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ID PMID Title PublicationDate abstract
22328565 No significant change in arterial stiffness in RA after 6 months and 1 year of rituximab t 2012 Jun OBJECTIVE: The excess cardiac risk, found in RA has been attributed to biological inflammation. Effective control of inflammation may be of benefit in reducing cardiovascular risk in RA patients. The aim of this study is to investigate the effects of 24 and 52 weeks of rituximab treatment on arterial stiffness and cardiovascular risk factors. METHODS: Arterial stiffness was measured by augmentation index (AIx) and pulse wave velocity (PWV), and other cardiovascular risk factors (lipid profile, blood pressure) were collected in active RA patients. RESULTS: Thirty-three patients, of whom 29 were females, with a mean age of 60.9 (12.0) years were included. Thirty patients had positive RFs, 27 had positive anti-CCP antibody and 93.9% (n = 31) were erosive. Nineteen patients were non-responders to anti-TNF-α treatments. After rituximab treatment, no change was observed in arterial stiffness, neither after 6 nor after 12 months [PWV 8.1 (3.1) m/s at baseline, 8.1 (2.8) at 6 months, 8.0 (2.7) at 1 year, P = 0.924; and AIx 30.4 (8.2)% at baseline, 28.6 (7.6) at 6 months, 29.4 (6.7) at 1 year, P = 0.216]. Total and low-density lipoprotein cholesterol levels increased significantly but high-density lipoprotein (HDL) and triglyceride levels were unchanged. The atherogenic index (total cholesterol/HDL cholesterol) was increased, but not to a level of significance. No change was found in other cardiovascular risk factors. DAS-28 according to levels of ESR and CRP and biologic inflammation were significantly improved. CONCLUSION: Arterial stiffness did not improve after 6 and 12 months of rituximab therapy. The treatment had a beneficial effect on biologic inflammation and disease activity, but caused a pro-atherogenic lipid profile.
23138379 Association of pre-miRNA-146a rs2910164 and pre‑miRNA-499 rs3746444 polymorphisms and su 2013 Jan Single nucleotide polymorphisms in pre‑microRNA (miRNA) may alter miRNA expression levels or processing and contribute to susceptibility in a wide range of diseases. The present study aimed to evaluate the possible association between rs2910164 and rs3746444 of the pre-miRNA (hsa-mir-146a and hsa-mir-499) polymorphisms and susceptibility to rheumatoid arthritis (RA) in an Iranian population. This case-control study was performed on 104 patients with RA and 110 healthy individuals. Tetra amplification refractory mutation system-polymerase chain reaction was used to genotype the hsa-mir-499 rs3746444 and hsa-mir-146a rs2910164 polymorphisms. The hsa-mir-499 rs3746444 polymorphism was a risk factor for predisposition to RA in codominant [TT vs. TC: odds ratio (OR), 2.11; 95% confidence interval (CI), 1.08-4.11; p=0.029; TT vs. CC: OR, 3.88; 95% CI, 1.68-8.98; p=0.002], dominant (TT vs. TC-CC: OR, 2.64; 95% CI, 1.48-4.72; p=0.001) and recessive (TC-CC vs. CC: OR, 3.05; 95% CI, 1.36-6.83; p=0.007) tested inheritance models. In addition, the rs3746444 C allele was a risk factor for RA (OR, 2.49; 95% CI, 1.63-3.81; p<0.0001). No significant difference was found between the groups concerning the rs2910164 polymorphism (χ2=0.348, p=0.841). Our findings demonstrated that the hsa-mir-499 rs3746444, but not mir-146a rs2910164, polymorphism is associated with an increased RA risk in a sample of the Iranian population. Larger studies with different ethnicities are required to validate our findings.
22113434 Cementless total hip arthroplasty in rheumatoid arthritis: a systematic review of the lite 2012 Apr BACKGROUND: Compromised rheumatic bone is a potential risk factor for mechanical complications in cementless total hip arthroplasty (THA) in cases of rheumatoid arthritis (RA). Increased rates of intra-operative fractures, component migration and (early) aseptic loosening are to be expected. Despite this, cementless THA is performed in cases of RA. METHODS: A literature search on cementless THA in RA was performed in EMBASE (1993-2011), Medline (1966-2011) and the Cochrane Library. A systematic review was conducted with a special emphasis on mechanical complications. RESULTS: Twenty-three case series and five studies of implant registries were included. Acetabular fractures and/or migration of the cup were reported in 9 out of 22 studies of the cup. Proximal femoral fractures and/or subsidence of the stem were reported in 14 out of 20 studies of the stem. Six studies compared failure rates of uncemented and cemented components due to aseptic loosening. The overall failure rate ratio (uncemented/cemented) for the cup was 0.6 (95% CI: 0.14-2.60) and for the stem 0.71 (95% CI: 0.06-8.55), both favoring uncemented fixation. The failure rates in case series without a control group were compared to the NICE criteria (failure rate/1). The overall failure rate for the cup was 0.97 (95% CI: 0.50-1.88) and for the stem 0.79 (95% CI: 0.44-1.41). Failure rates of aseptic loosening of higher than 1 (favoring cemented fixation) were reported in 6 out of 26 studies of the cup and in 2 out of 25 studies of the stem. In all these studies, the inferior implant designs were blamed, and not the type of fixation or the quality of the bone. CONCLUSIONS: Despite substantial rates of mechanical stem complications, no evidence was found to establish that cementless components perform less well than cemented components. The results justify the use of cementless THA in RA patients.
21406468 Magnetic resonance and ultrasonography real-time fusion imaging of the hand and wrist in o 2011 Aug OBJECTIVE: To investigate the role of a new hybrid imaging modality, integrated in the US equipment and derived by a real-time MRI and US fusion process, in the hand and wrist joints of a small group of rheumatic patients. METHODS: Consecutive patients with OA and RA with hand and wrist involvement were studied. Clinical assessment, physical examination, hand and wrist radiography and laboratory tests were carried out. After performing 0.2T MRI (T₁, T₂ and short time inversion recovery sequences) of the dominant hand and wrist, images were recorded in a US machine equipped with a virtual navigator system. Ultrasonography was performed in the same joints using an 18 MHz linear probe. Image MRI/US superposition was carried out, with real-time contemporary visualization of the US and related MRI images. Randomly selected stored images of different joints were subsequently re-analysed by a different operator. Concordance between the static and dynamic evaluations was assessed. RESULTS: Nine patients (six with OA and three with RA) were studied. The real-time MRI/US overlap provided fusion images of both tools. A striking concordance in the visualization of the bony profile was found with evidence of pronounced osteophytes in OA and bone erosions in RA. The analysis of stored selected images demonstrated a high concordance between real-time and static assessment. CONCLUSION: MRI/US fusion imaging gives a composite set of information with accurate anatomical correlations.
23237868 Association of the toll-like receptor 9 gene polymorphisms with Behcet's disease in a Japa 2012 Bacterial infection (i.e., Streptococcus sanguinis) has been suggested to be related to pathogenesis and/or symptom of Behcet's disease (BD). Toll-like receptor 9 (TLR9) plays an important role in both the innate and adaptive immune systems by recognizing a component of bacterial DNA (i.e., CpG-DNA). Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) in TLR9 were associated with infectious and autoimmune/autoinflammatory diseases. In this study, we detected five SNPs with BD patients in a Japanese population. Allele frequency analysis of the three common SNPs (-1486: T/C (promoter region), 1174: A/G (intron 1), 2848: G/A (exon 2; Pro545Pro)) showed no statistically significant difference between the BD patients and the healthy controls. However, genotyping analysis revealed that the homozygous genotypes -1486CC and 1174GG were significantly more frequent in the BD patients compared to the healthy controls (P = 0.048 and P = 0.027, respectively). The homozygous diplotype distribution C-G-A/C-G-A was significantly more frequent in the BD patients compared to the healthy controls (P = 0.041). For reporter gene assay, the plasmid construct carrying diplotype distribution C-G/C-G of the -1486T/C and 1174A/G SNPs showed significantly higher luciferase activity compared to the plasmid construct carrying diplotype distribution T-A/T-A (P = 0.019). These results suggested an association of the homozygous genotypes and homozygous diplotype configuration of the TLR9 SNPs with susceptibility to BD in the Japanese population.
23044167 Novel approach to identifying autoantibodies in rheumatoid synovitis with a biotinylated h 2013 Jan 31 Synovial tissue in rheumatoid arthritis (RA) shows dense infiltration of plasmacytes. The purpose of the present study is to identify and localize autoantibodies produced in these immunocytes in RA synovitis. We developed a novel screening system for detecting specific autoantigens. Protein antigens recognized by antibodies in the serum and synovial tissue extract from five RA patients were screened with the AlphaScreen method. For screening, a biotinylated human autoantigen library was constructed by the wheat germ cell-free protein synthesis system. The AlphaScreen analysis of 2183 proteins detected a limited number of antigens reactive with the serum and synovial tissue extract. Eighteen biotinylated proteins, containing top five showing high signals in each synovitis tissue extract, were utilized as probes for the enzyme-labeled antigen method, in order to visualize the site of specific antibody production in synovial lesions. Specific antibodies against two proteins, tripartite motif-containing 21 (TRIM21, also known as SSA/Ro52) and F-box only protein 2 (FBXO2), were visualized in the cytoplasm of plasmacytes in two RA synovitis lesions, respectively. Absorption experiments using unlabeled proteins confirmed the specificity of staining. No positive signals against these two proteins were identified in the additionally evaluated RA and osteoarthritis synovial lesions. The present study indicated 1) the usefulness of screening the human autoantigen library with the AlphaScreen assay for detecting autoantibodies in RA synovitis, and 2) the applicability of biotinylated proteins to the enzyme-labeled antigen method for visualizing the site of autoantibody production within the lesion.
21952999 Study of the frequency of HLA-DRB1 alleles in Brazilian patients with rheumatoid arthritis 2011 Sep The HLA-DRB1 alleles encoding an amino acid sequence (QKRAA/QRRAA/RRRAA) at position 70 74 of the third hypervariable region of the β1 chain of the HLA-DRB1 gene, called shared epitope (SE), are associated with increased susceptibility to and severity of rheumatoid arthritis (RA) in different populations. OBJECTIVE: To determine the frequency of HLA-DRB1 alleles in Brazilian patients with RA and their association with rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA). METHODS: Four hundred and twelve patients with RA (ACR 1987) and 215 controls were included. HLA-DRB1 typing was performed by use of polymerase chain reaction (PCR) with specific primers and hybridization with sequence-specific oligonucleotide probe (SSOP). ACPA was measured by use of the ELISA technique and RF by nephelometry. The statistical analysis comprised the chi-square and Student t tests and logistic regression. RESULTS: HLA-DRB1*04:01, *04:04, *04:05 alleles were associated with RA (P < 0.05); despite the wide confidence interval, it is worth noting the association between the DRB1*09:01 allele and RA (P < 0.05). HLA-DRB1 SE+ alleles were observed in 62.8% of the patients and in 31.1% of controls (OR 3.62; P < 0.001) and were associated with ACPA (OR 2.03; P < 0.001). DRB1-DERAA alleles showed a protective effect against RA (OR 0.42; P < 0.001). CONCLUSION: In a sample of Brazilian patients with RA, most of whom of mixed heritage, HLA-DRB1 SE+ alleles were associated with susceptibility to disease and presence of ACPA.
22252308 Longitudinal predictive ability of mapping models: examining post-intervention EQ-5D utili 2013 Apr OBJECTIVES: The purpose of this methodological study was to to provide insight into the under-addressed issue of the longitudinal predictive ability of mapping models. Post-intervention predicted and reported utilities were compared, and the effect of disease severity on the observed differences was examined. METHODS: A cohort of 120 rheumatoid arthritis (RA) patients (60.0% female, mean age 59.0) embarking on therapy with biological agents completed the Modified Health Assessment Questionnaire (MHAQ) and the EQ-5D at baseline, and at 3, 6 and 12 months post-intervention. OLS regression produced a mapping equation to estimate post-intervention EQ-5D utilities from baseline MHAQ data. Predicted and reported utilities were compared with t test, and the prediction error was modeled, using fixed effects, in terms of covariates such as age, gender, time, disease duration, treatment, RF, DAS28 score, predicted and reported EQ-5D. RESULTS: The OLS model (RMSE = 0.207, R(2) = 45.2%) consistently underestimated future utilities, with a mean prediction error of 6.5%. Mean absolute differences between reported and predicted EQ-5D utilities at 3, 6 and 12 months exceeded the typically reported MID of the EQ-5D (0.03). According to the fixed-effects model, time, lower predicted EQ-5D and higher DAS28 scores had a significant impact on prediction errors, which appeared increasingly negative for lower reported EQ-5D scores, i.e., predicted utilities tended to be lower than reported ones in more severe health states. CONCLUSIONS: This study builds upon existing research having demonstrated the potential usefulness of mapping disease-specific instruments onto utility measures. The specific issue of longitudinal validity is addressed, as mapping models derived from baseline patients need to be validated on post-therapy samples. The underestimation of post-treatment utilities in the present study, at least in more severe patients, warrants further research before it is prudent to conduct cost-utility analyses in the context of RA by means of the MHAQ alone.
23055694 Kinase inhibitors: a new class of antirheumatic drugs. 2012 The outlook for patients with rheumatoid arthritis has improved significantly over the last three decades with the use of disease-modifying antirheumatic drugs. However, despite the use of methotrexate, cytokine inhibitors, and molecules targeting T and B cells, a percentage of patients do not respond or lose their response over time. The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. In the past decade, small molecules targeting several kinases, such as p38 MAPK, Syk, and JAK have been developed. Several p38 MAPK inhibitors proved ineffective in treating rheumatoid arthritis. The Syk inhibitor, fostamatinib, proved superior to placebo in Phase II trials and is currently under Phase III investigation. Tofacitinib, a JAK1/3 inhibitor, was shown to be efficacious in two Phase III trials, while VX-509, a JAK3 inhibitor, showed promising results in a Phase II trial. Fostamatinib and tofacitinib were associated with increased rates of infection, elevation of liver enzymes, and neutropenia. Moreover, fostamatinib caused elevations of blood pressure and diarrhea, while tofacitinib was associated with an increase in creatinine and elevation of lipid levels.
23023071 In vivo two-photon imaging of T cell motility in joint-draining lymph nodes in a mouse mod 2012 Jul Recent imaging studies on intact lymph nodes (LNs) of naïve T cell receptor (TCR)-transgenic mice have reported that T cells reduce their motility upon contact with relevant antigen-presenting cells (APCs). Using in vivo two-photon imaging of T cells in joint-draining (JD) LNs, we examined whether similar changes in T cell motility are observed in wild type mice. Co-transfer of T cells from naïve mice and antigen-experienced T cells from mice with proteoglycan (PG)-induced arthritis into naïve or arthritic recipients resulted in prolonged interactions of antigen-experienced T cells with APCs upon intra-articular antigen (PG) injection, indicating that T cells from arthritic wild type mice recapitulate the motile behavior reported in naïve TCR-transgenic mice. However, naïve T cells also engaged in stable interactions with APCs in the JDLNs of arthritic recipients, suggesting an enhanced ability of APCs in the JDLNs of arthritic hosts to present antigen to either naïve or antigen-experienced T cells.
23338276 Bilateral asymptomatic fibrous-ankylosis of the temporomandibular joint associated with rh 2012 The American Academy of Orofacial Pain (AAOP) defines ankylosis of the temporomandibular joint (TMJ) as a restriction of movements due to intracapsular fibrous adhesions, fibrous changes in capsular ligaments (fibrous-ankylosis) and osseous mass formation resulting in the fusion of the articular components (osseous-ankylosis). The clinical features of the fibrous-ankylosis are severely limited mouth-opening capacity (limited range of motion during the opening), usually no pain and no joint sounds, marked deflection to the affected side and marked limitation of movement to the contralateral side. A variety of factors may cause TMJ ankylosis, such as trauma, local and systemic inflammatory conditions, neoplasms and TMJ infection. Rheumatoid arthritis (RA) is one of the systemic inflammatory conditions that affect the TMJ and can cause ankylosis. The aim of this study is to present a case of a female patient diagnosed with bilateral asymptomatic fibrous-ankylosis of the TMJ associated with asymptomatic rheumatoid arthritis. This case illustrates the importance of a comprehensive clinical examination and correct diagnosis of an unusual condition causing severe mouth opening limitation.
22891404 Clinical efficacy and adverse effects of golimumab in the treatment of rheumatoid arthriti 2012 Jun Golimumab is a fully human monoclonal antibody targeting tumor necrosis factor-alpha (TNFalpha), an important cytokine in the pathogenesis of rheumatoid arthritis (RA) and other arthritides. Golimumab was approved for the treatment of rheumatoid arthritis with methotrexate (MTX) and with or without MTX for psoriatic arthritis and ankylosing spondylitis. Administration is by monthly subcutaneous injection. In this review we present some of the major clinical trials evaluating the efficacy of golimumab with or without concomitant MTX in RA patients, including patients resistant to previous biologic treatments. In addition, we collected data on safety and adverse effects encountered in clinical trials. Current data show golimumab to be an effective and safe choice for the treatment of various inflammatory arthritides.
22401741 Latent tuberculosis in rheumatoid arthritis: evaluating cellular response and high-resolut 2012 May INTRODUCTION: The diagnosis of latent tuberculosis (LTB) in patients with rheumatoid arthritis (RA) has become important with the introduction of anti-tumor necrosis factor (anti-TNF-α) agents and the appearance of active tuberculosis cases in these patients. The tuberculin skin test (TST) has limited value in patients with RA. Tests based on the release of interferon-gamma (IFN-γ) are being studied, but their role has not been well established for this group of patients. OBJECTIVES: To compare the diagnosis of LTB in patients with RA by using cellular immune response to the TST and T.SPOT-TB. Additionally, findings of tomography studies compatible with LTB were used. METHODS: Clinical evaluation, TST, T.SPOT-TB and high-resolution computed tomography (HRCT) in a group of patients with RA at the University Hospital of the Federal University of Goiás. RESULTS: Response to the TST was lower in patients with RA (13.5%) compared to the predicted values of the general population. T.SPOT-TB identified a higher number of patients with LTB than the TST (36.8%). HRCT showed changes compatible with LTB in 52.9% of the patients, including 8 of the 11 patients with negative TST and T.SPOT-TB. CONCLUSIONS: The TST by itself is insufficient to diagnose LTB. A higher number of positive results were obtained with T.SPOT-TB when compared to the TST. Nevertheless, it was negative in a large percentage of patients with tomography findings consistent with LTB. HRCT is readily available in most large health-care centers and it could be incorporated into the diagnostic strategy for LTB in patients with RA.
22155554 Clinical impact of serum proteins on drug delivery. 2012 Jul 20 Among serum proteins albumin and transferrin have attracted the most interest as drug carriers in the past two decades. Prior to that, their potential use was overshadowed by the advent of monoclonal antibodies that was initiated by Milstein and Koehler in 1975. Meanwhile intensive pursuit of exploiting transferrin, but above all albumin as an exogenous or endogenous carrier protein for treating various diseases, primarily cancer, rheumatoid arthritis, diabetes and hepatitis has resulted in several marketed products and numerous clinical trials. While the use of transferrin has clinically been primarily restricted to immunotoxins, albumin-based drug delivery systems ranging from albumin drug nanoparticles, albumin fusion protein, prodrugs and peptide derivatives that bind covalently to albumin as well as physically binding antibody fragments and therapeutically active peptides are in advanced clinical trials or approved products. For treating diabetes, Levemir and Victoza that are myristic acid derivatives of human insulin or glucagon-like peptide 1 (GLP-1) act as long-acting peptides by binding to the fatty acid binding sites on circulating albumin to control glucose levels. Levemir from Novo Nordisk has already developed into a blockbuster since its market approval in 2004. Abraxane, an albumin paclitaxel nanoparticle as a water-soluble galenic formulation avoiding the use of cremophor/ethanol, transports paclitaxel through passive targeting as an albumin paclitaxel complex to the tumor site and is superior to conventional Taxol against metastatic breast cancer. INNO-206, an albumin-binding doxorubicin prodrug that also accumulates in solid tumors due to the enhanced permeability and retention (EPR) effect but releases the parent drug through acid cleavage, either intra- or extracellularly, is entering phase II studies against sarcoma. An expanding field is the use of albumin-binding antibody moieties which do not contain the fragment crystallizable (Fc) portion of, conventional immunoglobulin G (IgG) but are comprised of monovalent or bivalent light and/or heavy chains and incorporate an additional albumin-binding peptide or antibody domain. The most advanced antibody of this kind is ATN-103 (Ozoralizumab), a trivalent albumin-binding nanobody that neutralizes the pro-inflammatory tumor necrosis factor alpha (TNF-α) as a causative agent for exacerbating rheumatoid arthritis. ATN-103 is currently in multi-center phase II trials against this debilitating disease. In summary, because albumin as the most abundant circulating protein cannot only be used to improve the pharmacokinetic profile of therapeutically relevant peptides and the targeting moiety of antibodies but also for peptide-based targeting as well as low-molecular weight drugs to inflamed or malignant tissue, it is anticipated that R&D efforts of academia and the pharmaceutical industry in this field of drug delivery will prosper.
22045840 Biological drug treatment of rheumatoid arthritis and spondyloarthritis: effects on QT int 2012 Jan OBJECTIVE: Tumor necrosis factor-α (TNF-α) antagonists bring about significant improvement in chronic inflammatory diseases such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). There is some evidence that they can also have negative myocardial effects, but to date this issue has not been clarified. We evaluated changes in electrocardiographic measures [QT interval, corrected, dispersion, and dispersion corrected (QT, QTc, QTd, QTdc, respectively)] in patients with RA or SpA treated with anti-TNF agents (infliximab and etanercept), those treated with other biological agents (rituximab), and with methotrexate. METHODS: We studied 38 consecutive patients with RA (21 patients) or SpA (19 patients) being treated with TNF-α antagonists, 8 patients with RA being treated with rituximab, and 13 patients (8 with RA and 5 with SpA) taking methotrexate. Electrocardiographs (ECG) were performed on all participants at baseline and 12 months after initiation of treatment, and the QT, QTc, and QTd were calculated with standard procedures. RESULTS: After 12 months of treatment, significant increases over baseline values were observed in the mean QT (p < 0.009), QTd (p < 0.0001), and QTdc (p < 0.0001) of the anti-TNF group, but no significant changes were observed in those taking rituximab. QT changes in the anti-TNF group were unrelated to the disease (RA vs SpA) or drug (infliximab vs etanercept), and none were associated with clinical manifestations of cardiac disease. CONCLUSION: In patients with RA and SpA, TNF-α antagonists seem to increase the QT and QTd measures. Although these changes were completely asymptomatic, ECG may be indicated in patients being considered for anti-TNF therapy to identify those at risk for cardiac complications.
22337246 Hypothyroidism as a risk factor for development of cardiovascular disease in patients with 2012 May OBJECTIVE: To determine the frequency of hypothyroidism in patients with rheumatoid arthritis (RA), and to elucidate the association of hypothyroidism and development of cardiovascular disease (CVD) in these patients. METHODS: A retrospective medical record review was performed using all incident cases of adult-onset RA from Olmsted County, MN, USA, that fulfilled criteria for RA in the years 1988-2007. Patients with and without thyroid disease were followed longitudinally for the development of CVD. RESULTS: A cohort of 650 patients with RA and an age and sex-matched comparison cohort of 650 patients without RA was assembled (both cohorts mean age 55.8 yrs; 69% were women). There was no significant difference between cohorts in the presence of hypothyroid disease or subclinical hypothyroidism at time of RA diagnosis. No significant difference was found in the cumulative incidence of hypothyroid disease between the 2 cohorts. Hypothyroid disease was found to be significantly associated with CVD in patients with RA (hazard ratio 2.0; 95% CI 1.1, 3.6). This difference remained significant and unchanged after adjustment for traditional CV risk factors (HR 2.0; 95% CI 1.1, 3.6). CONCLUSION: No significant difference was found in either incidence or prevalence of hypothyroidism between patients with and those without RA. Hypothyroid disease was significantly associated with CVD in patients with RA, even after adjustment for other traditional CV risk factors.
20950126 The number needed to treat for second-generation biologics when treating established rheum 2011 Jan OBJECTIVE: To evaluate the number needed to treat (NNT) and the number needed to harm (NNH) of the second-generation biologics abatacept, certolizumab, golimumab, rituximab, and tocilizumab in patients with established rheumatoid arthritis (RA) taking concomitant methotrexate (MTX). METHODS: A systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Register of Controlled Trials was conducted up to 1 November 2009. We selected any published randomized, double-blind, MTX-controlled study including RA patients with a mean disease duration of at least 5 years before entering a pivotal trial on second-generation biological therapy. Studies eligible for inclusion involved patients, who had previously shown inadequate response to conventional disease-modifying anti-rheumatic drug (DMARD) therapy. Pre-specified binary outcomes were extracted with a preference for 1-year data (6-month data were used if no data were available for 1 year). Two reviewers independently extracted the data necessary to estimate the absolute measures in a non-responder intention-to-treat (ITT) analysis. RESULTS: Five randomized controlled trials, one for each of the drugs, were selected and data extracted according to published data at endpoint for American College of Rheumatology 50% (ACR50)-responding patients, and withdrawals due to adverse events. NNT ranged from four to six treated patients to achieve one ACR50 response, while withdrawals due to adverse events were few and non-significant compared to the placebo group, except for rituximab administered as 1000 mg. CONCLUSION: Comparable efficacy was shown by the five biological agents studied, with few adverse events. However, for rituximab, tocilizumab, and golimumab, only 6-month data were available, hampering the external validity with regard to long-term efficacy and tolerability. A low dose (500 mg) of rituximab may be as effective as the recommended dose of 1000 mg.
23066149 p16(INK4a) exerts an anti-inflammatory effect through accelerated IRAK1 degradation in mac 2012 Nov 15 Induction of cyclin-dependent kinase (CDK) inhibitor gene p16(INK4a) into the synovial tissues suppresses rheumatoid arthritis in animal models. In vitro studies have shown that the cell-cycle inhibitor p16(INK4a) also exerts anti-inflammatory effects on rheumatoid synovial fibroblasts (RSF) in CDK activity-dependent and -independent manners. The present study was conducted to discern how p16(INK4a) modulates macrophages, which are the major source of inflammatory cytokines in inflamed synovial tissues. We found that p16(INK4a) suppresses LPS-induced production of IL-6 but not of TNF-α from macrophages. This inhibition did not depend on CDK4/6 activity and was not observed in RSF. p16(INK4a) gene transfer accelerated LPS-triggered IL-1R-associated kinase 1 (IRAK1) degradation in macrophages but not in RSF. The degradation inhibited the AP-1 pathway without affecting the NF-κB pathway. Treatment with a proteosome inhibitor prevented the acceleration of IRAK1 degradation and downregulation of the AP-1 pathway. THP-1 macrophages with forced IRAK1 expression were resistant to the p16(INK4a)-induced IL-6 suppression. Senescent macrophages with physiological expression of p16(INK4a) upregulated IL-6 production when p16(INK4a) was targeted by specific small interfering RNA. These findings indicate that p16(INK4a) promotes ubiquitin-dependent IRAK1 degradation, impairs AP-1 activation, and suppresses IL-6 production. Thus, p16(INK4a) senescence gene upregulation inhibits inflammatory cytokine production in macrophages in a different way than in RSF.
22829198 Sample size determination in clinical trials with multiple co-primary endpoints including 2012 Sep In the field of pharmaceutical drug development, there have been extensive discussions on the establishment of statistically significant results that demonstrate the efficacy of a new treatment with multiple co-primary endpoints. When designing a clinical trial with such multiple co-primary endpoints, it is critical to determine the appropriate sample size for indicating the statistical significance of all the co-primary endpoints with preserving the desired overall power because the type II error rate increases with the number of co-primary endpoints. We consider overall power functions and sample size determinations with multiple co-primary endpoints that consist of mixed continuous and binary variables, and provide numerical examples to illustrate the behavior of the overall power functions and sample sizes. In formulating the problem, we assume that response variables follow a multivariate normal distribution, where binary variables are observed in a dichotomized normal distribution with a certain point of dichotomy. Numerical examples show that the sample size decreases as the correlation increases when the individual powers of each endpoint are approximately and mutually equal.
21162099 TSG-6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergis 2011 Apr OBJECTIVE: TSG-6 (the product of tumor necrosis factor [TNF]-stimulated gene 6) has a potent inhibitory effect on RANKL-mediated bone erosion. The aim of this study was to compare the activity of TSG-6 with that of osteoprotegerin (OPG) and to investigate its role as an autocrine modulator of cytokine-mediated osteoclast formation/activation. We also determined TSG-6 expression in inflammatory joint disease. METHODS: The effects of TSG-6, OPG, and the inflammation mediators TNFα, interleukin-1 (IL-1), and IL-6 on the formation of osteoclasts from peripheral blood mononuclear cells and synovial fluid (SF) macrophages were determined by tartrate-resistant acid phosphatase staining. Lacunar resorption and filamentous actin ring formation were measured as indicators of osteoclast activity. The amount of TSG-6 in culture media or SF was quantified by enzyme-linked immunosorbent assay, and expression of TSG-6 in synovial tissue was assessed by immunohistochemistry. RESULTS: TSG-6 acted in synergy with OPG to inhibit RANKL-mediated bone resorption and was produced by osteoclast precursors and mature osteoclasts in response to TNFα, IL-1, and IL-6. Expression of TSG-6 correlated with inhibition of lacunar resorption; this effect was ameliorated by an anti-TSG-6 antibody. The level of TSG-6 protein was determined in SF from patients with various arthritides; it was highest in patients with inflammatory conditions such as rheumatoid arthritis, in which it correlated with the amount of TSG-6 immunostaining in the synovium. TSG-6 inhibited the activation but not the formation of osteoclasts from SF macrophages. CONCLUSION: In the presence of inflammatory cytokines, osteoclasts produced TSG-6 at concentrations that are sufficient to inhibit lacunar resorption. This may represent an autocrine mechanism to limit the degree of bone erosion during joint inflammation.