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ID PMID Title PublicationDate abstract
27002226 THE EARLY BIRD CATCHES THE WORM: EARLY COST-EFFECTIVENESS ANALYSIS OF NEW MEDICAL TESTS. 2016 Jan OBJECTIVES: There is little specific guidance on performing an early cost-effectiveness analysis (CEA) of medical tests. We developed a framework with general steps and applied it to two cases. METHODS: Step 1 is to narrow down the scope of analysis by defining the test's application, target population, outcome measures, and investigating current test strategies and test strategies if the new test were available. Step 2 is to collect evidence on the current test strategy. Step 3 is to develop a conceptual model of the current and new test strategies. Step 4 is to conduct the early-CEA by evaluating the potential (cost-)effectiveness of the new test in clinical practice. Step 5 involves a decision about the further development of the test. RESULTS: The first case illustrated the impact of varying the test performance on the headroom (maximum possible price) of an add-on test for patients with an intermediate-risk of having rheumatoid arthritis. Analyses showed that the headroom is particularly dependent on test performance. The second case estimated the minimum performance of a confirmatory imaging test to predict individual stroke risk. Different combinations of sensitivity and specificity were found to be cost-effective; if these combinations are attainable, the medical test developer can feel more confident about the value of further development of the test. CONCLUSIONS: A well-designed early-CEA methodology can improve the ability to develop (cost-)effective medical tests in an efficient manner. Early-CEAs should continuously integrate insights and evidence that arise through feedback, which may convince developers to return to earlier steps.
26319714 Association of levels of antibodies against citrullinated cyclic peptides and citrullinate 2015 Aug 29 BACKGROUND: Periodontal disease could be a risk factor for rheumatoid arthritis (RA). It is assumed that the bacterial strain Porphyromonas gingivalis mediates citrullination of host peptides and thereby the generation of RA-associated autoantibodies in genetically predisposed individuals. For that reason non-RA individuals who suffered from generalized aggressive (GAgP, N = 51) and generalized chronic periodontitis (GChP, N = 50) were investigated regarding the occurrence of antibodies against citrullinated cyclic peptides (anti-CCP) and citrullinated α-enolase peptide-1 (anti-CEP-1) in comparison to non-RA non-periodontitis controls (N = 89). Furthermore, putative associations between infections with five periodontopathic bacteria or expression of certain human leucocyte antigens (HLA) to these autoantibodies were investigated. METHODS: The presence of anti-CCP and anti-CEP-1 in plasma samples was conducted with enzyme linked immunosorbent assay. Subgingival plaque specimens were taken from the deepest pocket of each quadrant and pooled. For detection of DNA of five periodontopathic bacteria PCR with sequence specific oligonucleotides was carried out. Low resolution HLA typing was carried out with PCR with sequence specific primers. Differences between patients and controls were assessed using Chi square test with Yates correction or Fisher`s exact test if the expected number n in one group was <5. RESULTS: Two patients with GAgP (3.9%), no patient with GChP and two controls (2.2%, pFisher = 0.662) were positive for anti-CEP-1 whereas no study participant was anti-CCP positive. Individuals with P. gingivalis were slightly more often anti-CEP-1 positive in comparison to individuals without P. gingivalis (3.2 vs. 1.1%, pFisher = 0.366). Carrier of HLA-DQB1*06 or the HLA combination DRB1*13; DRB3*; DQB1*06 were slightly more anti-CEP-1 positive (6.1 and 4.3%) than no carriers (0.7 and 0%, pFisher 0.053). CONCLUSIONS: GAgP and GChP and the presence of periodontopathic bacteria are not associated with an increased risk for occurrence of anti-CCP and anti-CEP-1 autoantibodies. The putative relationship between periodontitis and RA should be investigated in further studies.
26629845 Maternal cytokines and disease severity influence pregnancy outcomes in women with rheumat 2016 Oct OBJECTIVES: To assess the influence of maternal cytokine levels, disease activity and severity on preterm delivery, small for gestational age (SGA) and cesarean delivery in pregnant women with rheumatoid arthritis (RA). METHODS: A prospective study in 47 pregnant women with RA and 22 healthy pregnant controls. The main outcome measures were birth weight in relation to maternal serum levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and RA activity and severity at three different time points: preconception and during the first and third trimesters. RESULTS: During the third trimester, IL-10 was detectable in 23.4% of patients with RA, IL-6 in 76.6%. Mean birth weight born to mothers with RA was higher when IL-10 level was high compared with low (p = 0.001), and lower when IL-6 was high compared with low (p = 0.035). Also increase in disease activity score-28 (in 60.1%, p = 0.001), Health Assessment Questionnaire-Disability Index (in 87.5%, p = 0.013), and pain score (56.9 ± 11.4, p = 0.003) associated with increased risk of SGA. High patient's global scale was associated with unfavorable pregnancy outcome (preterm, SGA, and cesarean). CONCLUSION: High maternal IL-10 levels are associated with higher birth weight and high IL-6 levels are associated with lower birth weight (SGA). Among women with RA, disease activity and severity are predictive of unfavorable pregnancy outcomes suggesting that better disease management early in the pregnancy could improve pregnancy outcomes.
26475289 Effects of switching weekly alendronate or risedronate to monthly minodronate in patients 2016 Jan Switching weekly ALN or RIS to monthly MIN in patients with RA, of whom two-thirds were treated with low-dose PSL, significantly decreased bone turnover markers and increased BMD at 12 months, suggesting that monthly MIN may be an effective alternative treatment option of oral bisphosphonate treatment. INTRODUCTION: The aim of this prospective, observational study was to evaluate the effects of switching weekly alendronate (ALN 35 mg) or risedronate (RIS 17.5 mg) to monthly minodronate (MIN 50 mg) in patients with rheumatoid arthritis (RA). METHODS: Patient characteristics were as follows: n = 172; 155 postmenopausal women, age 65.5 (44–87) years; T-score of lumbar spine (LS), −1.4; total hip (TH), −1.8; femoral neck (FN), −2.1; dose and rate of oral prednisolone (2.3 mg/day), 69.1 %; prior duration of ALN or RIS, 46.6 months; were allocated, based on their preference, to either the (1) continue group (n = 88), (2) switch-from-ALN group (n = 44), or (3) switch-from-RIS group (n = 40). RESULTS: After 12 months, increase in BMD was significantly greater in group 3 compared to group 1: LS (4.1 vs 1.2 %; P < 0.001), TH (1.9 vs −0.7 %; P < 0.01), and FN (2.7 vs −0.5 %; P < 0.05); and in group 2 compared to group 1: LS (3.2 vs 1.2 %; P < 0.05) and TH (1.5 vs −0.7 %; P < 0.01). The decrease in bone turnover markers was significantly greater in group 3 compared to group 1: TRACP-5b (−37.3 vs 2.5 %; P < 0.001), PINP (−24.7 vs −6.2 %; P < 0.05), and ucOC (−39.2 vs 13.0 %; P < 0.05); and in group 2 compared to group 1: TRACP-5b (−12.5 vs 2.5 %; P < 0.05) at 12 months. CONCLUSIONS: Switching weekly ALN or RIS to monthly MIN in patients with RA may be an effective alternative treatment option of oral bisphosphonate treatment.
27895169 Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis v 2017 Jan 1 IL-23 activates the synthesis and production of leukotriene B(4) (LTB(4)) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB(4) and its receptor LTB(4)R1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB(4) and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB(4) pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-κB ligand bone marrow cells derived from BLT1(+/+) and/or BLT1(-/-) mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP(+) cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-κB and phosphorylated IκB levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF-κ-B ligand-induced activation of intracellular calcium flux in vitro. Our data show that LTB(4) and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB(4) and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.
25888654 Correlates of a Single-Item Quality-of-Life Measure in People Aging with Disabilities. 2015 Dec OBJECTIVE: Practical quality-of-life (QOL) screening methods are needed to help focus clinical decision-making on what matters to individuals with disabilities. DESIGN: A secondary analysis of a database from a large study of adults aging with impairments focused on four diagnostic groups: cerebral palsy (n = 134), polio (n = 321), rheumatoid arthritis (n = 99), and stroke (n = 82). Approximately 20% of cases were repeated measures of the same individuals 3-5 yrs later. Functional levels, depression, and social interactions were assessed. The single-item, subjective, seven-point Kemp Quality of Life Scale measured QOL. For each diagnostic group, Kemp Quality of Life Scale responses were divided into low, average, and high QOL subgroups. Analysis of variance and Tukey honestly significant difference tests compared clinical characteristics among these subgroups. RESULTS: Duration of disability varied among the four groups. Within each group, QOL subgroups were similar in age, sex, and duration of disability. Low mean QOL was associated with lower functional level, higher depression scores, and lower social interaction (P < 0.001) in all four groups. In contrast, high mean QOL was associated with higher social interaction (P < 0.001). CONCLUSION: The Kemp Quality of Life Scale relates significantly to clinically relevant variables in adults with impairments. The scale's utility in direct clinical care merits further examination.
27483449 Differences in the Spectrum of Anti-Citrullinated Protein Antibody Fine Specificities Betw 2017 Jan OBJECTIVE: Antibodies to the citrullinated protein antigens (ACPAs) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different fine specificities in different populations is unclear. This study sought to examine the fine specificity of the antibody responses toward citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in more frequently studied cohorts of Caucasian subjects. METHODS: A multiplex analytic microarray system was used to analyze the occurrence of antibodies to 10 different citrullinated peptides (filaggrin [fil307-324], vimentin [Vim2-17, Vim60-75], fibrinogen [Fibα563-583, Fibα580-600, Fibβ36-52, Fibβ62-81a, Fibβ62-81b], enolase [Eno5-21], and type II collagen [CitCII355-378]) in serum samples from 4,089 RA patients (1,231 Malaysian and 2,858 Swedish) and 827 healthy control subjects (249 Malaysian and 578 Swedish). The positive reaction threshold for each peptide was set separately for each population based on a specificity of 98%. RESULTS: Distinct differences in the frequencies of 5 ACPA fine specificities (Vim60-75, Vim2-17, Fibβ62-81b, Eno5-21, and CitCII355-378) were found between the Malaysian and Swedish RA populations, despite a nearly identical percentage of patients in each population who were positive for anti-cyclic citrullinated peptide 2 antibodies. In Malaysian RA patients compared with Swedish RA patients, the frequencies of antibodies to Vim60-75 (54% versus 44%, corrected P [P(corr) ] = 1.06 × 10(-8) ) and CitCII355-378 (17% versus 13%, P(corr)  = 0.02) were significantly higher, while the frequencies of antibodies to Vim2-17 (25% versus 32%, P(corr)  = 1.91 × 10(-4) ), Fibβ62-81b (15% versus 30%, P(corr)  = 2.47 × 10(-22) ), and Eno5-21 (23% versus 50%, P(corr)  = 3.64 × 10(-57) ) were significantly lower. CONCLUSION: Serum ACPA fine specificities differ between RA patients in different populations, although the total proportions of individuals positive for ACPAs are similar. Differing patterns of ACPA fine specificity could be attributed to variations in genetic and/or environmental factors.
27421886 The balance between Foxp3 and Ror-γt expression in peripheral blood is altered by tociliz 2016 Jul 16 BACKGROUND: The balance between Th17 cells and regulatory T (Treg) cells has been shown to play an important role in the development of rheumatoid arthritis (RA). Recent studies have shown that treatment with abatacept (ABT) or tocilizumab (TCZ) affects Th17 and Treg cell populations. Although not unanimously accepted, several reports have shown that Treg cells are decreased by ABT and increased by TCZ, and that Th17 cells are decreased by TCZ. To further investigate the effects of ABT and TCZ on the skewing of T cell populations, we analyzed the expression of master regulators genes of helper T cell lineages following ABT/TCZ treatment of RA patients. METHODS: Ten patients treated with ABT and 10 patients treated with TCZ were enrolled. Total RNA was extracted from peripheral blood cells at baseline, and after 12 and 24 weeks of therapy. The expression levels of T-bet, GATA3, Foxp3 and Ror-γt were semi-quantified using real-time PCR. The relative expression levels were expressed as the ratios of two genes (T-bet/GATA3, Foxp3/GATA3, Foxp3/T-bet, Foxp3/Ror-γt, Ror-γt/T-bet, Ror-γt/GATA3), and the changes in these ratios with treatment were determined. RESULTS: The Foxp3/Ror-γt ratio was decreased after ABT therapy (0.67 ± 0.16 at 24 weeks, P = 0.0034) but was increased after TCZ therapy (2.00 ± 1.03 at 24 weeks, P = 0.0013). In addition, the Ror-γt/GATA3 ratio was decreased after TCZ therapy (0.78 ± 0.37 at 24 weeks, P = 0.0008). Except for these ratios, no significant skewing in the expression of these factors was detected. No significant relationship between clinical response to the treatment and change in the ratios of these factors was determined. CONCLUSION: Treatment with TCZ or ABT differently affected the balance between Foxp3 and Ror-γt expression in the peripheral blood of patients with RA.
26153840 Isolated herpes simplex in the adult larynx as a rare complication of methotrexate-induced 2015 Jul OBJECTIVE: This report describes the clinical presentation and management of a rare case of herpes simplex virus infection in the larynx of a patient treated with methotrexate. CASE REPORT: We report a case of a clinically suspicious laryngeal lesion in an 82-year-old woman who started methotrexate treatment for rheumatoid arthritis. Shortly afterwards she developed dysphonia, which worsened over four months. On microlaryngoscopy, there was bilateral erythema and ulceration of the vocal folds. No other mucocutaneous lesions or systemic features were present. Biopsies revealed herpes simplex virus infection of the vocal folds; there was complete resolution with oral aciclovir. A brief literature review for this rare entity is presented and the diagnostic challenges arising from under-recognition of atypical presentations are discussed. CONCLUSION: To our knowledge, this is the first report of a rare complication of herpes simplex virus infection in the context of methotrexate-induced immunosuppression. It may present therapeutic challenges for conditions which rely on immunosuppressive treatments.
26605648 High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule. 2015 Oct 27 High mobility group box protein 1 (HMGB1) is an evolutionary ancient nuclear protein that exerts divergent biological tasks inside and outside of cells. The functions of HMGB1 depend on location, binding partners and redox states of the molecule. In the nucleus, HMGB1 organizes DNA and nucleosomes and regulates gene transcription. Upon cell activation or injury, nuclear HMGB1 can translocate to the cytoplasm, where it is involved in inflammasome activation and pyroptosis, as well as regulation of the autophagy/apoptosis balance. When actively secreted or passively released into the extracellular milieu, HMGB1 has cytokine, chemokine, neuroimmune and metabolic activities. Thus, HMGB1 plays multiple roles in the pathogenesis of inflammatory diseases and mediates immune responses that range from inflammation and bacterial killing to tissue repair. HMGB1 has been associated with divergent clinical conditions such as sepsis, rheumatoid arthritis and atherosclerosis. HMGB1 initiates and perpetuates immune responses during infectious and sterile inflammation, as the archetypical alarmin and damage-associated molecular pattern (DAMP) molecule. We here describe advances in the understanding of HMGB1 biology with focus on recent findings of its mission as a DAMP in danger sensing and as a therapeutic target in inflammatory diseases.
27638739 Biosimilar Monoclonal Antibodies for Inflammatory Bowel Disease: Current Comfort and Futur 2016 Oct Biosimilars are biologic medicines that enter the market after a patent for an original reference product expires. The European Medicines Agency (EMA) developed a stringent legislation process for biosimilar monoclonal antibodies, whereby similarity to the reference medicinal product in terms of quality characteristics, biological activity, clinical safety and efficacy must be demonstrated. Biosimilar infliximab CT-P13 was the first biosimilar monoclonal antibody to receive EMA marketing authorization, and further biosimilar molecules are being developed. The phase I and III clinical trials were conducted in ankylosing spondylitis and rheumatoid arthritis, and the use of CT-P13 in inflammatory bowel disease (IBD) was extrapolated on the results of these trials. Medical professionals were initially concerned about the reversed engineering process, the novel legal framework and the lack of clinical data in IBD. Emerging real-world data have confirmed the similarities between CT-P13 and the reference product in terms of efficacy, safety and immunogenicity in IBD. The cost reduction represented by biosimilars promotes industry competition and improves treatment access with sustained quality of care. This article reviews the existing and emerging clinical data for CT-P13 and a future perspective on biosimilar use in IBD.
27578588 [Evaluation of synovial thickness of the small joints of the wrist and hand using high-fre 2016 Aug 20 OBJECTIVE: To measure the synovial thickness in the bilateral wrist joints, metacarpophalangeal (MCP) joints and proximal interphalangeal (PIP) joints using high-resolution intraoperative ultrasound probe in healthy young and middle-aged volunteers to determine the normal reference ranges of synovial thickness in the joints. METHODS: This study was conducted in 100 healthy young and middle-aged volunteers, including 50 male (mean age 36.2∓5.0 years; range 18-54 years) and 50 female (mean age 38.8∓5.5 years; range 20-56 years) individuals. The synovial thickness in the bilateral wrist joints, MCP joints and PIP joints was measured using the GE Logiq S8 18 MHz polo stick-like linear probe array. RESULTS: s No statistical significance was found in the synovial thickness of the wrist joints, MCP joints and PIP joints between the left and right hands, between young (<40 years) and middle-aged (≥40 years) subjects, or between the flexor surface and the extensor surface. In the male subjects, however, the synovial thickness in the wrist joints, MCP joints and PIP joints was significantly greater than that in female subjects. A significant difference was noted in the synovial thickness between the wrist joints, MCP joints and PIP joints. CONCLUSION: Measurement of the synovial thickness of the wrist joints, MCP joints and PIP joints using high-resolution intraoperative ultrasound probe is beneficial for early diagnosis and therapy of rheumatoid arthritis.
26318712 Reversible oligohydramnios in the second trimester of pregnancy in two patients with long- 2015 Dec The use of non-steroidal anti-inflammatory drugs like diclofenac in the third trimester of pregnancy can cause severe side effects, in particular oligohydramnios, premature closure of ductus arteriosus, and fetal kidney damage. However, the treatment with non-steroidal anti-inflammatory drugs until gestational week 28 is accepted as relatively safe. Here we describe two retrospectively reported cases of early-onset oligohydramnios associated with long-term diclofenac exposure of at least 150mg per day. The pathological findings were detected at gestational weeks 22 and 23, respectively. Amniotic fluid turned to normal after discontinuation of diclofenac in both cases, suggesting causality. Although early-onset oligohydramnios is a rare complication, caution for long-term diclofenac use in high doses is recommended even before gestational week 28.
25757439 Topical therapies for rheumatoid arthritis by gel ointments containing indomethacin nanopa 2015 Indomethacin (IMC), a nonsteroidal anti-inflammatory drug, has been used in the treatment of rheumatoid arthritis (RA), although its clinical use has been limited by its systemic side effects that include gastrointestinal lesions. Therefore, the development of IMC formulations that do not cause gastrointestinal lesions is highly anticipated. In this study, we designed new topical formulations containing IMC solid nanoparticles (IMCnano gel ointment), and investigated their pharmacokinetics. In addition, we demonstrate the preventive effects of this topical application of IMC nanoparticles on inflammation in adjuvant-induced arthritis rat (AA rat). The IMCnano gel ointment was prepared using Bead Smash 12 (a bead mill) and additives including 2-hydroxypropyl-β-cyclodextrin, methylcellulose and Carbopol 934; the mean particle size of the IMC nanoparticles was 173 ± 91 nm (means ± S.D.). The application of the IMCnano gel ointment attenuated the increase in paw edema of the hind feet of AA rats in comparison with AA rats treated with gel ointment containing IMC microparticles (IMCmicro gel ointment, particle diameter 17.1 ± 11.6 mm, means ± S.D). In addition, the accumulation of IMC from the IMCnano gel ointment in skin tissue was significantly large than for the IMCmicro gel ointment; however, the plasma IMC concentrations were similar for the IMCmicro and IMCnano gel ointments. Our findings suggest that the dermal application of nanoparticles may enable a medication to be applied without high-systemic drug levels, which could provide efficient and effective therapy that spares patients from unwanted side effects. A formulation of a topical drug delivery system using IMC nanoparticles may provide a delivery option for the clinical treatment of RA.
26886813 Rampant infections of bone marrow stem cell niches as triggers for spondyloarthropathies a 2016 Mar Tropheryma Whipplei can induce rheumatism mimicking SpA or RA, but even more rampant bacterial/viral infections in epiphyseal bones could also contribute to the onset of RA and SpA. Indeed, as bone marrow stem cell niches are enriched in Tregs and myeloid derived suppressor cells, these areas are favourable for the persistence of quiescent viruses and/or dormant bacteria. This review focuses on the possibility that such silent infections of bone marrow stem cell niches might contribute to the pathogenesis of SpA and RA, at least during their onset. Some infections can affect the bone marrow mesenchymal stem cells, which can transmit these pathogens to their progeny. Transient but repeated revivals of viruses or dormant bacteria could promote the conversion of marrow regulatory T cells into effector phenotypes, leading to autoimmunity in the epiphyseal bone marrow, entheses and adjacent synovium. This scenario would also fit the flares of rheumatic disorders and explain why some joints or enthuses can be severely involved whereas their neighbours remain intact. The efficiency of anti-TNF drugs does not rule out a role of persistent infections in SpA and RA. These drugs do not affect chlamydial clearance, or the reactivation of latent Salmonella enterica serovar Typhimurium in mice or Epstein-Barr virus in humans. Anti-TNF might even prevent, rather than foster, the revival of dormant bacteria and viruses in marrow stem cell niches. Indeed, anti-TNF enhance the maturation of the immunosuppressive immature myeloid cells around stem cells into dendritic cells and macrophages, thus restoring immune responses in these areas.
25630309 Comparison of tocilizumab and tumour necrosis factor inhibitors in rheumatoid arthritis: a 2015 Apr Tocilizumab (TCZ) and tumour necrosis factor inhibitors (TNFi) are recommended for the treatment of rheumatoid arthritis (RA) in patients with inadequate response (IR) to prior disease-modifying antirheumatic drugs (DMARDs). This retrospective analysis assessed the efficacy of TCZ and TNFi, alone or in combination with DMARDs, in 1603 patients with IR to previous treatment with either DMARDs (DMARD-IR) and/or TNFi (TNFi-IR), initiating treatment with TCZ or a TNFi, managed in routine clinical practice. Patients were grouped according to treatment history and treatment initiated: DMARD-IR patients initiating treatment with TCZ + DMARD (DMARD-IR TCZ) or TNFi + DMARD (DMARD-IR TNFi), DMARD-IR and/or TNFi-IR patients initiating treatment with TCZ monotherapy (TCZ mono) or TNFi monotherapy (TNFi mono), and TNFi-IR patients initiating treatment with TCZ + DMARD (TNFi-IR TCZ) or TNFi + DMARD (TNFi-IR TNFi). Patients initiating treatment with TCZ generally had more severe disease and longer disease duration compared with the corresponding TNFi group. Significantly more patients achieved remission (DAS28 ESR <2.6) in the TCZ groups compared with corresponding TNFi groups (DMARD-IR, TCZ 44.0 % vs. TNFi 29.6 %; monotherapy, TCZ 37.2 % vs. TNFi 30.2 %; TNF-IR, TCZ 41.3 % vs. TNFi 19.2 %; p < 0.001 for all comparisons). More patients achieved moderate-good responses (EULAR criteria) in the TCZ treatment groups (79-85 %) compared with TNFi treatment groups (65-81 %). Patient-reported outcomes showed greater improvements in TCZ compared with TNFi groups. In patients with inadequate response to DMARDs and/or TNFi treated in routine clinical practice, TCZ in combination with DMARDs or as monotherapy resulted in significantly more patients achieving remission and more marked improvements in patient-reported outcomes compared with TNF inhibitors.
25553607 Safety of subcutaneous versus intravenous tocilizumab in combination with traditional dise 2015 Mar INTRODUCTION: Tocilizumab (TCZ), a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody, has demonstrated efficacy and tolerability in several large randomized, controlled trials for the treatment of rheumatoid arthritis (RA). AREAS COVERED: This article compares the safety profile of the newer, subcutaneous (SC) formulation of TCZ with the original intravenous (IV) formulation, in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in patients with RA. Several pivotal clinical trials are included, highlighting data from: i) trials of TCZ-IV; ii) trials of TCZ-SC; and iii) trials comparing IV to SC TCZ. TCZ use in pediatric populations is beyond the scope of this review. EXPERT OPINION: The efficacy and safety of TCZ-IV in the treatment of RA has been demonstrated in multiple clinical trials, both as monotherapy and in combination with traditional DMARDs. The data for TCZ-SC is similar, albeit with a higher frequency of injection site reactions (ISRs). With careful patient selection, the benefit: risk ratio is favorable, offering patients a rapid and sustained reduction in disease activity, improved function and reduced structural damage. Given that most patients prefer SC to IV medication, TCZ-SC will likely become a mainstay, along with other biologic agents, for the treatment of RA patients who have failed traditional non-biologic DMARDs.
28283529 Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE. 2017 Apr OBJECTIVES: Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, and an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells. METHODS: ROCK activity in peripheral blood mononuclear cells (PBMCs) from 29 patients with SLE, 31 patients with RA and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor) or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity and IL-17 and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology. RESULTS: ROCK activity levels were significantly higher in patients with SLE and RA than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y27632, KD025 or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors. CONCLUSIONS: ROCK activity is elevated in PBMCs from patients with SLE and RA. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches.
25963543 Identification of anti-inflammatory fractions of Geranium wilfordii using tumor necrosis f 2015 May 12 BACKGROUND: Geranium wilfordii is one of the major species used as Herba Geranii (lao-guan-cao) in China, it is commonly used solely or in polyherbal formulations for treatment of joint pain resulted from rheumatoid arthritis (RA) and gout. This herb is used to validate a target-based drug screening platform called Herbochip® and evaluate anti-inflammatory effects of Geranium wilfordii ethanolic extract (GWE) using tumor necrosis factor-alpha (TNF-α) as a drug target together with subsequent in vitro and in vivo assays. METHODS: A microarray-based drug screening platform was constructed by arraying HPLC fractions of herbal extracts onto a surface-activated polystyrene slide (Herbochip®). Using TNF-α as a molecular probe, fractions of 82 selected herbal extracts, including GWE, were then screened to identify plant extracts containing TNF-α-binding agents. Cytotoxicity of GWE and modulatory effects of GWE on TNF-α expression were evaluated by cell-based assays using TNF-α sensitive murine fibrosarcoma L929 cells as an in vitro model. RESULTS: The in vivo anti-inflammatory effects of GWE were further assessed by animal models including carrageenan-induced hind paw edema in rats and xylene-induced ear edema in mice, in comparison with aspirin. The hybridization data obtained by Herbochip® analysis showed unambiguous signals which confirmed TNF-α binding activity in 46 herbal extracts including GWE. In L929 cells GWE showed significant inhibitory effect on TNF-α expression with negligible cytotoxicity. GWE also significantly inhibited formation of carrageenan-induced hind paw edema and xylene-induced ear edema in animal models, indicating that it indeed possessed anti-inflammatory activity. CONCLUSION: We have thus validated effectiveness of the Herbochip® drug screening platform using TNF-α as a molecular target. Subsequent experiments on GWE lead us to conclude that the anti-RA activity of GWE can be attributed to inhibitory effect of GWE on the key inflammatory factor, TNF-α. Our results contribute towards validation of the traditional use of GWE in the treatment of RA and other inflammatory joint disorders.
25744280 Cross-sectional correlation of single-item health literacy screening questions with establ 2015 Sep Research suggests that health literacy (HL) is associated with rheumatoid arthritis (RA) patients' functional status. Single-item health literacy screening (SILS) questionnaires may establish patients' HL; however, the wording of SILS may be misinterpreted by RA patients as a query regarding physical limitations. Despite this threat to validity, multiple publications have employed the SILSs as a measure of health literacy. We assessed the construct validity of two SILS's versions by correlating scores with standardized HL measures. English-speaking adult RA patients at a hospital serving low-income patients were enrolled in a cross-sectional study. Subjects completed two SILS versions, as well as two longer HL measurement tools [short test of functional health literacy in adults (s-TOFHLA) and the rapid estimate of adult literacy in medicine (REALM)]. Spearman correlation was used to compare these tools. The study enrolled 110 subjects. There was a good correlation between the two SILS versions (r = 0.705). The correlation of SILS2 and REALM or s-TOFHLA was less robust. The distribution of scores within each SILS2 category demonstrated substantial variation. The SILS2 has construct validity in the assessment of HL in patients with RA, though its correlation with traditional methods of assessing HL is weak.