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ID PMID Title PublicationDate abstract
30060740 Combination of NF-kB targeted siRNA and methotrexate in a hybrid nanocarrier towards the e 2018 Jul 30 BACKGROUND: The transcription factor NF-kB plays an important role in the pathogenesis of rheumatoid arthritis (RA). Effective treatment of RA is hindered due to the lack of specificity of small molecules in the inflamed joints. In this study, we aimed to develop a unique hybrid-nanoparticles system comprised of calcium phosphate/liposome to deliver NF-kB-targeted siRNA and methotrexate (MTX) to diseased site. RESULTS: We have successfully demonstrated that the combination of siRNA and MTX in a calcium phosphate/liposome-based hybrid nanocarrier could effectively treat the RA. We have showed that folate receptor-targeted nanocarrier system significantly suppression the arthritis progression in mice model. Substantial accumulation of F-siRML was observed in LPS-activated macrophages. These kind of activated macrophages are generally present in the RA and osteoarthritis and folate-targeted nanoparticle enables the effective accumulation of therapeutics in the diseased site. The combinational nanoparticles effectively blocked the NF-kB signaling pathways and reduced the expression of pro-inflammatory cytokines. Furthermore, siRML and F-siRML did not show any decrease in the lymphocyte count indicating that it can avoid the adverse effect of MTX. CONCLUSION: Therefore, siRML and F-siRML provides unique benefits of excellent therapeutic efficacy with excellent safety profile in the arthritic mice and could be an promising approach in the treatment of rheumatoid arthritis.
29465348 Increased circulating CD14brightCD16+ intermediate monocytes are regulated by TNF-α and I 2018 Jul OBJECTIVES: Although circulating CD14brightCD16+ monocyte subsets are increased in inflammatory disease, the pathogenesis of the increase in the inflammatory condition of the cells is still unclear and the relationship to cytokines is unknown particularly in rheumatoid arthritis (RA). The purpose of this study was to investigate the influence anti-cytokine treatment has on CD14brightCD16+ monocytes in patients with RA. METHODS: Thirty-two RA patients and 14 healthy volunteers (HV) were enrolled in this study. All the patients had never been treated with methotrexate (MTX) or biological agents. Peripheral blood samples and clinical information of the patients were obtained at the time of 0, 12 and 24 weeks of treatment. Peripheral blood samples were also obtained from the HV. The expression levels of CD14 and CD16 on monocytes were measured by flow cytometry (FCM). RESULTS: Eight patients received anti-interleukin (IL)-6 receptor antibody, tocilizumab (TCZ) treatment alone, 12 patients received anti-tumour necrosis factor (TNF)-α antibody, adalimumab (ADA) with MTX treatment and the others received only MTX treatment. FCM analysis revealed that the proportion of CD14brightCD16+ monocytes significantly increased in patients at baseline compared with HV. The proportion of CD14brightCD16+ monocytes significantly decreased after TCZ, and ADA with MTX treatment. The proportion of intermediate monocytes was significantly and positively correlated with disease activity and it improved in accordance with the proportion of CD14brightCD16+ monocytes after inhibition of signal transduction of inflammatory cytokines. CONCLUSIONS: We showed that the population of CD14brightCD16+ monocytes significantly decreased with the change of disease activity by key cytokines, IL-6 or TNF-α signal blockade in RA. This result indicates that the proportion of those monocytes is important for reflecting disease activity in RA.
29303005 Bone-targeted methotrexate-alendronate conjugate inhibits osteoclastogenesis in vitro and 2018 Nov Rheumatoid arthritis (RA), a disease that causes joint destruction and bone erosion, is related to osteoclast activity. RA is generally treated with methotrexate (MTX). In this study, a MTX-Alendronate (ALN) conjugate was synthesized and characterized. The conjugate dramatically inhibited osteoclast formation and bone resorption compared with MTX and ALN used alone or in combination. Due to the characteristics of ALN, the MTX-ALN conjugate can adhere to the exposed bone surface and enhance drug accumulation in the pathological region for targeted therapy against osteoclastogenesis. Additionally, MTX was rapidly released in the presence of lysozyme under mildly acidic conditions, similar to inflammatory tissue and osteoclast-surviving conditions, which contributes to inflammatory inhibition; this was confirmed by the presence of pro-inflammatory cytokines. Our study highlights the use of the MTX-ALN conjugate as a potential therapeutic approach for RA by targeting osteoclastogenesis.
29738359 Genomic Profile and Pathologic Features of Diffuse Large B-Cell Lymphoma Subtype of Methot 2018 Jul Rheumatoid arthritis patients often develop the diffuse large B-cell lymphoma subtype of methotrexate-associated lymphoproliferative disorder (DLBCL). We characterized the genomic profile and pathologic characteristics of 20 biopsies using an integrative approach. DLBCL was associated with extranodal involvement, a high/high-intermediate international prognostic index in 53% of cases, and responded to MTX withdrawal. The phenotype was nongerminal center B-cell in 85% of samples and Epstein-Barr encoding region positive (EBER) in 65%, with a high proliferation index and intermediate MYC expression levels. The immune microenvironment showed high numbers of CD8 cytotoxic T lymphocytes and CD163 M2 macrophages with an (CD163/CD68) M2 ratio of 3.6. Its genomic profile was characterized by 3p12.1-q25.31, 6p25.3, 8q23.1-q24.3, and 12p13.33-q24.33 gains, 6q22.31-q24.1 and 13q21.33-q34 losses, and 1p36.11-p35.3 copy neutral loss-of-heterozygosity. This profile was closer to nongerminal center B-cell DLBCL not-otherwise-specified, but with characteristic 3q, 12q, and 20p gains and lower 9p losses (P<0.05). We successfully verified array results using fluorescent DNA in situ hybridization on PLOD2, MYC, WNT1, and BCL2. Protein immunohistochemistry revealed that DLBCL expressed high IRF4 (6p25.3) and SELPLG (12q24.11) levels, intermediate TNFRSF14 (1p36.32; the exons 1 to 3 were unmutated), BTLA (3q13.2), PLOD2 (3q24), KLHL6 (3q27.1), and MYC (8q24.21) levels, and low AICDA (12p13.31) and EFNB2 (13q33.3) levels. The correlation between the DNA copy number and protein immunohistochemistry was confirmed for BTLA, PLOD2, and EFNB2. The characteristics of EBER versus EBER cases were similar, with the exception of specific changes: EBER cases had higher numbers of CD163 M2 macrophages and FOXP3 regulatory T lymphocytes, high programmed cell death 1 ligand 1 expression levels, slightly fewer genomic changes, and 3q and 4p focal gains. In conclusion, DLBCL has a characteristic genomic profile with 3q and 12 gains, 13q loss, different expression levels of relevant pathogenic biomarkers, and a microenvironment with high numbers of cytotoxic T lymphocytes and M2 macrophages.
30593388 The importance of inhibition of a catabolic pathway of methotrexate metabolism in its effi 2019 Jan Methotrexate (MTX), an antifolate, is the anchor drug for the treatment of rheumatoid arthritis (RA). It is inexpensive, effective, and generally safe. When clinical response is inadequate, biological therapies are commonly used in combination with MTX. However, biological agents have safety concerns (i.e. infections, malignancy) and the addition of a biologic agent is expensive, making strategies to improve MTX efficacy important. Inhibition of pathways of folate metabolism involving purine metabolism by MTX, have been traditionally emphasized as important in MTX efficacy. However, inhibition MTX catabolism may also be important. MTX is irreversibly hydroxylated to form 7-hydroxy methotrexate (7-OH-MTX) by aldehyde oxidase (EC 1.2.3.1) (AOX). Catabolism of MTX to 7-OH-MTX is the first metabolic process imposed on an oral dose of MTX and will alter subsequent interactions of MTX with other enzymes. 7-OH-MTX is less potent than MTX in the treatment of rat adjuvant arthritis. RA patients with a low capacity to catabolize MTX to 7-OH-MTX do better clinically than individuals who are rapid formers of 7-OH-MTX. Therefore, altering the catabolism of MTX may be an innovative way to improve MTX efficacy. Raloxifene is a FDA-approved therapy for postmenopausal osteoporosis and for the reduction of invasive breast cancers but has no known activity in RA. Raloxifene is a potent inhibitor of human liver AOX. Postmenopausal women with RA frequently have low bone mineral density and would be candidates for raloxifene and MTX combination therapy. The effect of raloxifene on MTX metabolism has never been studied. Our hypothesis is that in postmenopausal women with RA and osteoporosis treated with MTX and raloxifene, the inhibition of AOX with resultant decreased formation of 7-OH MTX; will increase MTX levels and improve MTX efficacy. This hypothesis could be studied in an open-label, proof of concept clinical study in individuals before and after the addition of raloxifene. Red blood cell MTX and 7-OH-MTX levels and RA disease activity (DAS28) would be measured. In possible future studies, there are dietary substances, as supplements, (e.g. epigallocatechin gallate in green tea and resveratrol) which inhibit human liver AOX which could be evaluated.
29303709 Cost-effectiveness of early treatment of ACPA-positive rheumatoid arthritis patients with 2018 May OBJECTIVES: Studies have reported that the presence of elevated anti-citrullinated protein antibodies (ACPA)/RF levels, together with joint erosions, is associated with higher disease burden in terms of disability and mortality in rheumatoid arthritis (RA). Abatacept has been shown to be effective in this patient population with favourable comparative data against adalimumab. However, few studies have investigated the cost-effectiveness of abatacept in this population to similar treatments such as TNFs. The objective of the study was to compare the cost-effectiveness of abatacept to adalimumab as a first bDMARD in ACPA-positive RA patients who failed treatment with methotrexate (MTX) in Germany. METHODS: A decision tree model was used to estimate the cost-effectiveness, from a payer's perspective, of different treatment sequences in RA over a two year time frame. The effectiveness criteria were defined as achieving the treatment target measured by the Disease Activity Score 28 (DAS28(CRP)<2.6; "remission"). A treatment switch to a different biologic as 2nd line and 3rd line bDMARD was allowed - in case of not achieving remission with therapy - every 6 months over a two year time period. Effectiveness data was based on randomised controlled trials (RCT) identified by an updated previous systematic literature search by the Institute for Quality and Efficiency in Health Care (IQWiG). Costs of medication and other direct medical costs were considered. Cost-effectiveness of RA treatment was investigated in ACPA-positive patients and presented as overall costs per day in remission. RESULTS: For ACPA-positive patients, treatment strategies including early treatment with abatacept had lower total costs per clinical outcome compared to later use. Treatment sequences starting with abatacept resulted in lower costs per day in remission (mean 330 €/day, range 328-333 €/day) compared to sequences starting with adalimumab (mean 384 €/day, range 378-390 €/day). Choice of the second or third biologic in the treatment sequences appears to have little impact on the costs per outcome. CONCLUSIONS: The results of this analysis suggest that in ACPA-positive RA patients treatment with abatacept appears to have lower costs per response (remission) compared to treatment with adalimumab as a first bDMARD.
29340978 Methotrexate Aspasomes Against Rheumatoid Arthritis: Optimized Hydrogel Loaded Liposomal F 2018 Apr Aspasomes of methotrexate with antioxidant, ascorbyl palmitate, were developed and optimized using factorial design by varying parameters such as lipid molar ratio, drug to lipid molar ratio, and type of hydration buffer for transdermal delivery for disease modifying activity in rheumatoid arthritis (RA). Aspasomes were characterized by drug-excipients interaction, particle size analysis, determination of zeta potential, entrapment efficiency, and surface properties. The best formulation was loaded into hydrogel for evaluation of in vitro drug release and tested in vivo against adjuvant induced arthritis model in wistar rats, by assessing various physiological, biochemical, hematological, and histopathological parameters. Optimized aspasome formulation exhibited smooth surface with particle size 386.8 nm, high drug loading (19.41%), negative surface potential, and controlled drug release in vitro over 24 h with a steady permeation rate. Transdermal application of methotrexate-loaded aspasome hydrogel for 12 days reduced rat paw diameter (21.25%), SGOT (40.43%), SGPT (54.75%), TNFα (33.99%), IL β (34.79%), cartilage damage (84.41%), inflammation (82.37%), panus formation (84.38%), and bone resorption (80.52%) as compared to arthritic control rats. Free methotrexate-treated group showed intermediate effects. However, drug-free aspasome treatment did not show any effect. The experimental results indicate a positive outcome in development of drug-loaded therapeutically active carrier system which presents a non-invasive controlled release transdermal formulation with good drug loading, drug permeation rate, and having better disease modifications against RA than the free drug, thereby providing a more attractive therapeutic strategy for rheumatoid disease management.
30146566 Accelerated Progression of Hepatocellular Carcinoma during Immunosuppressive Therapy with 2019 Jan 1 Abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin recombinant fusion protein, is an immunosuppressive agent indicated for rheumatoid arthritis. Although no significant increase in malignancy has been reported in abatacept-treated patients, whether or not abatacept accelerates tumor progression in specific cancer types remains unclear. We herein report a 66-year-old woman who showed unusually rapid progression of hepatocellular carcinoma following abatacept therapy for rheumatoid arthritis. Abatacept was speculated to have accelerated her hepatocellular carcinoma progression in the setting of her preexisting risk factors: autoimmune hepatitis and long-term methotrexate use. We propose close tumor surveillance be performed during abatacept therapy, especially for high-risk patients.
29905411 Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a 2018 Jul BACKGROUND: Mesenchymal stem cells (MSCs) are of increased importance because of their capacity to counteract inflammation and suppress host immune responses. OBJECTIVES: The aim of the study was to compare the effectiveness of MSCs and hematopoietic stem cells (HSCs) in the treatment of rheumatoid arthritis (RA). MATERIAL AND METHODS: Paw swelling was assessed by measuring the thickness of the hind paws using a caliper. Cytokines - interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and IL-10 - and rheumatoid factor (RF) were measured using enzyme-linked immunosorbent assay (ELISA) kits. Oxidative stress biomarkers - malondialdehyde (MDA) and reduced glutathione (GSH) were assessed. Nuclear factor-kappaB (NF-κB) was detected by the western blot technique. Toll-like receptor-2 (TLR-2), matrix metalloproteinase-3 (MMP-3) and cartilage oligomeric matrix protein-1 (COMP-1) gene expression were assessed by the real-time quantitative analysis. Mesenchymal stem cells were isolated from the bone marrow (BM) of rats and HSCs were isolated from human umbilical cord blood (UCB). RESULTS: Paw edema, RA score, RF, cytokine assay, antioxidant state, NF-κB, TLR-2, MMP3, and COMP-1 showed improvement in the group that received MSCs compared to the group that received HSCs and the group that received methotrexate. CONCLUSIONS: Mesenchymal stem cells are very effective in reducing RA inflammation; they are superior to HSC and methotrexate treatment. Mesenchymal stem cells could become a better therapeutic opportunity for the treatment of RA.
30261687 Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and 2018 Sep 27 A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.
29380961 Experiences of a patient-initiated self-monitoring service in inflammatory arthritis: A qu 2018 Jun OBJECTIVES: The aim of the present study was to explore patients' experience of a patient-initiated self-monitoring service for people with rheumatoid or psoriatic arthritis who are on methotrexate. METHODS: The study took the form of qualitative semi-structured interviews, embedded within a randomized controlled trial. Twelve participants who were randomly assigned to the intervention arm were interviewed. Interviews digitally, transcribed verbatim and analysed using inductive thematic analysis. The study received full National Health Service ethics approval from Camden and Islington Community Local Research Ethics Committee (Ref. 09/H0722/91). RESULTS: Analysis revealed five key themes. Participants described usual care as burdensome and an inefficient use of time, particularly those in employment. Being able to self-monitor and initiate their own care increased patients' knowledge about their illness and its treatment, and enabled them to gain a sense of control and ownership over their arthritis. They appreciated the personalized nature of the new service, which allowed them to be seen at a time and by a method more appropriate to their needs. There were, however, some concerns about fidelity to the service protocol, confusion about the lack of consistency between symptoms and laboratory results, and anxiety about self-monitoring. CONCLUSIONS: Overall, participants were positive about the new service, in comparison with usual care, valuing its tailored approach and empowering effects. Further work is needed to ensure adherence to the service protocol and address anxieties around self-monitoring prior to any widespread implementation of the service.
28097393 Comparative efficacy and safety of baricitinib 2 mg and 4 mg in patients with active r 2018 May OBJECTIVE: This study aimed to assess the relative efficacy and safety of once-daily baricitinib 2 mg and 4 mg administration in patients with active rheumatoid arthritis (RA). METHODS: In this network meta-analysis, randomized controlled trials (RCTs) examining the efficacy and safety of baricitinib in patients with active RA were included. A Bayesian network meta-analysis was conducted to combine the direct and indirect evidence from the RCTs. RESULTS: Seven RCTs involving 3461 patients met the inclusion criteria. There were ten pairwise comparisons, including seven direct comparisons and five interventions. The ACR20 response rate was significantly higher in the baricitinib 4 mg in combination with disease-modifying antirheumatic drugs (DMARD) group than in the placebo+DMARD group (odds ratio, OR 3.13; 95% credible interval, CrI 2.32-4.33). Compared with the placebo+DMARD group, the baricitinib 4 mg, baricitinib 2 mg + DMARD, and adalimumab 40 mg + methotrexate (MTX) groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4 mg + DMARD was likely to elicit the best ACR20 response rate (SUCRA = 0.7930), followed by baricitinib 4 mg (SUCRA = 0.7034), baricitinib 2 mg + DMARD (SUCRA = 0.6304), adalimumab 40 mg + MTX (SUCRA = 0.3687), and placebo+DMARD (SUCRA = 0.0045). By contrast, the safety based on the number of treatment-emergent adverse events (TEAEs) did not differ significantly among the five interventions. CONCLUSION: Baricitinib 2 mg and 4 mg administered once daily, in combination with DMARD, were efficacious interventions for active RA that had no significant risk of TEAE development.
30701888 Efficacy and tolerability of abatacept treatment: results of 12 months observation. 2018 May 11 AIM: This article reports 1-year clinical outcomes of patients with rheumatoid arthritis (RA) receiving abatacept (ABA) therapy. MATERIALS AND METHODS: Patients (n=91) with high RA activity (DAS28 = 5.1 ± 1.0) and an inadequate response on synthetic DMARDs (mainly methotrexate, 70.3%) and biologics (mainly TNF-α inhibitors, 93%) were included in the study. The majority of patients were middle-aged (49 ± 13.5) womens, RF (72.5%) and ACPA (77%) positive, with moderate functional impairment - HAQ = 1.4 (0.9-2). ABA were administered IV, 10 mg/kg according to the standard scheme. The evaluation of the effectiveness of the therapy was carried out according to the EULAR / ACR 2011 criteria using SDAI, CDAI, HAQ and the intention to treat approach. RESULTS: ABA led to a significant (p <0.05) decrease activity of RA. Clinical improvement according to EULAR criteria after 6 months of treatment was registered in 70.9%, after 12 months 63%. Almost a third of patients (28.7%) achieved a good response after 3 months of therapy, 39,2% - after 6 months and 39% - after 12 months. The retention rate of ABA therapy after 6 months was 77%, after 12 months - 60%. There were no significant differences between "bio-naive", 1 Bio and ≥2 Bio groups in achieving EULAR response. A good response was achieved in 38%, 38% and 43%, respectively, but the lowest number of non-responders was registered in ≥2 Bio - 38%, 36% and 43%. ABA significantly improved functional status of patients, after 12 months a marked and moderate improvement in the HAQ was achieved in 39% and 21% of patients, respectively. Adverse events (AE) were registered in 22 patients. The most frequent AE were upper respiratory tract infections - 11 (12%) patients. CONCLUSION: Abatacept was effective in the overall population, and in all subgroups of patients. It has shown significant improvement of clinical and functional status in patients who had an inadequate response to previous therapy. ABA has a good safety profile. AE were registered only in a small number of patients.
29795407 Genome-wide association study of response to methotrexate in early rheumatoid arthritis pa 2018 Jul Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10(-7) for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.
28880684 Reduction of methotrexate and glucocorticoids use after the introduction of biological dis 2018 May OBJECTIVES: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice. METHODS: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD. RESULTS: A total of 470 RA patients who had initiated a bDMARD (IFX: n = 98, ETN: n = 181, TCZ: n = 90, and ADA: n = 101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation. CONCLUSION: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD.
30630793 A clinical study on the combined therapy of methotrexate and immuno adsorption in the trea 2018 Nov Objective of the present work was to study the effect and significance of the combined therapy of methotrexate and immune adsorption in the treatment of rheumatoid arthritis disease. 56 patients with rheumatoid arthritis disease who have received treatment in "The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China" during the period from May, 2016 to May, 2017 were selected as study objects and were randomized into control group and experimental group according to different therapies. Control group was given conventional therapy while experimental group was treated with the combined therapy of methotrexate and immune adsorption with 28 patients in each group. After a period of time, clinical symptoms, the experimental index, treatment effectiveness and the occurrence rate of adverse reactions were all compared between the two groups. Results revealed that the clinical symptoms and the experimental index of experimental group were less than those of control group and the occurrence rate of adverse reactions in experimental group was lower than that in control group. Additionally, the effective rate of experimental group was higher than that of control group and statistically significant difference was observed and revealed that the combined therapy of methotrexate and immune adsorption in the treatment of rheumatoid arthritis disease had vital significance in alleviating related symptoms, lowering adverse reactions occurrence rate and improving treatment effectiveness, being worthy of clinical application and promotion.
29266862 Orthopedic Surgery Among Patients With Rheumatoid Arthritis: A Population-Based Study to I 2018 Oct OBJECTIVE: To identify risk factors for large-joint surgery (LJS) versus small-joint surgery (SJS) in rheumatoid arthritis (RA) and evaluate trends in surgery rates over time. METHODS: A retrospective medical record review of all orthopedic surgeries following first fulfillment of the 1987 American College of Rheumatology criteria for adult-onset RA among residents of Olmsted County, Minnesota between 1980 and 2013 was performed. Risk factors were examined using Cox models adjusted for age, sex, and calendar year of RA incidence. Trends in incidence of joint surgeries were examined using Poisson regression models. RESULTS: A total of 1,077 patients with RA (mean age 56 years, 69% female, 66% seropositive for rheumatoid factor [RF] and anti-cyclic citrullinated peptide [anti-CCP] antibodies) were followed for a median of 10.7 years, during which 112 patients (90 women) underwent at least 1 SJS and 204 (141 women) underwent at least 1 LJS. Risk factors included advanced age, and RF and anti-CCP antibody positivity for both SJS and LJS, and body mass index ≥30 kg/m(2) for LJS. Risk factors for SJS and LJS at any time during followup included the presence of radiographic erosions, large-joint swelling, and methotrexate use. SJS rates decreased by calendar year of incidence (hazard ratio 0.53, P = 0.001), with significant decline in the rates of SJS after 1995. The cumulative incidence of SJS was higher in women than men (P = 0.008). CONCLUSION: In recent years, there has been a significant decline in the rates of SJS but not LJS in patients with RA. The incidence of SJS is higher among women. Traditional RA risk factors are strong predictors for SJS and LJS. Increasing age and obesity are predictive of LJS.
29548542 Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid art 2018 Oct OBJECTIVE: Rituximab (RTX) is an anti-CD20 monoclonal antibody that selectively depletes B-cell population. Thus, it presents a potential risk for the development of hypogammaglobulinemia and related infectious events. Our aim was to identify predictors of hypogammaglobulinemia in RA patients long-term treated with RTX. METHODS: Multicenter observational usual care study of patients with RA on RTX maintenance therapy (minimal exposition of 30 months). Serum protein electrophoresis was performed before each RTX infusion. Hypogammaglobulinemia and severe hypogammaglobulinemia were defined as total gammaglobulin <6g/L and <4g/L, respectively. The primary outcome was the occurrence within the follow-up period of hypogammaglobulinemia. RESULTS: 134 patients met inclusion criteria and were followed-up for 79.5 ± 24.6 months. Hypogammaglobulinemia occurred during the follow-up period in 23 patients (2.7 events per 100 pt-yrs). The mean time to development of hypogammaglobulinemia was 64 ± 23 months. Patients who developed hypogammaglobulinemia were more likely to experience severe infections (26.1% vs. 6.3%, P = 0.033). Multivariate Cox analysis identified gammaglobulin levels <8g/L at baseline as an independent predictor of hypogammaglobulinemia (HR 7.34 [95% CI: 2.00-26.90], P = 0.003). Concomitant methotrexate (MTX) intake was also predictive of a reduced risk of hypogammaglobulinemia occurrence (HR 0.26 [95% CI: 0.08-0.87], P = 0.03). CONCLUSION: Our results show that gammaglobulin levels of less than 8g/L at baseline is a strong independent risk factor for developing subsequent hypogammaglobulinemia, whereas concomitant MTX therapy seems to be a protective factor in RA patients treated long-term with RTX.
29605999 Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Amino 2018 Apr 26 A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of H(2)O(2) proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.
29566767 Methotrexate upregulates circadian transcriptional factors PAR bZIP to induce apoptosis on 2018 Mar 22 BACKGROUND: Effects of methotrexate (MTX) on the proliferation of rheumatoid arthritis (RA) synovial fibroblasts are incompletely understood. We explored actions of MTX in view of circadian transcriptions of synovial fibroblasts. METHODS: Under treatment with MTX, expression of core circadian clock genes, circadian transcriptional factor proline and acidic amino acid-rich basic leucine zipper (PAR bZIP), and proapoptotic molecule Bcl-2 interacting killer (Bik) was examined by real-time polymerase chain reaction. Protein expression of circadian clock gene PERIOD2 (PER2) and CYTOCHROME C was also examined by western blotting and ELISA. Promoter activities of Per2 and Bik were measured by Luciferase assay. Expression of PER2, BIK, and CYTOCHROME C and morphological changes of the nucleus were observed by fluorescent immunostaining. Synovial fibroblasts were transfected with Per2/Bik small interfering RNA, and successively treated with MTX to determine cell viabilities. Finally, synovial fibroblasts were treated with MTX according to the oscillation of Per2/Bik expression. RESULTS: MTX (10 nM) significantly decreased cell viabilities, but increased messenger RNA expression of Per2, Bik, and PAR ZIP including D site of the albumin promoter binding protein (Dbp), hepatic leukemia factor (Hlf), and thyrotroph embryonic factor (Tef). MTX also increased protein expression of PER2 and CYTOCHROME C, and promoter activities of Per2 and Bik via D-box. Under fluorescent observations, expression of PER2, BIK, and CYTOCHROME C was increased in apoptotic cells. Cytotoxicity of MTX was attenuated by silencing of Per2 and/or Bik, and revealed that MTX was significantly effective in situations where Per2/Bik expression was high. CONCLUSIONS: We present here novel unique action of MTX on synovial fibroblasts that upregulates PAR bZIP to transcribe Per2 and Bik, resulting in apoptosis induction. MTX is important in modulating circadian environments to understand a new aspect of pathogenesis of RA.