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ID PMID Title PublicationDate abstract
18196420 THA with hydroxyapatite granules at cement-bone interface: 15- to 20-year results. 2008 Feb To augment cement-bone bonding, we interposed hydroxyapatite granules at the cement-bone interface (bioactive bone cement technique). Hydroxyapatite granules (2-3 g) were smeared on the bone surface of the acetabulum and femur just before cementing. We used porous hydroxyapatite granules 300 to 500 microm in diameter from 1986 to 1988 (first generation) and granules 100 to 300 microm in diameter from 1989 to 1991 (second generation). We followed 151 patients (222 hips) in the first generation and 170 patients (252 hips) in the second generation. The minimum followup was 15 years (mean, 17.3 years; range, 15-20 years). Radiolucent lines or spaces less than 1 mm were observed in four hips (1.8%) in the first generation and in 15 hips (6.2%) in the second generation. Osteolysis was observed in one hip (0.5%) in the first generation and six hips (1.6%) in the second generation. We observed loosening in two cups (0.8%) in the second generation. The long-term clinical results suggest the interface bioactive bone cement technique combined with our other techniques results in low incidences of radiolucent lines (spaces) and osteolysis, and may increase the longevity of cemented THA. The data suggest the larger hydroxyapatite granules performed better than smaller ones. LEVEL OF EVIDENCE: Level III, therapeutic retrospective cohort series. See the Guidelines for Authors for a complete description of levels of evidence.
18461518 [A 47-year-old dog breeder with chronic polyarthritis, weight loss and high fever]. 2008 May A 47-year-old dog breeder had suffered from unclassified polyarthritis for four years. During immunomodulatory therapy of an assumed seronegative chronic polyarthritis with Leflunomid and Adalimumab he developed severe systemic inflammatory disease with high fever, weight loss, and severe arthralgia. Fever and arthralgias temporarily improved under antibiotic therapy, although a causative organism had not been found. The clinical picture led to the differential diagnosis of Whipple's disease, but PAS-positive macrophages were not detected in duodenal biopsies. The diagnosis was finally based on a positive PCR result for Tropheryma whipplii, typical clinical symptoms and a complete response on adequate antibiotic long-term treatment with cotrimoxazol. The diagnosis of Whipple's disease was possibly masked by the initial antibiotic therapies. Therapies with immunomodulators, TNF-inhibitors, and corticosteroids may transform an infection with Tropheryma whipplii, normally in a subacute stage, into a septic, life-threatening disease.
16585064 ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric mat 2006 May Degradative fragments of cartilage oligomeric matrix protein (COMP) have been observed in arthritic patients. The physiological enzyme(s) that degrade COMP, however, remain unknown. We performed a yeast two-hybrid screen (Y2H) to search for proteins that associate with COMP to identify an interaction partner that might degrade it. One screen using the epidermal growth factor (EGF) domain of COMP as bait led to the discovery of ADAMTS-7. Rat ADAMTS-7 is composed of 1595 amino acids, and this protein exhibits higher expression in the musculoskeletal tissues. COMP binds directly to ADAMTS-7 in vitro and in native articular cartilage. ADAMTS-7 selectively interacts with the EGF repeat domain but not with the other three functional domains of COMP, whereas the four C-terminal TSP motifs of ADAMTS-7 are required and sufficient for association with COMP. The recombinant catalytic domain and intact ADAMTS-7 are capable of digesting COMP in vitro. The enzymatic activity of ADAMTS-7 requires the presence of Zn2+ and appropriate pH (7.5-9.5), and the concentration of ADAMTS-7 in cartilage and synovium of patients with rheumatoid arthritis is significantly increased as compared to normal cartilage and synovium. ADAMTS-7 is the first metalloproteinase found to bind directly to and degrade COMP.
19165918 Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. 2008 Sep Systemic lupus erythematosus (SLE) is an autoimmune disease influenced by genetic and environmental factors. We carried out a genome-wide association scan and replication study and found an association between SLE and a variant in TNFAIP3 (rs5029939, meta-analysis P = 2.89 x 10(-12), OR = 2.29). We also found evidence of two independent signals near TNFAIP3 associated with SLE, including one previously associated with rheumatoid arthritis (RA). These results establish that variants near TNFAIP3 contribute to differential risk of SLE and RA.
17951663 Analyses of MT1-MMP activity in cells. 2007 Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a type I transmembrane protein which exhibits biological activities on the cell surface. One of the characteristic functions of this enzyme is activation of proMMP-2 on the cell surface (1). This process can be monitored using gelatin zymography to detect the pro- and active forms of MMP-2. Cellular MT1-MMP activity can also be directly detected by in situ degradation of layers of either gelatin or collagen. By combining inhibitors, western blotting, and immunohistochemistry, one can detect and conclude the presence of MT1-MMP activity in the cells.
19108784 Infliximab and methotrexate in the treatment of rheumatoid arthritis: a systematic review 2008 Nov BACKGROUND: Because of its long-term effectiveness in clinical practice, methotrexate (MTX) is currently the preferred disease-modifying antirheumatic drug (DMARD) for patients with active rheumatoid arthritis (RRA). However, many patients do not experience remission and continue to have signs and symptoms of active disease while receiving a maximally tolerated dose. OBJECTIVES: The aims of this meta-analysis were to estimate the efficacy and tolerability of the various dosage schemes of infliximab versus MTX for the treatment of active RA, to eliminate size-related uncertainty of effects, and to identify subgroups of patients who benefit most from infliximab + MTX therapy. METHODS: Using the MEDLINE online database (inception through November 2006) and the Cochrane Database of Systematic Reviews (Issue 4, 2006), we identified English-language articles on randomized controlled clinical trials. Studies investigating infliximab + MTX regimens versus a control group receiving MTX alone to assess efficacy in active RA, using the American College of Rheumatology (ACR) criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70), were considered eligible for the meta-analysis. Pooled odds ratios (ORs) and 95% CIs were calculated to compare the relative risks and benefits of adding infliximab to MTX. RESULTS: From a total of 78 initially identified studies, 42 were considered potentially eligible for this review and 12 were considered eligible for the meta-analysis. Overall, 4899 patients were randomized to either infliximab + MTX (3919 patients) or MTX alone (980 patients). Mean patient age ranged from 44.6 to 56 years in the MTX-only arms and from 45.8 to 56 years in the infliximab + MTX arms. The proportion of female patients ranged from 66.6% to 100% in the MTX arms and from 68% to 100% in the infliximab arms. Infliximab 3 mg/kkg + MTX was more effective than MTX alone (OR = 3.52 [2.14-5.79] for reaching ACR20; 2.87 [2.228-3.61] for ACR50; and 2.42 [1.87-3.13] for ACR70). Infliximab 10 mg/kkg + MTX was also more effective than MTX alone (OR = 5.06 [3.88-6.59] for reaching ACR20; 5.72 [4.05-8.08] for ACR50; and 7.32 [2.28-23.50] for ACR70). Infliximab 10-mm/kg regimens appeared to be more effective than infliximab 3-mg/kg regimens (P = NS, P = 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), without being associated with an increased risk for adverse events. Infliximab 10 mg/kg appeared to be more effective in trials of longer duration (> or = 54 weeks) compared with those of shorter duration (P = 0.03, P = 0.02, and P = 0.01 for reaching ACR20, ACR50, and ACR70, respectively) and in those that enrolled patients with severe disease activity (P = 0.05, P = 0.05, and P = NS for reaching ACR20, ACR50, and ACR70, respectively). Steroid coadministration (P < 0.001, P < 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), previous DMARD exposure (P < 0.001, P < 0.001, and P = 0.04 for reaching ACR20, ACR50, and ACR70, respectively), and MTX naivete (P = NS, P < 0.001, and P =0.013 for reaching ACR20, ACR50, and ACR70, respectively) correlated with higher infliximab efficacy. CONCLUSIONS: Based on this meta-analysis, higher dose infliximab (10 mg/kg) in combination with MTX appeared to be more effective than the standard 3 mg/kg dose, particularly for patients with severe disease activity.The benefits of high-dose treatment appeared to accrue over time, and patients who received higher doses of infliximab did not experience a higher incidence of severe adverse events. The addition of oral low-dose steroids significantly enhanced infliximab efficacy.
17692722 Efficacy and tolerability of valdecoxib in treating the signs and symptoms of severe rheum 2007 Jun OBJECTIVE: This study compared the efficacy and tolerability of the cyclooxygenase-2-selective inhibitor valdecoxib with the nonselective NSAID naproxen and with placebo in treating severe rheumatoid arthritis (RA). METHODS: This 12-week, multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and tolerability of valdecoxib 10 mg QD (n = 170) or naproxen 500 mg BID (n = 167) with placebo (n = 171) in treating the signs and symptoms of severe RA. Study patients were aged >or=18 years and were diagnosed as having RA for >or=6 months that was stable due to a treatment regimen. Severe RA was defined as a physician's and patient's global assessment of disease activity of fair, poor, or very poor at baseline; >or=6 tender or painful joints; >or=3 swollen joints; >or=45 minutes of morning stiffness; a visual analog scale pain rating of >or=40 mm; or increases since baseline in these measures. Efficacy outcome measures included the percentage of patients achieving an American College of Rheumatology Responder Index 20% (ACR-20) at weeks 1, 6 and 12. Adverse events (AEs) were graded by the investigator as mild, moderate, or severe at weeks 1, 6, and 12. RESULTS: Of the 508 patients randomized, 340 completed the study. The study groups were comparable for age, ethnic origin, weight, height, and concomitant medications, but the naproxen group had significantly more men (29% [49/167]) than the valdecoxib (18% [31/170]) and placebo (16% [27/171]) groups. The percentage of patients achieving an ACR-20 response was significantly greater in the valdecoxib and naproxen treatment groups (58.8% [100/170] and 60.8% [101/166], respectively) than in the placebo group (39.6% [67/169]) at week 12 (both, P < 0.001). The percentage of patients achieving an ACR-20 response was significantly greater in the naproxen group than in the placebo group at both week 1 (53.6% [89/166] vs 37.9% [64/169]; P = 0.003) and week 6 (64.5% [107/166] vs 46.7% [79/169]; P = 0.001), and in the valdecoxib group compared with placebo at week 1 (52.9% [90/170]; P = 0.008) but not at week 6. Patients in the valdecoxib and naproxen groups had significantly improved efficacy compared with placebo in most of the other secondary assessments of inflammation, pain, and function. The incidence of AEs was similar in all groups (valdecoxib, 54.1% [92/170]; naproxen, 55.4% [92/166]; and placebo, 52.9% [90/170]). CONCLUSION: Valdecoxib 10 mg QD administered over 12 weeks was significantly better than placebo and similar to naproxen 500 mg BID in treating the signs and symptoms of severe RA in these patients.
16700887 Filarial nematode secreted product ES-62 is an anti-inflammatory agent: therapeutic potent 2006 May 1. The 'hygiene hypothesis' postulates that the recent increased incidence of allergic or autoimmune diseases (e.g. asthma, type I diabetes) in the West reflects an absence of appropriate priming of the immune response by infectious agents, such as parasitic worms, during childhood. 2. Consistent with this, it has long been recognized that several autoimmune disorders, such as rheumatoid arthritis (RA), a T helper (Th) 1-mediated autoimmune disease characterized by excess production of pro-inflammatory cytokines, such as tumour necrosis factor-alpha, exhibit reduced incidence and severity in geographical regions with high parasite load, suggesting that environmental factors may subtly alter disease progression. 3. Infection with worms also appears to suppress Th2-biased inflammatory disorders, such as asthma, because there also appears to be an inverse correlation between parasite load and atopy. This is perhaps more surprising, given that helminths often induce strong Th2-type immune responses characterized by release of specific cytokines, such as interleukin (IL)-4, IL-5 and IL-13. 4. Therefore, these findings suggest that the co-evolution of helminths with hosts, which has resulted in the ability of worms to modulate inflammatory responses in order to promote parasite survival, may also have generated a predisposition for the host to develop autoimmunity and allergy in the absence of infection. 5. The mechanisms underlying such immunomodulation are not clear, but appear to involve the release of parasite-derived molecules that allow the worms to modulate or evade the host immune response by a number of mechanisms, including skewing of cytokine responses and the induction of T regulatory cells. 6. In the present review we discuss the properties of one such filarial nematode-derived immunomodulatory molecule, namely ES-62, its anti-inflammatory action and the therapeutic potential of small molecule derivatives and peptides that mimic its action.
17378700 The comparative safety and effectiveness of TNF-alpha antagonists [corrected]. 2007 Jan OBJECTIVE: To describe the current knowledge on safety and effectiveness of the tumor necrosis factor (TNF)-alpha antagonists and identify current knowledge/ evidence gaps for study by the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program. BACKGROUND: Evidence-based Practice Centers (EPCs) and the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) network of AHRQ's Effective Health Care Program will study the safety and effectiveness of biologic and nonbiologic disease-modifying antirheumatic drugs (e.g., TNF-alpha antagonists). The current knowledge of safety and effectiveness of TNF-alpha antagonists is reviewed. SUMMARY: Treatment of adult rheumatoid arthritis (RA) involves determining which agents are safe, effective, and cost effective for an individual. Each individual patient's health system may also play a role in which agents are chosen. Many agents are available for the management of RA, some with high cost and unknown safety. Section 1013 of the Medicare Modernization Act of 2003 authorizes AHRQ to study comparative effectiveness and safety of RA treatments through both EPCs and DEcIDE centers to develop scientific knowledge for RA management as well as through epidemiologic studies. Results will be compiled through a Clinical Decisions and Communications Science Center, then disseminated to all appropriate stakeholders, including patients, payers, and health care professionals. The current knowledge of safety and effectiveness of TNF-alpha antagonists in the treatment of RA is reviewed. Increased rates of serious infections, including Mycobacterium tuberculosis (MTB), or tuberculosis reactivation, may occur with the use of TNF-a antagonists. It is still unclear if RA increases the risk of developing cancer, or if use of TNF-alpha antagonists increases cancer risk. CONCLUSIONS: TNF-alpha antagonists are costly, yet effective treatments for early and late RA. Use of these agents provides rapid relief of RA symptoms and provides positive outcomes, defined as improvements in American College of Rheumatology 20, 50, 70 scores; Health Assessment Questionnaire ratings; activities of daily living; joint space narrowing; erosions; and acute-phase reactants. Reactivation of latent MTB or onset of other infections or cancers may occur in RA patients with TNF-alpha antagonists.
18952638 Ankylosing spondylitis monocytes show upregulation of proteins involved in inflammation an 2009 Oct OBJECTIVES: To determine if peripheral blood monocytes from patients with ankylosing spondylitis (AS) differed in protein expression compared to rheumatoid arthritis (RA) and healthy controls (HC). METHODS: Monocyte protein expression was characterised by 2D gel electrophoresis and by label-free quantitative expression profiling, using nano-ultra performance liquid chromatography coupled to electrospray ionisation mass spectrometry (ESI-MS(E), where (E) refers to low/high collision energy switching). Data sets were analysed using the Waters expression profiling system and Ingenuity pathway analysis (IPA). RESULTS: Two-dimensional gel electrophoresis showed upregulation of proteasomal constituents in AS monocytes, including the beta subunit of proteasome activator (PA)28. Monocyte expression profiling and IPA showed that significant changes in protein expression within the ubiquitin proteasome pathway (UPP) were restricted to AS monocytes. Statistically significant differences in protein expression involving the leucocyte extravasation, vascular endothelial growth factor, integrin and Toll-like receptor signalling pathways were seen in AS and RA monocytes compared to healthy controls. No evidence of upregulation of proteins involved in the endoplasmic reticulum stress response pathway was found in either AS or RA monocytes. Finally, the PA28 complex was shown to increase the generation of human leucocyte antigen (HLA)-B27 antigenic epitopes by the proteasome in vitro. CONCLUSIONS: Our proteomic analyses support the hypothesis that monocytes play an important role in the pathogenesis of AS and RA, and further suggest a specific role in AS for the UPP. Quantitative proteomic expression profiling constitutes a powerful new tool for rheumatology research.
18821705 Disrupted brain-immune system-joint communication during experimental arthritis. 2008 Oct OBJECTIVE: To explore the hypothesis that, in parallel with alterations in the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the course of arthritis development induced by type II collagen. This hypothesis was based on evidence that acute inflammatory processes induce cytokine expression in the brain and affect neuronal activity. We also studied whether depletion of hypothalamic noradrenaline can affect peripheral joint disease. METHODS: Hypothalamic cytokine gene expression and neurotransmitter concentration, parameters of inflammation, and joint innervation were evaluated during arthritis development in rats induced by injection of type II collagen in Freund's incomplete adjuvant. Noradrenergic neurons in the brain were depleted with 6-hydroxydopamine. RESULTS: Transiently increased corticosterone levels, followed by increased adrenaline levels and hypothalamic interleukin-1beta (IL-1beta) and IL-6 overexpression were observed only during the induction phase of the disease. Hypothalamic noradrenaline content was increased during the symptomatic phase and was paralleled by a gradual loss of noradrenergic fibers in the joints. The positive correlation between hypothalamic IL-1beta expression and noradrenaline content in control groups was not observed in rats in which arthritis developed. Depletion of hypothalamic noradrenergic neurons when arthritis was established did not affect the course of the disease. CONCLUSION: The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate a disruption in communication between afferent immune messages to the central nervous system and 2 main efferent antiinflammatory pathways under control of the brain during collagen-induced arthritis.
18339486 Colocalization of C4d deposits/CD68+ macrophages in rheumatoid nodule and granuloma annula 2008 Rheumatoid nodule (RN) represents a palisading granuloma with central fibrinoid necrosis, which is not only a classical manifestation of rheumatoid arthritis (RA) and part of the American College of Rheumatology (ACR)-criteria, but also is its diagnostic hallmark. The pathogenesis of RN is still not fully understood. At present, only data on serum analyses indicating a complement-mediated pathogenesis in the development of RA are available. Equivalent examinations for RN have not yet been performed. Granuloma annulare (GA) represents another type of palisading granuloma. A special subtype of GA, subcutaneous GA (SGA), is an important differential diagnosis to RN. Therefore, our aim was to examine RN and SGA regarding the complement deposition (C4d) by immunohistochemical means. All RN and GA were stained by hematoxylin/eosin and different special stains. In addition, all specimens were stained immunohistochemically with antibodies against CD68. Five GA and five RN were analyzed immunohistochemically with antibodies against C4d and CD68, and evaluated using single- and doublestaining immunohistochemistry. All RN and GA displayed depositions of C4d within their central necroses and between the surrounding palisading macrophages. Most importantly, C4d/CD68 double staining was visible in the palisading macrophages next to the necroses, while macrophages in the periphery were negative for C4d but positive for CD68. The main difference between RN and GA was a quantitative phenomenon with less positively reacting macrophages in a more incomplete palisade in GA. The positive reactions of all central necroses to C4d and colocalization of CD68 and C4d suggest that a complement-mediated mechanism may be operative in the formation of fibrinoid necrosis. This mechanism may be involved in any form of "fibrinoid necrosis", since no different patterns of C4d/CD68 expression could be observed in GA. This may explain why RG/GA are not distinguishable morphologically.
17431630 P wave dispersion in patients with rheumatoid arthritis: its relation with clinical and ec 2007 Jul P wave dispersion (PWD) is a sign for the prediction of atrial fibrillation (AF). The aim of this study was to assess P wave dispersion and its relation with clinical and echocardiographic parameters in patients with rheumatoid arthritis (RA). Thirty RA patients (mean age 49 +/- 10 years) and 27 healthy controls (mean age 47 +/- 8 years) were included in the study. We performed electrocardiography and Doppler echocardiography on patients and controls. Maximum and minimum P wave duration were obtained from electrocardiographic measurements. PWD defined as the difference between maximum and minimum P wave duration was also calculated. Maximum P wave duration and PWD was higher in RA patients than controls (P = 0.031 and P = 0.001, respectively). However, there was no significant difference in minimum P wave duration between the two groups (P = 0.152). There was significant correlation between PWD and disease duration (r = 0.375, P = 0.009) and isovolumetric relaxation time (r = 0.390, P = 0.006). P wave duration and PWD was found to be higher in RA patients than healthy control subjects. PWD is closely associated with disease duration and left ventricular (LV) diastolic dysfunction.
17979836 From death receptor to reactive oxygen species and c-Jun N-terminal protein kinase: the re 2007 Dec Death receptors (DRs) are more than simple killers: they control cell growth, proliferation, and survival, thereby playing a pivotal role in immune and inflammatory responses. Some of these phenomena might be explained by aberrant reactive oxygen species (ROS) production and metabolism, which can lead to oxidative stress. A key signaling molecule of DR-initiated intracellular pathways, receptor-interacting protein 1 (RIP1), orchestrates a complex control of multiple responses and may link DR-associated signaling complexes to ROS production by mitochondria. Yet, RIP1 is also an important regulator of endogenous anti-oxidants and ROS scavenging enzymes, because it is required for nuclear factor kappaB activation that results in expression of anti-apoptotic and anti-oxidant proteins. Alteration of RIP1 function may result in ROS accumulation and abnormal c-Jun N-terminal protein kinase activation, affecting inflammatory responses, innate immunity, stress responses, and cell survival. These molecular mechanisms may be involved in neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases.
18348311 Preliminary clinical measurement of the expression of TNF-related apoptosis inducing ligan 2008 It has recently been reported that tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) plays various roles in such autoimmune diseases as diabetes, multiple sclerosis (MS), and systemic lupus erythematosus (SLE). However, it has still remained unclear whether there is a close relationship between TRAIL and ankylosing spondylitis (AS). In this study, we investigated the association between the expression of TRAIL and AS. The specific messenger ribonucleic acid (mRNA) levels of TRAIL in peripheral blood mononuclear cells (PBMCs), serum sTRAIL, and TNF-alpha concentrations from 60 AS patients, 20 rheumatoid arthritis (RA) patients, and 30 healthy controls were determined by real-time fluorescent quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). The results indicated that the expression levels of TRAIL mRNA, and serum sTRAIL were significantly elevated in AS patients, compared with RA patients and healthy controls, and there was a close association between TRAIL mRNA and sTRAIL levels. However, there was no significant difference between human leukocyte antigen (HLA)-B27-positive and -negative AS patients. In HLA-B27-positive patients, TRAIL mRNA and sTRAIL closely correlated with serum TNF-alpha and C-reactive protein (CRP), but did not correlate in HLA-B27-negative patients. In conclusion, upregulated expression of TRAIL might be somewhat specific for evaluation of AS.
17053051 Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. 2007 Feb 1 The interleukin-12 (IL-12) cytokine induces the differentiation of naive T cells to the T helper cell type 1 (Th1) phenotype and is integral to the pathogenesis of Th1-mediated immunologic disorders. A more recently discovered IL-12 family member, IL-23, shares the p40 protein subunit with IL-12 and plays a critical role in the generation of effector memory T cells and IL-17-producing T cells. We introduce a novel compound, STA-5326, that down-regulates both IL-12 p35 and IL-12/IL-23 p40 at the transcriptional level, and inhibits the production of both IL-12 and IL-23 cytokines. Oral administration of STA-5326 led to a suppression of the Th1 but not Th2 immune response in mice. In vivo studies using a CD4+CD45Rbhigh T-cell transfer severe combined immunodeficiency (SCID) mouse inflammatory bowel disease model demonstrated that oral administration of STA-5326 markedly reduced inflammatory histopathologic changes in the colon. A striking decrease in interferon-gamma (IFN-gamma) production was observed in ex vivo culture of lamina propria cells harvested from animals treated with STA-5326, indicating a down-regulation of the Th1 response by STA-5326. These results suggest that STA-5326 has potential for use in the treatment of Th1-related autoimmune or immunologic disorders. STA-5326 currently is being evaluated in phase 2 clinical trials in patients with Crohn disease and rheumatoid arthritis.
18316338 Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients 2008 Apr OBJECTIVE: To identify factors predicting response to first TNF blocking treatment course in patients with established RA with a special focus on gender differences. METHODS: Patients with active RA initiating their first treatment course of TNF-blocking therapy were enrolled. The study period was March 1999 through September 2006. The prospective protocol included information on demographics, clinical characteristics of patients and response measures. Fulfilment of ACR 50-70% improvement and European League Against Rheumatism (EULAR) good response or remission [28-joint disease activity score (DAS28) <2.6] at 3 months were chosen as primary outcome measures. Potential predictors of responses were identified using multivariate binary logistic regression models. RESULTS: In total, 1565 patients were included in the study. Gender did not influence treatment response. Consistently, concomitant methotrexate (MTX) was significantly associated with EULAR remission, EULAR good response, ACR50 response and ACR70 response with odds ratios (ORs) 1.97, 2.13, 2.10 and 1.75, respectively. Concurrent treatment with other DMARDs was also significantly associated with EULAR remission, EULAR good response and ACR50 response (OR: 1.96, 2.24 and 1.94, respectively). Likewise, low HAQ at baseline consistently predicted good clinical outcome. Disease activity at baseline was directly associated with favourable response when measured by ACR50 and ACR70 (OR: 1.59 and 1.60, respectively), whereas DAS28 score at baseline was inversely associated with EULAR remission (OR: 0.78). CONCLUSIONS: In this observational study of patients with established RA, gender did not predict response to anti-TNF therapy, whereas treatment with concomitant DMARDs, especially MTX and low disability were associated with good response. Choice of outcome measures may influence the predictive value of baseline features.
18203309 Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and in 2008 Mar OBJECTIVE: Cytokines are the major mediators of joint damage in chronic arthritis. Data on synovial fluid (SF) concentration of Th17 cell-derived cytokine interleukin 17 (IL-17) in patients with juvenile idiopathic arthritis (JIA) are sparse. We measured levels of IL-17 in SF specimens from children with enthesitis-related arthritis (ERA) and polyarticular JIA (poly-JIA), and studied the ability of IL-17 to produce matrix metalloproteinases (MMP) and cytokines by fibroblast-like synoviocytes (FLS) from patients with ERA. METHODS: IL-17 levels were measured in SF of patients with ERA (n = 43), poly-JIA (n = 17), rheumatoid arthritis (RA; n = 35), and osteoarthritis (OA; n = 10) by ELISA. In patients with JIA, 10 paired serum samples were also assayed. FLS were cultured from SF of patients with ERA and subsequently stimulated for 48 h by IL-17 or tumor necrosis factor-alpha. Later the production of IL-6, IL-8, MMP-1, MMP-3, and tissue inhibitor of metalloproteinase (TIMP)-1 was measured in the culture supernatants by ELISA. RESULTS: Median IL-17 levels in SF were higher in patients with JIA [28 pg/ml (range 0-200)] compared to OA [0 pg/ml (range 0-84); p < 0.001] and RA (p < 0.05). The levels were comparable between poly-JIA patients and the ERA group. The median SF IL-17 levels were significantly higher compared to serum levels in children with JIA (p < 0.005). In ERA, SF IL-17 correlated with number of swollen joints (r = 0.35; p < 0.05), number of joints with limited mobility (r = 0.55; p < 0.001), and number of tender joints (r = 0.46; p < 0.01); however, no correlation was seen with erythrocyte sedimentation rate. IL-17 induced FLS to produce IL-6, IL-8, MMP-3, and MMP-1. However, there was no effect on the production of TIMP. CONCLUSION: Increased IL-17 levels in ERA SF correlate with disease activity and this may be due to increased production of MMP and cytokines by IL-17.
18218700 LGD-5552, an antiinflammatory glucocorticoid receptor ligand with reduced side effects, in 2008 May Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.
18032610 Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an alte 2007 Dec 4 Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.