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- Dijkshoorn, B, et al.
(författare)
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PROFOUND ANTICOAGULANT EFFECTS OF INITIAL ANTIRHEUMATIC TREATMENTS IN EARLY RHEUMATOID ARTHRITIS PATIENTS: A NORD-STAR SPIN-OFF STUDY
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 40-41
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Patients with rheumatoid arthritis (RA) are at an increased risk of venous thromboembolism. Thus far, there have not been any comparative studies investigating the effects of initial antirheumatic treatments in (very) early RA patients.ObjectivesTo assess the effects of different initial treatments on hemostatic parameters in patients with early RA.MethodsNORD-STAR is an international, multicentre, open-label, assessor-blinded, phase 4 study where patients with newly diagnosed RA started methotrexate (MTX) and were randomised 1:1:1:1 to a) conventional treatment (either prednisolone tapered to 5mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), b) certolizumab pegol, c) abatacept, d) tocilizumab1. This study is a spin-off from the main NORD-STAR study extensively investigating hemostatic system in 24 per protocol consecutive Dutch participants at baseline, 12 weeks and 24 weeks after the start of the treatment. Statistical analysis was done using paired samples t-test in SPSS version 28.ResultsThe mean age of investigated patients was 51.8 (± 12.7) years and 58.3% were female. At baseline patients had an average DAS28 score of 4.6 (± 0.9) and had elevated levels of investigated coagulation biomarkers: Factor 1 + 2, fibrinogen, D-dimer and parameters of the two global hemostatic assays, i.e. endogenous thrombin potential (ETP) and overall hemostasis potential (OHP). These biomarkers decreased significantly at 12 and 24 weeks in patients in all groups (Table 1). Overall fibrinolytic potential (OFP) was decreased and clot lysis time (CLT) was prolonged at baseline, demonstrating impaired fibrinolytic activity in early RA. The reduction of coagulation parameters was significantly higher in biological treatment arms in comparison to the standard MTX treatment arm. In addition, tocilizumab was more effective compared to certolizumab and abatacept, (Figure 1), which was expected considering the direct inhibitory effect of this drug on the IL-6 synthesis and consequently the coagulation activation as well. After 24 weeks of treatment with methotrexate and tocilizumab, the average fibrinogen of patients was reduced by 63% vs 31% and 36% in the certolizumab and abatacept groups, respectively. The changes in DAS-28 and the changes in fibrinogen had a correlation of 0.385 which did not reach statistical significance.Table 1.Measurements are marked with * if p<0.05, ** if p<0.01 and *** if p<0.001BaselineW12W24Factor 1 + 2 (pmol/L)270.25 (149.4)190.36 (108.6)**179.52 (85.3)***Fibrinogen (g/L)4.64 (1.5)3.61 (1.6)**2.63 (1.2)***D-dimer (mg/L)2.17 (3.0)0.33 (0.23)**0.29 (0.2)**OHP (Abs-sum)157.38 (64.9)120.62 (68.7)*100.49 (53.8)***OCP (Abs-sum)369.52 (58.8)305.04 (101.7)*275.91 (83.1)***OFP (%)57.97 (13.1)63.20 (12.7)*65.25 (11.4)***Lag time (s)304.5 (71.1)306.8 (71.8)312.7 (65.4)Slope0.07 (0.02)0.066 (0.03)0.094 (0.12)Max Abs1.17 (0.3)1.00 (0.4)*0.91 (0.3)**CLT (s)1405 (356)1317 (377)1231 (320)**ETP (nM*min)1480 (471)1395 (395)*1337 (429)*Peak (nM)231 (78)223 (68)223 (74)Lagtime (min)4.06 (2.1)3.28 (1.2)**2.87 (1.0)***ttPeak (min)7.40 (2.2)6.61 (1.5)*6.13 (1.4)**Figure 1.ConclusionOur results indicate an enhanced coagulation and fibrinolytic impairment in newly diagnosed RA patients. Effective antirheumatic treatments reduce this hemostatic imbalance, with significantly more pronounced effects of biologic drugs compared to conventional (MTX+glucocorticoids) treatment.References[1]Hetland M et al. BMJ. 2020Disclosure of InterestsBas Dijkshoorn: None declared, Aleksandra Antovic: None declared, Daisy Vedder: None declared, Anna Rudin: None declared, Dan Nordström Speakers bureau: Novartis, UCB, Consultant of: Abbvie, BMS, Lilly, Novartis, Pfizer, Roche, UCB, Björn Gudbjornsson Speakers bureau: Amgen and Novartis - not related to this work, Consultant of: Novartis - not related to this work, Kristina Lend: None declared, Till Uhlig Speakers bureau: Grünenthal, Novartis, Consultant of: Grünenthal, Novartis, Grant/research support from: NORDFORSK, Espen A Haavardsholm Consultant of: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly, UCB, Grant/research support from: NORDFORSK, Norwegian Regional Health Authorities, South-Eastern Norway Regional Health Authority, Gerdur Gröndal: None declared, Merete Lund Hetland Consultant of: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Grant/research support from: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Marte Heiberg: None declared, Mikkel Østergaard Speakers bureau: Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Orion, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB, Grant/research support from: Abbvie, Amgen, BMS, Merck, Celgene and Novartis, Kim Hørslev-Petersen: None declared, Jon Lampa Speakers bureau: Pfizer, Janssen, Novartis, Ronald van Vollenhoven Speakers bureau: Abbvie, Galapagos, GSK, Janssen, Pfizer, R-Pharma, UCB, Consultant of: Abbvie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pifzer, UCB, Grant/research support from: BMS, GSK, UCB, Michael Nurmohamed Speakers bureau: Abbvie, Janssen, Celgene, Consultant of: Abbvie, Grant/research support from: Abbvie, Amgen, Pfizer, Galapagos, BMS.
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| 7. |
- Heinicke, F, et al.
(författare)
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MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients
- 2021
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 663736-
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.
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- Smolen, JS, et al.
(författare)
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EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update
- 2023
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 82:1, s. 3-18
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Tidskriftsartikel (refereegranskat)abstract
- To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field.MethodsAn international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item.ResultsThe task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3–6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations.ConclusionsThese updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.
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| 12. |
- Stevens, D, et al.
(författare)
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PLASMA CALPROTECTIN WAS ASSESSED IN MULTIPLE BIOLOGICAL TREATMENT STRATEGIES FOR EARLY RHEUMATOID ARTHRITIS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 515-515
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Plasma calprotectin is a sensitive inflammatory marker in patients with rheumatoid arthritis (RA) and reflects activation of granulocytes and macrophages. Plasma calprotectin has not previously been studied in a head-to-head trial of multiple biological mechanisms of action versus active conventional therapy (ACT) with methotrexate and prednisolone.ObjectivesTo assess the effect of treatment on plasma calprotectin levels in patients with early RA by determining the 24-week change in the four arms of the NORD-STAR Study, a large multicenter randomized head-to-head clinical trial of ACT versus tumor necrosis factor inhibition, T-cell co-stimulation inhibition, and interleukin-6 inhibition (1).MethodsCalprotectin was analyzed in plasma samples at baseline, week 4 and week 24 from 400 treatment naïve patients with early RA in the NORD-STAR Study. Samples were analyzed using a calprotectin ELISA alkaline phosphatase (ALP) kit from CalproLab (Oslo, Norway) in a Dynex DS2 processing system (normal levels <910 µg/L). Patients were assessed by clinical (CRP, 28 SJC/TJC, physician global) and patients’ reported assessments. Crude and adjusted linear regression analyses were performed in R 4.0.3 with calprotectin levels at week 24 as the outcome. The four arms were represented by three dummy variables. The adjustment variables were age, sex, anti-CCP status and country. Both analyses were adjusted for baseline calprotectin levels.ResultsAt baseline, the mean time since diagnosis was 15.7 days (SD) (22.9), mean age 53.7 (15.0) years, ACPA positive 81%, and female 66%. Mean calprotectin levels were 1931 (1495) µg/L at baseline, 866 (951) µg/L at week 4, and 629 (661) µg/L at week 24. At baseline, normal calprotectin levels (<910 µg/L) were observed in 27% of all patients (ACT 22%, certolizumab-pegol and methotrexate 30%, abatacept and methotrexate 25%, tocilizumab and methotrexate 31%). At week 24, normal calprotectin levels were observed in 82% of all patients (ACT 68%, certolizumab-pegol and methotrexate 91%, abatacept and methotrexate 80%, tocilizumab and methotrexate 90%).Observed calprotectin levels at week 24 were significantly lower in patients treated with certolizumab-pegol and methotrexate -336µg/L (97) (p< 0.006) or tocilizumab and methotrexate -284 (99) (p < 0.004), versus ACT when adjusted for age, sex, anti-CCP status, baseline calprotectin level, and country; however, a significant difference was not observed in patients treated with abatacept and methotrexate -110 (96) (p = 0.25). The Figure 1 shows the average percentage change in calprotectin levels from baseline to week 24 for all treatment groups.Figure 1.Average percentage change in calprotectin levels from baseline to week 24. ACT: active conventional therapy, CZP+MTX: certolizumab-pegol and methotrexate, ABA+MTX: abatacept and methotrexate, TCZ+MTX: tocilizumab and methotrexate.ConclusionCalprotectin, a sensitive biomarker of inflammation, normalized in the majority of patients. The decline differed between treatment groups and was largest in patients treated with a TNF inhibitor and methotrexate, suggesting that calprotectin reflects the activity of specific inflammatory pathways rather than overall inflammation. The findings of this study should be further explored.References[1]Hetland ML, et. al., Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial. BMJ. 2020 Dec 2;371:m4328. doi: 10.1136/bmj.m4328. PMID: 33268527; PMCID: PMC7708829.AcknowledgementsI would like to acknowledge the NORD-STAR Study group.Disclosure of InterestsDavid Stevens: None declared, Marte Heiberg: None declared, Amirhossein Kazemi: None declared, Ronald van Vollenhoven: None declared, Jon Lampa: None declared, Anna Rudin: None declared, Kristina Lend: None declared, Merete Lund Hetland: None declared, Mikkel Østergaard: None declared, Michael Nurmohamed: None declared, Kim Hørslev-Petersen: None declared, Dan Nordström Consultant of: Abbvie, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB, Björn Gudbjornsson: None declared, Till Uhlig: None declared, Espen A Haavardsholm: None declared, Hilde Berner Hammer Speakers bureau: AbbVie, Novartis, and Lilly.
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