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ID PMID Title PublicationDate abstract
27734232 Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background met 2017 Jan Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (≥17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)-4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.
26814717 The Elevated Secreted Immunoglobulin D Enhanced the Activation of Peripheral Blood Mononuc 2016 Immunoglobulin D (IgD) is a surface immunoglobulin that is expressed as either membrane IgD (mIgD) or secreted IgD (sIgD). Researchers have shown that sIgD is often elevated in patients with autoimmune diseases. The possible roles of sIgD on the function of peripheral blood mononuclear cells (PBMCs) in rheumatoid arthritis (RA) are still unclear. In this study, we compared the expression of sIgD, mIgD and IgD receptor (IgDR) in RA patients and healthy controls, and investigated the effect of sIgD on the function of PBMCs. We found that the levels of sIgD, mIgD and IgDR were significantly higher in RA patients compared with healthy controls. The concentrations of sIgD were positively correlated with soluble receptor activator of nuclear factor-κB ligand (sRANKL), rheumatoid factor (RF) and C-reactive protein (CRP) in RA patients. Strikingly, IgD could enhance the proliferation of PBMCs and induce IL-1α, IL-1β, TNF-α, IL-6 and IL-10 production from PBMCs. Moreover, the percentage of activated T cell subsets (CD4+CD69+, CD4+CD154+) and activated B cell subsets (CD19+CD23+, CD19+CD21+, CD19+IgD+ and CD19-CD138+) were increased by IgD. The percentage of unactivated T cell subset (CD4+CD62L+) and immature B cell subset (CD19+IgM+IgD-) were decreased by IgD in PBMCs. Furthermore, the expressions of IgDR on T and B cells were significantly increased by treatment with IgD. Our results demonstrate that IgD enhanced the activation of PBMCs, which may contribute to RA pathogenesis. Therefore, IgD could be a potential novel immunotherapeutic target for the management of RA.
25834210 Predictors of longterm changes in body mass index in rheumatoid arthritis. 2015 Jun OBJECTIVE: Low body mass index (BMI) is a risk factor for poor longterm outcomes in rheumatoid arthritis (RA). The purpose of this study was to identify factors associated with longterm changes in BMI. METHODS: Subjects with RA from the Veterans Affairs (VA) Rheumatoid Arthritis (VARA) Registry (n = 1474) were studied. Information on inflammatory markers, presence of erosions, and smoking status were extracted from the VARA database. BMI was extracted from VA electronic medical records within 14 days of each visit date. VA pharmacy records were queried to identify prescriptions for specific RA therapies within 1 month of the visit date. We used robust generalized estimating equations marginal regression models to calculate independent associations between clinical variables and BMI over time. Similar models determined predictors of change in weight and risk of weight loss over the subsequent study observation period. RESULTS: Increasing age, active smoking, and the presence of erosions at baseline were associated with lower BMI. Weight decreased over time among older adults. Factors associated with greater reductions in BMI over time and a greater risk of weight loss were higher inflammatory markers, smoking, older age, higher BMI, and less subsequent improvement in inflammation. Methotrexate use was associated with a lower risk of weight loss. The use of prednisone or anti-tumor necrosis factor therapies was not associated with change in BMI or the risk of weight loss independent of other factors. CONCLUSION: Greater age, greater inflammatory activity, and active smoking are associated with greater weight loss in RA over time.
26494567 Real-world cost-effectiveness of infliximab, etanercept and adalimumab in rheumatoid arthr 2016 Feb Biological drugs have proven efficacy and effectiveness in treatment of rheumatoid arthritis (RA), although none has been shown to be superior. Few studies have evaluated the cost-effectiveness of biological drugs in real-life clinical conditions. The objective of this study was to compare the cost-effectiveness of infliximab, etanercept and adalimumab in achieving clinical remission (DAS28 < 2.6) when used as initial biological therapy. Patients were diagnosed with RA who began treatment with infliximab, etanercept or adalimumab in the Reina Sofia Hospital (Cordoba, Spain) between January 1, 2007, and December 31, 2012. Effectiveness was measured as the percentage of patients who achieved clinical remission after 2 years. The cost analysis considered the use of direct health resources (perspective of the healthcare system). Cost-effectiveness was calculated by dividing the total mean cost of each treatment by the percentage of patients who achieved remission. One hundred and thirty patients were included: 55 with infliximab, 44 with adalimumab and 31 with etanercept. After 2 years, 45.2 % of patients with adalimumab achieved clinical remission, versus 29.1 % with infliximab (p = 0.133) and 22.7 % with etanercept (p = 0.040), with no differences between etanercept and infliximab (p = 0.475). The average total cost at 2 years was €29,858, €25,329 and €23,309 for adalimumab, infliximab and etanercept, respectively, while the mean cost (95 %CI) to achieve remission was €66,057 (48,038–84,076), €87,040 (78,496–95,584) and €102,683 (94,559–110,807), respectively. Adalimumab was more efficient than etanercept (p < 0.001) and infliximab (p = 0.026), with no differences between etanercept and infliximab (p = 0.086). Adalimumab was the most cost-effective treatment in achieving clinical remission in real-life clinical conditions in RA patients during the study period.
27055270 Spontaneous Differentiation of Human Mesenchymal Stem Cells on Poly-Lactic-Co-Glycolic Aci 2016 INTRODUCTION: Mesenchymal stem cells (MSCs) have immunosuppressive activity and can differentiate into bone and cartilage; and thus seem ideal for treatment of rheumatoid arthritis (RA). Here, we investigated the osteogenesis and chondrogenesis potentials of MSCs seeded onto nano-fiber scaffolds (NFs) in vitro and possible use for the repair of RA-affected joints. METHODS: MSCs derived from healthy donors and patients with RA or osteoarthritis (OA) were seeded on poly-lactic-glycolic acid (PLGA) electrospun NFs and cultured in vitro. RESULTS: Healthy donor-derived MSCs seeded onto NFs stained positive with von Kossa at Day 14 post-stimulation for osteoblast differentiation. Similarly, MSCs stained positive with Safranin O at Day 14 post-stimulation for chondrocyte differentiation. Surprisingly, even cultured without any stimulation, MSCs expressed RUNX2 and SOX9 (master regulators of bone and cartilage differentiation) at Day 7. Moreover, MSCs stained positive for osteocalcin, a bone marker, and simultaneously also with Safranin O at Day 14. On Day 28, the cell morphology changed from a spindle-like to an osteocyte-like appearance with processes, along with the expression of dentin matrix protein-1 (DMP-1) and matrix extracellular phosphoglycoprotein (MEPE), suggesting possible differentiation of MSCs into osteocytes. Calcification was observed on Day 56. Expression of osteoblast and chondrocyte differentiation markers was also noted in MSCs derived from RA or OA patients seeded on NFs. Lactic acid present in NFs potentially induced MSC differentiation into osteoblasts. CONCLUSIONS: Our PLGA scaffold NFs induced MSC differentiation into bone and cartilage. NFs induction process resembled the procedure of endochondral ossification. This finding indicates that the combination of MSCs and NFs is a promising therapeutic technique for the repair of RA or OA joints affected by bone and cartilage destruction.
27855721 The lung microbiota in early rheumatoid arthritis and autoimmunity. 2016 Nov 17 BACKGROUND: Airway abnormalities and lung tissue citrullination are found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development. This suggests the possibility that the lung could be a site of autoimmunity generation in RA, perhaps in response to microbiota changes. We therefore sought to test whether the RA lung microbiome contains distinct taxonomic features associated with local and/or systemic autoimmunity. METHODS: 16S rRNA gene high-throughput sequencing was utilized to compare the bacterial community composition of bronchoalveolar lavage fluid (BAL) in patients with early, disease-modifying anti-rheumatic drugs (DMARD)-naïve RA, patients with lung sarcoidosis, and healthy control subjects. Samples were further assessed for the presence and levels of anti-citrullinated peptide antibodies (including fine specificities) in both BAL and serum. RESULTS: The BAL microbiota of RA patients was significantly less diverse and abundant when compared to healthy controls, but similar to sarcoidosis patients. This distal airway dysbiosis was attributed to the reduced presence of several genus (i.e., Actynomyces and Burkhordelia) as well as reported periodontopathic taxa, including Treponema, Prevotella, and Porphyromonas. While multiple clades correlated with local and systemic levels of autoantibodies, the genus Pseudonocardia and various related OTUs were the only taxa overrepresented in RA BAL and correlated with higher disease activity and erosions. CONCLUSIONS: Distal airway dysbiosis is present in untreated early RA and similar to that detected in sarcoidosis lung inflammation. This community perturbation, which correlates with local and systemic autoimmune/inflammatory changes, may potentially drive initiation of RA in a proportion of cases.
25854268 Vascular calcifications on hand radiographs in rheumatoid arthritis and associations with 2015 Sep OBJECTIVE: To examine whether vascular calcifications on hand films in RA might aid in determining mortality risk. METHODS: Hand radiographs from 906 RA patients were scored as positive or negative for vascular calcifications. Patient characteristics associated with vascular calcifications were assessed using multivariable logistic regression, and associations with mortality were examined using Cox proportional hazards regression. Cytokines and multiplex ACPA were measured in both groups. RESULTS: A total of 99 patients (11%) demonstrated radiographic vascular calcifications. Factors independently associated with vascular calcifications included diabetes [odds ratio (OR) 2.85; 95% CI 1.43, 5.66], cardiovascular disease at enrolment (OR 2.48; 95% CI 1.01, 6.09), prednisone use (OR 1.90; 95% CI 1.25, 2.91), current smoking (OR 0.06; 95% CI 0.01, 0.23) and former smoking (OR 0.36; 95% CI 0.27, 0.48) vs never smoking. In cytokine and ACPA subtype analysis, IL-4 and anti-citrullinated apolipoprotein E were significantly increased in patients with vascular calcifications in fully adjusted multivariable models. After multivariable adjustment, vascular calcifications were associated with an increase in all-cause mortality (hazard ratio 1.41; 95% CI 1.12, 1.78; P = 0.004). CONCLUSION: Vascular calcifications on hand radiographs were independently associated with increased all-cause mortality in RA. Mechanisms underpinning the associations of IL-4 and select ACPA with vascular calcifications and their utility as biomarkers predictive of cardiovascular disease risk in RA merit further study.
25871515 Association between interleukin 17A polymorphisms and susceptibility to rheumatoid arthrit 2015 Jul 15 BACKGROUND: Previous studies have revealed an association between interleukin 17A (IL17A) polymorphisms and the prevalence of rheumatoid arthritis (RA) in Japanese and Caucasian patients. We hypothesized that IL17A polymorphisms might also affect RA susceptibility in the Chinese population. METHODS: We studied IL17A rs2275913 G/A, rs3819024 A/G, rs3819025 G/A, rs4711998 A/G, rs8193036 C/T and rs8193037 G/A polymorphisms in 615 RA patients and 839 controls in a Chinese population. Genotyping was performed using a custom-by-design 48-Plex SNP scanâ„¢ Kit. RESULTS: Our results indicated that IL17A rs4711998 A/G and IL17A rs8193037 G/A polymorphisms were not associated with RA, and IL17A rs2275913 G/A and IL17A rs3819024 A/G variant alleles decrease the risk of RA, while IL17A rs3819025 G/A and IL17A rs8193036 C/T variant alleles increase the risk of RA. CONCLUSIONS: These findings suggest that IL17A polymorphisms may be associated with RA. Future larger studies with other ethnic populations are required to confirm current findings.
25296748 Structural and functional outcomes of a therapeutic strategy targeting low disease activit 2015 May OBJECTIVE: The aim of this study was to evaluate structural damage and physical disability in patients with elderly-onset RA (EORA) who were treated in clinical practice with a therapeutic strategy targeting low disease activity (LDA). METHODS: Data from 151 MTX-naive patients (mean age 74.9 years) with EORA from a prospective, monocentric registry were analysed. Treatment was adjusted every 3 months targeting LDA [28-joint DAS using ESR (DAS28-ESR) <3.2]. Treatment was initiated with non-biologic DMARDs (nbDMARDs), followed by TNF inhibitors (TNFis) or tocilizumab. The primary outcome was change from week 0 to week 52 in the modified total Sharp score (ΔmTSS). Secondary outcomes were derived from the HAQ Disability Index (HAQ-DI) and DAS28 at week 52. Predictors of clinically relevant radiographic progression [CRRP; ΔmTSS/year more than the smallest detectable change (2.1 points)] were examined using multivariate logistic regression models. RESULTS: Adherence to the treat-to-target strategy was observed in 83.4% of the 151 patients at week 24 and in 75.5% at week 52. At week 52, 67.6% of the patients were receiving a nbDMARD alone, 31.0% a TNFi with or without MTX and 1.4% tocilizumab. At week 52, structural remission (ΔmTSS/yr ≤0.5) was achieved in 49.7% of the patients, functional remission (HAQ-DI ≤0.5) in 63.4% and LDA in 51.0%. Clinical responses at weeks 12 and 24 were significant independent predictors of CRRP. Cumulative disease activity during the first 12 weeks predicted CRRP with a C-statistic of 0.888. CONCLUSION: Achieving structural remission, functional remission and LDA in clinical practice in EORA patients are realistic goals. Our results indicate significant benefits for a therapeutic strategy targeting LDA for EORA patients in clinical practice.
26233503 The Detection of Rheumatic Disease through Hospital Diagnoses with Examples of Rheumatoid 2015 Nov OBJECTIVE: We examined hospitalizations for patients with known rheumatoid arthritis (RA) or giant cell arteritis (GCA) to evaluate whether hospitalization-related diagnoses accurately identified patients with rheumatologic diseases. METHODS: Diagnosis codes for hospitalizations in 1996-2012 among previously identified population-based cohorts of patients with RA or GCA were examined for RA or GCA mentions. RESULTS: RA or GCA mention occurred in only 55% of 2407 hospitalizations among patients with RA and 31% of 502 hospitalizations among patients with GCA. RA or GCA was mentioned more often in recent years, younger patients, and rheumatic medication users. CONCLUSION: Coding for RA or GCA during hospitalizations was often missed. Research using hospital diagnoses alone could be biased.
27409408 Bone change after surgical treatment of mucous cyst at the interphalangeal joint of the gr 2019 Jan Digital mucous cysts are a type of benign cysts of the digits, typically located at the distal interphalangeal joints or in the proximal nail fold, which usually occur on the hands. The diagnosis of digital mucous cysts is relatively easy because of its light-transmitting property, but the treatment is often difficult because of complications including recurrence, infection, diminished range of motion, and nail deformity. We report a case of rheumatoid arthritis (RA) showing good course after surgical treatment of mucous cyst at the interphalangeal joint of the great toe. In a case of RA, combination of synovectomy with surgical treatment of mucous cyst might be effective.
26313244 MRI evidence of persistent joint inflammation and progressive joint damage despite clinica 2016 OBJECTIVES: To determine the value of magnetic resonance imaging (MRI) of bones and joints in patients with recent-onset rheumatoid arthritis (RA) treated for 2 years from diagnosis with disease-modifying anti-rheumatic drugs (DMARDs) and glucocorticoids. METHOD: Thirteen patients with early RA were treated according to clinical practice and followed with MRI, radiographs, and Disease Activity Score calculated on 28 joints (DAS28) at inclusion (baseline) and after 1, 4, 7, 13, and 25 months. MRI of the dominant wrist and metacarpophalangeal (MCP) joints were assessed for synovitis, bone oedema, and erosions using the RA MRI Score (RAMRIS) and for tenosynovitis by an MRI tenosynovitis scoring method. Radiographs were assessed by the van der Heijde modified Sharp score (SHS). Clinical remission was defined by a DAS28 < 2.6. RESULTS: MRI at baseline detected inflammation in joints and tendons in all patients as well as erosions in 10 out of 13 patients. Over time, the erosion score increased while the synovitis and tenosynovitis scores remained almost unchanged. Bone oedema strongly correlated with synovitis. Synovitis and tenosynovitis correlated well with the erosion score at baseline but not thereafter. The MRI changes showed that joint damage started early and continued in the presence of persistent synovial and tenosynovial inflammation. CONCLUSIONS: The observations made in this small study suggest that the treatment goal of 'clinical remission' should be supplemented by a 'joint remission' goal. To this end, MRI is an appropriate tool. Further studies are needed to evaluate the optimal use of MRI in early RA.
24081439 Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial 2015 Jan BACKGROUND: The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a 'treat-to-target' protocol of combination disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Patients with RA <12 months' duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4 g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy. RESULTS: In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti-cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events. CONCLUSIONS: FO was associated with benefits additional to those achieved by combination 'treat-to-target' DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.
27059693 Patient-Physician Discordance in Global Assessment in Rheumatoid Arthritis: A Systematic L 2016 Dec OBJECTIVE: The integration of the patient in therapeutic decision-making is important in the management of rheumatoid arthritis (RA), but the patient opinion regarding disease status may differ from the physician's opinion. The aim of this study was to assess in the published literature the frequency and drivers of patient-physician discordance in global assessment in RA. METHODS: A systematic literature review of all articles published up to January 2015 in Medline or Embase, reporting discordance in RA, was conducted by 2 investigators. Discordance was defined based on the absolute difference of patient global (PGA) and physician global assessments (PhGA) on 0-10-cm scales. The frequency of discordance and its predictors were collected in each study. Frequencies of discordance were pooled by meta-analysis using random effect. RESULTS: In all, 12 studies were selected (i.e., 11,879 patients): weighted mean ± SD age was 55.1 ± 13.9 years, weighted mean ± SD disease duration was 10.4 ± 9.3 years, and 80.7% were women. The value of the difference |PGA - PhGA| defining discordance varied between ≥0.5 cm (n = 2 studies) to ≥3 cm (n = 5 studies); the weighted mean value was 2.7 cm. The pooled percentage of patients with discordance was 43% (95% confidence interval 36%-51%; range 25%-76%). PGA was usually higher than PhGA. The drivers of PGA were pain and functional incapacity, whereas drivers of PhGA were joint counts and acute-phase reactants. CONCLUSION: Discordance in global assessment was most frequently defined as a difference of 3 points or more; even with such a stringent definition, up to half the patients were found to be discordant. The long-term consequences of this discordance remain to be determined.
26202019 Reverse shoulder prosthesis in patients with rheumatoid arthritis: a systematic review. 2016 May PURPOSE: To obtain detailed information on the outcomes of patients with rheumatoid arthritis (RA) undergoing reverse shoulder arthroplasty (RSA) METHODS: A literature search was conducted for studies reporting on the use of RSA in RA patients from 1990 to 2014. The inclusion criteria were a report of sufficient information on pre-operative status and surgical outcome allowing evaluation of the therapeutic potential of RSA in RA. The literature search resulted in 586 hits, but only five studies that met the inclusion criteria were assessed. RESULTS: There were 100 shoulders that had been operated on, of which 87 were followed for a mean of 55.4 months, the longest follow-up being 11.9 years Most patients had glenohumeral erosive lesions of Larsen Grade III or IV. The Delta III prosthesis was implanted in most cases and in three studies bone graft was used for severe glenoid lesions. The main outcome measures employed were the Constant score (Cs) and ASES questionnaire. The mean increase in Cs and ASES score after surgery was 42.4 and 54 points, respectively. The mean post-operative forward elevation was 120.6°, the average increment being 51° and the mean increase of abduction was 58.5°. The mean prevalence of scapular notching was 35.4 %. The rate of adverse events was 31 %, but the vast majority were of minor severity. Eight prostheses underwent revision, due to infection in four. CONCLUSIONS: RSA implanted in RA patients would appear to give similar results to those obtained in massive cuff tears with or without arthropathy.
25910895 Endogenous conversion of n-6 to n-3 polyunsaturated fatty acids attenuates K/BxN serum-tra 2015 Jul It is suggested that n-3 polyunsaturated fatty acids (PUFAs) can be used in the preventive or therapeutic management of rheumatoid arthritis (RA); however, controversial results have been reported. Here, we examined the effects of a decrease in the n-6/n-3 PUFA ratio on RA using fat-1 transgenic mice. First, we tested whether fat-1 expression modulated signaling pathways in fibroblast-like synoviocytes (FLSs) stimulated with tumor necrosis factor α (TNF-α). TNF-α activated p38 mitogen-activated protein kinase and increased phosphorylation of the signal transducer and activator of transcription 3 in wild type (WT) FLSs but not in fat-1 FLSs. Arthritis was induced by injection of K/BxN serum. Based on clinical scores, ankle thickness and pathological severity, we showed that WT mice developed clinically overt arthritis, whereas fat-1 mice showed attenuated arthritis. Moreover, fat-1 mice exhibited down-regulated local and systemic levels of inflammatory cytokines. Lastly, bone marrow-derived macrophages (BMMs) of WT mice differentiated into tartrate-resistant acid phosphatase-positive multinucleated osteoclasts, whereas the osteoclastogenenic process was suppressed in BMMs of fat-1 mice. The endogenous conversion of n-6 to n-3 PUFAs via fat-1 plays a key role in attenuation of RA; therefore, dietary supplementation of n-3 PUFAs may have therapeutic potential for the management of RA.
26821827 A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulat 2016 Jan 29 The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-α and IL-1β in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13. In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs. Collectively, our data demonstrates the existence of a novel NF-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-mediated inflammatory cytokines and the proliferation and migration of RA FLSs. Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment.
26568428 Twenty-eight-week results from the REALISTIC phase IIIb randomized trial: efficacy, safety 2015 Nov 15 INTRODUCTION: This 28-week, phase IIIb study assessed safety and maintenance of response to certolizumab pegol (CZP) in a diverse population of rheumatoid arthritis (RA) patients, stratified by prior anti-TNF exposure, concomitant methotrexate (MTX) use and disease duration. The ability to predict achievement of low disease activity (LDA) at week 28 from improvements in Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), swollen joint count (SJC) and Clinical Disease Activity Index (CDAI) up to week 12 was assessed. METHODS: The 28-week study population included all patients who completed the double-blind (DB) phase and entered the open-label (OL) phase, receiving 200 mg CZP every 2 weeks (Q2W) ≥16 weeks. In the 12-week DB period, patients with active RA and an inadequate response to ≥1 disease-modifying antirheumatic drug (DMARD) were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4 then 200 mg Q2W) or placebo (Q2W), stratified by prior anti-TNF use, concomitant use of MTX and disease duration (<2 years vs. ≥2 years). RESULTS: A total of 955 patients entered the OL phase. At week 28, similar clinical improvements were seen in those receiving CZP throughout (CZP → CZP; n = 771) and those receiving placebo during the DB phase and switching to CZP in the OL phase (placebo → CZP; n = 184) (ACR20 response rate = 59.7% vs. 53.3%; ACR50/ACR70 response rates were also similar). Effect of CZP treatment was similar regardless of prior anti-TNF use, disease duration and concomitant DMARDs, based on ACR20 response rates. The percentage of patients achieving DAS28(ESR) LDA at week 28 was calculated for DAS28(ESR), SJC or CDAI responders at earlier time points. Reductions from baseline (Δ) of DAS28(ESR) <1.2, ΔSJC <25% or ΔCDAI <10 by week 12 were associated with <9% chance of achieving LDA at week 28 regardless of prior anti-TNF exposure. Adverse event rates were similar for placebo → CZP and CZP → CZP patients, with no new safety signals identified. CONCLUSIONS: A diverse population of RA patients with varying disease duration showed rapid and sustained clinical improvements on CZP treatment, regardless of prior anti-TNF or concomitant DMARD use. Failure to achieve improvements in DAS28(ESR), SJC or CDAI within the first 12 weeks of CZP therapy was associated with a low chance of achieving LDA at week 28. No new safety signals were observed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00717236 , 15 July 2008.
25598390 The role of the lymphatic system in inflammatory-erosive arthritis. 2015 Feb Rheumatoid arthritis (RA) is a prevalent inflammatory joint disease with enigmatic flares, which causes swelling, pain, and irreversible connective tissue damage. Recently, it has been demonstrated in murine models of RA that the popliteal lymph node (PLN) is a biomarker of arthritic flare, as it "expands" in size and contrast enhancement during a prolonged asymptomatic phase, prior to when it "collapses" with accelerated synovitis and joint erosion. This PLN collapse is associated with adjacent knee flare, decreases in PLN volume and contrast enhancement, lymphatic pulse and pumping pressure, and an increase in PLN pressure. Currently, it is known that PLN collapse is accompanied by a translocation of B cells from the follicles to the sinuses, effectively clogging the lymphatic sinuses of the PLN, and that B cell depletion therapy ameliorates arthritic flare by eliminating these B cells and restoring passive lymphatic flow from inflamed joints. Here we review the technological advances that have launched this area of research, describe future directions to help elucidate the potential mechanism of PLN collapse, and speculate on clinical translation towards new diagnostics and therapies for RA.
25802976 Mechanisms and therapeutic potential of inhibiting drug efflux transporters. 2015 Jun INTRODUCTION: The ATP-binding cassette transporters are among the largest transmembrane protein families in humans and are expressed in a wide variety of tissues. By promoting outward transport, they protect cells from the accumulation of undesirable substrates. This protection might lead to suboptimal concentration of chemotherapeutics in the tumor cells, resulting in therapy resistance and poor disease prognosis. In the past decades, a considerable effort was made to reverse multidrug resistance (MDR). AREAS COVERED: We briefly summarize the present knowledge on the clinical efficacy of MDR reversing agents in various types of cancer and discuss their availability in a non-cancerous disease (rheumatoid arthritis). The classical and novel pharmacological approaches directly inhibiting the transporters' function and their extensive investigations in human clinical studies are also mentioned. Furthermore, the article highlights the methodological concerns raised by these investigations. EXPERT OPINION: The development of chemotherapeutics lacking transporter-inducing effects, gene therapy approaches, nanomedicinal formulations and the identification of natural compounds to modulate transporter function are intriguing but face serious delivery challenges. Understanding and mapping molecular mechanisms of drug resistance will make it easier to design clinical treatment regimes that avoid escalation of MDR, by utilizing collateral sensitivity.