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ID PMID Title PublicationDate abstract
19389237 Gene expression profiling in the synovium identifies a predictive signature of absence of 2009 INTRODUCTION: To identify markers and mechanisms of resistance to adalimumab therapy, we studied global gene expression profiles in synovial tissue specimens obtained from severe rheumatoid arthritis (RA) patients before and after initiation of treatment. METHODS: Paired synovial biopsies were obtained from the affected knee of 25 DMARD (disease-modifying antirheumatic drug)-resistant RA patients at baseline (T0) and 12 weeks (T12) after initiation of adalimumab therapy. DAS28-CRP (disease activity score using 28 joint counts-C-reactive protein) scores were computed at the same time points, and patients were categorized as good, moderate, or poor responders according to European League Against Rheumatism criteria. Global gene expression profiles were performed in a subset of patients by means of GeneChip Human Genome U133 Plus 2.0 Arrays, and confirmatory immunohistochemistry experiments were performed on the entire cohort. RESULTS: Gene expression studies performed at baseline identified 439 genes associated with poor response to therapy. The majority (n = 411) of these genes were upregulated in poor responders and clustered into two specific pathways: cell division and regulation of immune responses (in particular, cytokines, chemokines, and their receptors). Immunohistochemistry experiments confirmed that high baseline synovial expression of interleukin-7 receptor alpha chain (IL-7R), chemokine (C-X-C motif) ligand 11 (CXCL11), IL-18, IL-18 receptor accessory (IL-18rap), and MKI67 is associated with poor response to adalimumab therapy. In vitro experiments indicated that genes overexpressed in poor responders could be induced in fibroblast-like synoviocytes (FLS) cultures by the addition of tumor necrosis factor-alpha (TNF-alpha) alone, IL-1beta alone, the combination of TNF-alpha and IL-17, and the combination of TNF-alpha and IL-1beta. CONCLUSIONS: Gene expression studies of the RA synovium may be useful in the identification of early markers of response to TNF blockade. Genes significantly overexpressed at baseline in poor responders are induced by several cytokines in FLSs, thereby suggesting a role for these cytokines in the resistance to TNF blockade in RA.
21109518 Evaluating antirheumatic treatments using synovial biopsy: a recommendation for standardis 2011 Mar Inflammation of synovium is one of the hallmarks of rheumatoid arthritis (RA). Analysis of synovial tissue has increased our understanding of RA pathogenesis, aided in identifying potential therapeutic targets and has been used in the response and mechanistic evaluation of antirheumatic treatments. In addition, studies are ongoing, aimed at the identification of diagnostic and prognostic biomarkers in the synovium. This paper outlines the currently used procedures for sampling and processing of synovial tissue, and presents a standardised recommendation to support multicentre translational research.
20638761 Lung sarcoidosis induced by TNF antagonists in rheumatoid arthritis: a case presentation a 2011 Apr We report on a 72 year-old woman with long-standing rheumatoid arthritis diagnosed as granulomatosis due to pulmonary sarcoidosis after 49 months of treatment with etanercept. A clinical and radiological improvement was seen after tumor necrosis factor (TNF) antagonist withdrawal plus a course of steroids. Currently, 27 cases of histological proven sarcoidosis with pulmonary involvement have been reported in relation to anti-TNF therapy, with etanercept being more frequent in comparison with the anti-TNF monoclonal antibodies infliximab and adalimumab. Potential pathogenic mechanisms of the paradoxical effect of anti-TNF treatment is discussed. It is important for clinicians to be aware of this potential and uncommon complication of biological therapy with TNF antagonists.
19479876 The relationship between focal erosions and generalized osteoporosis in postmenopausal wom 2009 Jun OBJECTIVE: Among rheumatoid arthritis (RA) patients who have had the disease for 10 years, more than half have focal erosions, and the risk of fracture is doubled. However, there is little information about the potential relationship between focal erosions and bone mineral density (BMD). The aim of this study was to determine whether lower BMD is associated with higher erosion scores among patients with RA. METHODS: We enrolled 163 postmenopausal women with RA, none of whom were taking osteoporosis medications. Patients underwent dual x-ray absorptiometry at the hip and spine and hand radiography, and completed a questionnaire. The hand radiographs were scored using the Sharp method, and the relationship between BMD and erosions was measured using Spearman's correlation coefficients and adjusted linear regression models. RESULTS: Patients had an average disease duration of 13.7 years, and almost all were taking a disease-modifying antirheumatic drug. Sixty-three percent were rheumatoid factor (RF) positive. The median modified Health Assessment Questionnaire score was 0.7, and the average Disease Activity Score in 28 joints was 3.8. The erosion score was significantly correlated with total hip BMD (r=-0.33, P<0.0001), but not with lumbar spine BMD (r=-0.09, P=0.27). Hip BMD was significantly lower in RF-positive patients versus RF-negative patients (P=0.02). In multivariable models that included age, body mass index, and cumulative oral glucocorticoid dose, neither total hip BMD nor lumbar spine BMD was significantly associated with focal erosions. CONCLUSION: Our results suggest that hip BMD is associated with focal erosions among postmenopausal women with RA, but that this association disappears after multivariable adjustment. While BMD and erosions may be correlated with bone manifestations of RA, their relationship is complex and influenced by other disease-related factors.
19228653 Outcome and predictor relationships in fibromyalgia and rheumatoid arthritis: evidence con 2009 Apr OBJECTIVE: To compare outcome-predictor relationships in fibromyalgia (FM) and rheumatoid arthritis (RA), to provide information regarding the competing hypotheses that FM is a continuum or a discrete disorder. METHODS: We studied 3 outcome variables (work disability, opioid use, depression) and 12 clinical predictor variables in 2,046 patients with FM and 20,374 with RA. We determined whether outcome-predictor relationships were stronger in FM or RA by measuring the areas under the receiver-operating curves. We used fractional polynomial logistic regression to create graphic models for the outcome-predictor relationships. RESULTS: All measures of status and outcome were more abnormal in FM than in RA. Depression was reported in 33.4% of patients with FM compared with 15.1% of those with RA. The predictor-outcome relationship was significantly stronger in RA in 28 of the 36 tests, and not different in the remainder. The relationship between outcome and predictor variables was generally similar in patients with FM and RA. However, unmodeled depression that was not explained by study variables was noted in FM. CONCLUSION: Our data are consistent with the hypothesis that FM is the end of a severity continuum, but that additional psychological factors are an integral part of the syndrome.
20722034 The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in a 2010 Nov OBJECTIVE: To explore the effect of bortezomib in splenocytes and fibroblast-like synoviocytes (FLS) and its in vivo potency in a rat model of adjuvant-induced arthritis (AIA), which resembles human rheumatoid arthritis (RA). METHODS: AIA was induced with Freund's complete adjuvant. Splenocyte and FLS proliferation and apoptosis were measured by radioactivity incorporation and flow cytometry, respectively. The invasiveness of FLS from rats with AIA was tested in a Transwell system. The pattern of cytokine secretion was evaluated by cytometric bead array in splenocyte supernatants. Bortezomib was administered prophylactically or therapeutically, and arthritis was assessed clinically and histologically. Immunohistochemistry was performed for markers of inflammation and angiogenesis in joints. Hematologic and biochemical parameters were tested in peripheral blood (PB). Representative animals were examined by computed tomography (CT) scanning before and after bortezomib administration. The expression of Toll-like receptor 2 (TLR-2), TLR-3, and TLR-4 in PB and FLS was measured by real-time polymerase chain reaction, and alterations in specific cell populations in PB and spleen were determined by flow cytometry. RESULTS: In vitro, bortezomib exhibited significant inhibitory and proapoptotic activity in splenocytes and FLS from rats with AIA, altered the inflammatory cytokine pattern, and reduced the invasiveness of FLS from rats with AIA. In vivo, bortezomib significantly ameliorated disease severity. Remission was associated with improved histology and decreased expression of CD3, CD79a, CD11b, cyclooxygenase 1, and factor VIII in target tissues as well as down-regulation of TLR expression in PB and cultured FLS. CT scanning demonstrated a bone healing effect after treatment. CONCLUSION: Our findings suggest that bortezomib affects AIA in a pleiotropic manner and that this drug may be effective in RA.
19196465 Susceptibility of rheumatoid arthritis synovial fibroblasts to FasL- and TRAIL-induced apo 2009 INTRODUCTION: The rheumatoid arthritis (RA) synovium is characterised by the presence of an aggressive population of activated synovial fibroblasts (RASFs) that are prominently involved in the destruction of articular cartilage and bone. Accumulating evidence suggests that RASFs are relatively resistant to Fas-ligand (FasL)-induced apoptosis, but the data concerning tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) have been conflicting. Here, we hypothesise that the susceptibility of RASFs to receptor-mediated apoptosis depends on the proliferation status of these cells and therefore analysed the cell cycle dependency of FasL- and TRAIL-induced programmed cell death of RASFs in vitro. METHODS: Synovial fibroblasts were isolated from patients with RA by enzymatic digestion and cultured under standard conditions. Cell cycle analysis was performed using flow cytometry and staining with propidium iodide. RASFs were synchronised or arrested in various phases of the cell cycle with 0.5 mM hydroxyurea or 2.5 microg/ml nocodazol and with foetal calf serum-free insulin-transferrin-sodium selenite supplemented medium. Apoptosis was induced by stimulation with 100 ng/ml FasL or 100 ng/ml TRAIL over 18 hours. The apoptotic response was measured using the Apo-ONE Homogenous Caspase-3/7 Assay (Promega GmbH, Mannheim, Germany) and the Cell Death Detection (ELISAPlus) (enzyme-linked immunosorbent assay) (Roche Diagnostics GmbH, Mannheim, Germany). Staurosporin-treated cells (1 microg/ml) served as a positive control. Expression of Fas and TRAIL receptors (TRAILR1-4) was determined by fluorescence-activated cell sorting analysis. RESULTS: Freshly isolated RASFs showed only low proliferation in vitro, and the rate decreased further over time, particularly when RASFs became confluent. RASFs expressed Fas, TRAIL receptor-1, and TRAIL receptor-2, and the expression levels were independent of the cell cycle. However, the proliferation rate significantly influenced the susceptibility to FasL- and TRAIL-induced apoptosis. Specifically, proliferating RASFs were less sensitive to FasL- and TRAIL-induced apoptosis than RASFs with a decreased proliferation rate. Furthermore, RASFs that were synchronised in S phase or G2/M phase were less sensitive to TRAIL-induced apoptosis than synchronised RASFs in G0/G1 phase. CONCLUSIONS: Our data indicate that the susceptibility of RASFs to FasL- and TRAIL-induced apoptosis depends on the cell cycle. These results may explain some conflicting data on the ability of RASFs to undergo FasL- and TRAIL-mediated cell death and suggest that strategies to sensitise RASFs to apoptosis may include the targeting of cell cycle-regulating genes.
20190560 Certolizumab pegol. 2010 Mar Certolizumab pegol (Cimzia(®)) is currently the only PEGylated anti-TNFα biologic approved for the treatment of rheumatoid arthritis and Crohn disease. The product, developed by UCB, is a humanized antigen-binding fragment (Fab') of a monoclonal antibody that has been conjugated to polyethylene glycol. Certolizumab pegol was approved as a treatment for rheumatoid arthritis in the EU, US and Canada in 2009, and as a treatment for Crohn disease in Switzerland in 2007 and the US in 2008. Certolizumab pegol is entering into an increasingly competitive marketplace, especially in rheumatoid arthritis, but clinical data demonstrate benefits across a range of clinical, radiographic and patient reported outcomes.
20360402 Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular 2010 Jul A cardinal feature of inflammation is the tissue recruitment of leukocytes, a process that is mediated predominantly by chemokines via their receptors on migrating cells. CCR2 and CCR5, two CC chemokine receptors, are important players in the trafficking of monocytes/macrophages and in the functions of other cell types relevant to disease pathogenesis. This review provides a brief overview of the biological actions of CCR2 and CCR5 and a comprehensive summary of published data that demonstrate the involvement of both receptors in the pathogenesis of immunologic diseases (RA, CD, and transplant rejection) and cardiovascular diseases (atherosclerosis and AIH). In light of the potential for functional redundancy of chemokine receptors in mediating leukocyte trafficking and the consequent concern over insufficient efficacy offered by pharmacologically inhibiting one receptor, this review presents evidence supporting dual targeting of CCR2 and CCR5 as a more efficacious strategy than targeting either receptor alone. It also examines potential safety issues associated with such dual targeting.
19196726 Interleukin-1 is essential for systemic inflammatory bone loss. 2010 Jan OBJECTIVES: Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined. METHODS: To determine whether TNF directly triggers bone loss or requires IL1, human TNFalpha mice (hTNFtg) were crossed with mice lacking IL1alpha and IL1beta (IL1(-/-)hTNFtg). Systemic bone architecture was evaluated using CT scanning, static and dynamic bone histomorphometry and serum markers of bone metabolism. RESULTS: hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were thinner and decreased in numbers, resulting in increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice compared with wild-type mice. In contrast, IL1(-/-)hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL1 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice and the increased levels of RANKL in these mice. Structural parameters and osteoclast and osteoblast numbers were indistinguishable from wild-type mice. CONCLUSIONS: These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.
20950247 Antimalarial cutaneous side effects: a study in 209 users. 2011 Mar BACKGROUND: Antimalarial agents are commonly used drugs that may have skin side effects. OBJECTIVE: To study the prevalence of cutaneous side effects in antimalarial users. METHODS: We studied the prevalence of cutaneous manifestations in 209 antimalarial users, 127 with systemic lupus erythematosus (SLE) and 82 with rheumatoid arthritis (RA). As control we included 200 patients from the gynecologic and ophthalmologic departments who did not have antimalarial use. Patients were submitted to a structured questionnaire for demographic data, type of antimalarial drug used, and treatment time as well as skin complaints. Physical examination was performed by a dermatologist. RESULTS: In 159 of 209 (76%) of the antimalarial users, there were cutaneous findings. The most frequent was xerosis, followed by skin hyperpigmentation and pruritus. In 4.8% of the antimalarial users, allergic reactions led to drug withdrawal. When comparing them with the control group, skin hyperpigmentation and xerosis were more prevalent (p < .0001 for both), but pruritus was not (p = .39). No relationship could be found between the skin side effects and ethnic background, gender, antimalarial type, or treatment duration. Hair depigmentation was more common in SLE patients than in RA patients. CONCLUSION: Cutaneous side effects in antimalarial users are frequent. Xerosis and hyperpigmentation are the most common findings.
19924708 Gene- or region-based analysis of genome-wide association studies. 2009 With rapid advances in genotyping technologies in recent years and the growing number of available markers, genome-wide association studies are emerging as promising approaches for the study of complex diseases and traits. However, there are several challenges with analysis and interpretation of such data. First, there is a massive multiple testing problem, due to the large number of markers that need to be analyzed, leading to an increased risk of false positives and decreased ability for association studies to detect truly associated markers. In particular, the ability to detect modest genetic effects can be severely compromised. Second, a genetic association of a given single-nucleotide polymorphism as determined by univariate statistical analyses does not typically explain biologically interesting features, and often requires subsequent interpretation using a higher unit, such as a gene or region, for example, as defined by haplotype blocks. Third, missing genotypes in the data set and other data quality issues can pose challenges when comparisons across platforms and replications are planned. Finally, depending on the type of univariate analysis, computational burden can arise as the number of markers continues to grow into the millions. One way to deal with these and related challenges is to consider higher units for the analysis, such as genes or regions. This article summarizes analytical methods and strategies that have been proposed and applied by Group 16 to two genome-wide association data sets made available through the Genetic Analysis Workshop 16.
19122432 [Targeting therapy for inflammatory diseases by anti-TNFalpha biologics]. 2009 Jan TNFalpha (tumor necrosis factor-alpha) plays a critical role in the pathogenesis of inflammatory diseases including rheumatoid arthritis and Crohn's disease. Infliximab is a monoclonal antibody that recognizes human TNFalpha. Clinical trials have been persuasive that infliximab is effective and far superior to the conventional drug therapy in various inflammatory diseases. Combination of infliximab plus methotrexate is effective in patients with active rheumatoid arthritis who have not responded adequately to traditional disease-modifying anti-rheumatic drugs, and has produced significant improvement in clinical, radiographic, and functional outcomes. Infliximab is also an important treatment option in patients with active Crohn's disease who have not responded to conventional therapy and in those with this disease who have fistulae. Moreover, infliximab treatment has resulted in effective suppression of ankylosing spondylitis, psoriasis and ocular inflammation in patients with refractory uveoretinitis due to Behçet's disease. Thus, biologics targeting TNFalpha have revolutionized the therapy of inflammatory diseases. Here, the current status of clinical application of anti-TNFalpha biologics is reviewed by describing the clinical outcome of infliximab and future prospects of biologics are discussed.
19656031 Gingival crevicular fluid MMP-8 and -13 and TIMP-1 levels in patients with rheumatoid arth 2009 Aug BACKGROUND: The purpose of this study was to compare gingival crevicular fluid (GCF) levels of matrix metalloproteinase (MMP)-8 and -13 and tissue inhibitor of MMP (TIMP)-1 in patients with rheumatoid arthritis (RA) and systemically healthy counterparts with inflammatory periodontal disease. METHODS: Subjects (N = 74) were divided into five groups: 12 patients with RA and gingivitis; 13 patients with RA and periodontitis; 12 systemically healthy patients with gingivitis; 13 systemically healthy patients with periodontitis; and 24 periodontally and systemically healthy volunteers. Full-mouth clinical periodontal measurements were performed at six sites/tooth. GCF samples obtained from two sites in single-rooted teeth were analyzed by immunofluorometric assay and enzyme-linked immunosorbent assay. Data were assessed statistically by parametric tests. RESULTS: The total amounts of MMP-8 were lower in the healthy control group than in RA-gingivitis, RA-periodontitis, and healthy-periodontitis groups (P <0.05). MMP-13 levels were similar in all five study groups (P >0.05). Patients with RA and gingivitis or periodontitis exhibited levels of MMP-8 and -13 and TIMP-1 that were similar to systemically healthy counterparts (P >0.05). CONCLUSIONS: The coexistence of RA and periodontitis did not significantly affect the investigated parameters. GCF MMP-8 levels increased with periodontal inflammation. Despite the long-term usage of corticosteroids and non-steroidal anti-inflammatory drugs, similar GCF MMP-8 and -13 levels in patients with RA and systemically healthy counterparts suggest that RA may create a tendency to overproduce these enzymes.
20538267 Effects of hesperetin on the production of inflammatory mediators in IL-1beta treated huma 2010 This study was conducted to evaluate the efficacy of hesperetin in regulating interleukin-1beta (IL-1beta)-induced production of the matrix metalloproteinase (MMP)-3 and IL-6 in human synovial cell line, SW982. Treatment with hesperetin at 1 or 10 microM significantly (P<0.05) inhibited IL-1beta-induced MMP-3 and IL-6 production when measured by enzyme-linked immunosorbent assay (ELISA). The effects of hesperetin on the activation of mitogen-activated protein kinases (MAPKs) were also examined in SW982 cells by ELISA assay. IL-1beta-induced JNK activation was inhibited by hesperetin. These results suggest that hesperetin reduces the production of MMP and IL-6 in SW982 synovial cells by inhibiting JNK.
20041815 Omega-3 polyunsaturated fatty acids and immune-mediated diseases: inflammatory bowel disea 2009 Inflammation is part of the normal host response to infection and injury. However, inappropriate inflammation contributes to several diseases, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Both conditions are characterized by the excessive production of inflammatory cytokines, arachidonic acid (AA)-derived eicosanoids, and other inflammatory agents (e.g., reactive oxygen species, adhesion molecules). By virtue of their anti-inflammatory action, omega-3 polyunsaturated fatty acids (PUFA) may be beneficial in inflammatory diseases. A large body of evidence supports a protective effect of omega-3 PUFA in experimental animal and ex-vivo models of Crohn's disease (CD), Ulcerative colitis (UC) and Rheumatoid arthritis (RA). Although fish oil supplementation in patients with IBD results in omega-3 PUFA incorporation into gut mucosal tissue and modification of inflammatory mediator profiles, the evidence of clinical benefits of omega-3 PUFA is weak. On the other hand, more convincing data support the efficacy of omega-3 PUFA in reducing pain, number of tender joints, duration of morning stiffness, use of non-steroidal anti-inflammatory drugs and improving physical performance in RA patients. In both IBD and RA further clinical trials with large sample size are needed to clarify the efficacy of omega-3 PUFA as a treatment.
20947634 Rate of kidney function decline associates with mortality. 2010 Nov The effect of rate of decline of kidney function on risk for death is not well understood. Using the Department of Veterans Affairs national databases, we retrospectively studied a cohort of 4171 patients who had rheumatoid arthritis and early stage 3 chronic kidney disease (CKD; estimated GFR 45 to 60 ml/min) and followed them longitudinally to characterize predictors of disease progression and the effect of rate of kidney function decline on mortality. After a median of 2.6 years, 1604 (38%) maintained stable kidney function; 426 (10%), 1147 (28%), and 994 (24%) experienced mild, moderate, and severe progression of CKD, respectively (defined as estimated GFR decline of 0 to 1, 1 to 4, and >4 ml/min per yr). Peripheral artery disease predicted moderate progression of CKD progression. Black race, hypertension, diabetes, cardiovascular disease, and peripheral artery disease predicted severe progression of CKD. After a median of 5.7 years, patients with severe progression had a significantly increased risk for mortality (hazard ratio 1.54; 95% confidence interval 1.30 to 1.82) compared with those with mild progression; patients with moderate progression exhibited a similar trend (hazard ratio 1.10; 95% confidence interval 0.98 to 1.30). Our results demonstrate an independent and graded association between the rate of kidney function decline and mortality. Incorporating the rate of decline into the definition of CKD may transform a static definition into a dynamic one that more accurately describes the potential consequences of the disease for an individual.
20510238 Targeting IL-17 and Th17 cells in rheumatoid arthritis. 2010 May Identification of interleukin-17 (IL-17) as a powerful proinflammatory cytokine and the recent recognition of a T-helper cell subset that secretes it have focused attention on the role of IL-17 and Th17 cells in rheumatoid arthritis (RA) and other immune-mediated diseases. While understanding of its role in RA is still evolving, evidence from both animal models and human systems provides a compelling rationale for therapeutic targeting of IL-17 in RA. Both direct and indirect approaches to accomplish this are feasible. Mechanistic studies in the context of clinical trials will be required to understand why some strategies may be preferable from the perspectives of efficacy and safety.
19950299 MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmac 2009 Dec OBJECTIVE: To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). METHODS: In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >or=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group. RESULTS: MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P=0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>or=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay). CONCLUSION: MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.
20445285 [Secondary osteoporosis UPDATE. Rheumatoid arthritis and bone damage: trends in treatment] 2010 May Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis and bone damage. The bone manifestation in RA consists of joint destruction and systemic osteoporosis, which are brought about by different mechanisms. During the pathological processes, inflammatory cytokines such as TNF are largely produced from inflamed synovium and cause activation of osteoclasts deviated from bone remodelling cycle, resulting in joint destruction. But by the combinational use of methotrexate and TNF-inhibitors, clinical remission, structural remission and functional remission have become possible for the treatment of RA. Especially TNF-inhibitors remarkably suppress the progression of joint destruction in the vast majority of the patients. On the other side, systemic osteoporosis, mainly caused by menopause and glucocorticoid (GC), is often complicated in RA. However, bisphosphonate is well known to be effective for not only treatment but also prevention of GC-induced osteoporosis. Furthermore, anti-RANKL antibody denosumab possesses a potential to inhibit joint destruction as well as systemic and GC-mediated osteoporosis.