Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
29257239 Elevated expression of PD‑1 on T cells correlates with disease activity in rheumatoid ar 2018 Feb It is well known that lymphocytes are important in rheumatoid arthritis (RA). Programmed cell death-1 (PD‑1) is one of the immunosuppressive costimulatory molecules, which mediates an inhibitory effect. However, its role in RA remains to be fully elucidated. In the present study, the expression levels of PD‑1 on T cells in the peripheral blood (PB) and synovial fluid (SF) were determined using flow cytometry. In addition, the expression levels of PD‑1 on T cells in the PB and SF of patients with RA were further analyzed to determine correlation with markers of the autoimmune response, inflammation and disease activity in RA. Compared with healthy controls, the expression of PD‑1 on T cells in the PB was significantly elevated in patients with RA (P<0.0001). The expression of PD‑1 on T cells in the SF of patients with RA was significantly increased, compared with that in the autologous PB (P<0.0001). It was also found that the expression of PD‑1 on T cells in the PB of patients with RA was increased significantly in subjects with a high rheumatoid factor titer, high levels of inflammatory markers and a high disease activity score 28 (DAS28). The expression of PD‑1 on T cells in the SF of patients with RA was increased significantly in subjects with a high DAS28. These data showed that the expression of PD‑1 on T cells was elevated in patients with RA and was correlated with the disease activity.
29461232 NEPHROPATHY IN EARLY RHEUMATOID ARTHRITIS PATIENTS: DOES A SIGNIFICANT RISK EXIST? 2018 Jan Objective of the study layed in assessment of the pathophysiological relation between cell-mediated immunity (tumor necrosis factor-alpha (TNF-α) inflammatory cytokine) activation and renal dysfunction in the patients with early rheumatoid arthritis. We analyzed the data from 35 early rheumatoid arthritis (RA) patients of average age of 50,71±2,25 years (ranged 18-76 years, 80% of women) with 9,21±0,43 months mean duration of the disease by the time of the study initiation. Urine and blood tests were performed to verify the main indicators of kidney function and inflammation cytokines significant interaction. All signs of renal dysfunction at the baseline in the patients with early RA were associated with glomerular filtration rate decrease and excretion of urine protein increase. Dynamics of albuminuria, according to the analysis of variance for one-factor scheme, were significantly determined by the state of disease activity, reflecting the severity of joint damage. High urine β-2-microglobulin level was significantly associated with the expression rate of main inflammatory cytokines as per binary regression analysis. The obtained dependence showed the dynamics of expression of tubular disorders in early RA with a progressive deterioration which did associate with the levels of TNF-α expression, and variety of the urine miсroglobulin rates in the interval 200-350 μg/L. Reliable correlation (r=0.51, p<0.05) between beta-2-microglobulinuria and TNF-α levels was clearly shown, revealing the relationship described by the formula MGU=- 81+937×log10 (TNF-α) as per regression analysis. The severity of tubular damage in early RA is associated with TNF-α expression, especially in the patients with TNF-α above 250 pg/mL, when microalbuminuria rates were significantly higher (p=0.00043). We identified robust data that in the early RA patients with high TNF-α, the number of reported cases of microalbuminuria was significantly higher than in those with low levels.
30010538 An Observational Study of Cardiovascular Risks Associated with Rheumatoid Arthritis Therap 2018 BACKGROUND AND OBJECTIVES: Comparative safety studies typically use hierarchical treatment categories that lump monotherapy and combination therapy. The consequence of this approach on study results is not clear. For example, studies of tumor necrosis factor inhibitors usually lump users regardless of whether they are using the drug alone or in combination with other agents. This study explored the importance of lumping vs splitting users of monotherapy and combination therapy. We also explored whether the timing of disenrollment from Health Plan membership was informative as an outcome variable when interpreting unmeasured, time-varying confounding. METHODS: This observational cohort study included Kaiser Permanente Northern California 2003 to 2013 members with rheumatoid arthritis who started methotrexate. The study end point was a major cardiovascular event. In Cox proportional hazards analysis, we compared treatment classifications using five lumped categories with treatment classification using nine split categories. We also studied disenrollment as an outcome. RESULTS: Among 5885 patients, 238 experienced serious cardiovascular events during an average follow-up of 4.25 years. Analysis of drug treatments using 5 lumped categories was difficult to interpret because treatment effects and drug users were mixed. In contrast, analysis of 9 drug categories that split monotherapies from combination therapy was easier to interpret, although confidence intervals were wider. Analysis of drug treatment in relation to disenrollment provided useful information with which to assess study validity, although the power of the analysis was limited. CONCLUSION: In comparative safety studies, we recommend greater transparency in classifying treatment and evaluating disenrollment.
29267861 Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized p 2018 Feb 1 BACKGROUND: Androgens are generally immunosuppressive, and men with untreated hypogonadism are at increased risk for autoimmune conditions. To date, there has been no evidence linking androgen deprivation therapy (ADT) to autoimmune diseases, including rheumatoid arthritis (RA). We investigated the association between ADT and RA in patients with prostate cancer. PATIENTS AND METHODS: We identified 105 303 men age 66 years or older who were diagnosed with stages I-III prostate cancer from 1992 through 2006 using the Surveillance, Epidemiology, and End Results-Medicare linked database, excluding patients with a history of RA. χ2 test was used to compare 5-year Kaplan-Meier rates of RA diagnoses. Competing risk Cox regression using inverse probability of treatment weighting was utilized to examine the association between pharmacologic ADT and diagnosis of RA. RESULTS: The 43% of patients (N = 44 785) who received ADT experienced a higher 5-year rate of RA diagnoses compared with men who did not (5.4% versus 4.4%, P < 0.001). Receipt of any ADT was associated with a 23% increased risk of being diagnosed with RA (hazard ratio 1.23, 95% confidence interval 1.09-1.40, P = 0.001). The risk of being diagnosed with RA increased with a longer duration of ADT, from 19% with 1-6 months and 29% with 7-12 months to 33% with ≥13 months (Ptrend < 0.001). CONCLUSIONS: Consistent with the immunosuppressive properties of androgens, we demonstrated for the first time that ADT was associated with an elevated risk of being diagnosed with RA in this large cohort of elderly men with prostate cancer. The risk was higher with a longer duration of ADT. Linking ADT to an increased risk of being diagnosed with an autoimmune condition adds to mounting evidence of the adverse effects of ADT that should prompt physicians to thoughtfully weigh its risks and benefits.
30786829 Vitamin K(1) Supplementation Did Not Alter Inflammatory Markers and Clinical Status in Pat 2018 Dec Background: Rheumatoid arthritis (RA) is an inflammatory disorder in which the disease severity might be decreased by anti-inflammatory agents. There are several lines of evidence which support anti-inflammatory effects of vitamin K. The aim of this study was to examine whether vitamin K is a useful strategy for reducing inflammation in RA subjects. Materials and methods: In this double-blind placebo controlled trial, 58 patients with definitive RA were randomly allocated into two groups to receive vitamin K(1) as phylloquinone [10 mg/day] or placebo pills for 8 weeks. Clinical status using disease activity score-28 (DAS-28) and serum concentrations of some inflammatory markers (IL-6, hs-CRP, TNFα) were assessed at baseline and at the end of intervention. Results: There were no significant differences between the two groups regarding any of the baseline characteristics. In the vitamin K(1) group, a 27 % decrease in serum levels of IL-6 (P = 0.006) and a 13 % decrease in DAS-28 (P = 0.041) were observed. However, after adjusting for relevant confounders, i. e.; duration of RA, intake of folic acid supplements, energy intake, weight and baseline values of each variable, by comparing the two groups, we found no significant reduction in these markers. Conclusion: Vitamin K(1) supplementation at 10 mg/day for 8 weeks had no significant effects on blood biomarkers of inflammation and disease severity of patients with rheumatoid arthritis compared with the placebo group.
29681783 Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Em 2018 BACKGROUND: In rheumatoid arthritis, articular inflammation is a hallmark of disease, while the involvement of extra-articular tissues is less well defined. Here, we examined the feasibility of PET imaging with the macrophage tracer [(18)F]fluoro-PEG-folate, targeting folate receptor β (FRβ), to monitor systemic inflammatory disease in liver and spleen of arthritic rats before and after methotrexate (MTX) treatment. METHODS: [(18)F]Fluoro-PEG-folate PET scans (60 min) were acquired in saline- and MTX-treated (1 mg/kg, 4x) arthritic rats, followed by tissue resection and radiotracer distribution analysis. Liver and spleen tissues were stained for ED1/ED2-macrophage markers and FRβ expression. RESULTS: [(18)F]Fluoro-PEG-folate PET and ex vivo tissue distribution studies revealed a significant (p < 0.01) 2-fold lower tracer uptake in both liver and spleen of MTX-treated arthritic rats. Consistently, ED1- and ED2-positive macrophages were significantly (p < 0.01) decreased in liver (4-fold) and spleen (3-fold) of MTX-treated compared with saline-treated rats. Additionally, FRβ-positive macrophages were also significantly reduced in liver (5-fold, p < 0.005) and spleen (3-fold, p < 0.01) of MTX- versus saline-treated rats. CONCLUSIONS: MTX treatment reduced activated macrophages in liver and spleen, as markers for systemic inflammation in these organs. Macrophage PET imaging with [(18)F]fluoro-PEG-folate holds promise for detection of systemic inflammation in RA as well as therapy (MTX) response monitoring.
29316377 Medical Care Costs Associated With Rheumatoid Arthritis in the US: A Systematic Literature 2018 Oct OBJECTIVE: Rheumatoid arthritis (RA) is a morbid, mortal, and costly condition without a cure. Treatments for RA have expanded over the last 2 decades, and direct medical costs may differ by types of treatments. There has not been a systematic literature review since the introduction of new RA treatments, including biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: We conducted a systematic literature review with meta-analysis of direct medical costs associated with RA patients cared for in the US since the marketing of the first bDMARD. Standard search strategies and sources were used, and data were extracted independently by 2 reviewers. The methods and quality of included studies were assessed. Total direct medical costs as well as RA-specific costs were calculated using random-effects meta-analysis. Subgroups of interest included Medicare patients and those using bDMARDs. RESULTS: We found 541 potentially relevant studies, and 12 articles met the selection criteria. The quality of studies varied: one-third were poor, one-third were fair, and one-third were good. Total direct medical costs were estimated at $12,509 (95% confidence interval [95% CI] 7,451-21,001) for all RA patients using any treatment regimen and $36,053 (95% CI 32,138-40,445) for bDMARD users. RA-specific costs were $3,723 (95% CI 2,408-5,762) for all RA patients using any treatment regimen and $20,262 (95% CI 17,480-23,487) for bDMARD users. CONCLUSION: The total and disease-specific direct medical costs for patients with RA is substantial. Among bDMARD users, the cost of RA care is more than half of all direct medical costs.
29465346 IL-6 receptor inhibition modulates type III collagen and C-reactive protein degradation in 2018 Jul OBJECTIVES: The objective of this study was to examine the tissue degradation in response to anti-IL6 receptor treatment in rheumatoid arthritis (RA) patients which are anti-TNF-α inadequate responders. METHODS: RADIATE was a randomised, double-blinded, placebo-controlled, parallel-group, phase III trial. RA patients with previous inadequate response to anti-TNFα therapy (n=299) were randomly assigned to tocilizumab 4 or 8 mg/kg with methotrexate (10-25 mg weekly) or placebo with methotrexate. Type III collagen degradation (C3M) and CRP degradation (CRPM) were analysed in serum samples at baseline and 16 weeks. RESULTS: Treatment with 4 and 8 mg/kg tocilizumab significantly decreased C3M (p=0.0001 and p=0.0007) and CRPM (p<0.0001) levels after 16 weeks. Changes in C3M and CRPM levels after 16 weeks correlated well with the changes in disease activity score 28 (DAS28). Change in CRPM levels furthermore correlated moderately with the change in patient pain (VAS) (rpartial of 0.20) and Health assessment questionnaire disability index (HAQ-DI) (rpartial of 0.24). Changes in biomarker levels above median change led to an odds ratio of 1.95 (C3M) and 3.00 (CRPM) for achieving the American College of Rheumatology 20% improvement criteria (ACR20). CONCLUSIONS: This study shows that a decrease in inflammation leads to a decrease in excessive extracellular matrix degradation. It furthermore supports earlier shown evidence that tocilizumab works in the treatment of RA patients, although there is a clear need for identifying and selecting patients who are more likely to respond to treatment.
30456455 Role of miR-9-5p in preventing peripheral neuropathy in patients with rheumatoid arthritis 2019 Jan MicroRNAs (miRNAs) are found to play a key role in neural cell differentiation, peripheral nerve injury, and rheumatoid arthritis (RA). However, no study has yet been conducted highlighting their role in RA-induced peripheral neuropathy. Here, we investigated the role of miRNAs in RA-induced peripheral neuropathy. Levels of six miRNAs were detected in serum collected from 15 patients with RA and peripheral neuropathy and 16 patients with RA. In vitro, Schwann cells were treated with 0.1 ng/mL IL-6 and 20 ng/mL TNF-α. The expression level of miR-9-5p and its association with the repressor element-1 silencing transcription factor (REST) were investigated. The roles of miR-9-5p and REST in Schwann cell injury were examined after transfection of miR-9-5p mimics or REST siRNA. In patients with RA and peripheral neuropathy, serum miR-9-5p was significantly downregulated when compared with RA. In IL-6- and TNF-α-stimulated Schwann cells, apoptosis was induced, while the cell viability and level of miR-9-5p were inhibited. A significantly negative correlation was observed between miR-9-5p and REST. Transfection of miR-9-5p mimics and REST siRNA significantly reversed the inhibition of cell viability and induction of apoptosis caused by IL-6 and TNF-α. In addition, overexpression of miR-9-5p upregulated the expression of miR-132, miRNA targeting E1A binding protein EP300 (EEP300), phosphatase and tensin homolog (PTEN) and forkhead box O3 (FOXO3). These results showed that Schwann cells were protected by miR-9-5p from inflammatory damage by targeting REST/miR-132 pathway, which could provide new targets for treatment of RA-induced peripheral neuropathy.
30549501 Preoperative serum albumin as a predictor of complications following total hip replacement 2018 Jul BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease characterized by polyarthritis with progressive articular wear, immunologic abnormalities and increasing physical limitation. Surgical correction with hip replacement comes as a successful solution for patients with advanced articular destruction. Following intervention, surgical site infection (SSI), venous thromboembolism, sepsis, renal and major cardiovascular complications are among the most cited in the literature. No consensus exists as to the detection of preoperative hypoalbuminemia in patients with rheumatoid arthritis. METHODS: This study retrospectively evaluated the preoperative serum albumin of 75 patients with rheumatoid arthritis and analyzed its relevance in terms of appearance of postoperative complications with a six-month follow-up. Complications in the group of patients with low serum albumin and the group of patients with normal serum albumin were reviewed to identify the effect of each variable. Odds ratio for each variable was calculated (hospital readmission, surgical site infection, renal and cardiac complications, non-infectious wound complications and the presence of residual hip pain), as well as p-value and confidence intervals. RESULTS: Surgical site infection showed a statistically significant relation with low serum albumin (OR: 6.125, p = 0.018) as did non-infectious wound complications (OR: 3.714, p = 0.026) and residual hip pain (OR: 3.149, p = 0.022). CONCLUSION: Preoperative low serum albumin has a direct relation with the rate of postoperative complications including SSI, non-infectious wound complications (seroma formation, wound dehiscence) and residual hip pain. Preoperative serum albumin is a reliable marker of nutrition, which may establish preventive strategies to reduce postoperative complications in patients with rheumatoid arthritis.
29245178 Review: Transcriptional Regulation of CD4+ T Cell Differentiation in Experimentally Induce 2018 May Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the joint synovium and infiltration by activated inflammatory cells. CD4+ T cells form a large proportion of the inflammatory cells invading the synovial tissue, and are involved in the RA pathologic process. In general, CD4+ T cells differentiate into various T helper cell subsets and acquire the functional properties to respond to specific pathogens, and also mediate some autoimmune disorders such as RA. Because the differentiation of T helper cell subsets is determined by the expression of specific transcription factors in response to the cytokine environment, these transcription factors are considered to have a role in the pathology of RA. Treg cells control an excess of T cell-mediated immune response, and the transcription factor FoxP3 is critical for the differentiation and function of Treg cells. Treg cell dysfunction can result in the development of systemic autoimmunity. In this review, we summarize how the expression of transcription factors modulates T helper cell immune responses and the development of autoimmune diseases, especially in RA. Understanding the role of transcription factors in the pathogenesis of autoimmunity may lead to novel therapeutic strategies to control the differentiation and function of both T helper cells and Treg cells.
28696805 Relevance of P-glycoprotein on CXCR4(+) B cells to organ manifestation in highly active rh 2018 Mar INTRODUCTION: In rheumatoid arthritis (RA), P-glycoprotein (P-gp) expression on activated B cells is associated with active efflux of intracellular drugs, resulting in drug resistance. CXCR4 is associated with migration of B cells. This study was designed to elucidate the relevance of P-gp expression on CXCR4(+) B cells to clinical manifestations in refractory RA. METHODS: CD19(+) B cells were analyzed using flow cytometry and immunohistochemistry. RESULTS: P-gp was highly expressed especially on CXCR4(+)CD19(+) B cells in RA. The proportion of P-gp-expressing CXCR4(+) B cells correlated with disease activity, estimated by Simplified Disease Activity Index (SDAI), and showed marked expansion in RA patients with high SDAI and extra-articular involvement. In highly active RA, massive infiltration of P-gp(+)CXCR4(+)CD19(+) B cells was noted in CXCL12-expressing inflammatory lesions of RA synovitis and RA-associated interstitial pneumonitis. In RA patient with active extra-articular involvement, intracellular dexamethasone level (IDL) in lymphocytes diminished with expansion of P-gp(+)CXCR4(+) CD19(+) B cells. Adalimumab reduced P-gp(+)CXCR4(+) CD19(+) B cells, increased IDL in lymphocytes, and improved the clinical manifestation and allowed tapering of concomitant medications. CONCLUSIONS: Expansion of P-gp(+)CXCR4(+) B cells seems to be associated with drug resistance, disease activity and progressive destructive arthritis with extra-articular involvement in RA.
30176915 Increased DNA methylation variability in rheumatoid arthritis-discordant monozygotic twins 2018 Sep 4 BACKGROUND: Rheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease-discordant monozygotic twin pairs. METHODS: Genome-wide DNA methylation was assessed in 79 monozygotic twin pairs discordant for rheumatoid arthritis using the HumanMethylation450 BeadChip array (Illumina). Discordant twins were tested for both differential DNA methylation and methylation variability between rheumatoid arthritis and healthy twins. The methylation variability signature was then compared with methylation variants from studies of other autoimmune diseases and with an independent healthy population. RESULTS: We have identified a differentially variable DNA methylation signature that suggests multiple stress response pathways may be involved in the aetiology of the disease. This methylation variability signature also highlighted potential epigenetic disruption of multiple RUNX3 transcription factor binding sites as being associated with disease development. Comparison with previously performed epigenome-wide association studies of rheumatoid arthritis and type 1 diabetes identified shared pathways for autoimmune disorders, suggesting that epigenetics plays a role in autoimmunity and offering the possibility of identifying new targets for intervention. CONCLUSIONS: Through genome-wide analysis of DNA methylation in disease-discordant monozygotic twins, we have identified a differentially variable DNA methylation signature, in the absence of differential methylation in rheumatoid arthritis. This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders.
29509238 UCA1 impacts progress of rheumatoid arthritis by inducing the apoptosis of fibroblast-like 2018 Feb OBJECTIVE: Rheumatoid arthritis is a chronic autoimmune joint disease, which is characterized by the proliferation of fibroblast-like synoviocyte. Long non-coding RNA (lncRNA) has been reported to play an important role in the progression of many different diseases. The main objective of this research was to find out whether the lncRNAs influence the activity of fibroblast-like synoviocyte and the progression of this disease. PATIENTS AND METHODS: qRT-PCR was used to detect the expression of UCA1 in fibroblast-like synoviocyte from normal people and rheumatoid arthritis patients. MTT assay was used to detect the viability of cells. Apoptosis was detected by Caspase-3 Colorimetric Activity Assay Kit (Millipore, Billerica, MA, USA). Western blot was used to analyze the relationship of UCA1 and apoptosis. RESULTS: We found that the UCA1 was highly expressed in the normal fibroblast-like synoviocyte (NFLS), compared with the fibroblast-like synoviocyte of rheumatoid arthritis (RAFLS). We also found that the decrease in UCA1 expression increased the viability in NFLS and overexpressed UCA1 level in RAFLS decreased the viability. Caspase-3 was highly expressed in cells with higher viability. What's more, UCA1 could affect the viability of FLS by changing the expression of Wnt6. CONCLUSIONS: According to the results, we found that UCA1 was closely related to rheumatoid arthritis, which could be a potential target for treating it.
28379883 Rheumatoid arthritis and cancer risk[BULLET OPERATOR]results from the Greek European prosp 2018 Sep To investigate the relative risk of cancer development in rheumatoid arthritis (RA) patients in Greece after taking into consideration treatment modalities. The present analysis used data on the medical history of 26 331 participants in the Greek arm of the European Prospective Investigation into Cancer and Nutrition that were collected at enrollment and thereafter during active follow-up. A history of RA and of drug treatment for the disease, as reported at baseline examination, was linked to cases of cancer reported during follow-up. A total of 91 (9.9%) patients with RA developed a cancer compared with 1542 (6.1%) patients without RA. The overall hazard ratios of all cancers increased 25% [95% confidence interval (CI): 1-54] among participants with prevalent RA, and almost all the site-specific incident cancer sites considered had rate ratios above unity. In terms of the contribution of RA medication, the hazard ratios of patients treated with salicylates was close to unity (1.07, 95% CI: 0.69-1.65), whereas those who were not treated with salicylates had a 31% (95% CI: 3-67) increased risk for cancer incidence compared with those without RA at baseline. RA patients have excess cancer risk because of either underlying complex disease pathways or treatment agents targeting immune function. Administration of salicylates appears to reduce the risk of developing malignancies.
29995777 Depression and anxiety in systemic lupus erythematosus: The crosstalk between immunologica 2018 Jul Depression and anxiety cause severe loss of quality of life for patients with systemic lupus erythematosus. The causes and factors that contribute to these psychological manifestations in lupus are difficult to disentangle. This study compared clinical, psychological, and demographic factors between lupus patients, depressed patients, and rheumatoid arthritis patients to discover lupus-specific contributors to depression. Lupus-specific manifestations of depression were also investigated.Physiological, clinical, and psychosocial data were collected from 77 patients. ELISA was used to measure cytokine levels. Univariate and Multivariate analyses were used to compare the patient populations and identify correlations between key physical and psychological indicators.The prevalence of depression in the SLE cohort was 6 times greater than the healthy control subjects. Pain, IL-6, and Pittsburgh Sleep Quality index values were all significantly higher in SLE patients compared with the healthy control group (P < .001, P = .038, and P = .005, respectively). Anxiety levels were significantly higher in SLE patients compared to healthy and RA control patients (P = .020 and .011, respectively). Serum IL-10 concentrations, relationship assessment scale, and fatigue severity scale values were found to be correlated with depression among the SLE patients (P = .036, P = .007, and P = .001, respectively). Relationship assessment and fatigue severity scale scores were found to be the best indicators of depression for the SLE patients (P = .042 and .028, respectively).Fatigue Severity, relationship satisfaction, and IL-10 concentrations are indicators of depression in lupus patients. Despite also suffering from the pain and disability that accompanies chronic autoimmune disease, the rheumatoid arthritis patients had less anxiety and better relationship scores.
29602164 The impact of patient global assessment in the definition of remission as a predictor of l 2018 Jan BACKGROUND: Remission is the target for management of rheumatoid arthritis (RA) and intensification of immunosuppressive therapy is recommended for those that do not achieve this status. Patient global assessment (PGA) is the single patient reported outcome considered in the American College of Rheumatology/European League Against Rheumatism remission criteria, but its use as target has been questioned. The primary aim of this study is to assess whether excluding PGA from the definition of disease remission changes the association of disease remission with long-term radiographic damage and physical function in patients with RA. METHODS: Individual Patient Data Meta-analysis using data from randomized controlled trials of biological and targeted synthetic agents, identified through ClinicalTrials.gov and PubMed. Different remission states will be defined: (i) 4v-remission [tender (TJC28) and swollen 28-joint counts (SJC28) both≤1, C-reactive protein (CRP)≤1 (mg/dl), and PGA≤1 (0-10 scale)], (ii) 4v-near-remission (TJC28≤1, SJC28≤1, CRP≤1, and PGA>1), (iii) non-remission (TJC28>1 or SJC28>1 or CRP>1), all mutually exclusive, and (iv) 3v-remission (TJC28≤1, SJC28≤1, CRP≤1). Likelihood ratios will be used to descriptively compare whether meeting the 3v and 4v-remission criteria in a single visit (at 6 or 12 months) predicts good outcome in the second year (1-2y). Differences in the predictive value of PGA in the definition of remission will be assessed by comparing the three mutually exclusive disease states using logistic regression analysis. Good outcome is defined primarily by radiographic damage (no deterioration in radiographic scores, whatever the instrument used in each trial), and secondarily by functional disability (Health Assessment Questionnaire consistently ≤0.5 and no deterioration), and their combination ("overall good outcome"). Additional analyses will consider longer periods over which to (concurrently) define remission status and outcome (between 1-5y and 1-10y), different cut-offs to define good radiographic outcome (change ≤0.5, ≤3 and ≤5 in radiographic score), sustained remission and the influence of treatment and other clinical factors. DISCUSSION: If 4v-remission and 4v-near-remission are associated with a similar probability of good outcomes, particularly regarding structural damage, the 3v-remission (excluding PGA) could be adopted as the target for immunosuppressive therapy. Patients' perspectives would remain essential, but assessed separately from disease activity, using instruments adequate to guide adjunctive therapies. Systematic review registration: PROSPERO, CRD42017057099.
30612606 Extracellular vesicle-associated MMPs: A modulator of the tissue microenvironment. 2019 Extracellular vesicles (EVs) are small particles that mediate intercellular communications in local and distant microenvironments. Due to their ability to carry bioactive materials such as proteins, nucleic acids, and lipids, and to transfer their cargo into target cells, EVs are thought to be crucial mediators under pathological and physiological conditions. Recent investigations of their protein profiles have revealed the presence of metalloproteinases such as matrix metalloproteinases (MMPs) in EVs from various cell types and body fluids. Although information regarding the biological and clinical significance of MMPs in EVs is still limited, EV-associated MMPs can alter EV cargo by ectodomain shedding, exerting proteolytic activity following uptake by target cells, or directly contributing to degradation of extracellular matrix proteins surrounding cells. This review focuses on recent findings regarding EV-associated MMPs, and we further discuss their potential involvement in human diseases.
30551438 Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis followi 2019 Jan Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune arthropathy characterized by synovial hyperplasia leading to functional impairment. Although the exact cause of RA is unknown, there is evidence suggesting the role of T cell subtypes in the pathogenesis of RA. Conventional therapy in some RA patients is associated with mild or severe side effects, and resistance of some patients has been reported to these types of therapy. The therapeutic potential of mesenchymal stem cells (MSCs) introduced them as a novel therapeutic choice for the treatment of rheumatic diseases. The aim of our study was to evaluate the effects of intravenous administration of autologous bone marrow-derived MSCs on the immunological, clinical and para-clinical factors such as regulatory T cells, Th17 cells, CD8+ T cells, CD4+ T cells, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), visual analogue scale (VAS), ESR, C-reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) antibodies in patients with refractory RA. Nine refractory RA patients with no other rheumatologic disorders were included in this study. All patients received a single intravenous dose of 1 × 10(6) autologous bone marrow-derived MSCs/kg, and were followed up at 1, 6 and 12 months after injection of MSCs. We found a significant decreasing trend in Th17 percentage and geometric mean fluorescence intensity for IL-17A following injection of MSCs at 12 months compared to the time point zero. Furthermore, a significant increase in regulatory T cells percentage was observed at the end of the first month after the intervention. DAS28-ESR decreased significantly at 1 and 12 months after MSC therapy. VAS score showed a significant decreasing trend during the follow-up periods. No significant difference was found for serum CRP and anti-CCP levels after the intervention. In conclusion, our data indicated that clinical symptoms were significantly ameliorated following the intravenous injection of autologous bone marrow-derived MSCs to the patients with refractory RA.
29798702 Iguratimod, a synthetic disease modifying anti-rheumatic drug inhibiting the activation of 2019 May OBJECTIVE: To elucidate the clinical and radiographic outcomes for rheumatoid arthritis (RA) patients treated with a synthetic disease-modifying antirheumatic drug, iguratimod (IGU). METHODS: Clinical outcomes for 213 RA patients treated with 25 mg/day oral IGU or 50 mg/day after 4 weeks of 25 mg/day treatment for one day to 104 weeks were assessed. RESULTS: A total of 142 active RA patients (DAS28-ESR ≥3.2) treated for more than 12 weeks showed a significant reduction in both DAS and simplified disease activity index (SDAI) scores at week 4 (p < .001) to week 104. Good and moderate DAS responses were achieved in 54 (38%) and 66 (46%) patients, respectively. Total Genant-modified Sharp scores (GSS) of 31 patients at week 104 showed no progression (total GSS ≤0.84: the smallest detectable change) in 16 (52%) patients with a mean score reduction (95%CI) of -4.3 (-8.1∼-0.5) (p < .05). Predictors were an early response, moderate disease activity at baseline, and male gender. Eleven of the 213 patients had gastric and/or duodenal ulcer. A peculiar haemorrhage was seen in two patients treated concomitantly with IGU and warfarin potassium. CONCLUSION: IGU treatment shows an early and sustained efficacy. Radiographically, no progression of GSS was evident in 16 (52%) patients at week 104. Gastric bleeding or gastric perforation warrants careful attention, especially in patients with concomitant use of both a non-steroidal anti-inflammatory drug and oral prednisolone.