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ID PMID Title PublicationDate abstract
29520783 The KCNQ1 gene polymorphism as a shared genetic risk for rheumatoid arthritis and chronic 2018 Mar BACKGROUND: A number of studies have suggested a bidirectional relationship of periodontitis with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). However, the genetic factors that underlie these relationships have not been elucidated. METHODS: We conducted a multicenter case-control study that included 185 patients with RA and chronic periodontitis (CP), 149 patients with T2DM and CP, 251 patients with CP, and 130 systemically and periodontally healthy controls from a cohort of Japanese adults to assess the shared genetic risk factors for RA and CP as well as for T2DM and CP. A total of 17 candidate single nucleotide polymorphisms (SNPs) associated with RA, T2DM, and CP were genotyped. RESULTS: Multiple logistic regression analyses revealed that the KCNQ1 rs2237892 was significantly associated with comorbidity of RA and CP (P = 0.005) after adjustment for age, sex, and smoking status. The carriers of the T allele among patients with RA and CP showed significantly higher disease activity scores including 28 joints using C-reactive protein values than the non-carriers (P = 0.02), although the age, female percentage, and smoking status were comparable. Other SNPs were not associated with comorbidity of RA and CP, T2DM and CP, or susceptibility to CP. CONCLUSION: The results of the present pilot study suggest for the first time that the KCNQ1 rs2237892 may constitute a shared genetic risk factor for RA and CP, but not for T2DM and CP in Japanese adults.
29096934 A randomized trial of a motivational interviewing intervention to increase lifestyle physi 2018 Apr BACKGROUND: Arthritis is a leading cause of chronic pain and functional limitations. Exercise is beneficial for improving strength and function and decreasing pain. We evaluated the effect of a motivational interviewing-based lifestyle physical activity intervention on self-reported physical function in adults with knee osteoarthritis (KOA) or rheumatoid arthritis (RA). METHODS: Participants were randomized to intervention or control. Control participants received a brief physician recommendation to increase physical activity to meet national guidelines. Intervention participants received the same brief baseline physician recommendation in addition to motivational interviewing sessions at baseline, 3, 6, and 12 months. These sessions focused on facilitating individualized lifestyle physical activity goal setting. The primary outcome was change in self-reported physical function. Secondary outcomes were self-reported pain and accelerometer-measured physical activity. Self-reported KOA outcomes were evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for KOA (WOMAC scores range from 0 to 68 for function and 0 to 20 for pain) and the Health Assessment Questionnaire (HAQ) for RA. Outcomes were measured at baseline, 3, 6, 12, and 24 months. Multiple regression accounting for repeated measures was used to evaluate the overall intervention effect on outcomes controlling for baseline values. RESULTS: Participants included 155 adults with KOA (76 intervention and 79 control) and 185 adults with RA (93 intervention and 92 control). Among KOA participants, WOMAC physical function improvement was greater in the intervention group compared to the control group [difference = 2.21 (95% CI: 0.01, 4.41)]. WOMAC pain improvement was greater in the intervention group compared to the control group [difference = 0.70 (95% CI: -0.004, 1.41)]. There were no significant changes in physical activity. Among RA participants, no significant intervention effects were found. CONCLUSION: Participants with KOA receiving the lifestyle intervention experienced modest improvement in self-reported function and a trend toward improved pain compared to controls. There was no intervention effect for RA participants. Further refinement of this intervention is needed for more robust improvement in function, pain, and physical activity.
29369319 Endogenous sialic acid-engineered micelles: a multifunctional platform for on-demand metho 2018 Feb 8 Rheumatoid arthritis (RA) patients have suffered from the current drug therapeutic regimen because of its high toxicity and the absence of bone regeneration for existing erosion, seriously affecting the quality of life. Herein, a sialic acid-dextran-octadecanoic acid (SA-Dex-OA) conjugate was synthesized to form micelles with a 55.06 μg mL(-1) critical micelle concentration. The obtained micelles can encapsulate a disease-modifying anti-rheumatic drug, methotrexate (MTX), with 4.28% (w/w) drug content, featuring sustained drug release behavior over 48 h. In vitro and in vivo studies showed that SA-Dex-OA micelles significantly improved accumulation and transportation through a combination of SA and E-selectin receptors in inflamed cells and arthritic paws highly expressing E-selectin. MTX-loaded SA-Dex-OA micelles not only significantly inhibited the inflammatory response, but also diminished the adverse effects of MTX, as reflected by the reduced alanine aminotransferase, aspartate aminotransferase, creatinine, and urea nitrogen levels. Most importantly, the bone mineral density in rats treated with MTX-loaded SA-Dex-OA micelles was significantly higher as compared to in those treated with free MTX and Dex-OA/MTX micelles (increasing from 391.4 to 417.4 to 492.7 mg cc(-1)), benefiting from the effects of endogenous sialic acid in promoting MC3T3-E1 cell differentiation and mineralization. It is anticipated that SA-based micelles with bone repair activities have great potential for RA treatment and other metabolic bone diseases with serious bone erosion.
30373599 Radiographic and clinical outcomes of C1-C2 intra-articular screw fixation in patients wit 2018 Oct 29 BACKGROUND: The Magerl and Goel-Harms techniques have been reported to produce excellent treatment outcomes in cases of atlantoaxial subluxation, but they also carry a risk of vertebral artery injuries. In order to completely prevent such injuries, we developed a surgical procedure, involving bone grafting between the C1 posterior arch and C2 lamina with clamp- or hook-and-rod-based fixation combined with the insertion of an interference screw into the posterior atlantoaxial joint. METHODS: This was a retrospective single-center study. The subjects were 58 patients in whom atlantoaxial subluxation was treated with the abovementioned procedure after 1995 (33 patients with rheumatoid arthritis (RA group) and 25 patients without rheumatoid arthritis (non-RA group)). The clinical outcomes and imaging findings of anterior subluxation at ≥ 2 years after surgery were compared between the RA and non-RA groups. RESULTS: No vertebral artery injuries occurred during surgery. Seven and two patients died during the follow-up period in the RA and non-RA groups, respectively, but none of these deaths were associated with surgery. At ≥ 2 years after surgery, the visual analogue scale score, Japanese Orthopaedic Association score, and Ranawat classification had significantly improved in both groups (p < 0.001). Radiologically, bone fusion was noted in all patients. Significant changes in the atlas-dens interval (ADI) were seen immediately after surgery in both groups (p < 0.001). In the non-RA group, significant changes in the corrected atlantoaxial height were observed immediately after surgery (p < 0.01), and loss of correction was seen at the final follow-up, but it was not significant (p = 0.1965). No significant changes were noted in any other parameter. Regarding the postoperative alignment of the cervical spine, lordosis tended to decrease, but additional surgery was only performed in one patient, who had developmental stenosis at the mid-lower level and belonged to the RA group. No reoperations due to fused adjacent segmental disease or exacerbated curvature were required. CONCLUSION: In the present study, no vertebral artery injuries occurred during surgery, and no major perioperative complications developed. Favorable clinical outcomes were observed at ≥ 2 postoperative years although the patients' diseases varied. This procedure produced superior outcomes, especially in terms of spinal correction and the maintenance of the ADI.
30459400 Variations in oral microbiome profiles in rheumatoid arthritis and osteoarthritis with pot 2018 Nov 20 The key to arthritis management is early diagnosis and treatment to prevent further joint destruction and maximize functional ability. Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common types of arthritis that the primary care provider must differentiate, in terms of diagnosis and treatment. Effective and non-invasive strategies for early detection and disease identification are sorely needed. Growing evidence suggests that RA has a correlation with oral microbiome and may be affected by its dynamic variations. There is already a study comparing oral microbiome in patients with RA and OA, however, it did not screen for potential biomarkers for arthritis. In this study, we assessed the oral microbiome in saliva samples from 110 RA patients, 67 OA patients and 155 healthy subjects, using 16S rRNA gene amplicon sequencing. The structure and differences in oral microbiome between RA, OA and healthy subjects were analyzed. Eight oral bacterial biomarkers were identified to differentiate RA from OA. This report provides proof of oral microbiota as an informative source for discovering non-invasive biomarkers for arthritis screening.
29426578 TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methot 2018 Jun Rheumatoid arthritis (RA) is an autoimmune arthropathy characterized by chronic articular inflammation. Methotrexate (MTX) remains the first-line therapy for RA and its anti-inflammatory effect is associated with the maintenance of high levels of extracellular adenosine (ADO). Nonetheless, up to 40% of RA patients are resistant to MTX treatment and this is linked to a reduction of CD39 expression, an ectoenzyme involved in the generation of extracellular ADO by ATP metabolism, on circulating regulatory T cells (Tregs). However, the mechanism mediating the reduction of CD39 expression on Tregs is unknown. Here we demonstrated that the impairment in TGF-β signalling lead to the reduction of CD39 expression on Tregs that accounts for MTX resistance. TGF-β increases CD39 expression on Tregs via the activation of TGFBRII/TGFBRI, SMAD2 and the transcription factor CREB, which is activated in a p38-dependent manner and induces CD39 expression by promoting ENTPD1 gene transcription. Importantly, unresponsive patients to MTX (UR-MTX) show reduced expression of TGFBR2 and CREB1 and decreased levels of p-SMAD2 and p-CREB in Tregs compared to MTX-responsive patients (R-MTX). Furthermore, RA patients carrying at least one mutant allele for rs1431131 (AT or AA) of the TGFBR2 gene are significantly (p = 0.0006) associated with UR-MTX. Therefore, we have uncovered a molecular mechanism for the reduced CD39 expression on Tregs, and revealed potential targets for therapeutic intervention for MTX resistance.
29718743 A real-world, multi-site, observational study of infusion time and treatment satisfaction 2018 Jul OBJECTIVES: To assess real-world infusion times for golimumab (GLM-IV) and infliximab (IFX) for rheumatoid arthritis (RA) patients and factors associated with treatment satisfaction. METHODS: An observational study assessed infusion time including: clinic visit duration, RA medication preparation and infusion time, and infusion process time. Satisfaction was assessed by a modified Treatment Satisfaction Questionnaire for Medication (patient) and study-specific questionnaires (patient and clinic personnel). Comparative statistical testing for patient data utilized analysis of variance for continuous measures, and Fisher's exact or Chi-square test for categorical measures. Multivariate analysis was performed for the primary time endpoints and patient satisfaction. RESULTS: One hundred and fifty patients were enrolled from six US sites (72 GLM-IV, 78 IFX). The majority of patients were female (80.0%) and Caucasian (88.7%). GLM-IV required fewer vials per infusion (3.7) compared to IFX (4.9; p = .0001). Clinic visit duration (minutes) was shorter for GLM-IV (65.1) compared to IFX (153.1; p < .0001), as was total infusion time for RA medication (32.8 GLM-IV, 119.5 IFX; p < .0001) and infusion process times (45.8 GLM-IV, 134.1 IFX; p < .0001). Patients treated with GLM-IV reported higher satisfaction ratings with infusion time (p < .0001) and total visit time (p = .0003). Clinic personnel reported higher satisfaction with GLM-IV than IFX specific to medication preparation time, ease of mixing RA medication, frequency of patients requiring pre-medication, and infusion time. LIMITATIONS: Findings may not be representative of care delivery for all RA infusion practices or RA patients. CONCLUSIONS: Shorter overall clinic visit duration, infusion process, and RA medication infusion times were observed for GLM-IV compared to IFX. A shorter duration in infusion time was associated with higher patient and clinic personnel satisfaction ratings.
30455959 Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in al 2018 Dec ω3-polyunsaturated free fatty acids (ω3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3-azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3-PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis was scrutinized. Cpd A did not alter the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease-like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3-PUFAs, this also suggests that GPR120/FFA4 activation by ω3-PUFAs does not significantly contribute to the health-promoting effects of ω3-PUFAs in autoimmune diseases.
29329602 Abatacept used in combination with non-methotrexate disease-modifying antirheumatic drugs: 2018 Jan 2 BACKGROUND: Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce. METHODS: In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials. RESULTS: Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n = 152; sulfasalazine n = 123; azathioprine n = 59; and leflunomide n = 397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were -0.54 vs -0.44 (ATTAIN), -0.43 vs -0.43 (ASSURE), and -0.39 vs -0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE). CONCLUSIONS: Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX. TRIAL REGISTRATION: ClinicalTrials.gov NCT00048581 . Registered 2 November 2002. ClinicalTrials.gov NCT00048932 . Registered 11 November 2002. ClinicalTrials.gov NCT00124982 . Registered 30 June 2005. ClinicalTrials.gov NCT02109666 . Registered 8 April 2014.
29490959 Design of a phase IV randomised, double-blind, placebo-controlled trial assessing the ImPa 2018 Feb 28 INTRODUCTION: The current American College of Rheumatology and European League Against Rheumatism treatment recommendations advise tapering biological disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) who achieve stable clinical remission while receiving bDMARDs. However, not all patients maintain remission or low disease activity after tapering or discontinuation of bDMARDs. The aim of the ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) study, or PREDICTRA, is to generate data on patient and disease characteristics that may predict the clinical course of a fixed dose-tapering regimen with the bDMARD adalimumab. METHODS AND ANALYSIS: PREDICTRA is an ongoing, multicentre, phase IV, randomised, double-blind, parallel-group study of adalimumab dose tapering controlled by withdrawal in participants with RA who achieved stable clinical remission while receiving adalimumab. The study includes a screening period, a 4-week lead-in period with open-label adalimumab 40 mg every other week and a subsequent 36-week double-blind period during which participants are randomised 5:1 to adalimumab 40 mg every 3 weeks (taper arm) or placebo (withdrawal arm). The primary explanatory efficacy variables are lead-in baseline hand and wrist MRI-detected synovitis and bone marrow oedema scores, as well as a composite of both scores; the dependent variable is the occurrence of flare up to week 40. Additional efficacy variables, safety, pharmacokinetics, biomarkers and immunogenicity will also be assessed, and an ultrasound substudy will be conducted. ETHICS AND DISSEMINATION: The study is conducted in accordance with the International Conference on Harmonisation guidelines, local laws and the ethical principles of the Declaration of Helsinki. All participants are required to sign a written informed consent statement before the start of any study procedures. TRIAL REGISTRATION NUMBER: EudraCT 2014-001114-26 and NCT02198651; Pre-results.
30599401 Inhibition of tumor necrosis factor-alpha (TNF-alpha) in patients with early rheumatoid ar 2019 Feb OBJECTIVE: Dicckopf-1 (Dkk-1) is a potent inhibitor of the Wnt canonical pathway. In rheumatoid arthritis (RA), Dkk-1 is upregulated by tumor necrosis factor-α (TNF). Certolizumab pegol (CMZ) is a biologic TNF-inhibitor (TNFi) effective in RA and slows radiographic progression. Data on the immediate effects (≤1-8 weeks) of TNFi on Wnt modulators are lacking. This study investigated the acute influence of TNFi treatment on Wnt modulators (Dkk-1 and sclerostin) and bone turnover markers (BTM), including intact N-terminal propeptide of collagen type I (PINP) and C-terminal telopeptide of type I collagen (CTX-I). METHODS: This longitudinal, uncontrolled study involved female RA patients with inadequate response to conventional methotrexate who underwent treatment with CMZ. ESR, Dkk-1, sclerostin, BTM, parathyroid hormone (PTH), and 25OH-vitamin D levels were evaluated at baseline, week 1, week 4, and week 8. Radiographs of the hands and feet were obtained at baseline and the total and erosion scores were assessed using the Simple Erosion Narrowing Score method (SENS). RESULTS: Seventeen patients were enrolled. Dkk-1 and CTX-I significantly decreased after one week of treatment with CMZ (-49.1 ± 17.1% and -25.0 ± 20.6%, respectively, p < 0.01), whereas PINP increased (+43.2 ± 31.5%, p < 0.01). These changes persisted at week 4 and 8. CONCLUSIONS: Our study showed that TNF-alpha inhibition with CMZ promptly results in a rapid decline of serum Dkk-1 levels, alongside decreased bone resorption and increased bone formation.
29903793 Effectiveness and safety of golimumab in patients with rheumatoid arthritis, psoriatic art 2018 Jun 14 OBJECTIVE: The Non Interventional Evaluation with Golumimab (GO-NICE) study aimed to document patient and treatment characteristics as well as clinical effectiveness and safety in adult patients newly treated with the tumour necrosis factor inhibitor golimumab (GLM). DESIGN: Prospective non-interventional study with 24-month observation per patient. SETTING: 158 office-based and clinical-based physicians in Germany. INTERVENTION: GLM administered in the 50 mg dose subcutaneously in monthly intervals under real-life conditions. RESULTS: Of the 1613 included patients, 1458 patients were eligible for final analysis: 474 patients with rheumatoid arthritis (RA, 54.9±13.4 years, 72.8% women, 64.7% biologic-naïve), 501 with psoriatic arthritis (PsA, 50.5±12.1 years, 54.1% women, 56.5% biologic-naïve) and 483 with ankylosing spondylitis (AS, 43.6±12.3 years, 66.5% men, 61.0% biologic-naïve). 664 patients completed follow-up (2-year retention rate 45.5%). Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28-ESR) decreased from 5.0 to 2.9 after 24 months (p<0.0001) in patients with RA, and Bath Ankylosing Spondylitis Disease Index score decreased from 5.1 to 2.4 (p<0.0001) in patients with AS. Response rate calculated in patients with PsA by modified Psoriatic Arthritis Response Criteria was 67.9% after 24 months. Most adverse events were of mild or moderate nature, and no new safety signals were detected. According to the physicians' clinical assessments, treatment with GLM was successful (no adverse drug reaction and a clear or moderate therapeutic effect in an individual patient) in 55.0%-56.6% of patients with RA, PsA and AS, respectively, at month 3, increasing from 74.5% to 76.1% at month 24. CONCLUSIONS: GLM subcutaneously once monthly led to substantial improvements in clinical effectiveness in patients with various inflammatory rheumatic diseases who could be followed up in a real-life setting in Germany. The treatment was well tolerated, and the safety profile of GLM was consistent with that observed in the previous randomised controlled trials. TRIAL REGISTRATION NUMBER: NCT01313858.
29578474 Relationship of hematologic markers with IL-17 and IL-1 beta in patients with rheumatoid a 2018 OBJECTIVES: In this study, we aimed to investigate the relationship of NLR (Neutrophil lymphocyte ratio), MPV (mean platelet volume), PDW (distribution width) rates in rheumatoid arthritis (RA) patients with IL-17 and IL-1 beta which are within the cytokines playing an important role in etiopathogenesis and activity of the disease. PATIENTS AND METHODS: Fifty-seven RA patients diagnosed according to RA classification criteria of ACR/EULAR 2010 and 37 controls were included into the study. WBC (white blood cell), NEU (neutrophil), PLT (platelet), LYM (lymphocyte) values in complete blood count received from routine blood examination of patients were recorded, and NLR, PLR (platelet lymphocyte ratio) rates were recorded. IL-17 and IL-1 beta were studies in serum samples. Disease activity of RA patients was evaluated with Disease Activity Score (DAS28). Age, gender, disease age, BMI (body mass index), medications used, co-morbid diseases, smoking of the patients were recorded. RESULTS: Fifty-seven RA patients (46 (80.7%) females, 11 (19.3%) males), and 34 patients (24 (70.6% females and 10 (29.4) males) as a control group were involved. Demographic characteristics were similar between two groups, and statistically significant difference was not detected between patient and control groups in terms of gender, age, and BMI (p> 0.05). We found higher NLR, MPV, PDW, IL-17 values in RA patients compared to control group (p< 0.05). There was a positive correlation of NLR with DAS28, CRP. While erythrocyte sedimentation rate (ESR) had negative correlation with MPV and PDW, it had positive correlation with PLT. We found positive correlation of C-reactive protein (CRP) with NLR and PLT. We could not find correlation of IL-1 beta and IL-17 with hematologic markers. CONCLUSION: In this study, we investigated the relationship of IL-17 and IL-1 beta which play an important role in pathogenesis of RA patients with the parameters analyzed in routine complete blood count, providing information about disease activity such as DAS 28, CRP, and ESR. We illuminated on an issue which has not discussed before by looking from a different angle. More extensive, follow-up studies are needed to emphasize the importance of these parameters and to reveal the relationship between cytokines during the follow-up of the disease activity.
30384383 Circulating Exosomal miR-17 Inhibits the Induction of Regulatory T Cells via Suppressing T 2018 BACKGROUND/AIMS: A reduced prevalence of circulating regulatory T cells (Tregs)is a hallmark of inflammatory rheumatoid arthritis (RA). However, the underlying mechanisms of alterations of Tregs are unclear. METHODS: The ratio of Tregs in peripheral blood of healthy controls (HCs) and patients with RA was determined by flow cytometry. MicroRNA (miRNA) expression profiles in exosomes derived from RA patients (RA-exosomes) and in those from HCs (HC-exosomes) were detected by microarray analysis, and miR-17 was measured by quantitative real-time PCR. Transforming growth factor beta receptor II (TGFBR II) expressed by T cells was measured by flow cytometry. The interaction between miR-17 and TGFBR II was evaluated by dual-luciferase reporter assay. RESULTS: We found that RA-exosomes can selectively affect Treg differentiation in vitro. Several miRNAs are more abundant in the RA-exosomes than in HC-exosomes. Among those upregulated in patients with RA, miR-17 can suppress Treg induction by inhibiting the expression of TGFBR II. CONCLUSION: Our findings imply that altered miRNA expression in RA-exosomes may contribute to the pathogenesis of RA by disrupting the homeostasis of Tregs.
30054785 The analgesic effect and possible mechanisms by which koumine alters type II collagen-indu 2019 Jan Gelsemium elegans Benth. is a toxic plant that has been used as an ancient Chinese herbal remedy for rheumatoid arthritis (RA) and nervous pain, spasticity, skin ulcers, and cancers. Koumine, one of its representative alkaloids, shows numerous promising pharmacological activities, including anti-inflammatory and analgesic activities. Here, we investigated the analgesic effect of koumine on the collagen-induced arthritis (CIA) rat model of RA and explored the potential pharmacological mechanisms underlying the analgesia. In the CIA rats, repeated koumine treatments significantly reduced pain compared to controls and attenuated the collagen-induced increase in levels of glial fibrillary acidic protein (GFAP) and the pro-inflammatory cytokines tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Cultured astrocytes showed reduced astrocyte reactivation and decreased production of both tested cytokines. Based on our results, koumine exerted both analgesic and anti-inflammatory effects on the CIA rat model that were apparently mediated by inhibiting astrocyte reactivation and pro-inflammatory cytokine production.
29477401 Cost-Effectiveness Analysis of Abatacept Compared with Adalimumab on Background Methotrexa 2018 Feb OBJECTIVES: To assess cost effectiveness of abatacept versus adalimumab, each administered with methotrexate, in treating patients with rheumatoid arthritis (RA) stratified according to baseline anticitrullinated protein antibody (ACPA) levels (marker of poor prognosis in RA). METHODS: A payer-perspective cost-effectiveness model simulated disease progression in patients with RA who had previously failed conventional disease-modifying antirheumatic drugs and were starting biologic therapy. Patients commenced treatment with abatacept or adalimumab plus methotrexate and were evaluated after 6 months. Therapy continuation was based on the European League Against Rheumatism treatment response; disease progression was based on the Health Assessment Questionnaire Disability Index score. These score changes were used to estimate health state utilities and direct medical costs. Quality-adjusted life-years (QALYs) and incremental cost per QALY gained were calculated by baseline ACPA groups (Q1, 28-234 AU/ml; Q2, 235-609 AU/ml; Q3, 613-1045 AU/ml; and Q4, 1060-4894 AU/ml). Scenario analysis and one-way and probabilistic sensitivity analyses were used to evaluate robustness of model assumptions. RESULTS: Abatacept resulted in QALY gain versus adalimumab in ACPA Q1, Q3, and Q4; between-treatment difference (difference: Q1, -0.115 Q2, -0.009 Q3, 0.045; and Q4, 0.279). Total lifetime discounted cost was higher for abatacept versus adalimumab in most quartiles (Q2, £77,612 vs. £77,546; Q3, £74,441 vs. £73,263; and Q4, £78,428 vs. £76,696) because of longer time on treatment. Incremental cost per QALY for abatacept (vs. adalimumab) was the lowest in the high ACPA titer group (Q4, £6200/QALY), followed by the next lowest titer group (Q3, £26,272/QALY). CONCLUSIONS: Abatacept is a cost effective alternative to adalimumab in patients with RA with high ACPA levels.
28744796 Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-Targeted Dual-Variable Domain Immunoglob 2018 May BACKGROUND AND OBJECTIVE: ABT-122 is a dual-variable domain immunoglobulin that neutralizes both tumor necrosis factor-α and interleukin-17A, with the goal of achieving greater clinical efficacy than can be achieved by blocking either cytokine alone. This work characterized the pharmacokinetics of ABT-122 in healthy subjects and in patients with rheumatoid arthritis. METHODS: ABT-122 pharmacokinetics was evaluated in three phase I studies. In Study 1, single intravenous (0.1, 0.3, 1, 3, and 10 mg/kg) and subcutaneous (0.3, 1, and 3 mg/kg) doses were evaluated in healthy subjects. In Studies 2 and 3, multiple subcutaneous doses (1 mg/kg every other week or 0.5-3 mg/kg every week) were evaluated for 8 weeks in patients with rheumatoid arthritis on stable methotrexate therapy. Pharmacokinetic data were available from 48 healthy subjects and 31 patients with rheumatoid arthritis. RESULTS: ABT-122 showed multi-exponential disposition with more than dose-proportional exposures at the 0.1-1 mg/kg doses and approximately dose-proportional exposures at doses ≥1 mg/kg. ABT-122 absolute subcutaneous bioavailability was approximately 50% with maximum serum concentrations observed 3-4 days after dosing. Steady state was achieved by week 6 of subcutaneous dosing. ABT-122 maximum serum concentration-to-trough concentration ratio was 2.6 for every other week dosing and 1.3 for every week dosing, corresponding to an effective half-life of 10-18 days. ABT-122 median area under the serum concentration-time curve accumulation ratio was 3.8-4.8 with every week dosing. Measureable antidrug antibodies were observed in all 48 subjects in Study 1 by day 15 post-dose and 19 of 31 ABT-122-treated patients in Studies 2 and 3 [median time to appearance of antidrug antibodies of 64 days (range 15-92 days)]. No dose-limiting toxicities were observed in these studies and the maximum tolerated dose was not identified. CONCLUSIONS: Results from these three phase I studies supported testing ABT-122 every week and every other week regimens in phase II trials in subjects with rheumatoid and psoriatic arthritis. Study 2 (EudraCT: 2012-003448-54); Study 3 (NCT01853033).
29242008 Immune responses to peptides containing homocitrulline or citrulline in the DR4-transgenic 2018 May Antibodies to proteins/peptides containing citrulline are hallmarks of Rheumatoid Arthritis (RA). These antibodies are strongly associated with the expression of the Shared Epitope (SE). RA patients also generate antibodies to homocitrulline-containing proteins/peptides (also referred to as anti-carbamylated protein antibodies (Anti-CarP)). This study was undertaken to investigate the relationship between homocitrulline and citrulline immune responses using an established mouse model of RA: DR4-transgenic (DR4tg) mice that express the human SE. C57BL/6 (B6) and DR4tg (on a B6 background) mice were immunized subcutaneously with a homocitrullinated peptide (HomoCitJED). Splenic T cell proliferation was evaluated by (3)H-thymidine incorporation assay. Antibodies to homocitrullinated and citrullinated antigens were screened by enzyme-linked immunosorbent assay (ELISA). Antibody cross-reactivity was examined by inhibition with HomoCitJED and its citrullinated counterpart peptide, CitJED (the number of homocitrullines in HomoCitJED is equal to the number of citrullines in CitJED). HomoCitJED-immunized DR4tg mice developed early T and B cell responses to HomoCitJED and late responses to CitJED. These mice also developed anti-CCP2 antibodies. In some mice, antibodies to HomoCitJED were also reactive to CitJED. B6 mice immunized with HomoCitJED developed late T and B cell responses to HomoCitJED, but did not generate responses to citrullinated antigens. Unlike DR4tg mice, anti-HomoCitJED antibodies from B6 mice did not react to CitJED. In conclusion, DR4tg mice immunized with HomoCitJED developed immune responses to CitJED, indicating cross-reactivity. CitJED immune responses were dependent on the SE. HomoCitJED responses occurred in the absence of the SE (B6 mice); however, they developed earlier in DR4tg SE-expressing mice.
30672200 [Effects of moxibustion at different time points on foot swelling, serum level of TNF-α a 2018 Nov 12 OBJECTIVE: To study the effects of moxibustion at different time points on serum level of tumor necrosis factor-α (TNF-α) in rats with rheumatoid arthritis (RA), and to explore its regulation mechanism on circadian rhythm. METHODS: A total of 96 Sprague-Dawley (SD) adult rats were randomly assigned into a blank group, a model group, a moxibustion at 5-7 AM group and a moxibustion at 5-7 PM group, 24 rats in each group, half male and half female. Each group was further divided into a 0 AM group, a 6 AM group, a 12 N group and a 6 PM group, 6 rats in each group. All rats were treated with the 12 h/12 h light-dark cycle in the whole process of experiment. Except for the blank group, all rats were treated with intracutaneous injection of freund's complete adjuvant (FCA) at right foot pad to establish the RA model. The rats at the two moxibustion groups were treated with grain-sized moxibustion at "Shenshu" (BL 23) and "Zusanli" (ST 36) at 5-7 AM and 5-7 PM, respectively, one side per treatment, once a day; six treatments were taken as one course and 3 courses were given with an interval of one day between courses. The rats in the remaining groups were treated with identical fixation but without moxibustion intervention. The right foot volume was measured before model establishment, after model establishment and after treatment. The blood samples were collected after treatment and the serum level of TNF-α was measured by ELISA. The SPSS 21.0 software and Halberg Cosinor were adopted to analyze the experiment data. RESULTS: After treatment, compared with the blank group, the foot swelling severity was significantly increased in the model group, moxibustion at 5-7 AM group and moxibustion at 5-7 PM group (all P<0.01); compared with the model group, the foot swelling severity was significantly reduced in the moxibustion at 5-7 AM group and moxibustion at 5-7 PM group (both P<0.01). Compared with the blank group, the serum level of TNF-α was increased significantly in the model group and moxibustion at 5-7 AM group (both P<0.05); compared with the model group, the serum level of TNF-α was reduced significantly in the moxibustion at 5-7 AM group and moxibustion at 5-7 PM group (both P<0.05). The serum level of TNF-α showed circadian rhythm in all the groups (all P<0.05), and the peak appeared at night phase; compared with the blank group, the median value of TNF-α was increased significantly in the model group (P<0.05), the peak phase was delayed and the amplitude was increased (P<0.05); compared with the model group, the median value of TNF-α was significantly reduced in the moxibustion at 5-7 AM group and moxibustion at 5-7 PM group (P<0.01), the peak phase was advanced and the amplitude was reduced (P<0.05). CONCLUSION: Moxibustion could effectively reduce the serum level of TNF-α to relieve the foot swelling severity in RA rats. Moxibustion could regulate the circadian rhythm of TNF-α to play its effects on the inhibition of the synthesis of TNF-α. No efficacy is observed between the treatment at 5-7 AM and 5-7 PM.
30388179 Effect of medication adherence on disease activity among Japanese patients with rheumatoid 2018 For the optimum efficacy of disease-modifying anti-rheumatic drugs (DMARDs), patients need to be adherent to their medication regimen. To clarify the effects of medication adherence on disease activity in Japanese patients with rheumatoid arthritis (RA), we conducted a cohort study in patients with various stages of RA. Patients were enrolled from the Kyoto University RA Management Alliance cohort, and followed up prospectively for 12 months. In this study, a total of 475 patients were analyzed and divided into 9 groups according to their medication adherence and the RA disease duration. The primary outcomes were based on the rate of a disease flare. The secondary outcomes were the changes in disease activity score using 28 joints (DAS28-ESR), simplified disease activity index (SDAI) and physical disability by health assessment questionnaire-disability index (HAQ). The changes in DAS28-ESR, HAQ, and the risk of disease flare in the highly adherent patients were significantly lower than those of the less adherent patients among the groups with RA ≤ 4.6 years but not those among the other groups. Taken together, this study identified a significant association between medication adherence and the disease flare during early-stage RA or short disease duration. These results emphasize the need to pay more attention to medication adherence in preventing the disease progression of RA.