scholarly journals P215 Filgotinib, a janus kinase 1 selective inhibitor, modulates disease-associated cytokines in patients with active RA

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Peter C Taylor ◽  
Emon Elboudwarej ◽  
Wanying Li ◽  
Rachael E Hawtin ◽  
Jinfeng Liu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Disease Activity ◽  
Clinical Response ◽  
Immune Cell ◽  
Selective Inhibitor ◽  
Janus Kinase ◽  
Stock Ownership ◽  
Inadequate Response ◽  
Bone Biology ◽  
Immune Cell Migration

Abstract Background Filgotinib (FIL), an oral JAK1-selective inhibitor, was safe and effective in FINCH2, a randomised, double-blind, placebo (PBO)-controlled, phase 3 study in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX) and ≥1 biologic disease-modifying antirheumatic drug. A longitudinal study of cytokines from patients in FINCH2 was conducted to identify RA-associated biomarkers related to bone biology, immune cell migration, and inflammation that are altered by FIL therapy; and FIL-associated biomarkers that correlate with clinical response (DAS28CRP, swollen and tender joint counts, pain, and fatigue). Methods Plasma, serum and urine samples from RA patients (n = 449) receiving FIL (100mg, 200mg) or PBO once daily plus MTX were analysed at baseline (BL) and week 12 (W12) for 42 disease-relevant cytokines using validated, commercially available single- or multiplex assays. PBO corrected on-treatment changes in cytokine levels from BL to W12 were compared between treatment arms (Wilcoxon rank sum). Spearman rank correlation was used to compare changes in cytokine level from BL to W12 and clinical response. P-values <0.05 were considered significant. Results At W12, 18 of 42 cytokines significantly decreased with FIL 100mg treatment relative to PBO; FIL 200mg decreased these cytokines to a similar or greater degree. An additional 6 cytokines were significantly decreased by FIL 200mg. Conversely, 2 cytokines increased relative to PBO with FIL 100mg, and 6 cytokines increased with FIL 200mg (sIL-6R, IL10, GMCSF, IL2, leptin, and IL17A). Biomarkers most significantly modulated by FIL 200mg (p < 0.0001) included markers related to bone biology (MMP1 [-22.8%], MMP3 [-24.7%], CTX1 [-27.4% ], and NTX [-16.4%]), immune cell migration (VCAM1 [-20.0%], ICAM1 [-14.2%], CXCL13 [-45.0%], and CXCL10 [-32.3%]), and inflammation (TNFRI[-20.7%], CRP [-77.4%], SAA [-61.8%], and resistin [-20.2%]). Hierarchical clustering of BL biomarker levels revealed distinct groups of cytokines that were strongly correlated with each other. Among them, SAA, IL6 and CXCL10, were significantly positively correlated with each other (rho>0.6) and with RA disease activity (DAS28CRP) at BL (rho>0.3). Biomarkers, including CRP (IL6, SAA), PainVAS (CRP, SAA), and SJC28 (CRP, IL6, CXCL10), were also significantly correlated with individual components of DAS28CRP. Several biomarkers associated with RA disease activity at BL were decreased with FIL at W12 relative to PBO (FIL 100mg: CRP [-48.7%], SAA [-36.9%], and IL6 [-2.6%] and FIL 200mg: CRP [-77.4%], SAA [-61.8%], IL6 [-13.6%], CXCL10 [-32.3%]), suggesting FIL impacts these disease activities at a molecular level. Conclusion Twelve weeks of FIL treatment significantly reduced 24 disease-relevant cytokines in patients with active RA. Effects were dose-dependent and suggest a shift toward restored immune homeostasis. Findings are consistent with the clinical efficacy of FIL in FINCH2. Disclosures P.C. Taylor: Consultancies; Consultant for AbbVie, BMS, Jansses, Pfizer, Roche, Lilly, Sanofi, MSD, Novartis, Celgene and Gilead. E. Elboudwarej: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. W. Li: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R.E. Hawtin: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. J. Liu: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. A.M. Mirza: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc.

scholarly journals FRI0136 PERIPHERAL PROTEIN BIOMARKER CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH PRIOR INADEQUATE RESPONSE TO METHOTREXATE (FINCH1)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 650.2-651
Author(s):  
P. C. Taylor ◽  
E. Elboudwarej ◽  
B. Downie ◽  
J. Liu ◽  
R. E. Hawtin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Active Rheumatoid Arthritis ◽  
Immune Cell ◽  
Janus Kinase ◽  
Inadequate Response ◽  
Bone Biology ◽  
Janus Kinase 1 ◽  
Immune Cell Migration ◽  
Dose Dependent

Background:Filgotinib (FIL), an oral selective Janus kinase 1 (JAK1) inhibitor has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA), including those with prior inadequate response to methotrexate (MTX) therapy (FINCH1;NCT02889796).Objectives:A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2, and inflammation2was conducted to identify RA-associated markers altered by FIL vs MTX or adalimumab (ADA).Methods:FINCH1 RA patients (pts) were randomized to receive either a stable dose of MTX with placebo (PBO+MTX), ADA+MTX, and either FIL100mg+MTX or FIL200mg+MTX, once daily. Plasma, serum, and urine samples were taken from a subset of pts (~548) at baseline (BL) and weeks (wks) 4 and 12. Twenty-six pre-defined cytokines (biomarkers) were evaluated using ELISA. BL correlation between biomarkers and clinical response measures (DAS28CRP, SJC28, TJC28, CDAI, Patient Assessment and FACIT), were analyzed by Spearman Rank. Multiscale bootstrap resampling evaluated significant intra-cluster biomarker membership. Mean changes in biomarker levels from BL to wks 4 and 12 were compared between arms using PBO-adjusted estimates from a linear mixed effects model. A 5% false-discovery rate was applied for all analyses.Results:At BL, distinct biomarker-based pt clusters (CL) were identified. The strongest intra-group correlations were in bone-cartilage resorption/inflammation (CL1; Rho range 0.37–0.88) and JAK activity (CL2; Rho range 0.41–0.71). Individual BL cytokine levels were significantly associated with DAS28CRP, with unique biomarkers specific to various subcomponents of the score. Eleven biomarkers were associated with DAS28CRP, while 5, 3, and 2 were associated with CDAI, SJC28, and TJC28, respectively. The magnitude of FIL-associated treatment effects was time- and dose-dependent. Significant biomarker changes from BL were observed in FIL pts, relative to PBO+MTX pts. FIL100mg+MTX led to a significant change in 8 biomarkers by either 4 or 12 wks of treatment; FIL200mg+MTX significantly changed these and an additional 4 biomarkers by either time point. The greatest effect of FIL200mg+MTX was at 12 wks for CXCL13 (-38.4%) and IL6 (-53.7%). All treatment arms led to significant reductions in TNFα relative to PBO+MTX. FIL200mg+MTX treatment led to larger reductions of TNFα than ADA+MTX treatment at both wk4 (-24.7% vs -17.9%) and wk12 (-20.5% vs -12.2%), although the differences were not statistically significant.FIL and ADA caused differential patterns of cytokine response at either wks 4 or 12. Of 12 biomarkers with a significant FIL200mg+MTX treatment effect, there was a significantly larger reduction in TNFSF13B and CTX1 relative to ADA+MTX at 12 wks. Of 8 biomarkers with FIL100mg+MTX effects, only 2 (CXCL10 at wk 4; CXCL13 at wks 4 and 12) had significant differences from ADA+MTX. Relative either to FIL200mg+MTX or FIL100mg+MTX, and despite the same direction of effect, ADA+MTX led to a significantly larger reduction in CCL2, CXCL10, CCL4, and CXCL13.Conclusion:Compared with PBO, 12 wks of FIL treatment significantly reduced cytokines associated with JAK activity1, bone biology2, inflammation2, and immune cell migration2in MTX-IR pts. The effects were largely FIL dose-dependent; most cytokines exhibited similar effects regardless of treatment arms, but differential changes between FIL+MTX and ADA+MTX were observed, supportive of the different mechanisms of action of these therapies.References:[1]Majoros A, et al. Front Immunol. 2017;8:29[2]Brennan F, and McInnes I. J Clin Invest. 2008;118:3537-45Acknowledgments:This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

scholarly journals THU0216 PERIPHERAL PROTEIN BIOMARKER CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN METHOTREXATE NAÏVE ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS (FINCH3)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 333.2-334
Author(s):  
P. C. Taylor ◽  
A. M. Mirza ◽  
B. Downie ◽  
J. Liu ◽  
R. E. Hawtin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Active Rheumatoid Arthritis ◽  
Immune Cell ◽  
Selective Inhibition ◽  
Rapid Onset ◽  
Janus Kinase ◽  
Bone Biology ◽  
Protein Biomarkers ◽  
Immune Cell Migration

Background:Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA), including those who are naïve to methotrexate (MTX) therapy (FINCH3;NCT02886728).Objectives:A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2, and inflammation2was conducted in FINCH3 pts to identify disease relevant biomarkers that are altered by FIL vs MTX.Methods:MTX-naive RA pts enrolled in FINCH3 received a stable dose of MTX (MTX mono), FIL200mg monotherapy (FIL200mg mono) or one of two doses of FIL once daily with MTX (FIL100mg+MTX, FIL200mg+MTX). Up to 27 disease relevant biomarkers were evaluated. Baseline (BL) correlation between biomarkers and clinical response measures were analyzed by Spearman Rank. Multiscale bootstrap resampling was used to evaluate significant intra-cluster biomarker membership. Mean changes in biomarker levels from BL to wks 4, 12 and 24 were compared between arms using MTX-adjusted estimates from a linear mixed effects model, adjusted for age, sex, race and BL biomarker level. A false discovery rate of 5% was applied for all analyses.Results:At BL, distinct clusters (CL) of biomarkers differentiated by JAK signaling were identified. The strongest intra-group correlations were in biomarkers upstream of JAK2 signaling (CL1; Rho range 0.88–0.98) and cytokines associated with JAK1 signaling (CL2; Rho range 0.72–0.77). Within MTX-naïve RA pts, there were significant BL correlations between 15 biomarkers and clinical measures. The strongest associations observed were between DAS28CRP and IL6, CXCL10, TNFRI, YKL-40, and CXCL13 (Rho >0.3).Relative to MTX mono, 23 biomarkers exhibited significantearly responsesto treatment (any arm, wk 4). The strongest treatment effect observed at wk 4 was a reduction by FIL+MTX (regardless of dose) and FIL200mg mono for CXCL13 (FIL100mg+MTX: -28.2%; FIL200mg+MTX: -40%; FIL200mg: -34%). This reduction was sustained in each arm through 24 wks, with the greatest reduction by FIL200mg+MTX (-37.8%). Dose differences were observed relative to FIL100mg+MTX, where FIL200mg+MTX led to anearly(wk 4) and significantly greater reduction of 9 biomarkers. There was a significant dose difference as adelayedresponse (wk 24) with a greater reduction by FIL200mg+MTX for 8 biomarkers.FIL200mg mono produced a greater effect on 18 biomarkers vs MTX mono, remaining significant through wk 24. The greatest effect in FIL200mg mono were reductions by wk 24 in CTX1 (-29.1%), CXCL13 (-33.2%), and IL6 (-29.5%), all of which were biomarkers associated with DAS28CRP at BL. Effects observed at any time point were largely similar between FIL200mg as a mono or in combination with MTX. Four biomarkers were uniquely different between FIL200mg mono and FIL200mg+MTX arms by wk 24: greater increase of MMP7 and decrease of GMCSF in FIL200mg+MTX; greater decrease of TRACP5B and ICAM1 in FIL200mg alone.Conclusion:Treatment through 24 weeks with FIL200mg (mono or with MTX) reduced many of the disease-relevant biomarkers tested; markers related to JAK signaling1, bone biology2, inflammation2, and immune cell migration2in the MTX-naïve RA setting. Changes were significantly reduced relative to MTX mono at wk 4, supporting the rapid onset of FIL clinical efficacy. The current study identified significant reductions of RA-associated disease markers that were unique to FIL mono, supporting the FIL mechanisms of action in the treatment of RA.References:[1]Majoros A, et al. Front Immunol. 2017;8:29[2]Brennan F, and McInnes I. J Clin Invest. 2008;118:3537-45Acknowledgments :This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests: :Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

scholarly journals POS0407 PROTEOMICS ANALYSIS COMPARING THE MODE OF ACTION OF UPADACITINIB BETWEEN NON-BIOLOGIC-DMARD-IR AND BIOLOGIC-DMARD-IR PsA PATIENTS IDENTIFIES DISTINCT PATHOGENIC PATHWAYS IN THE SELECT-PsA 1 AND SELECT-PsA 2 PHASE 3 STUDIES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 433.1-433
Author(s):  
T. Sornasse ◽  
J. Anderson ◽  
K. Kato ◽  
A. Lertratanakul ◽  
I. McInnes ◽  
...  
Keyword(s):  
Disease Activity ◽  
Clinical Response ◽  
Rheumatic Diseases ◽  
Inadequate Response ◽  
Protein Biomarkers ◽  
Research Support ◽  
Positive Correlation ◽  
Disease Biology ◽  
Biologic Dmard ◽  
Favorable Clinical Response

Background:Treatment of non-biologic-DMARD-IR1 (DMARD-IR) and biologic-DMARD-IR2 (bio-IR) PsA patients with upadacitinib (UPA) at 15 mg QD, an oral JAK1 selective inhibitor, resulted in significant improvement in signs and symptoms compared to placebo.Objectives:Using a pre-defined set of inflammation-related plasma protein biomarkers (pBM), to explore immunological pathway modulation by UPA 15 mg QD in PsA patients with active disease despite treatment with non-biologic or biologic DMARDs in the context of clinical response vs. non-response to treatment.Methods:Patients from the SELECT-PsA 1 (DMARD-IR) and the SELECT-PsA 2 (bio-IR) studies were randomly selected (PBO, n=100; UPA 15 mg QD, n=100 for each study). The levels of 92 inflammation related protein biomarkers (pBM) were analyzed using a multiplexed Proximity Extension Assay platform in plasma samples collected at baseline, week 2, and 12; change from baseline in protein levels was expressed as Log2 Fold Change; a Repeated Measure Mixed Linear Model was used to identify pBM modulated by UPA compared to Baseline, and those differentially modulated between responders (R) and non-responders (NR) according to ACR50, PASDAS Minimal Disease Activity, and PASI75 at week 12. Correlation of disease activity measures with relative levels of pBM were derived using Pearson’s correlation; PASI score was transformed as Log10 (x+1) prior to the analysis. Functional pathway prediction was performed in silico with a commercial distributed software.Results:At baseline, the relative levels of 37 pBM correlated with at least one baseline disease activity measure, with a marked positive correlation of IL6 with musculoskeletal end points (PASDAS and DAS28CRP), and a strong positive correlation of IL20, IL17A, IL17C, and TGFA with baseline PASI.At the single pBM-level, treatment with UPA 15 mg QD resulted in a down modulation of pBM associated with T cells, myeloid cells, and IFN-, IL6-, and TNF-related pathways in both DMARD-IR and bio-IR PsA patients. Overall effects of UPA on single pBMs were broadly similar between DMARD-IR and bio-IR patients. However, analysis of pBMs differentially modulated by UPA in R vs NR indicated that favorable clinical response (achievement of ACR50, PASDAS MDA, and PASI75) in DMARD-IR patients was associated with the down modulation of pBMs predicted to be linked to IFN, IL10, IL17, IL22, and IL27 pathways; while favorable clinical response in bio-IR patients was associated with the down modulation of multiple pBM predicted to be linked to the IL17, IL23, and IL1 pathways.Conclusion:UPA effects in both DMARD-IR and bio-IR PsA patients likely stem from the direct and indirect inhibition of multiple biological pathways belonging to the adaptive and innate immune systems. Responder/Non-Responder analysis suggests a possible shift from a TH1 biased biology in DMARD-IR PsA patients to a more TH17 biased biology in bio-IR PsA patients. This apparent change in the disease biology of PsA patients after inadequate response to prior therapy could be attributed to the actual alteration of the disease biology, treatment outcome-based patient selection, or both. Considering the clinical efficacy of UPA in both DMARD-IR and bio-IR PsA patients, this observation highlights the importance of targeting multiple pathways with drugs such as UPA for the treatment of a broad range of PsA patients.References:[1]McInnes, I. et al. Annals of the Rheumatic Diseases 79, 16-17 (2020).[2]Mease, P.J. et al.Annals of the Rheumatic Diseases, annrheumdis-2020-218870 (2020).Acknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.Disclosure of Interests:Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Jaclyn Anderson Shareholder of: AbbVie, Employee of: AbbVie, Koji Kato Shareholder of: AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB Pharma, Grant/research support from: AbbVie, Amgen, UCB

scholarly journals Changes in Adhesion Molecule Expression During Distinct Patterns of Immune Cell Migration in the Inflamed Lung.

1996 ◽  
Vol 59 (5) ◽  
pp. 443-452 ◽  
Author(s):  
Sanae ICHIKAWA ◽  
Yasuhide GOTO ◽  
Shigeo UCHINO ◽  
H. Benfer KALTREIDER ◽  
Edward J. GOETZL ◽  
...  
Keyword(s):  
Cell Migration ◽  
Adhesion Molecule ◽  
Immune Cell ◽  
Adhesion Molecule Expression ◽  
Immune Cell Migration

scholarly journals Subcellular optogenetic activation of Cdc42 controls local and distal signaling to drive immune cell migration

2016 ◽  
Vol 27 (9) ◽  
pp. 1442-1450 ◽  
Author(s):  
Patrick R. O’Neill ◽  
Vani Kalyanaraman ◽  
N. Gautam
Keyword(s):  
Cell Migration ◽  
Intracellular Signaling ◽  
Immune Cell ◽  
Leading Edge ◽  
Signaling Networks ◽  
Membrane Protrusions ◽  
A Cell ◽  
Immune Cell Migration ◽  
Directional Cell Migration ◽  
Rhoa Signaling

Migratory immune cells use intracellular signaling networks to generate and orient spatially polarized responses to extracellular cues. The monomeric G protein Cdc42 is believed to play an important role in controlling the polarized responses, but it has been difficult to determine directly the consequences of localized Cdc42 activation within an immune cell. Here we used subcellular optogenetics to determine how Cdc42 activation at one side of a cell affects both cell behavior and dynamic molecular responses throughout the cell. We found that localized Cdc42 activation is sufficient to generate polarized signaling and directional cell migration. The optically activated region becomes the leading edge of the cell, with Cdc42 activating Rac and generating membrane protrusions driven by the actin cytoskeleton. Cdc42 also exerts long-range effects that cause myosin accumulation at the opposite side of the cell and actomyosin-mediated retraction of the cell rear. This process requires the RhoA-activated kinase ROCK, suggesting that Cdc42 activation at one side of a cell triggers increased RhoA signaling at the opposite side. Our results demonstrate how dynamic, subcellular perturbation of an individual signaling protein can help to determine its role in controlling polarized cellular responses.

scholarly journals CelltrackR: an R package for fast and flexible analysis of immune cell migration data

2019 ◽  
Author(s):  
Inge M. N. Wortel ◽  
Katharina Dannenberg ◽  
Jeffrey C. Berry ◽  
Mark J. Miller ◽  
Johannes Textor
Keyword(s):  
Cell Migration ◽  
Immune Cell ◽  
Time Lapse ◽  
R Package ◽  
Management Quality ◽  
Analysis Methods ◽  
Migration Dynamics ◽  
Immune Cell Migration ◽  
Imaging Artifacts ◽  
Track Analysis

AbstractSummaryVisualization of cell migration via time-lapse microscopy has greatly advanced our understanding of the immune system. However, subtle differences in migration dynamics are easily obscured by biases and imaging artifacts. While several analysis methods have been suggested to address these issues, an integrated tool implementing them is currently lacking. Here, we present CelltrackR, an R package containing a diverse set of state-of-the-art analysis methods for (immune) cell tracks. CelltrackR supports the complete pipeline for track analysis by providing methods for data management, quality control, extracting and visualizing migration statistics, clustering tracks, and simulating cell migration.Availability and ImplementationCelltrackR is an open-source package released under the GPL-2 license, and is freely available on GitHub at https://github.com/ingewortel/[email protected], [email protected]

scholarly journals P216 Effects of filgotinib on anaemia, thrombocytopoenia and leukopoenia: results from a Phase 3 study in patients with active RA and prior inadequate response or intolerance to bDMARDs

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
David Walker ◽  
Mark C Genovese ◽  
Kenneth Kalunian ◽  
Jacques-Eric Gottenberg ◽  
Beatrix Bartok ◽  
...  
Keyword(s):  
Janus Kinase ◽  
Stock Ownership ◽  
Inadequate Response ◽  
Phase 3 ◽  
Double Blind ◽  
Treatment Groups ◽  
Normal Platelet ◽  
Haematopoietic Growth Factor ◽  
Baseline Haemoglobin ◽  
Low Levels

Abstract Background Cytopoenias are common in patients treated for rheumatoid arthritis (RA) with non-janus kinase 1 (JAK1)-selective inhibitors, possibly due to JAK2-mediated haematopoietic growth factor inhibition. We investigated the extent of cytopoenia in patients with active RA, despite prior treatment with biological disease-modifying antirheumatic drugs (bDMARDs), treated with the JAK1-selective inhibitor filgotinib (FIL), in a Phase 3 trial (FINCH2; NCT02873936). Methods In the double-blind, Phase 3 FINCH2 trial, patients were randomised 1:1:1 to receive oral FIL 200mg, 100mg, or placebo (PBO) once daily for 24 weeks (W) + conventional synthetic DMARDs. We assessed shifts from baseline at 12 and 24 weeks in haemoglobin, platelets, neutrophils and lymphocytes. Results 448 patients were treated: FIL 200mg, n = 147; FIL 100mg, n = 153; PBO, n = 148. Overall, haemoglobin, platelet, lymphocyte and neutrophil levels remained consistent throughout the study. At baseline, 129 (28.8%), 4 (0.9%), 10 (2.2%) and 26 (5.8%) patients had mild-moderate low levels of haemoglobin, platelets, neutrophils and lymphocytes, respectively, and 5 (1.1%) had severely low levels of lymphocytes. Of the patients with mild-moderate low haemoglobin levels at baseline, 10-13% achieved normal levels by W24 vs 8% receiving PBO (Table). Of those with normal baseline haemoglobin levels, 6-10% had mild low levels at W24. All patients with baseline mild-moderate low platelets and neutrophils had normal levels at W24, except one patient with mild neutropoenia receiving FIL 100mg. Of the patients with normal platelet and neutrophil levels at baseline, >94% maintained these at W24 in all treatment groups. By W24, 3.2%, 5.2% and 2.2% of patients treated with FIL 200mg, FIL 100mg and PBO, respectively in the baseline mild-moderate subgroup and 1.7% in the severe subgroup treated with FIL 100mg had normal lymphocyte counts. Conclusion In this study, most patients in the baseline normal cell count subgroups maintained this status over 24 weeks of FIL treatment. Of the patients with mild-to-moderately low haemoglobin at baseline, >9% shifted towards haemoglobin normalisation. Similar patterns of improvement from baseline were observed for platelet, lymphocyte and neutrophil counts. FIL appears not to increase the incidence of cytopenias in patients with active RA despite prior biologic therapies. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis, Roche. M.C. Genovese: Other; Received support from Gilead Sciences Inc., Galapagos NV, AbbVie Inc. Eli Lilly and Company, Pfizer. K. Kalunian: Grants/research support; Grand support from Gilead. J. Gottenberg: None. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Tan: Corporate appointments; Employee of Gilead Sciences, Inc... Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Other; Employee of Galapagos. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. K. de Vlam: None. T. Takeuchi: None.

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