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Assessing the feasibility of NaF-PET/CT versus FDG-PET/CT to detect abdominal aortic calcification or inflammation in rheumatoid arthritis patients.
Seraj, SM, Raynor, WY, Revheim, ME, Al-Zaghal, A, Zadeh, MZ, Arani, LS, Rojulpote, C, Werner, TJ, Gerke, O, Høilund-Carlsen, PF, et al
Annals of nuclear medicine. 2020;(6):424-431
Abstract
OBJECTIVE We aimed to determine whether NaF-PET/CT or FDG-PET/CT can detect abdominal aortic molecular calcification and inflammation in patients with rheumatoid arthritis (RA). METHODS In this study, 18 RA patients (4 women, 14 men; mean age 56.0 ± 11.7) and 18 healthy controls (4 women, 14 men; mean age 55.8 ± 11.9) were included. The controls were matched to patients by sex and age (± 4 years). All subjects of this study underwent NaF-PET/CT scanning 90 min following the administration of NaF. FDG-PET/CT imaging was performed 180 min following intravenous FDG injection. Using OsiriX software, the global mean standardized uptake value (global SUVmean) in abdominal aorta was calculated for both FDG and NaF. The NaF SUVmean and FDG SUVmean were divided by the blood pool activity providing target-to-background ratios (TBR) namely, NaF-TBRmean and FDG-TBRmean. The CT calcium volume score was obtained using a growing region algorithm based on Hounsfield units. RESULTS The average NaF-TBRmean score among RA patients was significantly greater than that of healthy controls (median 1.61; IQR 1.49-1.88 and median 1.40; IQR 1.23-1.52, P = 0.002). The average CT calcium volume score among RA patients was also significantly greater than that of healthy controls (median 1.96 cm3; IQR 0.57-5.48 and median 0.004 cm3; IQR 0.04-0.05, P < 0.001). There was no significant difference between the average FDG-TBRmean scores in the RA patients when compared to healthy controls (median 1.29; IQR 1.13-1.52 and median 1.29; IQR 1.13-1.52, respectively, P = 0.98). CONCLUSION Quantitative assessment with NaF-PET/CT identifies increased molecular calcification in the wall of the abdominal aorta among patients with RA as compared with healthy controls, while quantitative assessment with FDG-PET/CT did not identify a difference in aortic vessel wall FDG uptake between the RA and healthy control groups.
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Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis.
Ho Lee, Y, Gyu Song, G
Journal of clinical pharmacy and therapeutics. 2020;(4):674-681
Abstract
WHAT IS KNOWN AND OBJECTIVE Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed. METHODS We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA. RESULTS AND DISCUSSION Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo. WHAT IS NEW AND CONCLUSION All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.
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Levels of the Novel Endogenous Antagonist of Ghrelin Receptor, Liver-Enriched Antimicrobial Peptide-2, in Patients with Rheumatoid Arthritis.
Francisco, V, Tovar, S, Conde, J, Pino, J, Mera, A, Lago, F, González-Gay, MA, Dieguez, C, Gualillo, O
Nutrients. 2020;(4)
Abstract
Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1β, MIP1α, MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia.
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The effects of garlic (Allium sativum) supplementation on inflammatory biomarkers, fatigue, and clinical symptoms in patients with active rheumatoid arthritis: A randomized, double-blind, placebo-controlled trial.
Moosavian, SP, Paknahad, Z, Habibagahi, Z, Maracy, M
Phytotherapy research : PTR. 2020;(11):2953-2962
Abstract
Based on the antiinflammatory properties of garlic, current study was conducted to evaluate the garlic supplement effects on serum levels of some inflammatory biomarkers, clinical symptoms, and fatigue in women with active rheumatoid arthritis. In this randomized, double-blind, placebo-controlled trial study, 70 women with RA were randomly divided into two groups: The intervention group was supplemented with 1,000 mg of garlic, and the control group received placebo for 8 weeks. At baseline and at the end of the study, clinical symptoms, fatigue, serum level of C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), and erythrocyte sedimentation rate (ESR) were determined. After intervention, serum levels of CRP (p = .018) and TNF-a (p < .001) decreased significantly in the garlic group as compared with the placebo group. Also, pain intensity, tender joint count, disease activity score (DAS-28), and fatigue were significantly decreased in the intervention group compared with the control group (p < .001; for all). Swollen joint count was significantly decreased in the garlic group (p < .001), but not in the placebo group (p = .123). No significant changes were observed for ESR. Garlic supplementation by improving inflammatory mediators and clinical symptoms can be considered as a potential adjunct treatment in patients with RA. However, further studies with larger duration are needed.
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Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.
Zhu, T, Moy, S, Valluri, U, Cao, Y, Zhang, W, Sawamoto, T, Chindalore, V, Akinlade, B
Clinical drug investigation. 2020;(9):827-838
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Abstract
BACKGROUND Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf®), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate. OBJECTIVE The objective of this study was to investigate potential drug-drug interactions of peficitinib with methotrexate and the short-term safety of coadministration. PATIENTS AND METHODS This phase I, open-label, single-sequence study included patients with rheumatoid arthritis taking a stable dose of methotrexate. Patients received their prescribed methotrexate dose (Day 1) and then peficitinib (100 mg) twice daily from Day 3 until the morning of Day 9; a second methotrexate dose was coadministered with peficitinib on Day 8. Serial blood samples were collected for methotrexate concentration after dosing on Days 1 (methotrexate alone) and 8 (methotrexate plus peficitinib) and for peficitinib concentration after dosing on Days 7 (peficitinib alone) and 8 (methotrexate plus peficitinib). Pre-dose concentrations of peficitinib were measured (Days 3-8). RESULTS Peficitinib concentrations reached steady state on Day 5. Administration of peficitinib did not result in changes to methotrexate area under the concentration-time curve from time zero to infinity or maximum observed concentration following a methotrexate dose (15-25 mg), and there was no significant effect of methotrexate (15-25 mg) on peficitinib area under the concentration-time curve within a 12-hour dosing interval. There were no new tolerability or safety signals after coadministration of peficitinib and methotrexate. One patient experienced two serious adverse events and withdrew from the study without receiving peficitinib. CONCLUSIONS Pharmacokinetic results showed no significant interactions between peficitinib and methotrexate. CLINICALTRIALS. GOV IDENTIFIER NCT01754805.
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The role of Chinese herbal medicine in the management of adverse drug reactions of leflunomide in treating rheumatoid arthritis.
Wang, W, Zhou, H, Liu, L
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2020;:153136
Abstract
BACKGROUND The high discontinuation rate in RA patients who use LEF might be attributed to their intolerance rather than irresponsibility. The concomitant administration of Leflunomide (LEF) with Chinese herbal medicine (CHM) provides a potential solution to preventing the adverse drug reactions (ADRs) induced by LEF during the treatment of rheumatoid arthritis (RA). PURPOSE To investigate whether co-administration of LEF with CHM could bring in both increased therapeutic outcomes and reduced ADRs due to the framework of treatment at the level of entire body. STUDY DESIGN The mechanism of LEF in RA treatment and the ADRs it induced was introduced based on recent papers. Reported clinical examples of CHM concurrent use with LEF was revealed to provide more evidence. The management of the ADRs caused by LEF was suggested by current researches on the concomitant therapy of CHM with LEF. RESULTS The active ingredients, compounds and medicinal herbs all demonstrated properties in relieving toxicities and reducing ADRs when used with LEF and reported in several clinical cases. The wide application of concurrent use of CHM with LEF is however hindered by the complex pathogenesis of RA which requires further scientific grounds for diagnosis and treatment. CONCLUSION This review introduced that the adoption of CHM is emerging as a novel strategy for the management of ADRs caused by LEF.
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Phytochemicals targeting matrix metalloproteinases regulating tissue degradation in inflammation and rheumatoid arthritis.
Alamgeer, , Hasan, UH, Uttra, AM, Qasim, S, Ikram, J, Saleem, M, Niazi, ZR
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2020;:153134
Abstract
PURPOSE Matrix metalloproteinases, zinc dependent proteolytic enzymes, have significant implications in extracellular matrix degradation associated with tissue damage in inflammation and Rheumatoid arthritis. Numerous orchestrated pathways affects instigation and blockade of metalloproteinases as well as various factors that increase the expression of MMPs including inflammatory cytokines, hormones and growth factors. Direct inhibition of these proteolytic enzymes or modulation of these pathways can provide protection against tissue destruction in inflammation and rheumatoid arthritis. Inclination towards use of plant derived phytochemicals to prevent tissue damage has been increasing day by day. Diversity of phytochemicals have been known to directly inhibit metalloproteinases. Hence, thorough knowledge of phytochemicals is very important in novel drug discovery. METHODS Present communication evaluates various classes of phytochemicals, in effort to unveil the lead molecules as potential therapeutic agents, for prevention of MMPs mediated tissue damage in inflammation and rheumatoid arthritis. Data have been analyzed through different search engines. RESULTS Numerous phytochemicals have been studied for their role as MMPs inhibitors which can be processed further to develop into useful drugs for the treatment of inflammation and rheumatoid arthritis. CONCLUSION In search of new drugs, phytochemicals like flavonoids, glycosides, alkaloids, lignans & terpenes offer a wide canvas to develop into valuable forthcoming medicaments.
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Traditional Chinese medicine on treating active rheumatoid arthritis: A protocol for systematic review and meta-analysis.
Zhang, L, Cao, Z, Yang, Y, Tan, X, Mao, J, Su, L
Medicine. 2020;(24):e20642
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BACKGROUND Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with progressive joint damage and disability. There is a lack of effective methods in the treatment of RA currently. Many clinical trials have proved that traditional Chinese medicine (TCM) has obvious advantages in the treatment of RA. In this systematic review, we intend to evaluate the efficacy and safety of TCM for active RA. METHODS We will search PubMed, the Cochrane Library, Embase, Web of Science, the Chinese National Knowledge Infrastructure Database, Wanfang Data, and Chinese Science and Technology Periodical Database. Simultaneously we will retrieval relevant meeting minutes, eligible research reference lists, symposium abstracts, and grey literatures. Included criteria are randomized controlled trials (RCTs) about TCM for active RA to assess its efficacy and safety. We will use the Revman 5.3 and Stata 13.0 software for data synthesis, sensitivity analysis, meta regression, subgroup analysis, and risk of bias assessment. The Grading of Recommendations Assessment, Development, and Evaluation standard will be used to evaluate the quality of evidence. RESULTS This systematic review will provide a synthesis of TCM for patients with active RA from various evaluation aspects including tender joint count, swollen joint count, RF, CRP, ESR, DAS28, TCM syndrome evaluation criteria, and adverse events. CONCLUSION The systematic review will provide evidence to assess the efficacy and safety of TCM in the treatment of patients with active RA. PROSPERO REGISTRATION NUMBER PROSPERO CRD42019146726.
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A Randomized, Double-Blind Study Comparing Pharmacokinetics and Pharmacodynamics of Proposed Biosimilar ABP 798 With Rituximab Reference Product in Subjects With Moderate to Severe Rheumatoid Arthritis.
Burmester, G, Chien, D, Chow, V, Gessner, M, Pan, J, Cohen, S
Clinical pharmacology in drug development. 2020;(8):1003-1014
Abstract
ABP 798 is a proposed biosimilar to rituximab reference product (RP), an anti-CD20 monoclonal antibody. Pharmacokinetics (PK), pharmacodynamics (PD), and safety results from the comparative clinical study that evaluated the PK, PD, safety, efficacy, and immunogenicity of ABP 798 versus rituximab RP are presented here. Subjects with moderate to severe rheumatoid arthritis (RA) received 2 doses of ABP 798, United States-sourced RP (rituximab US) or European Union-sourced RP (rituximab EU), each consisting of two 1000-mg infusions 2 weeks apart. For the second dose (week 24), ABP 798- and rituximab EU-treated subjects received the same treatment; rituximab US-treated subjects transitioned to ABP 798. End points included area under the serum concentration-time curve from time 0 extrapolated to infinity and maximum observed serum concentration following the second infusion of the first dose (PK) and percentage of subjects with complete CD19+ cell depletion days 1-33 (PD). Primary analysis established PK similarity between ABP 798 and rituximab RP based on 90% confidence intervals of the adjusted geometric mean ratios being within a prespecified equivalence margin of 0.8 and 1.25. Complete CD19+ B-cell depletion on day 3 among groups confirmed PD similarity. These findings demonstrated PK/PD similarity between ABP 798 and rituximab RP in subjects with moderate to severe RA.
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Targeted drug-delivery systems in the treatment of rheumatoid arthritis: recent advancement and clinical status.
Gorantla, S, Singhvi, G, Rapalli, VK, Waghule, T, Dubey, SK, Saha, RN
Therapeutic delivery. 2020;(4):269-284
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that is characterized by synovial inflammation, cellular infiltration in joints which leads to progressive joint destruction and bone erosion. RA is associated with many comorbidities including pulmonary disease, rheumatoid nodules and can have a pessimistic impact on quality of life. The current therapies of RA treatment comprise conventional, small molecule and biological antirheumatic drugs. Their utility as therapeutic agents is limited because of poor absorption, rapid metabolism and adverse effects (dose-escalation, systemic toxicity, lack of selectivity and safety). To overcome these limitations, the novel drug delivery systems are being investigated. This review has compiled currently approved therapies along with emerging advanced drug-delivery systems for RA treatment. Further, active targeting of therapeutic agents to inflamed joints via folate receptor, CD44, angiogenesis, integrins and other provided an improved therapeutic efficacy in the treatment of RA.