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ID PMID Title PublicationDate abstract
20494473 The novel anti-rheumatic compound Rabeximod impairs differentiation and function of human 2011 Jan Rabeximod (9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b]quinoxaline) is a synthetic compound that is currently being developed for the treatment of rheumatoid arthritis (RA). Here, we investigated the effects of Rabeximod on the functionality of human antigen-presenting cells (APCs) of myeloid origin. Different subsets of professional APCs were generated from human monocytes in vitro and simultaneously treated with different doses of Rabeximod. Although Rabeximod had no effect on the differentiation of monocytes into anti-inflammatory macrophages (AI-MÏ•s), this compound impaired monocyte differentiation into monocyte-derived dendritic cells (MDCs) and pro-inflammatory allostimulated macrophages (Allo-MÏ•s). MDCs that were treated with Rabeximod resulted in a significant decrease in their ability to pinocytose antigens, while no effect was exerted by the drug on the ability of Allo-MÏ•s and AI-MÏ•s to phagocytose. Furthermore, we observed a significant reduction in the allostimulatory ability of MDCs and Allo-MÏ•s after treatment with Rabeximod, although this compound did not affect the low immunostimulatory capacity of AI-MÏ•s. Conversely, the effect of Rabeximod in influencing cytokine secretion by APCs appeared to be limited. In conclusion, Rabeximod impairs differentiation of monocytes into different pro-inflammatory APCs, leading to impaired immunostimulatory abilities of these cells. Our observations shed light on the cellular mode of action and the immunomodulatory effect of Rabeximod.
23146195 The immunoreceptor tyrosine-based activation motif (ITAM) -related factors are increased i 2012 Nov 12 INTRODUCTION: The immunoreceptor tyrosine-based activation motif (ITAM) pathway provides osteoclast co-stimulatory signals and regulates proliferation, survival and differentiation of effector immune cells. In the osteoclast, the receptors Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Osteoclast Associated Receptor (OSCAR) and their respective adaptor proteins, DAP12 and FcRγ mediate ITAM signals and induce calcium signaling and the crucial transcription factor, NFATc1. In rheumatoid arthritis (RA), OSCAR expression by monocytes is inversely correlated with disease activity. Additionally, serum levels of OSCAR are reduced in RA patients versus healthy controls suggesting that expression and secretion or cleavage of soluble (s) OSCAR is immune modulated. Recent data suggest that endothelial cells may also be a source of OSCAR. METHODS: ITAM receptors, their adaptor proteins, and NFATc1 and cathepsin K were detected in human synovial tissues by immunohistochemistry. Synovial tissues from patients with active RA were compared with tissue from patients in remission, osteoarthritis (OA) patients and healthy individuals. OSCAR was measured by immunoassay in synovial fluids recovered from active RA and OA patients. Endothelial cells were cultured with or without 5 ng/mL TNF-α or IL-1β over 72 hours. Temporal expression of OSCAR mRNA was assessed by qRT PCR and OSCAR protein in the supernatant was measured by ELISA. RESULTS: Significantly higher (P < 0.05) NFATc1-positive inflammatory cell aggregates were found in active RA tissues than in healthy synovial tissue. Similarly, the percentage of OSCAR, FcRγ, DAP12 and TREM2 positive cells was significantly higher in active RA tissues compared to the healthy synovial tissue. Notably, OSCAR was strongly expressed in the microvasculature of the active RA tissues (9/9), inactive RA (8/9) weakly in OA (4/9) but only in the lumen of healthy synovial tissue (0/8). OSCAR levels were detected in synovial fluids from both RA (47 to 152 ng/mL) and OA (112 to 145 ng/mL) patients. Moreover, OSCAR mRNA expression and soluble OSCAR release was stimulated by TNF-α and IL1-β in cultured endothelial cells. CONCLUSIONS: Increased levels of ITAM related factors were present in synovial tissue from active RA joints compared to OA and healthy joints. OSCAR was strongly expressed by the vasculature of active RA patients and membrane bound and soluble OSCAR was stimulated by inflammatory mediators in endothelial cells in vitro.
22997971 Evaluation of status of zinc, copper, and iron levels in biological samples of normal and 2012 BACKGROUND: A great number of studies have investigated the possible role of trace elements in the etiology and pathogenesis of rheumatoid arthritis (RA). METHODS: The aim of the study was to evaluate copper (Cu), iron (Fe), and zinc (Zn) levels in three biological samples (scalp hair, blood, and urine) in patients with rheumatoid arthritis (RA) in two groups, age ranges 46 - 60 and 61-75 years, of both genders compared to age-matched healthy individuals. A microwave assisted wet acid digestion procedure was developed as a sample pretreatment for the determination of Cu, Fe, and Zn in biological samples. The digests of all biological samples were analysed for Cu, Fe, and Zn by flame atomic absorption spectrometry (FAAS) using an air/acetylene flame. The proposed method was validated by analyzing certified reference samples of hair, blood, and urine. RESULTS: The results indicated significantly lower levels of Fe, Cu, and Zn in the biological samples (blood and scalp hair) of male and female rheumatoid arthritis patients as compared to control subjects of both genders (p < 0.01). CONCLUSIONS: These data present guidance to clinicians and other professional investigating deficiency of essential trace metals in biological samples (scalp hair and blood) of RA patients.
21786185 Fibrinolysis is down-regulated in mouse collagen-induced arthritis, but its normalization 2011 Nov OBJECTIVE: Down-regulation of fibrinolysis and increased fibrin deposition in joints are hallmarks of rheumatoid arthritis (RA), and are believed to be involved in disease progression. The mouse model of collagen-induced arthritis (CIA) closely resembles RA and has been used to explore mechanism and treatments of RA, but neither the fibrinolytic system nor pro-fibrinolytic therapies were investigated in CIA. MATERIALS AND METHODS: Plasmin activity, levels of plasminogen activator inhibitor (PAI-1), D-dimer, and IL-6 were measured in plasma of CIA mice. Fibrin deposition and PAI-1 levels were also measured in inflamed joints. Mice were treated with plasminogen activators uPA (urokinase-type plasminogen activator) or tPA (tissue-type plasminogen activator). Effects of treatment on disease severity and fibrinolytic system were assessed. RESULTS: CIA caused decrease in plasmin activity, accompanied by increase in PAI-1 levels, in both blood and inflamed joints. This resulted in massive fibrin deposition in synovium. PAI-1 levels correlated negatively with plasmin activity and positively with IL-6. Treatments with uPA and tPA improved plasmin activity and removed fibrin deposits in inflamed joints. However, disease severity remained unchanged. CONCLUSIONS: Fibrinolytic changes in CIA parallel changes in RA, making CIA a suitable model to study fibrinolysis in RA. Normalization of plasmin activity in CIA after treatment with plasminogen activators had no effect on disease severity.
23083039 Serum proteome analysis in patients with rheumatoid arthritis receiving therapy with etane 2012 Oct AIM: Rheumatoid arthritis (RA) is a chronic inflammatory disorder of the synovium resulting in the destruction of affected joint cartilage and bone structures. Etanercept is a biological agent that blocks the tumor necrosis factor-α (TNF-α)-mediated inflammatory processes in RA patients, and has a regenerative effect on cartilage. In order to identify novel disease-related proteins and candidate biomarkers, we performed proteomic profiling of the serum in patients with RA who were treated with etanercept. METHOD: Serum samples were obtained from eight RA patients before and after etanercept treatment. The low molecular weight proteins in the serum were concentrated and analyzed by liquid chromatography-tandem mass spectrometry. The results before and after etanercept treatment were compared by the spectrum count method. RESULTS: Among a total of 477 proteins identified, 12 were found to be decreased and five were increased by etanercept treatment. Some of the changed proteins were known to be related to RA, and most of the other changed proteins may play possible roles in the TNF-α signaling pathway or the state of cartilage and extracellular matrix. CONCLUSION: The present proteomic study identified several proteins that could be involved in the pathogenesis of RA. These findings could thus lead to the identification of novel candidate disease-related protein biomarkers for RA, or indicate new targets for therapy.
21752570 An experimental evaluation of patient decision aid design to communicate the effects of me 2012 Mar OBJECTIVE: To explore how effectively information presentation formats used in a patient decision aid communicated the ability of a disease modifying anti-rheumatic drug to slow the rate of progression of rheumatoid arthritis related structural joint damage (SJD). METHODS: 91 first year psychology students and 91 RA patients participated in a prospective randomized, single blind, factorial experimental design evaluating the effect of four information formats on: satisfaction with risk communication, verbatim and gist recall of a hypothetical anti-rheumatic drug's ability to slow the rate of progression of SJD. RESULTS: Both groups underestimated the hypothetical drug's ability to slow SJD. Formats that supported the narrative statement with a reinforcing graphic element resulted in recall closer to the true value. Comparison of the results from testing of RA patients and college students were remarkably similar across formats. CONCLUSION: Rate of progression as communicated by narrative statement plus a graphic element (i.e. speedometer metaphor or pictograph) aided recall better than a narrative statement alone. Our results suggest that testing decision aid components with non-patients may provide data generalizable to patient populations. PRACTICE IMPLICATIONS: Graphics must be used carefully in patient decision aids as they can enhance recall, but may also introduce unintended recall bias.
22864458 Total hip replacement arthroplasty with Mallory-Head system--minimum ten-year follow-up re 2012 Oct PURPOSE: The purpose of this study was to assess the clinical and radiographic results of a total hip arthroplasty with the double tapered Mallory-Head system. METHODS: The clinical and radiographic results of a consecutive series of 81 total hip replacements in 75 patients were reviewed 10-15 years (average 11.4 years) postoperatively. The patients' underlying conditions were avascular necrosis in 46 hips (57 %), osteoarthritis in 12 hips (15 %), RA in nine hips (11 %), and others. Clinical results were evaluated based on the modified Harris hip score and modified Merle d'Aubigné-Postel score. A radiographic analysis was performed. RESULTS: The average modified Harris hip score improved from a preoperative score of 56 points to a postoperative 92 points. The average modified Merle d'Aubigné-Postel score was 15 points at the latest follow up, and 55 hips (68 %) were classified as the clinical grades of excellent or good results. One acetabular component was revised because of loosening, and one was revised for recurrent dislocation. CONCLUSION: The clinical and radiological evaluations of the total hip replacements using the Mallory-Head system showed good results.
22045522 [Proteins in rheumatology and clinical immunology]. 2011 Nov Twelve years ago the tumour necrosis factor (TNF) inhibitors revolutionised the therapy of rheumatoid arthritis and other inflammatory rheumatic diseases. Today, in addition to anti-cytokine strategies, immunosuppressive biologicals have been developed that delete B-lymphocytes or inhibit the activation of T-lymphocytes. The spectrum of indications for these protein drugs will broaden substantially in the near future and will likely include also diseases with orphan status (incidence below 1:10'000). Used in the right indication and with knowledge of molecular effects as well as clinical adverse effects these new drugs do not appear to be more dangerous than conventional disease modifying agents (DMARDs).
21592952 [Effectiveness of biological treatments based on ACR70 response in rheumatoid arthritis: i 2011 Jun 5 The therapy of rheumatoid arthritis has been changed by biological treatments. Their efficacy was evaluated in several randomized controlled trials. These trials were different in patient characteristics and the administration regimen. Placebo was the control and direct comparison of biological treatments is missing. OBJECTIVES: In the present study the efficacy of biological treatments in patients with rheumatoid arthritis was compared based on the randomized controlled trials available in the literature. A meta-analysis was conducted and meta-regression was used to explore the relationship between disease characteristic variables and observed efficacy. RESULTS: The related scientific literature is broad. Thirty two trials involving 18,500 patients were included into the current meta-analysis. The relative odds ratios of biological treatments compared to placebo varied between 3.6 and 20.0, and between 6.4 and 35.5 in case of monotherapy and combination with non-biological therapy, respectively. Disease duration and added non-biological therapy were in positive relationship with relative efficacy. More severe disease resulted smaller relative effect. CONCLUSIONS: The results show that the efficacy of biological treatments is similar. The relative efficacy worsens with more severe disease and improves with disease duration.
21988491 MicroRNAs: Emerging Regulators of Immune-Mediated Diseases. 2012 Feb MicroRNAs (miRNAs) represent the most abundant class of regulators of gene expression in humans: they regulate one-third of human protein-coding genes. These small noncoding ∼22-nucleotides (nt)-long RNAs originate by multistep process from miRNA genes localized in the genomic DNA. To date, more than 1420 miRNAs have been identified in humans (miRBase v17). The main mechanism of miRNA action is the posttranscriptional regulation via RNA interference with their target mRNAs. The majority of target mRNAs (more than 80%) undergo degradation after recognition by complementary miRNA; the translational inhibition with little or no influence on mRNA levels has been also reported. Each miRNA may suppress multiple mRNA targets (average ∼200), and at the same time, one mRNA can be targeted by many miRNAs enabling to control a spectrum wide range of cellular processes. Recently, the role of miRNAs in the development of immune cells and the maintenance of immune system homeostasis gained attention, and the involvement of miRNAs in the pathogenesis of several immune system diseases has emerged. This review focuses on the role of miRNAs in autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and psoriasis), inflammatory pathologies of distinct organ (atherosclerosis, osteoarthritis and atopic eczema) and/or systemic locations such as allergy. The role of miRNAs, their predicted and known mRNA targets and description of their actions in physiological immune reactions and in the pathological processes ongoing in immune-mediated human disorders will be discussed. Finally, miRNA-based diagnostics and therapeutic potentials will be highlighted.
21071478 'If I didn't have RA I wouldn't give them house room': the relationship between RA, footwe 2011 Mar OBJECTIVES: The aim of this study was to develop a greater understanding of the impact of RA on women's self-image and self-presentation via an exploration of their clothing choices. METHODS: Located within a qualitative symbolic interactionist approach, 15 women with RA (age range 38-74 years, disease duration 1-47 years) each participated in two interviews. The first explored the impact of RA on their feelings about their bodies and their appearance; the second explored the factors that informed their clothing choices and the way they presented themselves. All interviews were digitally recorded and transcribed verbatim, digital photographs of the women's clothes and shoes were taken. Data were analysed jointly by both authors using thematic network analysis. RESULTS: Shoes were identified as greatly influencing the women's clothing choices and how they presented themselves. Three themes were identified that explored the structural and symptomatic impact of RA on the women's feet, the strategies they had developed to resolve their footwear needs outside of prescription footwear and the significant impact that footwear had on their clothing choices and self-presentation. Insights from these data highlight the polarity that exists between the clinical, functional attitudes towards shoes and their social status. CONCLUSION: While aesthetic issues challenge the acceptability of prescription footwear, problems also exist with the functionality and comfort of footwear available on high streets. A more collaborative approach to the design of footwear is required for both prescription and mainstream footwear to meet the needs of women with RA.
22264497 Nanomedicines for chronic non-infectious arthritis: the clinician's perspective. 2012 Sep Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic health conditions. However, despite recent advances in medical therapeutics, their treatment still represents an unmet medical need because of safety and efficacy concerns with currently prescribed drugs. Accordingly, there is an urgent need to develop and test new drugs for RA and OA that selectively target inflamed joints thereby mitigating damage to healthy tissues. Conceivably, biocompatible, biodegradable, disease-modifying antirheumatic nanomedicines (DMARNs) could represent a promising therapeutic approach for RA and OA. To this end, the unique physicochemical properties of drug-loaded nanocarriers coupled with pathophysiological characteristics of inflamed joints amplify bioavailability and bioactivity of DMARNs and promote their selective targeting to inflamed joints. This, in turn, minimizes the amount of drug required to control articular inflammation and circumvents collateral damage to healthy tissues. Thus, nanomedicine could provide selective control both in space and time of the inflammatory process in affected joints. However, bringing safe and efficacious DMARNs for RA and OA to the marketplace is challenging because regulatory agencies have no official definition of nanotechnology, and rules and definitions for nanomedicines are still being developed. Although existing toxicology tests may be adequate for most DMARNs, as new toxicity risks and adverse health effects derived from novel nanomaterials with intended use in humans are identified, additional toxicology tests would be required. Hence, we propose that detailed pre-clinical in vivo safety assessment of promising DMARNs leads for RA and OA, including risks to the general population, must be conducted before clinical trials begin.
23168699 A pilot study on short term heart rate variability & its correlation with disease activity 2012 Oct BACKGROUND & OBJECTIVES: Cardiovascular complications may lead to mortality in patients with rheumatoid arthritis (RA). We assessed heart rate variability (HRV), an important autonomic function, to quantify the risk for cardiovascular complications in Indian patients with RA. METHODS: The study was carried out in RA patients (n=45) diagnosed as per American College of Rheumatology criteria and healthy controls. HRV recording and analysis was done using Nevrokard software using time and frequency domain analyses. The overall autonomic tone, parasympathetic drive, sympathetic drive and sympatho-vagal ratio were quantified by using various parameters. It included standard deviation of all R-R intervals (SDNN), standard deviation of successive differences between adjoining normal cycles (SDSD), root-mean square of successive differences (RMSSD), and number of R-R intervals differing by >50 ms from adjacent intervals (NN50) in the time domain analysis. In frequency domain analysis, low frequency (LF) and high frequency (HF), LF/HF and total power were assessed. RESULTS: Demographic profile was comparable between groups; however, systolic BP was higher in patients with RA. SDNN, SDSD, RMSSD, NN50, LF and HF power and total power (ms x ms) were significantly lower in patients with RA versus healthy controls (P<0.001). Disease activity score at 28 joints indicating severity of the disease was significantly and positively correlated with SDSD (r=0.375, R 2 =14.06; P=0.045) while LF and HF power (ms × ms) were significantly and inversely correlated with rheumatoid factor (r=-0.438 and -0.445; R 2 =19.1 and 19.8; P=0.017 and 0.016, respectively). INTERPRETATION & CONCLUSIONS: HRV was significantly altered in patients with RA and independently associated with disease activity. Hence autonomic function testing, using HRV, may be useful as part of cardiovascular risk assessment in these patients.
22841983 Potential roles for CD8(+) T cells in rheumatoid arthritis. 2013 Jan CD8(+) T cells have long been suggested to play a role in rheumatoid arthritis (RA). The current paradigm on the pathogenesis and maintenance of the disease would endorse these cells with predominantly protective and minor influences. However, several animal studies suggest that these cells may have a predominantly proinflammatory (cytotoxic) effect in the disease. Other studies claim otherwise, that they have a mainly regulatory role in inflammatory joints. The evidence in human disease is remarkably scarce. Studies in human samples indicate that CD8(+) T cells play an important role in the establishment of germinal centers observed in nearly 50% of RA patients, which may have a decisive role in the initiation and maintenance of the disease process. The conflicting results of experimental studies, the scarcity of data and the complexity of research needed to unravel these complex interactions may explain the relative oblivion of CD8 cells in the field of arthritis over recent decades. Is this a wise decision or may we run the risk of not finding the key to RA because we search for it where there is light as opposed to its probable location? The present review brings together available data on the potential role of CD8(+) T cells in inflammation, with emphasis on rheumatoid arthritis, hoping to foster interest and fresh research in this area.
22131127 Is monocyte chemotactic protein 1 elevated in aseptic loosening of TKA? A pilot study. 2012 Jul BACKGROUND: Failure of TKA from aseptic loosening is a growing concern, as TKA is performed with increasing frequency. Loosening is multifactorial and may be associated with elevated inflammatory cytokines in addition to biomechanical failure. QUESTIONS/PURPOSES: We asked whether proinflammatory cytokines and chemokines are elevated in synovial fluid from patients undergoing revision surgery as compared to those with osteoarthritis (OA) or rheumatoid arthritis (RA). METHODS: We obtained synovial fluid samples from 20 patients: six with aseptic loosening of TKA (all with bone loss), 10 with primary OA, and four with RA. A panel of cytokines/chemokines was screened using a SearchLight(®) Array (Pierce Biotechnology, Rockford, IL, USA) in one revision sample. Using these data, we assayed the synovial fluids for monocyte chemotactic protein 1 (MCP-1) by ELISA. RESULTS: We observed an increase in synovial MCP-1 levels in samples from patients planned for TKA revision compared to those with OA or RA. In patients undergoing revision arthroplasty, the mean (± SD) MCP-1 concentration was 21,233 ± 18,966 pg/mL (range, 1550-50,657 pg/mL; n = 6). In patients with OA, the mean MCP-1 level was 3012 ± 3321 pg/mL. In patients with RA, the mean MCP-1 concentration was 690 ± 561 pg/mL. CONCLUSIONS: All patients undergoing revision TKA showed elevated concentrations of MCP-1 compared to patients with OA and RA, suggesting MCP-1 may serve as a potential marker or predictor of bone loss in patients undergoing revision surgery. CLINICAL RELEVANCE: MCP-1 may be a novel biomarker in patients showing early symptoms of aseptic loosening of TKA.
22471260 Reconstruction of the trapeziometacarpal joint in inflammatory joint disease using interpo 2012 Apr Interposition arthroplasty with bioreplaceable poly-L-D-lactic acid (PLDLA) implants has yielded promising results in reconstruction of rheumatoid hands. In this prospective clinical study we compared the PLDLA implant arthroplasty (n = 17) with that of tendon interposition (n = 12) for destruction of the trapeziometacarpal joint in arthritic patients. There was no significant difference between the two groups preoperatively. At one-year follow-up, the mean pain and function scores were 5 and 13 in the PLDLA group, and 19 and 43 in the tendon interposition group, respectively. At one-year follow-up the visual analogue scale (VAS) for function of the PLDLA group differed significantly from that of the tendon interposition group (p = 0.03). This difference was not found at three months postoperatively, and disappeared again at two-year follow-up. Otherwise, no significant difference was found between the groups in the pain or function scores, functional tests, or range of movement. Bioreplaceable interposition arthroplasty works at least as well as tendon interposition. The operation is easier.
21794809 [Differences in the management of early and established rheumatoid arthritis]. 2011 May OBJECTIVE: To assess the differences in the clinical and therapeutic management of early and established rheumatoid arthritis (RA) in clinical practice. METHODS: Retrospective and multicentre study including 360 patients diagnosed with RA. During the 12 months prior to the study, onset, sociodemographic, clinical and therapeutic data were collected by clinical chart review. RESULTS: A total of 152 patients with early RA and 208 with established RA were studied. 97.5% had received disease-modifying anti-rheumatic drugs (DMARDs) and 43.6% a TNFa blocker between the diagnosis and the start of the study. Established RA patients used TNFa blockers more frequently than early RA patients (60,1% vs 21,1%, p<0,001). Methotrexate was the most commonly used drug (70.6%). A treatment change was seen in 79% of patients with early RA and 60.6% of those with established RA. A dose change was the most frequent modification and an inadequate response the most frequent reason. A 25.8% of treatments were stopped due to adverse events. The mean (SD) decrease on DAS28 score was 0.9 (1.5) on early RA and 0.2 (1.0) on established RA patients. A 35.8% of early RA patients showed a good EULAR response, while only 16.2% among established RA patients (p<0.001). Rheumatoid factor and radiological progression assessment were the most requested determinations in early RA (p<0.05). CONCLUSIONS: Spanish rheumatologists used biological drugs with a higher frequency in patients with more advanced disease, as recommended in the main clinical practice guidelines.
22174211 Mortality and incidence of malignancy in Korean patients with rheumatoid arthritis. 2012 Feb OBJECTIVE: To determine the standardized mortality ratio (SMR) and standardized incidence ratio (SIR) for malignancy in Korean patients with rheumatoid arthritis (RA). METHODS: We enrolled 1534 patients with RA who fulfilled the American College of Rheumatology criteria, from October 2001 to December 2007. Baseline assessment included sociodemographic variables, laboratory findings including rheumatoid factor, anticitrullinated protein antibody, functional class, radiological stage, medication, and the Korean version of the Health Assessment Questionnaire. We used the national mortality rate from 2001 to 2007 from the Korean National Statistical Office (KNSO) and the incidence rate from the Korean Central Cancer Registry (KCCR) from 2001 to 2007 as comparison data for estimates of SMR and SIR. Confidence intervals were calculated based on the Poisson distribution. RESULTS: There were 57 deaths in 6683 person-years of followup. The number of expected deaths (derived from the KNSO) was 42.33 and the SMR for patients with RA was 1.35 (95% CI 1.02-1.74). The main causes of death were malignancy, cardiovascular disease, and respiratory disease. In the cause-specific SMR, deaths from respiratory disease, especially from interstitial lung disease (ILD) and pneumonia, were significantly higher than expected: 4.66 (95% CI 2.13-8.85) for all respiratory disease, 18.18 (95% CI 2.20-65.64) for ILD, and 10.26 (95% CI 2.79-26.26) for pneumonia. Thirty malignancies had occurred in 1501 patients. The number of expected malignancies derived from the KCCR was 34.91, yielding a SIR for cancer of 0.86 (95% CI 0.58-1.23). CONCLUSION: Our study demonstrates that the SMR was slightly higher in patients with RA, but the incidence rates of malignancies were not significantly different from the general population. But deaths from respiratory diseases were significantly higher.
21494268 Overcoming hurdles in developing successful drugs targeting chemokine receptors. 2011 May Chemokines and their receptors are central to the inflammatory process and are attractive therapeutic targets. Drugs that inhibit chemokine receptors are approved for the treatment of HIV infection and for stem cell mobilization, but none have been approved yet for the treatment of inflammatory and/or autoimmune diseases. We analyse the challenges of developing chemokine receptor antagonists, and propose that inappropriate target selection and ineffective dosing, not the 'redundancy' of the chemokine system, are the main barriers to their use as anti-inflammatory therapies. We highlight evidence suggesting that chemokine receptor inhibition will prove to be an effective therapy in inflammatory diseases.
21791449 Treatment benefit or survival of the fittest: what drives the time-dependent decrease in s 2011 Nov OBJECTIVE: To examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA). METHODS: Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis. Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRR(adj)) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment. RESULTS: Data were available on 5044 patients, in whom 392 serious infections occurred. The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years). This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function. Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age >60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5-14 mg/day, IRR(adj) 2.1 (95% CI 1.4 to 3.2); ≥ 15 mg/day, IRR(adj) 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFα inhibitors (IRR(adj) 1.8 (95% CI 1.2 to 2.7)). CONCLUSION: Reasons for the decline in infection rates observed at the group level were identified. The results enable expected infection rates to be calculated in individual patients based on their risk profiles.