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ID PMID Title PublicationDate abstract
28002318 Brahma-related gene 1 induces apoptosis in a p53-dependent manner in human rheumatoid fibr 2016 Dec Blocked apoptosis and aggressive inflammatory responses occur in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA) patients. Although Brahma-related gene 1 (BRG1) is considered as a tumor suppressor, few research covers its role in RA. This study aims to reveal effects and potential mechanisms of BRG1 in human FLS cell line MH7A.BRG1 expression in MH7A cells was altered by transfection of overexpression vectors or short hairpin RNAs (shRNAs). Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry after transfection. Factors involved in inflammation and apoptosis were quantified by qPCR and Western blot. The interaction between BRG1 and p53 was assessed by immunoprecipitation (IP).Results showed that BRG1 overexpression significantly suppressed MH7A cell viability and induced apoptosis (P < 0.01), and its knockdown had opposite effects. BRG1 reduced mRNA levels of matrix metallopeptidase 3, TIMP metallopeptidase inhibitor 2, cyclooxygenase 2, and interleukin 6, implying its suppressive effects on inflammation. BRG1 interacted with and promoted p53 (P < 0.05). B-cell chronic lymphocytic leukemia/lymphoma 2 was suppressed (P < 0.05), while cytochrome c, caspase 3 (CASP3) and CASP9 were activated (P < 0.01) by BRG1. However, the regulation on these factors was abrogated by p53 knockdown (P < 0.01).These findings suggest that BRG1 may induce apoptosis and suppress inflammation in MH7A cells. Potential functional mechanisms involve the regulation of apoptotic factors by BRG1, which may depend on the recruitment and promotion of p53. This study provides the essential proof for applying BRG1 to the molecular therapy of RA.
26971256 Comparison of the clinical effectiveness of tumour necrosis factor inhibitors and abatacep 2016 Nov The aim of this study is to compare the clinical effectiveness of tumour necrosis factor inhibitors (TNFi) and abatacept (ABT) after insufficient response to tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). Among 527 RA patients treated with TCZ, 63 patients were enrolled who switched TCZ to alternative biologic agents because of moderate or high disease activity assessed by the Clinical Disease Activity Index (CDAI). They were divided into two groups, TNF inhibitors (TNFi) or abatacept (ABT), and compared for clinical effectiveness and adverse events at week 24. Forty-two were switched to TNFi, and 21 to ABT. TNFi included 19 infliximab, 3 adalimumab, 8 etanercept, 9 golimumab, and 3 certolizumab-pegol. Baseline characteristics at the switch were comparable except for the concomitant methotrexate use (TNFi 71.4 vs ABT 28.6 %, P = 0.003). The proportion of patients achieving CDAI ≤ 10 (remission or low disease activity) at week 24 was significantly higher in TNFi than ABT (64.3 vs 23.8 %, P = 0.003), and the values of the CDAI at week 24 was significantly better in TNFi than ABT (mean, 11.8 vs 16.4, P = 0.021) although the drug retention rate was not different between the two groups (73.8 vs 71.4 %, P = 0.803). No serious adverse event was observed in both groups. TNFi may be more effective than ABT to achieve clinical remission or low disease activity after insufficient response to TCZ in patients with RA, although drug retention rate and safety are comparable.
27716324 Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synov 2016 Oct 6 BACKGROUND: Interleukin 6 (IL-6) signaling plays a key role in the pathophysiology of rheumatoid arthritis (RA) and is inhibited by sarilumab, a human monoclonal antibody blocking the IL-6 receptor alpha (IL-6Rα). The effects of sarilumab plus methotrexate (MTX) on serum biomarkers of joint damage and bone resorption were assessed in two independent studies (phase II (part A) and phase III (part B)) of patients with RA with a history of inadequate response to MTX from the MOBILITY study (NCT01061736). METHODS: Serum samples were analyzed at baseline and prespecified posttreatment time points. Biomarkers of tissue destruction, cartilage degradation, and synovial inflammation were measured in part A; assessment of these markers was repeated in part B and included additional analysis of biomarkers of bone formation and resorption (including soluble receptor activator of nuclear factor-kB ligand (sRANKL)). A mixed model for repeated measures was used to compare treatment effects on change in biomarkers. Additionally, changes from baseline in biomarkers were compared between American College of Rheumatology 50 % responders and nonresponders and between patients who achieved or did not achieve low disease activity (LDA), separately by treatment group, at week 24. RESULTS: In part A, sarilumab 150 and 200 mg every 2 weeks (q2w) significantly reduced biomarkers of tissue destruction, cartilage degradation, and synovial inflammation at both 2 and 12 weeks posttreatment (p < 0.05 vs placebo). These results were replicated in part B, with markers of these damaging processes reduced at weeks 2 and 24 (p < 0.05 vs placebo). Additionally, sarilumab 200 mg q2w significantly reduced both sRANKL and sRANKL/osteoprotegerin ratio at week 24 (p < 0.01 vs placebo). Trends for reduction were noted for several biomarkers in patients who achieved LDA compared with those who did not. CONCLUSIONS: Sarilumab plus MTX significantly suppressed biomarkers of bone resorption and joint damage, as compared with placebo plus MTX, in patients with RA. Additional work is needed to determine whether differences in biomarker profiles at baseline or posttreatment can identify patients who achieve improvement in disease activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01061736 , February 2, 2010.
27696731 Incidence and Management of Cardiovascular Risk Factors in Psoriatic Arthritis and Rheumat 2017 Jan OBJECTIVE: To examine the prevalence and incidence of cardiovascular (CV) risk factors, including hypertension, hyperlipidemia, diabetes mellitus (DM), and obesity among patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) compared to the general population, and to examine the treatment of incident CV risk factors in PsA and RA compared to controls. METHODS: A cohort study was conducted within The Health Improvement Network, a medical record database in the UK, using data from 1994 to 2014. Patients ages 18-89 years with PsA or RA were matched to controls on practice and start date. The prevalence and incidence of CV risk factors identified by diagnostic codes were calculated. Cox proportional hazards models were used to examine the relative incidence of these CV risk factors. Finally, pharmacologic therapies for incident CV risk factors were examined. RESULTS: Study subjects included patients with PsA (n = 12,548), RA (n = 53,215), and controls (n = 389,269). The prevalence of all CV risk factors was significantly elevated in PsA. Only the prevalence of DM and obesity was increased in RA. Incidence of hypertension, hyperlipidemia, and DM was elevated in PsA and RA. Receipt of therapy within 1 year following incident diagnosis of CV risk factors was not substantially different between the groups; approximately 85%, 65%, and 45% of patients received prescriptions for hypertension, hyperlipidemia, and DM, respectively. CONCLUSION: Patients with PsA have an increased prevalence of CV risk factors, and both patients with PsA and patients with RA have increased incidence of a new diagnosis of CV risk factors. Pharmacologic treatment of CV risk factors in patients with PsA and RA was similar to controls in the UK.
25726324 Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: 2015 Apr BACKGROUND: To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. METHODS: We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453,411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746,171 total participants). FINDINGS: For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p = 9.3 × 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1.7%; p = 3.5 × 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p = 7.7 × 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p = 1.8 × 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p = 3.9 × 10(-10)). Per-allele odds ratios were 0.97 (0.95-0.99; p = 9.9 × 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p = 0.47) for type 2 diabetes, 1.00 (0.98-1.02; p = 0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p = 1.8 × 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. INTERPRETATION: Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations.
25545293 Increased expression of human leucocyte antigen class I free heavy chains on monocytes of 2015 Feb Human leucocyte antigen (HLA)-B27 expression is correlated with spondyloarthritis (SpA), but its role in disease pathogenesis remains unclear. The aim of the study was to determine whether HLA-B27 free heavy chain (FHC) contributes to SpA pathogenesis. Flow cytometry was used to analyse the FHC expression on CD3+ and CD14+ cells in the peripheral blood (PB) and synovial fluid (SF) from SpA patients, healthy controls, and rheumatoid arthritis (RA) patients. Human monocytic U937 cell lines stably expressing enhanced green fluorescence protein (EGFP)/HLA-B27, EGFP/HLA-A2 or EGFP alone were created to further investigate the relation between HLA-B27 and FHC expression. The relative FHC level on CD14+ PB cells was significantly higher in SpA patients than in controls, but lower than on the SF cells of SpA patients. No significant correlation was found for relative FHC expression with HLA-B27 or β2-microglobulin expression. HLA-B27-transfected U937 cells expressed higher FHC levels than either EGFP/HLA-A2- or EGFP-transfected cells. HLA class I FHC expression was significantly increased on monocytes of SpA patients and HLA-B27-transfected cells, implying that FHC, perhaps mostly derived from HLA-B27, plays an important role in SpA pathogenesis.
27522465 Calcium supplementation and inflammation increase mortality in rheumatoid arthritis: A 15- 2017 Feb OBJECTIVE: To investigate whether osteoporosis or use of calcium supplementations predict all-cause mortality, or death from CVD, in a longitudinal cohort of patients with rheumatoid arthritis (RA). METHODS: Patients in the Oslo RA register (ORAR) were examined, and bone mineral density was measured in 1996. The cohort was linked to the Norwegian Cause of Death registry on December 31, 2010. Death from CVD was defined in 3 following different outcomes: (1) primary atherosclerotic death, (2) atherosclerotic death as one of the 5 listed causes of death, and (3) CVD according to World Health Organization (WHO) definition as primary cause of death. Baseline predictors of all-cause mortality and death from CVD were identified in separate Cox regression models, using backwards selection. Sensitivity analyses were performed including analyses of interactions and competing risk. RESULTS: A total of 609 patients were examined in 1996/1997. By December 31, 2010, 162 patients (27%) had died, resulting in 7439 observed patient-years. Of the deceased, 40 (24.7%) had primary atherosclerotic death. In the final model of all-cause mortality increased baseline ESR [hazard ratio (HR) 1.02 per mm/h, 95% CI: 1.01-1.03], calcium supplementation (1.74, 1.07-2.84), and osteoporosis, defined as a T score ≤2.5 SD at any location, (1.58, 1.07-2.32) predicted higher mortality rates, in models adjusted for age, gender, and a propensity score. In the final model of primary atherosclerotic death, increased ESR (1.03 per mm/h, 1.01-1.05) and calcium supplementation (3.39, 1.41-8.08), predicted higher mortality. CONCLUSIONS: Increased baseline ESR and use of calcium supplementation were predictors of increased all-cause mortality and risk of death from CVD in this longitudinal study of patients with RA.
25884815 Implementing a patient-initiated review system in rheumatoid arthritis: a qualitative eval 2015 Apr 15 BACKGROUND: The management of Rheumatoid Arthritis (RA), a chronic relapsing condition primarily affecting joints usually entails regular hospital reviews with a specialist. These reviews can occur when the patient is well. This study forms part of a service evaluation of a system wide implementation of a patient initiated review appointment system which we have called Direct Access (DA). The aim was to explore the experiences of patients and staff of a DA system in order to understand the process of the implementation and to identify potential improvements. METHODS: Twenty-three patients with RA that had completed one year of follow-up on the DA system and seven healthcare professionals (HCPs) involved in the implementation of the DA review system took part in semi-structured interviews. Thematic analysis was used to analyse the interview data and field notes. RESULTS: Four themes emerged in the data: (1) building patient confidence and empowerment, (2) right place right time, (3) safety, (4) the everyday challenges of managing change. These show that in order for implementation to be successful the patient needs to have confidence in using a new system of requesting a medical review, which, in turn, needs to be offered quickly and in a setting convenient to both patient and clinician. Embedded in the change process need to be systems for ensuring regular disease monitoring and general issues surrounding team working, communication and ownership of the change process also need to be considered from the outset. CONCLUSION: The clinics offer increased patient autonomy and the opportunity for greater self-management of chronic disease. This fits with new models of care where the patient is considered to be 'the expert'.
26233510 Health Literacy Rates in a Population of Patients with Rheumatoid Arthritis in Southwester 2015 Sep OBJECTIVE: To determine the rate of low health literacy in the rheumatoid arthritis (RA) population in southwestern Ontario. METHODS: For the study, 432 patients with RA were contacted, and 311 completed the assessment. The health literacy levels of the participants were estimated using 4 assessment tools administered in the following order: the Single Item Literacy Screener (SILS), the Medical Term Recognition Test (METER), the Rapid Estimate of Adult Literacy in Medicine (REALM), and the Shortened Test of Functional Health Literacy in Adults (STOFHLA). RESULTS: The rates of low literacy as estimated by STOFHLA, REALM, METER, and SILS were 14.5%, 14.8%, 14.1%, and 18.6%, respectively. All 4 assessment tools were statistically significantly correlated. STOFHLA, REALM, and METER were strongly correlated with each other (r = 0.59-0.79), while SILS only demonstrated moderate correlations with the other assessment tools (r = 0.33-0.45). Multiple linear regression and binary logistic regression analyses revealed that low levels of education and a lack of daily reading activity were common predictors of low health literacy. Using a non-English primary language at home was found to be a strong predictor of low health literacy in STOFHLA, REALM, and METER. Male sex was found to be a significant predictor of poor performance in REALM and METER, but not STOFHLA. CONCLUSION: Low health literacy is an important issue in the southwestern Ontario RA population. About 1 in 7 patients with RA may not have the necessary skills to become involved in making decisions regarding their personal health. Rheumatologists should be aware of the low health literacy levels of patients with RA and should consider identifying patients at risk of low health literacy.
27333153 Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in t 2016 Nov OBJECTIVE: The intestinal microbiota is involved in the pathogenesis of arthritis. Altered microbiota composition has been demonstrated in patients with rheumatoid arthritis (RA). However, it remains unclear how dysbiosis contributes to the development of arthritis. The aim of this study was to investigate whether altered composition of human intestinal microbiota in RA patients contributes to the development of arthritis. METHODS: We analyzed the fecal microbiota of patients with early RA and healthy controls, using 16S ribosomal RNA-based deep sequencing. We inoculated fecal samples from RA patients and healthy controls into germ-free arthritis-prone SKG mice and evaluated the immune responses. We also analyzed whether the lymphocytes of SKG mice harboring microbiota from RA patients react with the arthritis-related autoantigen 60S ribosomal protein L23a (RPL23A). RESULTS: A subpopulation of patients with early RA harbored intestinal microbiota dominated by Prevotella copri; SKG mice harboring microbiota from RA patients had an increased number of intestinal Th17 cells and developed severe arthritis when treated with zymosan. Lymphocytes in regional lymph nodes and the colon, but not the spleen, of these mice showed enhanced interleukin-17 (IL-17) responses to RPL23A. Naive SKG mouse T cells cocultured with P copri-stimulated dendritic cells produced IL-17 in response to RPL23A and rapidly induced arthritis. CONCLUSION: We demonstrated that dysbiosis increases sensitivity to arthritis via activation of autoreactive T cells in the intestine. Autoreactive SKG mouse T cells are activated by dysbiotic microbiota in the intestine, causing joint inflammation. Dysbiosis is an environmental factor that triggers arthritis development in genetically susceptible mice.
25623388 The efficacy of motivational counseling and SMS-reminders on daily sitting time in patient 2015 Jan 27 BACKGROUND: Patients with RA (Rheumatoid Arthritis) are more sedentary than the general population. Reduction of Sedentary Behaviour (SB) has been suggested as a mean for improvement of health in patients with chronic diseases and mobility problems. Short-term intervention studies have demonstrated that SB can be reduced by behavioural interventions in healthy populations. However, it remains unexplored whether it is valid for patients with RA also. Therefore, the aim of this trial is to investigate the efficacy of an individually tailored, theory-based motivational counseling intervention on reducing daily sitting time in sedentary patients with RA. Additionally, to explore whether a reduction in daily sitting time is associated with reduced pain and fatigue, self-reported physical function, self-efficacy, improved health-related quality of life (HR-QoL) and cardiovascular biomarker levels, and finally to assess the cost-effectiveness of the intervention. METHODS/DESIGN: For this parallel group randomized trial, 150 patients with RA and at least 5 hours of sitting time per day, will be recruited from a rheumatology outpatient clinic, and block-randomized to the intervention group or the control group receiving usual care. The intervention includes: 1) individual motivational counseling (in total 3 sessions) on reduction of daily sitting time in combination with 2) individual Short Text Message Service (SMS) reminders over a 16-week intervention period. Primary outcome is change in daily sitting time (minutes) from baseline to 16 weeks measured objectively using an ActivPAL® Activity Monitor. Secondary outcomes include fatigue, pain, physical function, HR-QoL, self-efficacy, costs and cost-effectiveness. Furthermore, anthropometric measures will be included as well as measurement of blood pressure and serum lipids. All outcomes are assessed at baseline and repeated after 16 weeks. Follow-up assessments are made at 6 and 18 months post-intervention. DISCUSSION: The intervention is simple, non-invasive and may be implemented at low costs. If the study confirms the positive results expected, the intervention might be implemented in clinical practice and potentially transferred to other clinical populations. TRIAL REGISTRATION: ClinicalTrial.gov registration number: NCT01969604 . Date of registration: 17 October 2013.
27585689 Differences in Predictive Factors for Sustained Clinical Remission with Abatacept Between 2016 Nov OBJECTIVE: To differentiate predictive factors for sustained clinical remission between elderly and younger patients with rheumatoid arthritis (RA) receiving abatacept (ABA) as an initial biological disease-modifying antirheumatic drug. METHODS: The study involved 277 biologic-naive patients with RA with high or moderate disease activity, who were treated with intravenous ABA and evaluated for 48 weeks in 43 Japanese hospitals and rheumatology clinics (the ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD study: UMIN000004651). Predictive factors associated with sustained clinical remission defined by the 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) during the 24-48-week or 36-48-week periods were determined in elderly (≥ 65 yrs, n = 148) and younger patient groups (< 65 yrs, n = 129) using logistic regression analysis. RESULTS: Clinical remission was achieved at 24 and 48 weeks in 35.1% and 36.5% of patients in the elderly group and 34.9% and 43.4% in the younger group, respectively. In elderly patients, anticitrullinated protein antibody (ACPA) positivity and a lower DAS28-CRP score were significantly associated with sustained clinical remission; however, a lower Health Assessment Questionnaire-Disability Index (HAQ-DI) score was not related to sustained clinical remission. In younger patients, lower DAS28-CRP and HAQ-DI scores were predictive factors for sustained clinical remission, whereas ACPA positivity was not a useful predictive factor for sustained clinical remission. CONCLUSION: Although the effectiveness of ABA in biologic-naive patients with RA was equally recognized in elderly and younger patients, the baseline clinical characteristics associated with sustained clinical remission were substantially different.
27209200 Cross-sectional imaging of adult crystal and inflammatory arthropathies. 2016 Sep This article highlights the key aspects and current perspectives of the role of cross-sectional imaging in adult crystal and inflammatory arthropathies in adults, briefly discussing CT, and particularly focusing on MRI and US imaging as it supplements the conventional radiography. The role of conventional and advanced MR imaging techniques and imaging findings in this domain is discussed and illustrated with case examples. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article contains images and data, which were collected from patients as a part of a retrospective IRB from the institutional teaching files and informed consent was waived.
27354686 Nonadherence to disease modifying antirheumatic drugs in the first year after diagnosis: c 2016 Oct OBJECTIVES: The aim of this study was to compare three measurement methods for non-adherence to DMARDs in early arthritis patients: the Compliance Questionnaire Rheumatology (CQR), the intracellular uptake of MTX in the form of MTX-polyglutamates (MTX-PGs) and electronic measurement with Medication Event Monitoring Systems (MEMS). METHODS: DMARD naïve early arthritis patients were included in an ongoing cohort study. MEMS were used to measure adherence continuously, while every 3 months MTX-PGs were collected together with the CQR. The associations between the measures were estimated with Spearman rank correlations. Sensitivity and specificity of the CQR against a MEMS cut-off was compared at 3, 6, 9 and 12 months. The same applied to MTX-PGs against a MEMS cut-off and MTX-PGs against a CQR cut-off. For the association between MEMS, the CQR and MTX-PGs, a multilevel linear regression model was performed with age, gender, weeks of treatment and MTX dosage as covariates. RESULTS: We included 206 patients. Non-adherence measured with MEMS varied over time and between DMARDs. The CQR score was not associated with MEMS non-adherence at 3, 9 and 12 months. At 9 months, MTX-PGs was associated with MEMS non-adherence, as well as with the CQR. All correlations were below 0.30. CONCLUSION: Associations between the three measures are weak. Explanations are individual differences in the uptake of MTX, and little variance in adherence between patients. Moreover, the measurement domains differ: perceptions (CQR), behaviour (MEMS) and pharmacokinetics (MTX).
27671823 Natural Withanolides in the Treatment of Chronic Diseases. 2016 Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000 years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types. Subsequently, extensive pharmacologic research has identified multiple mechanisms of action across key inflammatory pathways. In this chapter we identify and describe the major withanolides with anti-inflammatory properties, illustrate their role within essential and supportive inflammatory pathways (including NF-κB, JAK/STAT, AP-1, PPARγ, Hsp90 Nrf2, and HIF-1), and then discuss the clinical application of these withanolides in inflammation-mediated chronic diseases (including arthritis, autoimmune, cancer, neurodegenerative, and neurobehavioral). These naturally derived compounds exhibit remarkable biologic activity across these complex disease processes, while showing minimal adverse effects. As novel compounds and analogs continue to be discovered, characterized, and clinically evaluated, the interest in withanolides as a novel therapeutic only continues to grow.
22700600 Unconditional tests for comparing two ordered multinomials. 2016 Feb We consider two exact unconditional procedures to test the difference between two multinomials with ordered categorical data. Exact unconditional procedures are compared to other approaches based on the Wilcoxon mid-rank test and the proportional odds model. We use a real example from an arthritis pain study to illustrate the various test procedures and provide an extensive numerical study to compare procedures with regards to type I error rates and power under the unconditional framework. The exact unconditional procedure based on estimation followed by maximization is generally more powerful than other procedures, and is therefore recommended for use in practice.
27296719 Mast cell depletion in the preclinical phase of collagen-induced arthritis reduces clinica 2016 Jun 13 BACKGROUND: Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, which is characterized by inflammation of synovial joints leading to the destruction of cartilage and bone. Infiltrating mast cells can be found within the inflamed synovial tissue, however their role in disease pathogenesis is unclear. Therefore we have studied the role of mast cells during different phases of experimental arthritis. METHODS: We induced collagen-induced arthritis (CIA), the most frequently used animal model of arthritis, in an inducible mast cell knock-out mouse and determined the effect of mast cell depletion on the development and severity of arthritis. RESULTS: Depletion of mast cells in established arthritis did not affect clinical outcome. However, depletion of mast cells during the preclinical phase resulted in a significant reduction in arthritis. This reduction coincided with a decrease in circulating CD4(+) T cells and inflammatory monocytes but not in the collagen-specific antibody levels. Mast cell depletion resulted in reduced levels of IL-6 and IL-17 in serum. Furthermore, stimulation of splenocytes from mast cell-depleted mice with collagen type II resulted in reduced levels of IL-17 and enhanced production of IL-10. CONCLUSIONS: Here we show that mast cells contribute to the preclinical phase of CIA. Depletion of mast cells before disease onset resulted in an altered collagen-specific T cell and cytokine response. These data may suggest that mast cells play a role in the regulation of the adaptive immune response during the development of arthritis.
27193610 Benefit and Risk of Tofacitinib in the Treatment of Rheumatoid Arthritis: A Focus on Herpe 2016 Sep The biologics have revolutionized the treatment of rheumatoid arthritis (RA). However, there are still patients that are difficult to control and a cure is still not achievable. Tofacitinib, a Janus kinase (JAK) inhibitor is an orally available, new-in-class, disease-modifying anti-rheumatic drug with similar efficacy to biologics. JAK is activated by multiple cytokines involved in the pathology of RA, and affects non-immune and immune cells, mainly the lymphocytes. Besides its anti-rheumatic effect, the recent focus has been on adverse events. As with other biologics, serious infections have been observed especially with patients with lymphopenia, consistent with the mechanism of action. The major difference in adverse events from other disease-modifying anti-rheumatic drugs is the prominent increase in the occurrence of herpes zoster; it is increased worldwide, especially in Asia. There are other concerns such as malignancies and hyperlipidemia that may cause cardiovascular events that deserve further attention. The first JAK inhibitor for RA is demonstrating great benefit along with some risk, providing insights into the post-biologic era.
27716430 A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid ar 2016 Oct 6 BACKGROUND: Increased expression of toll-like receptor 4 (TLR4) and its endogenous ligands, is characteristic of rheumatoid arthritis (RA) synovitis. In this study, we evaluated how these TLR4 ligands may drive pathogenic processes and whether the fine profiling of anti-citrullinated protein antibodies (ACPA) based on their target specificity might provide a simple means to predict therapeutic benefit when neutralizing TLR4 in this disease. METHODS: The capacity of RA synovial fluids (RASF) to stimulate cytokine production in monocytes from patients with RA was analyzed by ELISA. The presence of TLR4 activators in RASF was determined by measuring the levels of ACPA, ACPA subtypes with reactivity to specific citrullinated peptides and other TLR4 ligands. Neutralization of TLR4 signaling was investigated using NI-0101, a therapeutic antibody that targets TLR4. RESULTS: RASF exhibited a heterogeneous capacity to induce production of proinflammatory cytokines by monocytes isolated from patients with RA. Such cytokine responses were significantly modified by TLR4 blockade achieved using NI-0101. The analysis of the content of RASF and matched sera demonstrated that ACPA fine specificities in patient samples predict cellular response to anti-TLR4 exposure in vitro. CONCLUSION: TLR4 represents a possible therapeutic target in RA. Our study demonstrates that TLR4 inhibition in an ex vivo model of RA pathogenesis can significantly modulate cytokine release and does so in specific subgroups of RA patient-derived samples. It also suggests that ACPA fine profiling has the potential to identify RA patients with a predominantly TLR4-driven pathotype that could be used to predict preferential response to TLR4 antagonism.
27709830 A Truncated IL-17RC Peptide Ameliorates Synovitis and Bone Destruction of Arthritic Mice. 2016 Nov Peptide-based therapy, such as modified peptides, has attracted increased attention. IL-17 is a promising therapeutic target for autoimmune diseases, and levels of circulating bioactive IL-17 are associated with rheumatoid arthritis severity. In this study, a modified truncated IL-17RC is generated to ameliorate inflammation and bone destruction in arthritis. The truncated IL-17RC binds to both IL-17A and IL-17F with higher binding capacity compared to nonmodified IL-17RC. In addition, the truncated IL-17RC reduces the secretion of inflammatory and osteoclastogenic factors induced by IL-17A/F in vitro. Moreover, the administration of truncated IL-17RC dramatically improves symptoms of inflammation and inhibited bone destruction in collagen-induced arthritis mice. Collectively, these data demonstrate that modified truncated IL-17RC peptide may be a more effective treatment strategy in the simultaneous inhibition of both IL-17A and IL-17F signaling, whereas the existing agents neutralize IL-17A or IL-17F alone. These suggest that the truncated IL-17RC may be a potential candidate in the treatment of inflammatory associated bone diseases.