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ID PMID Title PublicationDate abstract
28088452 Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfor 2017 Feb 15 AIMS: Extracts of Tripterygium wilfordii Hook F (TwHF), a traditional Chinese herbal medicine, have been widely used for treating rheumatoid arthritis (RA) in combination with methotrexate (MTX) in China for several decades. However, the efficacy and safety of MTX plus TwHF treatment remain unclear. MAIN METHODS: A comprehensive search of databases in both Chinese and English was performed. Data from the selected studies were extracted and analyzed independently by two authors. KEY FINDINGS: Six randomized controlled trials were included in the final analysis with a total of 643 patients. All trials added TwHF (in the form of Tripterygium glycosides) to the MTX-based therapy. For efficacy, the addition of TwHF increased 50% responder rates (RR) (RR 1.337, 95% confidence interval [CI]: 1.188-1.505, P<0.001), and it reduced swollen and tender joint counts, shortened the duration of morning stiffness, decreased the erythrocyte sedimentation rate, and decreased the level of C-reactive protein and rheumatoid factor. For safety, the addition of TwHF did not increase the rate of adverse events (RR 0.824, 95% CI: 0.635-1.068, P=0.143). SIGNIFICANCE: MTX plus TwHF therapy may be a more effective and similar safe strategy for treating RA compared to MTX monotherapy. Further large clinical trials to investigate the TwHF add-on therapy are warranted.
27998044 Primary Care Screening and Comorbidity Management in Rheumatoid Arthritis in Ontario, Cana 2017 Oct OBJECTIVE: Quality measurement for rheumatoid arthritis (RA) patients has largely focused on care provided by rheumatologists. Our aim was to develop and assess quality measures related to the screening and management of comorbidity in RA patients in primary care. METHODS: We used the primary care Electronic Medical Record Administrative data Linked Database in Ontario, Canada. We harmonized Canadian general population and RA clinical recommendations to develop and assess screening, process, and outcome measures. For each RA patient, 10 non-RA patients were matched by age and sex. Stratified analyses were performed, comparing patients with RA to those without RA, to assess the performance of quality measures. RESULTS: We compared 1,405 RA patients to 14,050 matched non-RA patients (72.8% female; mean age 62.5 years). Compared to non-RA patients, RA patients more frequently had influenza (44.9% versus 40.0%) and pneumococcal (40.4% versus 34.1%) vaccinations and bone mineral density testing (67.4% versus 58.1%). Herpes zoster vaccinations were less frequent among RA patients (13.8% versus 19.5%), as was screening for cervical cancer (58.6% versus 64.0%). No significant differences were observed between RA and non-RA patients in screenings for breast (70.7% versus 73.8%) or colorectal (31.7% versus 34.5%) cancers. Only a quarter of RA patients had a comprehensive cardiovascular risk assessment. No definitive differences were detected in the management of patients who had co-occurring cardiovascular disease or diabetes mellitus. CONCLUSION: For both RA and non-RA patients, compliance with Canadian recommendations for preventive medical services and screening for comorbid conditions in primary care was less than optimal. This indicates key targets for improvement.
28807995 Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor LBH 2017 Oct 1 Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development (LBH) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to S-phase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase α. Decreased DNA polymerase α was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1. Because DNA fragments can increase arthritis severity in preclinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. Lbh knockout exacerbated disease severity, which is associated with elevated levels of IL-1β and checkpoint kinase 1 phosphorylation. These studies indicate that LBH deficiency induces S-phase arrest that, in turn, exacerbates inflammation. Because LBH gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases.
28886017 B-cell phenotype and IgD-CD27- memory B cells are affected by TNF-inhibitors and tocilizum 2017 BACKGROUND: The use of TNF-inhibitors and/or the IL-6 receptor antagonist, tocilizumab, in rheumatoid arthritis (RA) have pleiotropic effects that also involve circulating B-cells. The main goal of this study was to assess the effect of TNF-inhibitors and tocilizumab on B-cell phenotype and gene expression in RA. METHODS: Blood samples were collected from untreated early RA (ERA) patients, established RA patients under methotrexate treatment, established RA patients before and after treatment with TNF-inhibitors and tocilizumab, and healthy donors. B-cell subpopulations were characterized by flow cytometry and B-cell gene expression was analyzed by real-time PCR on isolated B-cells. Serum levels of BAFF, CXCL13 and sCD23 were determined by ELISA. RESULTS: The frequency of total CD19+ B cells in circulation was similar between controls and all RA groups, irrespective of treatment, but double negative (DN) IgD-CD27- memory B cells were significantly increased in ERA and established RA when compared to controls. Treatment with TNF-inhibitors and tocilizumab restored the frequency of IgD-CD27- B-cells to normal levels, but did not affect other B cell subpopulations. TACI, CD95, CD5, HLA-DR and TLR9 expression on B-cells significantly increased after treatment with either TNF-inhibitors and/ or tocilizumab, but no significant changes were observed in BAFF-R, BCMA, CD69, CD86, CXCR5, CD23, CD38 and IgM expression on B-cells when comparing baseline with post-treatment follow-ups. Alterations in B-cell gene expression of BAFF-R, TACI, TLR9, FcγRIIB, BCL-2, BLIMP-1 and β2M were found in ERA and established RA patients, but no significant differences were observed after TNF-inhibitors and tocilizumab treatment when comparing baseline and follow-ups. Serum levels of CXCL13, sCD23 and BAFF were not significantly affected by treatment with TNF-inhibitors and tocilizumab. CONCLUSIONS: In RA patients, the use of TNF-inhibitors and/ or tocilizumab treatment affects B-cell phenotype and IgD-CD27- memory B cells in circulation, but not B-cell gene expression levels.
29101672 Association between leptin and IL-6 concentrations with cardiovascular risk in patients wi 2018 Mar Pro-inflammatory cytokines such as leptin and IL-6 play an important role in the development of cardiovascular risk. Determine the relationship between leptin and IL-6 concentrations with cardiovascular risk in patients with rheumatoid arthritis. We determined IL-6 and leptin levels in 77 patients with the diagnosis of rheumatoid arthritis. The cardiovascular risk was calculated using the modified Framingham scale. Statistical analysis was performed using SPSS 22 considering a significant p < 0.05. Serum leptin concentrations and cardiovascular risk (CVR) factors were compared and found that there was a significant difference between higher leptin values and disease activity (p 0.047), obesity (p 0.038), positive rheumatoid factor (p 0.009), tobacco (p 0.009), and metabolic syndrome (p 0.001). Likewise, a significant relationship was found between lower leptin concentrations and hydroxychloroquine consumption (p = 0.023). We found significant difference between IL-6 concentrations and disease activity (p 0.028), hypertriglyceridemia (p 0.023), LDL-C (p 0.029), and smoking (0.005). Similarly, an association between hydroxychloroquine consumption and low concentrations of IL-6 was found (p 0.005). Framingham CVR was calculated and the result obtained was multiplied by 1.5. The 35.2% of the population studied had a low Framingham CVR, 38.9% moderate, and 25.9% presented a high risk. We compared the level of CVR and serum leptin and IL-6 concentrations, finding that the highest CVR was the leptin and IL-6 values. There is a positive association between CVR and serum leptin concentrations. It is also significantly associated with traditional and non-traditional risk factors.
28003164 Comparison of Transarticular Screw Fixation and C1 Lateral Mass-C2 Pedicle Screw Fixation 2017 Mar BACKGROUND: Many surgical procedures have been introduced to manage atlantoaxial instability caused by rheumatoid arthritis (RA) to prevent complications and improve fusion rate. We report the surgical outcome between transarticular screw fixation (TAF) and C1 lateral mass-C2 pedicle screw fixation (C1LM-C2P) in patients with atlantoaxial instability from RA. METHODS: Between 2002 and 2012, 58 patients were enrolled in the study. According to surgical procedures, patients were divided into 2 groups: group I who received TAF (n = 33) and group II who received C1LM-C2P (n = 25). Bony fusion was assessed by radiologic comparison immediately after the operation and 1 year postoperatively. In addition, complications and clinical and functional outcomes were evaluated. RESULTS: Overall, bone fusion was achieved in 32 patients in group I (97%). In group II, the fusion rate was evaluated in 100% of patients. Complications (regardless of neurologic deterioration) were cable loosening and screw malposition in group I and violation into the vertebral canal and spinal canal in group II. There was no statistical significance in fusion rate, clinical outcomes, or complications. The 12-month atlantodental interval after operation for the C1LM-C2P group was significantly lower than that for the TAF group after adjusting for all variables. CONCLUSIONS: Two surgical techniques showed a good fusion rate by rigid fixation in the immediate postoperative period and fewer surgery-related complications in patients with RA. Because surgical complications are more likely during the learning curve (as with other surgical techniques), surgeons should carefully evaluate patients before surgery by radiologic and neurologic examinations.
28395174 Loss of Parkin reduces inflammatory arthritis by inhibiting p53 degradation. 2017 Aug Parkin is associated with various inflammatory diseases, including Parkinson's disease (PD) and rheumatoid arthritis (RA). However, the precise role of Parkin in RA is unclear. The present study addressed this issue by comparing the development of RA between non-transgenic (non-Tg) mice and PARK2 knockout (KO) mice. We found that cyclooxygenase-2 and inducible nitric oxide synthase expression and nuclear factor-κB activity were reduced but p53 activation was increased in PARK2 KO as compared to non-Tg mice. These effects were associated with reduced p53 degradation. Parkin was found to interact with p53; however, this was abolished in Parkin KO mice, which prevented p53 degradation. Treatment of PARK2 KO mice with p53 inhibitor increased Parkin expression as well as inflammation and RA development while decreasing nuclear p53 translocation, demonstrating that PARK2 deficiency inhibits inflammation in RA via suppression of p53 degradation. These results suggest that RA development may be reduced in PD patients.
28412703 Self-reported Diagnosis of Rheumatoid Arthritis or Ankylosing Spondylitis Has Low Accuracy 2017 Aug OBJECTIVE: Self-reported diagnoses of inflammatory arthritis are not accurate. The primary study aim was to ascertain self-reported diagnoses of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in the Norwegian population-based Nord-Trøndelag Health Study (HUNT) using hospital case files. The secondary aim was to provide updated estimates of the prevalence and incidence of RA and AS. METHODS: All inhabitants ≥ 20 years old from the county of Nord-Trøndelag were invited. Data from 70,805 unique participants from HUNT2 (1995-1997) and HUNT3 (2006-2008) were included. For participants who self-reported RA or AS, case files from all 3 hospitals in the catchment area were evaluated using standardized diagnostic criteria. RESULTS: Of 2703 self-reported cases of RA, 19.1% were verified in hospital files. Of 1064 self-reported cases of AS, 15.8% were verified. Of 259 cases self-reporting both RA and AS, 8.1% had RA and 5.4% had AS. Overall, a self-report of 1 or both diagnoses could not be verified in 82.1%, including 22.8% with insufficient information or no case file. The prevalence of RA was 768 (95% CI 705-835) per 100,000. The incidence of RA from HUNT2 to HUNT3 was 0.48 (0.41-0.56) per 1000 per year. The prevalence of AS was 264 (228-305) per 100,000. The incidence of AS from HUNT2 to HUNT3 was 0.19 (0.15-0.24) per 1000 per year. CONCLUSION: Self-reported diagnoses of RA and AS are often false-positive. The prevalence and incidence of RA were comparable to reports from similar populations. The incidence of AS was higher than previously reported in a mixed population from Norway.
27117700 Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. 2017 Jan OBJECTIVES: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities. METHODS: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×10(6), 3×10(6) or 10×10(6) tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood. RESULTS: There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×10(6) tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high. CONCLUSION: IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×10(6) tolDC but no systemic clinical or immunomodulatory effects were detectable. TRIAL REGISTRATION NUMBER: NCT01352858.
28701103 Lipid management among individuals with inflammatory arthritis in the national REasons for 2018 Jan Objective Hyperlipidemia guidelines do not currently identify inflammatory arthritis (IA) as a cardiovascular disease (CVD) risk factor. We compared hyperlipidemia treatment of individuals with and without IA (rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis) in a large national cohort. Methods Participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were classified as having IA (without diabetes or hypertension); diabetes (but no IA); hypertension (but no diabetes or IA); or no IA, diabetes, or hypertension. Multivariable logistic regression models examined the odds of medical treatment among those with hyperlipidemia. Results Thirty-nine participants had IA, 5423 had diabetes, 7534 had hypertension, and 5288 had no diabetes, hypertension, or IA. The fully adjusted odds of treatment were similar between participants with IA and those without IA, hypertension, or diabetes. Participants with diabetes and no IA and participants with hypertension and no IA were twice as likely to be treated for hyperlipidemia as those without IA, diabetes, or hypertension. Conclusion Despite their higher CVD risk, patients with IA were as likely to be treated for hyperlipidemia as those without diabetes, hypertension, or IA. Lipid guidelines should identify IA as a CVD risk factor to improve CVD risk optimization in IA.
28864556 Massive splenomegaly due to concurrent primary Epstein-Barr virus and cytomegalovirus infe 2017 Sep 1 A 32-year-old man who was receiving adalimumab for seronegative rheumatoid arthritis presented with a 4-week history of fever, night sweats, fatigue, myalgias and diarrhoea. On examination, he had obvious splenomegaly but no lymphadenopathy or pharyngitis. Full blood count revealed mild neutropenia and significant lymphocytosis, with a blood film showing atypical lymphocytes. Liver function tests were mildly deranged with a mixed hepatitic and obstructive pattern. Ultrasound confirmed massive splenomegaly with a span of 21 cm in the long axis. Serological tests confirmed the presence of both primary Epstein-Barr virus and cytomegalovirus infections. The patient had his adalimumab withheld, was treated with supportive measures and improved over a period of 8 weeks. He remained well 5 months after the onset of illness with complete normalisation of blood count and a resolution of the splenomegaly.
27883999 Low Prevalence of Nodules in Rheumatoid Arthritis Patients in Kuwait: A Description and a 2017 OBJECTIVES: To describe the prevalence of rheumatoid nodules (RN) in patients with rheumatoid arthritis (RA) and to compare their features with those of patients without RN. SUBJECTS AND METHODS: Adult RA patients (n = 952) in the Kuwait Registry for Rheumatic Diseases from February 2013 to December 2015 were evaluated for RN. Demographic and serological features and disease activity and severity were obtained from the registry. RESULTS: Of the 952 RA patients, 22 (2.3%) had RN and 930 (97.7%) did not. Age, sex, disease duration, smoking, and family history of an autoimmune rheumatic disease were similar. Obesity was more prevalent in the RN group, i.e. 11 (50%) vs. 326 (35.1%), p = 0.016. There was no difference in rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibody positivity. Patients with RN had more sicca symptoms, i.e. 8 (36.4%) vs. 152 (16.3%), p = 0.025, a higher mean score on the visual analogue scale pain (3 ± 2.9 vs. 2 ± 2.7, p < 0.001), more tender joints (6.4 ± 8.8 vs. 4.2 ± 7.2, p = 0.001), a higher patient global assessment of disease activity (3.3 ± 2.7 vs. 2.3 ± 2.7, p < 0.001), and more deformities, i.e. 3 (13.6%) vs. 74 (8%), p = 0.034. The mean health assessment questionnaire score in RN patients was 1.1 versus 0.9 in patients without RN (p = 0.08). Patients with RN had a low disease activity (means: disease activity score [DAS-28], 3.02; clinical disease activity index, 7.7; and simple disease activity index, 10.4), similar to the other group. While the rates of methotrexate treatment were comparable, biologic therapy was administered more in patients with RN (i.e. 15 [68.2%] vs. 478 [51.4%], p < 0.001). CONCLUSION: In Kuwait, the prevalence of RN is low among RA patients. Patients with and without RN are similar in terms of demographics and serologic features, except for more obesity. However, patients with RN have more sicca symptoms, joint deformities, and painful and tender joints. Disease activity scores are low with more frequent biologic therapy.
28679392 Factors associated with initial or subsequent choice of biologic disease-modifying antirhe 2017 Jul 5 BACKGROUND: Biologic disease-modifying antirheumatic drugs (DMARDs) are increasingly used for rheumatoid arthritis (RA) treatment. However, little is known based on contemporary data about the factors associated with DMARDs and patterns of use of biologic DMARDs for initial and subsequent RA treatment. METHODS: We conducted an observational cohort study using claims data from a commercial health plan (2004-2013) and Medicaid (2000-2010) in three study groups: patients with early untreated RA who were naïve to any type of DMARD and patients with prevalent RA with or without prior exposure to one biologic DMARD. Multivariable logistic regression models were used to examine the effect of patient demographics, clinical characteristics and healthcare utilization factors on the initial and subsequent choice of biologic DMARDs for RA. RESULTS: We identified a total of 195,433 RA patients including 78,667 (40%) with early untreated RA and 93,534 (48%) and 23,232 (12%) with prevalent RA, without or with prior biologic DMARD treatment, respectively. Patients in the commercial insurance were 87% more likely to initiate a biologic DMARD versus patients in Medicaid (OR = 1.87, 95% CI = 1.70-2.05). In Medicaid, African-Americans had lower odds of initiating (OR = 0.59, 95% CI = 0.51-0.68 in early untreated RA; OR = 0.71, 95% CI = 0.61-0.74 in prevalent RA) and switching (OR = 0.71, 95% CI = 0.55-0.90) biologic DMARDs than non-Hispanic whites. Prior use of steroid and non-biologic DMARDs predicted both biologic DMARD initiation and subsequent switching. Etanercept, adalimumab, and infliximab were the most commonly used first-line and second-line biologic DMARDS; patients on anakinra and golimumab were most likely to be switched to other biologic DMARDS. CONCLUSIONS: Insurance type, race, and previous use of steroids and non-biologic DMARDs were strongly associated with initial or subsequent treatment with biologic DMARDs.
27768831 Repair of Bone Erosion in Rheumatoid Arthritis by Denosumab: A High-Resolution Peripheral 2017 Aug OBJECTIVE: To compare the bone healing effects of denosumab and alendronate in female rheumatoid arthritis (RA) patients by high-resolution peripheral quantitative computed tomography. METHODS: This is a post hoc analysis of a randomized controlled trial. Forty patients were randomized in a 1:1 ratio to receive either subcutaneous denosumab (60 mg) once or oral alendronate (70 mg) weekly for 6 months. The size of individual bone erosions and the presence and extent of erosion-associated sclerosis (marginal osteosclerosis) were measured in the second metacarpal head of the nondominant hand at baseline, 3 months, and 6 months. RESULTS: Forty-two erosions were identified at baseline. After 6 months, the width, depth, and volume of erosion significantly decreased in the denosumab group (-0.23 mm, -0.16 mm, -0.91 mm(3) , respectively; all P < 0.01), whereas these parameters significantly increased in the alendronate group (0.19 mm, 0.32 mm, and 1.38 mm(3) , respectively; all P < 0.01; between-group differences, P < 0.01 for all). Quantitative analysis showed that the bone mineral density of the erosion margin significantly increased only after treatment by denosumab (19.75 mg/cm(3) ; P < 0.05 for denosumab, and -5.44 mg/cm(3) ; P = 0.51 for alendronate; P < 0.05 for between-group differences). CONCLUSION: Inhibition of receptor activator of NF-κB ligand by denosumab can induce partial repair of erosions in patients with RA, while erosions continued to progress in patients treated with alendronate. Combining denosumab with disease-modifying antirheumatic drugs may be considered for RA patients with progressive bone erosions.
29071975 [Mechanism of Heat-reinforcing Needling for Rheumatoid Arthritis Rabbits with Cold Syndrom 2017 Jun 25 OBJECTIVE: To explore the specific mechanism of heat-reinforcing needling (HRN) for rheumatoid arthritis (RA) rabbits with cold syndrome based on metabolomics. METHODS: A total of 40 healthy rabbits were randomly divided into a normal group, a model group, a reinforcing-reducing needling(RRN) group, a twirling-reinforcing needling (TRN) group and a HRN group (n=8 rabbits/group). The RA model with cold syndrome was established with ovalbumin and freezing. Except the normal and model groups, RRN, TRN and HRN were given at "Zusanli" (ST 36) in the corresponding acupuncture groups for 30 min, once a day for 7 days. After the interventions, the pain threshold and the local skin temperature of each group were observed. The endogenous metabolites in the serum were analyzed by the gas chromatography mass spectrometry (GC-MS) technology combined with the pattern-recognition method. RESULTS: The pain threshold and the local skin temperature in the model group were lower than those in the normal group (P<0.05). The pain thresholds and the local skin temperatures in the three acupuncture groups were higher than those in the model group after interventions (P<0.05), and those in the HRN group were obviously higher than those in the RRN and TRN groups (P<0.05). The serum metabolites of leucine, valine, isoleucine, and arachidonic acid in the model group were increased compared with those in the normal group (P<0.05), and the metabolites of α-ketoglutaric acid, citric acid, succinic acid, glucose, inositol, palmitic acid, stearic acid, lactose, d-ribose, and D-mannose were decreased (P<0.05). The above-mentioned metabolites in the three acupuncture groups were significantly reversed relevant to the model group (P<0.05), and the effect of HRN group was significantly superior to those of the RRN and TRN groups in regulating α-ketoglutaric acid, citric acid, succinic acid, glucose, inositol, d-ribose, and D-mannose (P<0.05). CONCLUSIONS: HRN for RA with cold syndrome is effective, which may be related to the specific regulation for the krebs cycle and glycometabolism.
29254845 Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumato 2018 Feb T helper 17 (Th17) cells are important mediators of immune responses against extracellular bacteria and fungi, and as such play critical regulatory roles in maintaining mucosal homeostasis. Conversely, Th17 cells and their effector molecules interleukin 17A (IL-17A), IL-17F, interferon (IFN)γ, tumor necrosis factor (TNF)α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the pathology of rheumatoid arthritis (RA). Interactions between Th17 cells and other immune cells or stromal cells that are present in the synovial tissue during the earliest phases of the disease, may eventually lead to chronic inflammation, irreversible cartilage degradation and bone erosions. Recent evidence points towards Th17 cell plasticity as an essential contributing process in RA pathology, since Th17 cells are able to adopt a pathogenic phenotype under the influence of environmental, inflammatory and genetic factors. A remarkable feature of this pathogenic Th17 cell phenotype is the high production of GM-CSF and TNFα and the co-appearance of Th1 cell characteristics, such as transcription factor T-box 21 (T-bet) and IFNγ expression. Recently, much progress has been made in unravelling the mechanisms underlying Th17 cell plasticity and pathogenicity. Of interest, many of the environmental and inflammatory factors associated with RA pathology, such as pro-inflammatory mediators and cytokines, microbiome dysbiosis, metabolism and diet, obesity, vitamins, steroids and hormones are linked to the development of pathogenic Th17 cells. Moreover proteins encoded by established genetic risk factors for RA including CCR6, CD226, CSF2, EOMES, ETS1, GATA3, IL2, IL6R, IL23R, IKZF3, IRAK1, IRF4, IRF8, PRKCQ, PRDM1, RBPJ, RUNX1 and TAGAP are directly involved in Th17 cell differentiation and/or function. This review provides a detailed overview of the molecular mechanisms involved in the heterogeneity and pathogenicity of Th17 cells in the context of autoimmune diseases, with a focus on RA. Understanding these mechanisms creates great potential to identify and select novel therapeutic targets which could improve current therapies or lead to development of new treatment strategies in RA.
28987944 MiR-140-5p inhibits synovial fibroblasts proliferation and inflammatory cytokines secretio 2017 Dec OBJECTIVES: This study was aimed to investigate the effects of miR-140-5p on the proliferation and inflammatory cytokines secretion of rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Synovial tissue samples from 23 rheumatoid arthritis (RA) patients and 18 normal synovial tissue samples were collected. The RASFs were isolated and cultured. Then, miR-140-5p and TLR4 expression in both synovial tissue and RASFs were detected using the quantitative real-time PCR (qPCR) and western blot. Dual luciferase reporter gene assay was employed to evaluate the interaction between miR-140-5p and 3'UTR of TLR4. Western blotting and qPCR were used to examine TLR2 expression after upregulation or downregulation of miR-140-5p in RASFs. After RASFs co-infected with TLR4 overexpression lentivirus and lentivirus containing miR-140-5p or miR-control respectively, the cellular proliferation and secretion of IL-6 and IL-8 level were detected through the MTS assay and enzyme-linked immunosorbent assay, respectively. RESULTS: MiR-140-5p was significantly down-regulated, and TLR4 was significantly up-regulated in synovial tissue samples from 23 RA patients and RASFs. Dual luciferase activity assay showed that miR-140-5p could specifically bind to the 3'UTR of TLR4. Down-regulation or up-regulation of miR-140-5p not only significantly increased or decreased the expression of TLR4, but also could promote or inhibit RASF proliferation and secretion of IL-6, and IL-8 in RASFs. Furthermore, overexpression of TLR4 can reverse the inhibitory effects of miR-140-5p on proliferation and inflammatory cytokines release of RASFs. CONCLUSIONS: MiR-140-5p could inhibit the proliferation and secretion of IL-6 and IL-8 through regulation of TLR4 expression.
28295271 NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibrob 2017 Apr In the present study, we investigated the role of nucleotide oligomerization domain-like receptor family pyrin domain containing 6 (NLRP6) in rheumatoid arthritis (RA) and explored the underlying mechanism. We found that both mRNA and protein levels of NLRP6 are attenuated in synovial tissues and fibroblast-like synoviocytes (FLS) of RA patients compared to patients with osteoarthritis. We also observed that pro-inflammatory cytokine production is decreased and nuclear factor-kappa B activation is inhibited in NLRP6-overexpressing RA-FLS. Furthermore, we found that NLRP6 overexpression promotes transforming growth factor-b-activated kinase 1-binding protein 2/3 lysosome-dependent degradation, and we provide evidence showing that NLRP6 plays the role of providing the docking site to facilitate the interaction between transforming growth factor-b-activated kinase 1-binding protein 2/3 and tripartite motif 38 in RA-FLS.
27599663 Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With 2017 Apr Tocilizumab is a humanized anti-interleukin-6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24-week double-blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2-compartment population pharmacokinetic model, with first-order absorption (for subcutaneous) and linear and Michaelis-Menten elimination was used. Mean observed steady-state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every-week and every-2-week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population-predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every-2-week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every-2-week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every-week subcutaneous and every-4-week intravenous regimens and less pronounced with the every-2-week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every-week subcutaneous regimen to the every-4-week intravenous regimen and the superiority of the every-2-week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.
28224284 Complementary and Alternative Medicine Use in Rheumatoid Arthritis: Considerations for the 2017 Apr Complementary and alternative medicines (CAMs) are widely used by patients with rheumatoid arthritis (RA); however, a significant proportion of these patients do not inform their physicians. This has many potential implications in a group of predominantly elderly patients with altered pharmacokinetics, comorbidities and polypharmacy of potentially toxic drugs. CAM usage may affect compliance and pharmacokinetics of conventional therapy for RA and comorbidities; therefore, physicians should engage patients in dialogues regarding CAM usage. This review introduces common CAMs used by RA patients, such as herbal remedies, supplements, and fish and plant oils, and their potential impact on conventional therapy. Efficacy of these treatments are not reviewed in detail but references for reviews and trials are provided for further reading. Fish oils and vitamin D supplementation may generally be recommended, while thunder god vine should be avoided. Patients should also be made aware of the risks of contamination and adulteration of less reputable sources of CAMs, and directed to evidence-based sources of information. Physicians should acknowledge the limitations of scientific evidence and not be prejudiced or dogmatic; however, they should remain resolute against therapies that are known to be ineffective or unsafe.