DARWIN 1 and 2 was provided by Galapagos NV, and funding for DARWIN 3, FINCH 1, 2, 3, and 4 was provided by Gilead Sciences, Inc., Foster City, CA. Funding for this analysis was provided by Gilead Sciences, Inc. The sponsors participated in the planning, execution, and interpretation of the research. Medical writing support was provided by Gregory Bezkorovainy, MA, of AlphaScientia, LLC, San Francisco, CA; and funded by Gilead Sciences, Inc., Foster City, CA.Disclosure of InterestsKevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, Roche, Regeneron, Sanofi, and UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, and Pfizer, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol Myers Squibb, Eisai, Chugai, AbbVie, Astellas, Pfizer, Sanofi, Asahi-Kasei, GSK, Mitsubishi-Tanabe, Gilead Sciences, Inc., and Janssen, Consultant of: AbbVie, Ayumi, Daiichi-Sankyo, Eli Lilly, GSK, Taisho, and Sanofi, Grant/research support from: AbbVie, Asahi-Kasei, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, and Takeda, Tsutomu Takeuchi Speakers bureau: AbbVie, AYUMI, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Mitsubishi-Tanabe, Novartis, Pfizer Japan, and Sanofi, Consultant of: Astellas, Chugai, and Eli Lilly Japan, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan, Alan Kivitz Shareholder of: Amgen, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, and Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, and Sanofi, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, and Sanofi, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead Sciences, Inc., Janssen, Novartis, Pfizer, Regeneron, Sanofi, and SUN Pharma Advanced Research, Mark C. Genovese Shareholder of: Gilead Sciences, Inc., Consultant of: AbbVie, Amgen, Beigene, Eli Lilly and Co., Genentech, Inc., Gilead Sciences, Inc., Sanofi Genzyme, RPharm, and SetPoint, Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Kun Chen Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos BV, Employee of: Galapagos BV, Sander Strengholt Shareholder of: Galapagos BV, Employee of: Galapagos BV, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., and Pfizer, Consultant of: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., and Pfizer, Jacques-Eric Gottenberg Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos BV, Gilead Sciences, Inc., Roche, Sanofi Genzyme, and UCB, Consultant of: Bristol Myers Squibb, Sanofi Genzyme, and UCB, Grant/research support from: Bristol Myers Squibb and Pfizer

BackgroundVagus nerve stimulation (VNS) activates innate neuroimmune reflexes that have been shown to reduce pro-inflammatory cytokines and clinical disease activity in subjects with rheumatoid arthritis (RA).1 We previously reported primary clinical outcomes from a first-in-human, double-blind study of a novel, implanted VNS device called a MicroRegulator (MR). That study showed 5/10 subjects with drug-refractory RA met or exceeded the minimal clinically important difference (MCID) in DAS28-CRP; 2 subjects achieved DAS28 remission (DAS28-CRP < 2.6); and pro-inflammatory cytokines were decreased by >30% following 12 weeks of VNS.2 We now report 24-week efficacy and safety findings from this study.ObjectivesDetermine the long-term safety and exploratory efficacy of neurostimulation using a novel, miniaturized VNS device in patients with multiple drug refractory RA who were previously enrolled in a first in human study.MethodsThe primary study enrolled adult patients with active moderate-to-severe RA with incomplete response or intolerability to at least two biologic and/or targeted synthetic DMARDs having at least two different mechanisms of action. The study was enrolled in 2 Stages: Stage 1 (n=3) was open-label, and Stage 2 (n=11) was randomized and sham-controlled (Figure 1). Three weeks after MR implantation, the first 3 subjects in Stage 1 received active VNS for 1 minute, once per day (QD). Following safety review board approval, 11 patients in Stage 2 were implanted with the MR and randomized 1:1:1 into one of two active VNS groups (1 minute of VNS QD or 1 minute of active VNS four times per day [QID]) or a sham group. At Week 12, the blind was lifted, sham subjects were re-randomized and crossed over to either QD or QID active VNS dosing, and all actively treated subjects remained on their dosing through Week 24. Safety and tolerability were determined, and several secondary efficacy endpoints were evaluated measuring the change in disease activity from the start of active VNS to Week 24.Figure 1.Study SchematicResultsThere were no device-related adverse events from Week 12 through Week 24. Improvement in clinical disease activity was sustained through Week 24: 5/9 patients within the original, active VNS treatment groups met or exceeded EULAR response criteria for DAS28-CRP at Week 24 (Table 1) vs. 5/10 at Week 12 (one Week 12 responder was lost to follow-up). Similarly, 6/9 patients in the original, active VNS treatment groups met or exceeded the MCID in CDAI at Week 24 vs. 5/10 at Week 12. In the long-term extension, 1/4 sham crossover patients had both EULAR and CDAI response after 12 weeks of VNS (1/2 QD, 0/2 QID). Co-therapy with a b/tsDMARD was initiated in 2 subjects (Table 1). One crossover subject was treated with oral methylprednisolone at week 19 due to worsening RA disease activity. VECTRA composite scores and component analysis revealed an 18-point decrease in median multi-analyte disease activity index in the QD group over 24 weeks of VNS with a decrease in serum levels of several analytes in key component categories (IL-6, serum amyloid A, and VCAM-1). Erosion progression by hand MRI was stabilized or decreased in all but 1 of the stimulated patients at Week 24.Table 1.Change in DAS28-CRP at Week 24SubjectTreatmentDAS28-CRP (MCID -1.2) *added b/tsDMARD co-therapy005-01QD-2.4005-03QD-2.21006-01QD-0.07002-01QD-4.95 *005-06QD-0.72 *006-03QID-0.69008-01QID0.49008-03QID-3.14008-04QID1.43005-05Sham to QD0.39006-04Sham to QD-0.78006-02Sham to QID-0.22008-02Sham to QID-0.09ConclusionImprovements in clinical disease activity and pro-inflammatory cytokine suppression were maintained through 24 weeks of VNS treatment. Safety outcomes continue to support the risk/benefit profile of VNS as a treatment option for patients with multiple-drug refractory RA.References[1]Koopman PNAS 2016[2]Genovese et al. Lancet Rheum 2020.AcknowledgementsAuthors wish to thank the patients for participating in the studyDisclosure of InterestsNorman Gaylis Grant/research support from: Primary investigator at AARDS Research Inc, Mark C. Genovese Shareholder of: Gilead Sciences, Consultant of: SetPoint Medical Inc, Vorso, InMedix, Galvani, Employee of: Gilead Sciences, David Sikes: None declared, Alan Kivitz Shareholder of: Amgen, Gilead, GSK, Sanofi, Pfizer, Speakers bureau: Abbvie, Celegene, Pfizer, Horizon, Merck, Genzyme, Sanofi, Flexion, Paid instructor for: Abbvie, Celegene, Pfizer, Horizon, Merck, Genzyme, Sanofi, Flexion, Consultant of: Abbvie, Janssen, Pfizer, Genzyme, Sanofi, Regeneron, Sun Pharma, Boehringer Ingelheim, Gilead, Diane M Horowitz: None declared, Charles Peterfy Speakers bureau: Amgen, Bristol-Myers Squibb, Consultant of: Abbvie, Five Prime, Genentech, Modern Bioscience, Myriad, Novartis, Roche, SetPoint Medical, Vorso, Employee of: Spire Sciences Inc, Yaakov Levine Employee of: Setpoint Medical, Melissa Evangelista Employee of: SetPoint Medical, David Chernoff Employee of: SetPoint Medical

BackgroundCurrent pharmacological treatments remain inadequate for a significant proportion of patients with rheumatoid arthritis (RA), and thus alternative treatment approaches are needed. Prior results from the first 12 weeks of a proof-of-concept (POC) study showed that ATHENS, a non-invasive high-frequency vagus nerve therapy, was well-tolerated with meaningful reductions in RA disease severity as measured by the American College of Rheumatology response criteria (ACR) and the Disease Activity Score using 28 joints (DAS28)[1].ObjectivesThe current analysis assessed long-term changes (52 weeks total follow-up) in disease activity as measured by ACR, DAS28, and the following MRI-assessed changes: synovitis, osteitis, bone erosion, and cartilage loss.MethodsFollowing the completion of the 12-week POC study, patients achieving a reduction in DAS28-CRP of ≥1.2 were given the option to enroll in the 9-month open-label extension (OLE) study. During the extension phase, patients were to use the wearable device for 15 minutes per day. Adjustment of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic disease-modifying antirheumatic drugs (bDMARDs) were allowed during the OLE. Changes from baseline were assessed at 12 weeks (end of initial POC) and 52 weeks (end of the OLE). Structural damage and disease progression were evaluated by standardized MRI of the wrist and hand, with and without intravenous gadolinium-based contrast. MRIs were evaluated by two independent, central readers, blinded to clinical information and visit-order of the images, and were scored for synovitis, osteitis and bone erosion using the OMERACT-RAMRIS method. Cartilage loss was also determined using the 9-point cartilage loss scale (CARLOS).ResultsTwenty-seven of 30 patients completed the initial 12-week study, of whom 19 consented and entered the OLE. Of those 19 patients, 4 (21%) discontinued due to lack of efficacy, while the remaining 15 completed the 9-month extension. Due to the COVID-19 pandemic, 7 patients were unable to complete a 52-week MRI scan; MRI evaluations at baseline, 12 weeks, and 52 weeks were available for 8 patients.DAS28-CRP mean (standard deviation [SD]) change from baseline was -1.78 (1.01) at 12 weeks (n=19; pTable 1.Change in MRI OMERACT-RAMRIS from baseline to week 52ScoreBaseline (n=8)Week 12 (n=8)Week 52 (n=8)Change Week 12 vs BL (n=8)Change Week 52 vs BL (n=8)CARLOS, mean (SD)3.9 (5.6)3.9 (5.6)3.9 (5.6)0.0 (0.0)0.0 (0.0)Erosion, mean (SD)10.8 (10.3)10.5 (10.3)10.6 (10.3)-0.3 (0.4)-0.1 (0.8)Osteitis, mean (SD)2.8 (4.1)2.3 (3.7)1.0 (1.1)-0.5 (1.1)-1.8 (3.1)Synovitis, mean (SD)4.0 (4.2)4.1 (4.7)3.3 (4.0)0.1 (0.6)-0.7 (1.0)CARLOS = Cartilage loss score; OMERACT = Outcome Measures in Rheumatology; RAMRIS = Rheumatoid Arthritis Magnetic Resonance Imaging Scoring SystemDuring the 9-month extension study, two new adverse events were reported (cornea transplant and right hand dysesthesia) in 2 (11%) patients; neither was treatment-related and both resolved without intervention. No serious adverse events were reported.ConclusionIn patients with an initial treatment response to the Nēsos ATHENS therapy in the 12-week POC study, reductions in DAS28-CRP were sustained through 52 weeks. Although results should be interpreted cautiously given the small sample size and lack of control arm, MRI evaluation of synovitis, osteitis, bone erosion, and cartilage loss suggested no disease progression.References[1]Marsal, S., The Lancet Rheumatology, 2021. 3(4): p. e262-e269.Disclosure of InterestsCharles Peterfy Consultant of: Nesos Corp, Employee of: Spire Sciences, Héctor Corominas: None declared, Juan Jose de Agustin: None declared, Carolina Perez-Garcia: None declared, Maria Lopez Lasanta: None declared, Helena Borrell Paños: None declared, D Reina-Sanz: None declared, Raimón Sanmartí: None declared, J. Narváez: None declared, Jose Antonio Narvaez: None declared, Vivek Sharma Shareholder of: Nesos Corp., Employee of: Nesos Corp., Konstantinos Alataris Shareholder of: Nesos Corp., Employee of: Nesos Corp., Mark C. Genovese Shareholder of: Nesos Corp. and Gilead, Employee of: Gilead, Matthew Baker Shareholder of: Nesos Corp., Consultant of: Nesos Corp., Sara Marsal Consultant of: Nesos, Pfizer, Sandoz, Novartis, Gilead, Grant/research support from: Nesos, BMS, Celgene, Merck Sharp and Dohme, Pfizer, Sandoz, Novartis, Sanofi, Janssen, Union Chimique Belge Pharma

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

Tabalumab, a fully human IgG4 monoclonal antibody, neutralizes soluble and membrane-bound BAFF. The aim of this study was to examine the tolerability and efficacy of tabalumab in patients with active rheumatoid arthritis receiving methotrexate.In this randomized, double-blind, placebo-controlled, parallel, multiple-dose study, patients who were naive to biologic therapy received infusions of tabalumab (30, 60, or 160 mg) or placebo at weeks 0, 3, and 6 in combination with methotrexate and were evaluated for 24 weeks. The primary efficacy end point was the percentage of patients meeting American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16.At week 16, the percentages of patients achieving an ACR20 response in the 30-mg (57.6%), 60-mg (67.6%), and 160-mg (51.5%) groups were significantly greater than the percentage of patients achieving an ACR20 response in the placebo group (29.4%; P0.05). There were initial transient increases from baseline in the frequency of CD20+ and IgD+/CD27- B cells, followed by reductions, although B cells were not completely depleted. Also, the frequency of IgD-/CD27+ B cells increased in all tabalumab groups compared with the placebo group and returned toward baseline levels by the end of the study. The incidence of adverse events was similar across all treatment groups; no deaths occurred. Serum IgM levels decreased significantly in all tabalumab groups combined compared with the placebo group. There were no significant decreases in serum IgG or IgA levels in the tabalumab groups compared with the placebo group.Tabalumab treatment significantly reduces the signs and symptoms of rheumatoid arthritis and has a safety profile similar to that seen with placebo treatment.

Rheumatoid arthritis (RA) is a prevalent systemic disease that causes significant joint dysfunction and disability. Dramatic improvements in the management of RA have been achieved with the use of biologic therapies aimed at cytokines, and B and T lymphocytes. Abatacept, a soluble receptor-IgG fusion protein that interferes with T-cell co-stimulation, has now been shown to improve symptoms, signs and function in RA, while also slowing radiographic progression. The degree of improvement in these measures is comparable to that seen with other biologic agents.Abatacept is effective in a range of RA patients that are encountered in clinical practice, namely methotrexate-inadequate responders, as well patients with inadequate responses to tumor necrosis factor inhibitors and patients with co-morbidities common in an aging population. When used for up to 2 years, abatacept appears to be safe and remains efficacious, although there is a trend toward increased infection rates when used in combination with other biologic therapies, as well as a trend toward more adverse events when used in a background of chronic obstructive pulmonary disease. Backed by these data, ongoing extensions of these trials, and additional new studies, abatacept represents the first co-stimulation modulator approved for RA, and is a welcome addition to the biologic therapies available for the management of this disease.

The development of tumor necrosis factor alpha (TNFalpha) inhibitor therapy is arguably the most significant achievement in the treatment of rheumatic diseases to date. One serious potential side effect associated with these agents is the onset of neurologic signs and symptoms. In this paper we will examine the relationship of TNFalpha antagonism and demyelinating disease. Reviewing early laboratory and animal models, we discuss the mechanism of TNFalpha in central nervous system (CNS) injury and repair. Two negative studies of TNFa inhibitor therapy in the treatment of refractory multiple sclerosis (MS) are considered. From the manufacturers' clinical development programs and post-marketing adverse event reporting data, we report the current incidence of demyelinating symptoms associated with each of the commercially available anti-TNFa agents. Comparing these reports to the incidence of MS in society as a whole, we find the rate of new cases of neurologic disease in exposed patients is not different from the rate of expected cases. Finally we explore arguments that support and refute a potential biologic relationship between TNFa neutralization and demyelinating disease.

The Early Rheumatoid Arthritis (ERA) trial compared monotherapy with etanercept or methotrexate in patients with early erosive rheumatoid arthritis. Over the initial period of 12, and subsequently 24, months both treatments were associated with a profound reduction in radiographic progression of joint damage, as well as a reduction in signs and symptoms of disease. Etanercept showed slight superiority to methotrexate in reducing subsequent radiographic erosions and in the rapidity of the clinical response. Both therapies proved to be safe and well tolerated and, importantly, the relative safety and tolerance of a rapidly escalated dosing regimen for methotrexate was demonstrated. In summary, early aggressive treatment of RA is associated with clinical and radiographic benefit that can be demonstrated after a relatively short period of treatment.

The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.

Mucosae-associated epithelial chemokine (MEC) is a novel chemokine whose mRNA is most abundant in salivary gland, with strong expression in other mucosal sites, including colon, trachea, and mammary gland. MEC is constitutively expressed by epithelial cells; MEC mRNA is detected in cultured bronchial and mammary gland epithelial cell lines and in epithelia isolated from salivary gland and colon using laser capture microdissection, but not in the endothelial, hemolymphoid, or fibroblastic cell lines tested. Although MEC is poorly expressed in skin, its closest homologue is the keratinocyte-expressed cutaneous T cell-attracting chemokine (CTACK; CCL27), and MEC supports chemotaxis of transfected lymphoid cells expressing CCR10, a known CTACK receptor. In contrast to CTACK, however, MEC also supports migration through CCR3. Consistent with this, MEC attracts eosinophils in addition to memory lymphocyte subsets. These results suggest an important role for MEC in the physiology of extracutaneous epithelial tissues, including diverse mucosal organs.