scholarly journals Predictive Factors of Response to Biological Disease Modifying Antirheumatic Drugs: Towards Personalized Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Claire I. Daïen ◽  
Jacques Morel
Keyword(s):  
Clinical Response ◽  
Immune Cell ◽  
Smoking Status ◽  
Therapy Response ◽  
Inadequate Response ◽  
Disease Characteristics ◽  
Cytokine Levels ◽  
Cell Phenotypes ◽  
The Impact ◽  
Necrosis Factor

Many therapies are now available for patients with rheumatoid arthritis (RA) who have an inadequate response to methotrexate including tumor necrosis factor inhibitors, abatacept, tocilizumab, and rituximab. Clinical response to drugs varies widely between individuals. A part of this variability is due to the characteristics of the patient such as age, gender, concomitant therapies, body mass index, or smoking status. Clinical response also depends on disease characteristics including disease activity and severity and presence of autoantibodies. Genetic background, cytokine levels, and immune cell phenotypes could also influence biological therapy response. This review summarizes the impact of all those parameters on response to biological therapies.

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.

Impaired response to treatment with tumour necrosis factor α inhibitors in smokers with axial spondyloarthritis

2015 ◽  
Vol 75 (3) ◽  
pp. 532-539 ◽  
Author(s):  
Adrian Ciurea ◽  
Almut Scherer ◽  
Ulrich Weber ◽  
Pascale Exer ◽  
Jürg Bernhard ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Disease Activity ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Axial Spondyloarthritis ◽  
Smoking Status ◽  
Response To Treatment ◽  
Asas Classification Criteria ◽  
The Impact ◽  
Necrosis Factor

ObjectivesTo investigate the impact of smoking on the response to treatment with a first tumour necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) in a real-life cohort.MethodsPatients fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA in the Swiss Clinical Quality Management Cohort were included in this study. The potential association between smoking status and differential response to TNFi in terms of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) was analysed using multiple adjusted longitudinal mixed effect models. Binary response rates at 1 year were assessed with multiple adjusted logistic analyses.ResultsA first TNFi was initiated in 698 patients with axSpA with available smoking status and a baseline or follow-up BASDAI assessment, of which 490 (70%) had complete covariate data. In comparison to non-smokers, current smokers demonstrated significantly smaller reductions in BASDAI and ASDAS scores upon treatment with TNFi (0.75 BASDAI units and 0.69 ASDAS units less, p=0.005 and 0.001, respectively) for patients with elevated baseline C-reactive protein (CRP) level. This effect was numerically smaller in patients with normal CRP. The odds for reaching a 50% improvement in BASDAI response or the ASAS criteria for 40% improvement after 1 year were significantly lower in current smokers than in non-smokers (0.54, 95% CI 0.31 to 0.95, p=0.03 and 0.43, 95% CI 0.24 to 0.76, p=0.004, respectively).ConclusionsCurrent smoking is associated with an impaired response to TNFi in axSpA.

74 Novel approach for profiling immune-tumor cell interactions and mutations in the same tumor section by multiplex immunohistochemistry and NGS in immuno-oncology trials

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A80-A80
Author(s):  
Nathan Riccitelli ◽  
Jennifer Bordeaux ◽  
Nancy Valencia ◽  
Ju Young Kim ◽  
Sarah Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Clinical Response ◽  
Tumor Tissue ◽  
Immune Cell ◽  
Meta Analysis ◽  
Novel Approach ◽  
Cell Phenotypes

BackgroundBoth proteins (e.g., PD-L1 IHC) and tumor mutation burden (NGS-based) are known to independently predict clinical response to anti-PD-1/PD-L1 therapies. In a meta-analysis of tumor specimens from 8135 patients treated with PD-1/PD-L1 blockers, multiplex fluorescence immunohistochemistry (mFIHC) had significantly higher diagnostic accuracy than PD-L1 IHC, tumor mutational burden (TMB), or gene expression profiling alone in predicting clinical response1 or equivalent to a multimodality approach (e.g., PD-L1IHC + TMB). While the benefits of combining mFIHC (tumor-immune interplay) and NGS approaches in selection of patients for next generation immunotherapies is appealing, tumor tissue is a key limiting factor for multimodality analyses in clinical trials. To address this critical limitation, we developed a novel approach for sequential profiling of tumor and immune cell interactions by 7-parameter mFIHC assays, followed by analyses of nucleic acid extracted from same tissue sections.MethodsFormalin-fixed paraffin-embedded (FFPE) tumor tissue and cell line blocks were sectioned, and then stained using mFIHC followed by isolation of nucleic acids, or direct isolation of total nucleic acids. NanoString, qPCR, and NGS were performed on isolated nucleic acids. Nucleic acid quality, transcript abundance, and TMB scores were compared before and after mFIHC staining.Results mFIHC revealed a broad range of immune cell phenotypes and spatial interactions, including T cells, B cells, NK cells, monocytes, neutrophils, and their functional status. Isolation of testable quantities of DNA from mFIHC treated slides was achieved when using a DNA-only isolation method, and TMB scores were robust across tested conditions. Cell phenotypes identified by mFIHC were compared to TMB scores across the tested samples. Following mFIHC treatment, RNA yields were reduced relative to the non-mFIHC treated replicates, but still sufficient for optimal input into a 770-target NanoString gene expression panel. However, for mFIHC treated samples, transcript levels were not distinguishable from background for the assessed targets.ConclusionsIn summary, integrating mFIHC testing and TMB analysis on the same samples allows for comprehensive biomarker evaluation. The real world benefits of the combined approach will be described in upcoming clinical trials.ReferenceLu, et al., Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade, a systematic review and meta-analysis. JAMA Oncology 2019; 5(8):1195–1204

scholarly journals Systemic inflammation in COPD in relation to smoking status

2019 ◽  
Vol 6 ◽  
Author(s):  
Danielius Serapinas ◽  
Andrius Narbekovas ◽  
Jonas Juskevicius ◽  
Raimundas Sakalauskas
Keyword(s):  
Tumor Necrosis Factor ◽  
Systemic Inflammation ◽  
Tumor Necrosis ◽  
Smoking Status ◽  
Tumor Necrosis Factor Receptor ◽  
Chronic Obstructive ◽  
Copd Patients ◽  
Never Smokers ◽  
The Impact ◽  
Necrosis Factor

Background and aims: Smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) that has been recently defined as a systemic pul- monary inflammatory disease. However, the impact of smok- ing itself on systemic inflammation in COPD patients has not yet been well established. The aim of our study was to inves- tigate the association between inflammatory markers and smoking status. Material and methods: We compared 202 current smokers, 61 ex-smokers and 57 never-smokers, all COPD patients. Assessments included medical history, spirometry, alpha-1 antitrypsin (AAT) genotyping, serum AAT, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and soluble tumor necrosis factor receptor (sTNFR)-1 and sTNFR-2 concentra- tions. Results: AAT and CRP concentrations in smokers (1.75 ± 0.51 g/L and 14.4 [9.5–20.5] mg/L) and ex-smokers (1.69 ± 0.43 g/L and 12.3 [8.7–16.3] mg/L) were higher than in never-smokers (1.49 ± 0.38 g/L and 5.1 [2.5–8.7] mg/L; p < 0.05). sTNFR-1 level was higher in smokers than ex-smokers or never-smok- ers (241.2 pg/mL [145.3–349.4] vs. 213.7 pg/mL [147.1– 280.3] and 205.2 pg/mL [125–275]; p < 0.05). Conclusions: Our data confirm that smoking is associated with increased levels of AAT, CRP, and sTNFR-1 in COPD patients, an array of systemic inflammation markers that continue to be active even after smoking cessation.

Current smoking negatively affects the response to methotrexate in RA in a dose-responsive way, independently of concomitant prednisone use

2021 ◽  
pp. jrheum.200213
Author(s):  
Mary Safy-Khan ◽  
Maria J.H. de Hair ◽  
Paco M.J. Welsing ◽  
Jacob M. van Laar ◽  
Johannes W.G. Jacobs
Keyword(s):  
Clinical Response ◽  
Disease Activity Score ◽  
Smoking Status ◽  
Current Smoking Status ◽  
Current Smoking ◽  
Negative Effect ◽  
Mixed Modelling ◽  
The Impact ◽  
Dose Dependent ◽  
Relevant Covariates

Objective Current smoking reduces clinical response to several disease-modifying antirheumatic drugs (DMARDs). It is unknown if this is also the case for prednisone. We aimed to determine whether current smoking affects the clinical response to concomitant prednisone in a methotrexate (MTX)-based treatment strategy. Methods In the CAMERA-II trial, early rheumatoid arthritis (RA) patients initiated an MTX-based strategy and were randomized to concomitant prednisone (MTX+pred) or placebo (MTX+plac) for 24 months. Linear mixed modelling was performed with disease activity score assessing 28 joints (DAS28) as dependent variable and strategy group and current smoking status as independent variables, correcting for relevant covariates. The interaction between current smoking and strategy was tested to find out whether the impact of current smoking on clinical response was different between the strategy groups with prednisone or placebo. Results Current smoking was significantly associated with higher DAS28 over time (mean difference with non-smokers 0.57 (95% confidence interval 0.22 to 0.92), p<0.01). This association was not different between the strategy groups with prednisone or placebo (p=0.73). This negative effect of current smoking on DAS28 was dose dependent. Conclusion Current smoking in early RA patients significantly reduces the clinical effect of an MTX-based strategy, independent of whether concomitant prednisone is used or not. This effect is dose dependent.

scholarly journals Phagocytosis and activation of bone marrow‐derived macrophages by Plasmodium falciparum gametocytes

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yolanda Corbett ◽  
Silvia Parapini ◽  
Federica Perego ◽  
Valeria Messina ◽  
Serena Delbue ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Plasmodium Falciparum ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Murine Bone Marrow ◽  
Inflammatory Protein ◽  
Life Cycle Stages ◽  
Cytokine Levels ◽  
Necrosis Factor

Abstract Background The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. Methods Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. Results The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. Conclusions These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.

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