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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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Folinic acid alleviates side effects of methotrexate in arthritis patients with side effects despite folic acid supplementation: an observational cohort study.
Fischer, EA, Hetland, ML, Krabbe, S
Rheumatology (Oxford, England). 2020;(11):3566-3568
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Gender Is a Risk Factor for Annual Decline in Estimated Glomerular Filtration Rate in Patients Treated with Biological DMARDs in Rheumatoid Arthritis and Ankylosing Spondylitis: a Retrospective Observational Study.
Kim, SK, Choe, JY
Journal of Korean medical science. 2018;(30):e188
Abstract
BACKGROUND This study identified the risk factors of changes in renal function in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) treated with biological disease-modifying anti-rheumatic drugs (bDMARDs). METHODS We retrospectively enrolled patients with RA (n = 293) and AS (n = 125) treated with bDMARDs. The estimated glomerular filter rate (eGFR) using the Modification of Diet in Renal Disease equation was applied for assessment of annual changes in renal function between initiation and last visit after bDMARD therapy. The annual change in eGFR was used as an indicator for change in renal function. Statistical significance was assessed by Mann-Whitney test, Spearman's correlation coefficient, and multivariate linear regression analysis. RESULTS The positive annual change in eGFR in women was significantly noted, compared to that in men (P = 0.004). The annual change in eGFR was different between men and women (P = 0.038) in RA, but not in AS patients (P = 0.126). In multivariate linear regression analysis, women patients and increased serum creatinine at baseline were closely associated with positive annual change in eGFR in both RA and AS patients. In RA patients, younger age and lower ESR level were considered risk factors of positive annual change in eGFR (P = 0.013 and P = 0.022, respectively). However, disease duration and duration of bDMARD use were not associated with annual change in eGFR. CONCLUSION This study found that gender, especially men, might be responsible for annual decline in eGFR in RA and AS patients treated with bDMARDs.
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Fatigue independently predicts different work disability dimensions in etanercept-treated rheumatoid arthritis and ankylosing spondylitis patients.
Druce, KL, Aikman, L, Dilleen, M, Burden, A, Szczypa, P, Basu, N
Arthritis research & therapy. 2018;(1):96
Abstract
BACKGROUND Work disability remains a significant problem in ankylosing spondylitis (AS) and rheumatoid arthritis (RA), despite biological therapy. This study aimed to test the hypothesis that the prevalent symptom of fatigue longitudinally predicts work disability among RA and AS patients commencing etanercept. METHODS Two observational studies, comprising RA and AS etanercept commencers, respectively, were analysed. Both provided data on work disability over 1 year and a comprehensive set of putative predictors, including fatigue. A series of repeated measures models were conducted, including baseline variables, visit (6/12 months), and the interaction between visit and each of the explanatory variables. RESULTS A total of 1003 AS and 1747 RA patients were assessed. For AS, fatigue was significantly associated with presenteeism (linear mixed model coefficient 3.75, 95% confidence interval (CI) 2.14 to 5.36) and activity impairment (2.62, 1.26 to 3.98), but not with work productivity loss (1.81, -0.40 to 4.02) or absenteeism (generalised linear mixed model odds ratio (OR) 1.18, 95% CI 0.92 to 1.51). In RA, fatigue was associated with presenteeism (coefficient 3.44, 95% CI 2.17 to 4.70), activity impairment (1.52, 0.79 to 2.26), work productivity loss (4.16, 2.47 to 5.85), and absenteeism (OR 1.23, 95% CI 1.02 to 1.49). The lack of significant interactions between fatigue and visit supported a consistent effect of baseline fatigue over time. CONCLUSIONS Among patients beginning etanercept therapy, fatigue has a significant and independent effect on absenteeism, presenteeism, productivity loss, and activity impairment for RA patients and a significant but dimension-selective effect on work disability among AS patients. TRIAL REGISTRATION ClinicalTrials.gov, NCT00544557 . Registered on 16 October 2007. ClinicalTrials.gov, NCT00488475 . Registered on 20 June 2006.
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4β-Hydroxycholesterol Level in Patients With Rheumatoid Arthritis Before vs. After Initiation of bDMARDs and Correlation With Inflammatory State.
Wollmann, BM, Syversen, SW, Lie, E, Gjestad, C, Mehus, LL, Olsen, IC, Molden, E
Clinical and translational science. 2017;(1):42-49
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Abstract
Systemic inflammation has been linked to suppressed CYP3A(4) activity. We determined 4β-hydroxycholesterol (4βOHC), an endogenous CYP3A4 metabolite, in patients with rheumatoid arthritis (RA) before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs). The 4βOHC was compared in 41 patients before and 2-5 months after initiating TNFα inhibitors (n = 31), IL-6 inhibitors (n = 5), or B-cell inhibitors (n = 5). Correlations between 4βOHC and inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) were also tested before and after bDMARDs. 4βOHC did not differ following bDMARD treatment (P = 0.6), nor in patients who started with IL-6 inhibitors (median 51.6 vs. 50.6 nmol/L). The 4βOHC and CRP/ESR did not correlate before treatment (P > 0.5), but correlated significantly after bDMARDs (CRP = Spearman r -0.40; P < 0.01; ESR = r -0.34; P = 0.028) suggesting that mainly non-CYP3A4-suppressive cytokines were reduced during treatment. Thus, this study does not support a generally regained CYP3A4 phenotype in patients with RA following initiation of bDMARDs.
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The role of circulating miR-146a in patients with rheumatoid arthritis treated by Tripterygium wilfordii Hook F.
Chen, ZZ, Zhang, XD, Chen, Y, Wu, YB
Medicine. 2017;(20):e6775
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Abstract
Rheumatoid arthritis (RA) is polygenic autoimmune disease with unclear etiology. MicroRNAs (miRNAs) play a critical role in the pathogenesis of RA. The objective of this study was to evaluate the role of miR-146a in patients with RA receiving Tripterygium wilfordii Hook F (TwHF) treatment.In total, 69 patients with RA and 69 healthy controls (HC) were included in the study, and patients with RA received TwHF treatment for 24 weeks. Blood samples were collected from RA patients and HC, and peripheral blood mononuclear cells (PBMCs) were isolated. Expression of miR-146a was analyzed in RA patients (baseline, 12 weeks and 24 weeks) and HC.Circulating miR-146a expression was markedly increased in patients with RA compared with healthy controls (P < .001), ROC analysis of miR-146a for diagnosis for RA showed that the AUC was 0.908 (95% CI: 0.862-0.955) with a sensitivity of 87.0% and a specificity of 82.6% at best cutoff. And miR-146a expression was positively associated with the DAS28 score and CRP level (P = .002 and P = .019). Moreover, miR-146a expression was markedly reduced after TwHF therapy (P < .001), and baseline miR-146a level was observed to present an increased tendency in responders compared with non-responders at 24 weeks (P = .066).Our study presented that circulating miR-146a level was correlated with risk and disease activity of RA patients by TwHF treatment, which could strikingly decrease expression of miR-146a in RA patients, and miR-146a may have a value in predicting clinical response of TwHF treatment. It indicates that circulating miR-146a plays a prominent role in RA patients treated by TwHF.
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The Effects of 5-year Etanercept Therapy on Cardiovascular Risk Factors in Patients with Psoriatic Arthritis.
Agca, R, Heslinga, M, Kneepkens, EL, van Dongen, C, Nurmohamed, MT
The Journal of rheumatology. 2017;(9):1362-1368
Abstract
OBJECTIVE To investigate the effects of etanercept (ETN) on lipid metabolism and other known cardiovascular disease (CVD) risk factors in patients with psoriatic arthritis (PsA). METHODS In an observational cohort of 118 consecutive patients with PsA, CVD risk factors were assessed over 5 years. Mixed-model analyses were performed to investigate the effects of ETN therapy on CVD risk factors over time. RESULTS Disease Activity Score in 28 joints, C-reactive protein (CRP), and erythrocyte sedimentation rate decreased during therapy with ETN. There was an increase in total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol. The TC/HDLc ratio remained unaltered. The apolipoprotein B to apolipoprotein A-I (apoB/apoA-I) ratio decreased significantly. An increase in CRP was associated with an increase in the apoB/apoA-1 ratio. CONCLUSION Serum lipid concentrations showed small changes over a 5-year period of ETN therapy and were inversely associated with inflammatory markers. Other CVD risk factors remained stable. The apoB/apoA-1 ratio decreased over time and an increase in disease activity was associated with an increase in this ratio. However, this modest lipid modulation cannot explain the observed beneficial CV effects of ETN, and ETN likely exerts those effects through inflammation-related mechanisms.
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Real-world experiences of folic acid supplementation (5 versus 30 mg/week) with methotrexate in rheumatoid arthritis patients: a comparison study.
Koh, KT, Teh, CL, Cheah, CK, Ling, GR, Yong, MC, Hong, HC, Gun, SC
Reumatismo. 2016;(2):90-6
Abstract
The objective of this study was to compare the tolerability of methotrexate in two different regimes of folic acid (FA) supplementation in rheumatoid arthritis (RA). We performed a multicenter, cross-sectional observational cohort study on 240 RA patients with 120 patients each in 5 mg of FA weekly and 30 mg of FA weekly supplementation. There were no significant differences for side effects (14.2 versus 22.5%, P=0.523) and discontinuation of methotrexate (3.6 versus 13.3%, P=0.085). RA patients given 5 mg of FA weekly supplementation had a lower disease activity score 28 compared to 30 mg of FA weekly supplementation [3.44 (1.10) versus 3.85 (1.40), P=0.014]. FA supplementation of 5 mg per week and 30 mg per week was associated with similar tolerability of methotrexate in RA patients.
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Disease-modifying antirheumatic drug use and the risk of incident hyperlipidemia in patients with early rheumatoid arthritis: a retrospective cohort study.
Desai, RJ, Eddings, W, Liao, KP, Solomon, DH, Kim, SC
Arthritis care & research. 2015;(4):457-66
Abstract
OBJECTIVE To compare the risk of incident hyperlipidemia in early rheumatoid arthritis (RA) patients after initiation of various disease-modifying antirheumatic drugs (DMARDs). METHODS We conducted a cohort study using insurance claims data (2001-2012) in early RA patients. Early RA was defined by the absence of any RA diagnosis or DMARD prescriptions for 12 months. Four mutually exclusive groups were defined based on DMARD initiation: tumor necrosis factor α (TNFα) inhibitors ± nonbiologic (nb) DMARDs, methotrexate (MTX) ± nonhydroxycholorquine nbDMARDs, hydroxychloroquine ± non-MTX nbDMARDs, and other nbDMARDs only. The primary outcome was incident hyperlipidemia, defined by a diagnosis and a prescription for a lipid-lowering agent. For the subgroup of patients with laboratory results available, change in lipid levels was assessed. Multivariable Cox proportional hazard models and propensity score (PS) decile stratification with asymmetric trimming were used to control for confounding. RESULTS Of the 17,145 early RA patients included in the study, 364 developed incident hyperlipidemia. The adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) for hyperlipidemia were 1.41 (95% CI 0.99, 2.00) for TNFα inhibitors, 0.81 (95% CI 0.63, 1.04) for hydroxychloroquine, and 1.33 (95% CI 0.95, 1.84) for other nbDMARDs compared with MTX in the full cohort, while HRs for the PS trimmed cohort were 1.18 (95% CI 0.80, 1.73), 0.75 (95% CI 0.58, 0.98), and 1.41 (95% CI 1.01, 1.98), respectively. In the subgroup analysis, hydroxychloroquine use showed significant reduction in low-density lipoprotein (-8.9 mg/dl, 95% CI -15.8, -2.0), total cholesterol (-12.3 mg/dl, 95% CI -19.8, -4.8) and triglyceride levels (-19.5 mg/dl, 95% CI -38.7, -0.3) from baseline compared with MTX. CONCLUSION Use of hydroxychloroquine may be associated with a lower risk of hyperlipidemia among early RA patients.
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Outcome of rheumatoid arthritis following adjunct statin therapy.
Das, S, Mohanty, M, Padhan, P
Indian journal of pharmacology. 2015;(6):605-9
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Abstract
OBJECTIVE Rheumatoid arthritis (RA) is characterized by symmetric peripheral polyarthritis, inflammatory synovitis, and articular destruction. Statins, 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors, mediate significant vascular risk reduction in patients with coronary artery disease by promoting reduction in plasma levels of low-density-lipoprotein cholesterol. Extensive in vitro data, experimental studies and more recently few clinical trials have strongly suggested statins to possess an important role in RA mainly mediated by their anti-inflammatory and immunomodulatory properties. The objective of this study was to evaluate the effect of adjunct statin therapy in comparison to standard disease modifying antirheumatic drugs (DMARD) therapy in patients with RA. MATERIALS AND METHODS In this observational study, diagnosed RA patients of age group between 40 and 60 years were selected as per the inclusion criteria from the rheumatology outdoor. From the selected patients, we identified two separate groups of patients. Group 1 included 30 patients of RA currently under DMARD therapy with adjunct statin medication. Group 2 included 30 patients of RA currently under DMARD therapy. Patients were followed up over 6 months. Standard parameters such as disease activity score (DAS28), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were recorded for comparing the outcome of RA in both groups. RESULTS Out of a total of 60 patients who took part in the study, significant beneficial role of adjunct statin medication was found in this study when prescribed along with conventional DMARDs in active RA patients. The mean DAS28, considered by far as the most important index of clinical disease activity in RA, was found to be significantly lower (P < 0.05) in the adjunct statin-treated group (group 1) than that of the conventional DMARD treated group (group 2) after 6 months of continuous therapy. Other two important biochemical markers of RA disease activity, that is, ESR and CRP were also found to be significantly lower (P < 0.05) in RA patients who were on adjunct statin medication (group 1) than in group 2 comprising RA patients only under conventional DMARDs therapy without statin medication. CONCLUSION The results suggest an adjunct and potentially beneficial role of statin therapy in active cases of RA, producing significant clinical and biochemical improvement.