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Antirheumatic treatment is associated with reduced serum Syndecan-1 in Rheumatoid Arthritis.
Deyab, G, Reine, TM, Vuong, TT, Jenssen, T, Hjeltnes, G, Agewall, S, Mikkelsen, K, Førre, Ø, Fagerland, MW, Kolset, SO, et al
PloS one. 2021;(7):e0253247
Abstract
The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.
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Similar lipid level changes in early rheumatoid arthritis patients following 1-year treat-to-target strategy with adalimumab plus methotrexate versus placebo plus methotrexate: secondary analyses from the randomised controlled OPERA trial.
Mašić, D, Stengaard-Pedersen, K, Løgstrup, BB, Hørslev-Petersen, K, Hetland, ML, Junker, P, Østergaard, M, Ammitzbøll, C, Möller, S, Christensen, R, et al
Rheumatology international. 2021;(3):543-549
Abstract
To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI - 0.05 to 0.42], total cholesterol 0.27 mmol/l [- 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [- 0.06 to 0.15], triglycerides 0.11 mmol/l [- 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [- 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [- 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.
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Cardiovascular Safety of Tocilizumab Versus Etanercept in Rheumatoid Arthritis: A Randomized Controlled Trial.
Giles, JT, Sattar, N, Gabriel, S, Ridker, PM, Gay, S, Warne, C, Musselman, D, Brockwell, L, Shittu, E, Klearman, M, et al
Arthritis & rheumatology (Hoboken, N.J.). 2020;(1):31-40
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Abstract
OBJECTIVE To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept. METHODS This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open-label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group. RESULTS By week 4 of treatment, the serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow-up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77-1.43). Results were similar in sensitivity analyses and in the on-treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation. CONCLUSION The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non-CV safety of tocilizumab.
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Comprehensive exploratory autoantibody profiling in patients with early rheumatoid arthritis treated with methotrexate or tocilizumab.
Teitsma, XM, Devenport, J, Jacobs, JWG, Pethö-Schramm, A, Borm, MEA, Budde, P, Bijlsma, JWJ, Lafeber, FPJG
PloS one. 2020;(12):e0241189
Abstract
BACKGROUND We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. MATERIALS AND METHODS In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. RESULTS Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens-DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)-and in the tocilizumab arm against one antigen-neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm-G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor-positive versus-negative or anti-cyclic citrullinated test-positive versus test-negative rheumatoid arthritis (p ≥ 0.06). CONCLUSIONS Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare.
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Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial.
Fleischmann, R, Pangan, AL, Song, IH, Mysler, E, Bessette, L, Peterfy, C, Durez, P, Ostor, AJ, Li, Y, Zhou, Y, et al
Arthritis & rheumatology (Hoboken, N.J.). 2019;(11):1788-1800
Abstract
OBJECTIVE To evaluate the efficacy, including capacity for inhibition of radiographic progression, and safety of upadacitinib, a JAK1-selective inhibitor, as compared to placebo or adalimumab in patients with rheumatoid arthritis (RA) who have experienced an inadequate response to methotrexate (MTX). METHODS In total, 1,629 RA patients with an inadequate response to MTX were randomized (2:2:1) to receive upadacitinib (15 mg once daily), placebo, or adalimumab (40 mg every other week) while continuing to take a stable background dose of MTX. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) of <2.6 in the upadacitinib group compared to the placebo group at week 12; inhibition of radiographic progression was evaluated at week 26. The study was also designed and powered to test for the noninferiority and superiority of upadacitinib compared to adalimumab, as measured both clinically and functionally. RESULTS At week 12, both primary end points were met in patients receiving upadacitinib compared to those receiving placebo (P ≤ 0.001). An ACR20 improvement response was achieved by 71% of patients in the upadacitinib group compared to 36% in the placebo group, and a DAS28-CRP score of <2.6 was observed in 29% of patients receiving upadacitinib compared to 6% of patients receiving placebo. Upadacitinib was superior to adalimumab based on the ACR50 response rate, achievement of a DAS28-CRP score of ≤3.2, change in pain severity score, and change in the Health Assessment Questionnaire disability index. At week 26, more patients receiving upadacitinib than those receiving placebo or adalimumab achieved low disease activity or remission (P ≤ 0.001). Radiographic progression was significantly inhibited in patients receiving upadacitinib and was observed in fewer upadacitinib-treated patients than placebo-treated patients (P ≤ 0.001). Up to week 26, adverse events (AEs), including serious infections, were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with creatine phosphokinase (CPK) elevations were highest in the upadacitinib group. Three malignancies, 5 major adverse cardiovascular events, and 4 deaths were reported among the groups, but none occurred in patients receiving upadacitinib. Six venous thromboembolic events were reported (1 in the placebo group, 2 in the upadacitinib group, and 3 in the adalimumab group). CONCLUSION Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms, and physical function in RA patients who were receiving background MTX. In addition, radiographic progression was significantly inhibited by upadacitinib as compared to placebo. The overall safety profile of upadacitinib was generally similar to that of adalimumab, except for higher rates of herpes zoster and CPK elevations in patients receiving upadacitinib.
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Effect of cream, prepared with Tripterygium wilfordii Hook F and other four medicinals, on joint pain and swelling in patients with rheumatoid arthritis: a double-blinded, randomized, placebo controlled clinical trial.
Jiao, J, Tang, X, Gong, X, Yin, H, Jiang, Q, Wei, C
Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan. 2019;(1):89-96
Abstract
OBJECTIVE To investigate the effectiveness a cream onjoint pain and swelling in patients with rheumatoid arthritis (RA). The cream, topically used, in was prepared with Tripterygium wilfordii Hook F (TwHF), Mangxiao (Nalrii Sulfas), Chuanxiong (Rhizoma Chuanxiong), stir-frying with liquid adjuvant Ruxiang (Olibanum), and stir-frying with liquid adjuvant Moyao (Myrrh). METHODS Patients were 1∶1 randomized to add-on TwHF cream twice a day or placebo for 4 weeks. The primary endpoint was achievement rate of 20% improvement in American College of Rheumatology criteria (ACR20) at week 4. Secondary endpoints were ACR50, 28-joint count Disease Activity Score (DAS28) improvement and safety profiles. Statistical analyses were performed using intention to treat analysis (ITT) set. RESULTS A total of 70 active RA patients were enrolled. At week 4, the ACR20 was 34.3% (12/35) in TwHF cream group and 11.4% (4/35) in placebo group (P = 0.015). Similarly, a higher ACR50 responder proportion was seen in TwHF cream group with 17.1% (6/35) comparing to it in placebo group with 2.9% (1/35) (P = 0.046). The TwHF cream group also had more improvement than the placebo group on DAS28-ESR (1.1 vs 0.5, P = 0.001), DAS28- CRP (1.4 vs 0.7, P = 0.001), tender joint count (5.5 vs 2.6, P = 0.018), swollen joint count (3.5 vs 1.6, P = 0.003) and Physician's global assessment (25.8 vs 13.0, P = 0.002), as well as C-reactive protein (11.2 vs 2.7, P = 0.048). Except 2 skin allergy events in TwHF cream group, no other substantive adverse events were observed. CONCLUSION On the short term, TwHF cream is likely to be an effective and safety complimentary treatment in patients with active RA.
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Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology.
Teitsma, XM, Yang, W, Jacobs, JWG, Pethö-Schramm, A, Borm, MEA, Harms, AC, Hankemeier, T, van Laar, JM, Bijlsma, JWJ, Lafeber, FPJG
Arthritis research & therapy. 2018;(1):230
Abstract
BACKGROUND We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA. METHODS Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites. RESULTS In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was "histidine metabolism" (p < 0.001); in the tocilizumab strategy it was "arachidonic acid metabolism" (p = 0.018); and in the methotrexate strategy it was "arginine and proline metabolism" (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate. CONCLUSION In early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated. TRIAL REGISTRATION ClinicalTrials.gov, NCT01034137 . Registered on January 2010.
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Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the AMPLE trial of patients with rheumatoid arthritis.
Charles-Schoeman, C, Gugiu, GB, Ge, H, Shahbazian, A, Lee, YY, Wang, X, Furst, DE, Ranganath, VK, Maldonado, M, Lee, T, et al
Atherosclerosis. 2018;:107-114
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Abstract
BACKGROUND AND AIMS To evaluate changes in the high-density lipoprotein (HDL) proteome and HDL function in active rheumatoid arthritis (RA) patients initiating therapy with abatacept or adalimumab in the Abatacept Versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) study. METHODS Ultra high-pressure liquid chromatography (UHPLC) coupled with ion mobility mass spectrometry (LC-IM-MS) was used to analyze proteins associated with immunoaffinity-captured HDL from plasma of 30 patients with RA randomized to either abatacept (n = 15) or adalimumab (n = 15) therapy. Paraoxonase 1 (PON1) activity, HDL anti-oxidant capacity, cholesterol profiles, and homocysteine levels were also measured at baseline and following treatment. Repeated-measures analyses were performed using mixed-effect linear models to model the within-subject covariance over time. RESULTS In models controlling for age, sex and treatment group, improvement in inflammation measured by decreases in CRP was associated with improvement in HDL function and changes in several HDL-associated proteins including significant decreases in lipopolysaccharide-binding protein, serum amyloid A-I (SAA-I) and inter-alpha-trypsin inhibitor heavy chain H4 (p values < 0.05). Improvement in disease activity was also associated with changes in multiple HDL-associated proteins. Adalimumab was associated with higher PON1 activity, HDL-associated serotransferrin, and HDL-associated immunoglobulin J chain, and lower HDL-associated SAA-I over time compared with abatacept. CONCLUSIONS Improvement in inflammation associated with treatment of RA, using either abatacept or adalimumab in the AMPLE study, was associated with improvement in HDL function and significant alterations in the HDL proteome, including proteins involved in the immune response, proteinase inhibition, and lipid metabolism.
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Baicalin reduces blood lipids and inflammation in patients with coronary artery disease and rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial.
Hang, Y, Qin, X, Ren, T, Cao, J
Lipids in health and disease. 2018;(1):146
Abstract
BACKGROUND Patients with rheumatoid arthritis (RA) have an increased risk of coronary artery disease (CAD) above the baseline. Baicalin possesses beneficial effects against both RA and CAD, but little is know on its clincial efficacy among patients manifesting both CAD and RA. METHODS Three hundred seventy four patients with CAD and RA were randomized to receive either 500 mg baicalin or placebo orally everyday for 12 weeks. Lipid profile, cardiotrophin-1 (CT-1), high sensitivity C-reactive protein (hs-CRP), European League Against Rheumatism (EULAR) response were analyzed at the end of study period. RESULTS After 12 week treatment, levels of triglycerides, total cholesterol, LDL-cholesterol and apolipoproteins, as well as CT-1 and hs-CRP, were all significantly improved in the baicalin group compared to the placebo group (1.12 ± 0.36 vs 1.87 ± 0.46 mmol/L, 2.87 ± 1.23 vs 3.22 ± 1.07 mmol/L, 1.38 ± 0.41 vs 1.16 ± 0.32 mmol/L, 1.31 ± 0.41 vs 1.23 ± 0.29 g/L, 42.9 ± 13.7 vs 128.4 ± 24.3 ng/mL, 1.64 ± 0.38 vs 3.9 ± 1.4 mg/dL, respectively). Significantly higher proportion of patients in the baicalin group (71%) reported good/moderate EULAR response than the placebo group (53%). CONCLUSION Baicalin reduces blood lipids and inflammation in patients with both CAD and RA, supporting its further clinical application.
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Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial.
Colombel, JF, Panaccione, R, Bossuyt, P, Lukas, M, Baert, F, Vaňásek, T, Danalioglu, A, Novacek, G, Armuzzi, A, Hébuterne, X, et al
Lancet (London, England). 2017;(10114):2779-2789
Abstract
BACKGROUND Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. METHODS CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. FINDINGS Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. INTERPRETATION CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. FUNDING AbbVie.