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ID PMID Title PublicationDate abstract
17437161 A relationship between pharmacokinetics (PK) and the efficacy of infliximab for patients w 2007 Infliximab, a chimeric anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody, has been recognized as significantly improving the course of rheumatoid arthritis (RA); however, a subset of patients shows poor responses. To understand the mechanism underlying such unresponsiveness, I examined the clinical pharmacokinetics (PK) of infliximab, using time-serum concentration profiles obtained from 21 RA patients who had received infliximab therapy in combination with methotrexate (MTX). At week 14 of therapy, 15 cases achieved good or moderate responses in the European League Against Rheumatism (EULAR) criteria, and 3 cases resulted in nonresponders. The others discontinued therapy because of severe adverse effects or aggravation of disease activities. The means of distribution volume and elimination half-life (t (1/2)) during the first 2 weeks were 0.05 l/kg and 9.5 days, respectively. Through 14 weeks, most good and moderate responders maintained serum concentrations of more than 1 microg/ml, even immediately before the next infusions. Only 3 cases among good or moderate responders showed undetectable levels of trough serum concentration at week 14. In contrast, the PK profiles of all nonresponders except one showed rapid clearance during therapy. These data support the idea that the rapid clearance of infliximab is the main cause of poor therapeutic responses. I also found that the t (1/2) during the first 2 weeks is inversely correlated to the disease activity scores for 28 joints at the start of treatment, suggesting that TNF-alpha levels may determine the disease activity of RA. For patients who showed a rapid clearance of infliximab, the increased use of prednisone or MTX was beneficial to achieve sufficient clinical responses. The addition of tacrolimus was effective to improve the clinical outcomes of nonresponders. Thus PK data apparently offer guidance when modified treatment for infliximab-resistant RA patients is being considered.
16645967 Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone co 2006 May OBJECTIVE: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect. METHODS: Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg. RESULTS: At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group. CONCLUSION: Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups.
17086603 Association of rheumatoid arthritis with ergothioneine levels in red blood cells: a case c 2006 Nov OBJECTIVE: The dietary thiol compound and erythrocyte ingredient ergothioneine (ET) is the preferential physiological substrate of the organic cation transporter OCTN1, found to be associated with rheumatoid arthritis (RA) in genetic studies, but the biological roles of ET and OCTN1 are unclear. We investigated the association between ET concentrations in peripheral blood erythrocytes and the occurrence of RA. METHODS: Erythrocyte ET concentrations in patients with mildly active RA (n = 73) were compared to ET levels in patients with coronary heart disease (CHD; n = 62) and osteoarthritis (OA; n = 148), serving as non-RA chronic inflammatory disease controls. Correlation of ET levels in erythrocytes with levels of ET and OCTN1 mRNA in CD14+ monocytes was determined in 10 healthy subjects. RESULTS: Erythrocyte ET levels were significantly higher in patients with RA, with a median (interquartile range) of 12.6 micromole/l of erythrocytes (IQR 8.1-18.3), compared to 7.7 (IQR 5.0-12.0; p < 0.001) in CHD and 7.8 (IQR 4.8-12.8; p < 0.001) in OA. The prevalence of RA compared to non-RA controls increased with increasing blood ET concentrations, with an odds ratio of 0.23 (95% CI 0.13-0.41; p < 0.001) in the lowest quartile of RA erythrocyte ET levels to 3.11 (95% CI 1.54-6.29; p = 0.002) in the highest quartile. The group differences in ET values were maintained after adjustment for disease-related anthropometric and clinical variables (age, sex, body mass index, smoking, duration of disease, hemoglobin, C-reactive protein, and medication) and were also independent of erythrocyte glutathione levels and of polymorphisms of the OCTN1 gene. ET levels in erythrocytes were linearly correlated with ET concentrations (R2 = 0.936, p < 0.001) and OCTN1 mRNA levels (R2 = 0.946, p < 0.001) in CD14+ cells. CONCLUSION: Mildly active cases of RA are associated with an unexplained high level of ET in red blood cells.
16882589 The effect of methotrexate (MTX) on expression of signalling lymphocytic activation molecu 2006 Jul OBJECTIVE: To investigate the effect of methotrexate (MTX) on cytokine production by activated CD4+ T-cells in patients with rheumatoid arthritis (RA). METHODS: The effect of MTX on intracellular expression of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), and cell surface expression of signalling lymphocytic activation molecule (SLAM) from freshly isolated peripheral blood mononuclear cells (PBMCs), and after in vitro culture with or without MTX, was analysed with flow cytometry in 18 patients with RA and 20 healthy controls. RESULTS: Intracellular expression of IFN-gamma and IL-4 on freshly isolated CD4+ T-cells was significantly higher in patients with RA than in the controls (p<0.05). Intracellular expression of both IFN-gamma and IL-4 after culture with MTX was significantly lower than those after culture without MTX in patients with RA. Although no significant difference was observed in SLAM expression on freshly isolated CD4+ T-cells between patients with RA and the controls, MTX significantly decreased SLAM expression on both activated IFN-gamma+ and IL-4+CD4+ T-cells in patients with RA. CONCLUSION: In vitro modulation of the cytokine network by MTX, IFN-gamma, and IL-4 is one of the major targets for MTX, and production of IFN-gamma and IL-4 by PBMCs may be suppressed by SLAM on activated CD4+ T-cell in patients with RA.
18543352 Computerized definitions showed high positive predictive values for identifying hospitaliz 2008 Sep PURPOSE: Computerized definitions are used to identify serious infections and congestive heart failure leading to hospitalizations in studies of medication safety. However, information on their accuracy is limited. We evaluated the ability of computerized definitions to identify these conditions as the reason for admission among patients diagnosed with rheumatoid arthritis (RA). METHODS: Medical charts were randomly selected from a systematic sample of hospitalizations for selected conditions in a cohort of Medicaid patients with RA. We calculated positive predictive values (PPVs) for computerized definitions for community-acquired pneumonia, invasive pneumococcal disease, sepsis, opportunistic mycoses, and congestive heart failure using charts reviews as gold standard and computed inter-reviewer agreement statistics. RESULTS: From 2667 hospitalizations, 336 (13%) records were selected for review. A total of 277 charts (82%) were available. Based on any discharge diagnosis, PPVs for hospitalizations due to community-acquired pneumonia, invasive pneumococcal disease, sepsis, and opportunistic mycoses were 84, 100, 80, and 62%, respectively. Restricting definitions to principal diagnoses yielded higher PPVs, 95% for pneumonia and 100% for other diagnoses. The PPV of a principal diagnosis for congestive heart failure was 100%. Inter-reviewer agreement was at least 77% for all outcomes. CONCLUSION: These findings suggest that computerized definitions can identify congestive heart failure and selected infections leading to hospitalization in Medicaid patients with RA.
17726671 Treatment choices, preferences and decision-making by patients with rheumatoid arthritis. 2008 Mar OBJECTIVES: To explore rheumatoid arthritis (RA) patient treatment preferences, their decision-making and the treatment choices they would make when faced with three anti-tumour necrosis factor-alpha (TNF-alpha) therapy options. METHODS: Two methods of enquiry were used: postal questionnaire and one-to-one interviews. RA patients not taking anti-TNF-alpha medications were asked to complete a questionnaire after reading a written scenario, which involved choosing and identifying factors that influenced their treatment choice from three anti-TNF-alpha therapies: etanercept (Enbrel), adalimumab (Humira) and infliximab (Remicade). Patients who had tried more than one anti-TNF-alpha medication were asked at one-to-one interviews for their treatment preferences and how their current treatment had been decided. RESULTS: Both interviewees and questionnaire respondents chose adalimumab as their preferred treatment. Interviewees identified lack of control, convenience and technical issues as influencing treatment choice. Questionnaire respondents were less likely than interviewees to want to participate in making decisions about the selection of anti-TNF-alpha therapy. There were few gender differences. Patients younger than 61 years old were more confident about self-administering treatment, and preferred subcutaneous (sc) over intravenous (iv) medication, as this reduced regular hospital attendance. Older patients preferred health care staff to administer treatment and more readily identified 'contact with other patients/meeting others' and 'staff availability if problems arise' as factors influencing choice. CONCLUSIONS: RA patients demonstrate a clear treatment preference. Different factors influence patients who choose sc compared with iv medications. Many RA patients either wished to share in treatment decisions or relinquish responsibility to the health professional when choosing anti-TNF-alpha therapy. Patients require reassurance and continuing dialogue with clinicians to manage their condition optimally.
17296461 Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rhe 2006 Dec OBJECTIVE: This study evaluated the efficacy and tolerability of tramadol 37.5-mg/acetaminophen 325-mg combination tablets (tramadoUAPAP) as add-on therapy in subjects with rheumatoid arthritis (RA) pain that was inadequately controlled by NSAIDs and disease-modifying antirheumatic drugs alone. METHODS: Subjects in this multicenter, double-blind trial were randomized in a 3:1 ratio to receive 1 tramadol/ APAP tablet TID or a matching placebo for 1 week. Stable doses of previous medications were continued during the study. The primary efficacy variable was the mean daily pain relief score over 1 week, measured on a 6-point scale (4 = complete; ' = a lot; 2 = some; 1 = a little; 0 = none; -1 = worse). Secondary outcomes included the mean daily pain intensity score, measured on a 100-mm visual analog scale (VAS) (from 0 mm = no pain to 100 mm = extreme pain); pain intensity and pain relief at day 7; subjects' and investigators' mean overall assessments of study drug, measured on a Likert scale (from 2 = very good to -2 = very poor); and subjects' assessments of 8 aspects of physical function (measured on the Health Assessment Questionnaire). RESULTS: Of 277 subjects randomized to treatment, 267 (201 tramadol/APAP, 66 placebo) were included in the intent-to-treat population. Mean (SD) daily pain relief scores at the end of 1 week were significantly greater in the tramadol/APAP group compared with the placebo group (1.04 [0.89] vs 0.78 [0.80], respectively; P = 0.037), and mean daily pain intensity scores at the end of 1 week were significantly lower (47.23 [19.96] vs 53.81 [16.59]; P = 0.018). Physical function at the end of 1 week did not differ significantly between tramadol/APAP and placebo. Two hundred seventy-two subjects (205 tramadol/APAP, 67 placebo) were evaluable for tolerability. One hundred thirty-three of these subjects had at least 1 adverse event. The incidence of adverse events was significantly higher in the tramadol/APAP group than in the placebo group (57.6% vs 22.4%; P < 0.001). Discontinuations due to adverse events occurred in 19.0% of the tramadol/APAP group and 3.0% of the placebo group (P = 0.001). Of 213 treatment-related adverse events in tramadol/APAP subjects, nausea (34.1%) was the most frequent, followed by dizziness (20.0%) and vomiting (15.6%). One serious adverse event--chest discomfort, nausea, and vomiting after taking study medication-occurred in a subject receiving tramadol/APAP The symptoms resolved 1 day after discontinuing tramadol/APAP. CONCLUSIONS: In this study, tramadol/APAP used as add-on therapy in subjects with symptomatic RA was associated with a significant improvement in pain relief and a significant reduction in pain intensity compared with placebo, with no improvement in physical function. Use of tramadol/APAP may be considered when analgesics are needed in addition to conventional NSAIDs and disease-modifying antirheumatic drugs in subjects with RA.
16292516 All-trans-retinoic acid suppresses interferon-gamma and tumor necrosis factor-alpha; a pos 2006 Jul OBJECTIVES: To study the effects of all-trans-retinoic acid (ATRA), we determined the proliferation and cytokine production by peripheral blood mononuclear cells (PBMCs) and CD4+ T cells in healthy volunteers and patients with rheumatoid arthritis (RA), and explored the possibility of using ATRA as a therapeutic agent for autoimmune diseases. METHODS: Proliferation of these cells was determined by modified MTT assay, and expression of CC chemokine receptors 4 (CCR4) and CCR5 was determined by flow cytometry. Production and expression of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and tumor necrosis factor (TNF)-alpha was determined by Enzyme-Linked Immunosorbent Assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). The presence of STAT6 protein was determined by Western blot analysis. RESULTS: ATRA did not affect the proliferation or production of IL-2 and IL-4. We did not detect STAT6 protein, and saw no evidence of the differentiation of PBMCs to Th1 or Th2 cells. In contrast, ATRA suppressed the production of IFN-gamma and TNF-alpha significantly. There were no significant differences between the healthy volunteers and RA patients. CONCLUSIONS: ATRA was demonstrated to affect the cytokine production of IFN-gamma and TNF-alpha. ATRA might be useful in the treatment of autoimmune diseases such as RA.
16574073 Mu-calpain is involved in the regulation of TNF-alpha-induced matrix metalloproteinase-3 r 2006 May 12 Calpain is secreted by intra-articular synovial cells and degrades the main components of cartilage matrix proteins, proteoglycan, and collagen, causing cartilage destruction. Matrix metalloproteinase-3 (MMP-3) has also been detected in synovial fluid and serum, and is involved in the development and progression of rheumatoid arthritis by degradation of the extracellular matrix and cartilage destruction. To investigate the relationship between calpain and MMP-3 in rheumatic inflammation, we utilized the rheumatic synovial cell line, MH7A. Tumor necrosis factor (TNF-alpha) stimulation-induced increased expression of mu-calpain, m-calpain, and MMP-3 in these cells, as well as the release of calpain and MMP-3 into the culture medium. The calpain inhibitors, ALLN (calpain inhibitor I) and calpeptin, did not affect the intracellular expression of MMP-3, but reduced the secretion of MMP-3 in a concentration-dependent manner. Down-regulation of mu- but not m-calpain by small interfering RNAs abolished TNF-alpha-induced MMP-3 release from the synovial cells. These findings suggest that calpain, particularly mu-calpain, regulates MMP-3 release by rheumatic synovial cells, in addition to exerting its own degradative action on cartilage.
18567920 Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD14 2008 Sep OBJECTIVES: To investigate whether cyclophilin A (CypA) can up-regulate the expression of MMP-2 and MMP-9 in monocytes/macrophages and whether CD147 facilitates this regulation in RA. Methods. Peripheral blood monocytes were isolated from RA patients and differentiated into macrophages by M-CSF (15 ng/ml). Under CypA stimulation (200 ng/ml), the protein release and activation of MMPs were detected by gelatin zymography and invasion assay. Human monocyte cell line THP-1 cells were selected for the advanced searching for potential interaction between CypA and CD147 in production of MMPs and cell adhesion to extracellular matrix (ECM). RESULTS: CypA significantly increased production and activation of MMP-9, not MMP-2, in the monocytes/macrophages derived from RA SF. CSA and HAb18G/CD147 antagonistic peptide AP-9 against CD147, respectively, dramatically decreased MMP-2 and MMP-9 expression, both in the absence or presence of CypA. Similar effects of CypA on MMP-9 production and cell invasion were observed in THP-1 cells. CypA-induced nuclear factor kappaB (NF-kappaB) activity for MMP-9 transcription were strongly blocked by extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK) inhibitors (U0126 and SP600125, respectively), but not by p38 mitogen-activated protein kinase (MAPK) inhibitors (SB203580). CypA also induced calcium mobilization and increased the adhesion of THP-1 cells to ECM. CONCLUSIONS: These findings suggest that in RA, the abundant CypA, by its direct binding to CD147, up-regulates MMP-9 expression and adhesion of monocytes/macrophages to ECM, and the cyclophilin-CD147 interactions might contribute to the destruction of cartilage and bone.
17614976 The epitope study of alpha-fodrin autoantibody in primary Sjögren's syndrome. 2007 Sep Alpha-fodrin, an intracellular organ-specific cytoskeleton protein, was identified recently as an autoantigen associated with Sicca- and Sjögren's syndrome (SS). Identification of the antigenic determinants of alpha-fodrin is a prerequisite to developing highly sensitive and specific anti-alpha-fodrin antibodies, which provides potential means for the diagnosis of primary Sjögren's syndrome (pSS) in patients. Based on the structure and predicted antigenic sites of alpha-fodrin protein with 560 amino acids (alpha-fodrin 560), we prepared a set of overlapping recombinant protein fragments covering antigenic epitopes and synthesized a set of peptides derived from the alpha-fodrin protein. These recombinant proteins and synthesized peptides were subjected to screening with pSS patients sera, respectively. The peptide with the strongest immunoreactivity was used as antigenic peptide to define further the role of anti-alpha-fodrin-peptide antibodies in the sera of 135 patients with pSS, 48 patients with systemic lupus erythematosus (SLE), 88 patients with rheumatoid arthritis (RA) and 83 normal controls. Our data showed that the N-terminal peptide of amino acids 46-59 (N46) of alpha-fodrin 560 was the epitope with strongest antigenicity. The prevalences of anti-N46 peptide antibodies (alpha-N46PA) in patients with pSS, SLE, RA and normal controls were 78.5%, 10.4%, 21.6% and 6.0%, respectively. The sensitivity and specificity of the autoantibodies in pSS were 78.5% and 86.8%, respectively. These results suggest the alpha-N46PA which shows highest sensitivity and specificity is of significance to develop an effective diagnostic approach for pSS.
16793915 Neutrophil apoptosis in rheumatoid arthritis is regulated by local oxygen tensions within 2006 Sep Neutrophils are normally short-lived cells and die by apoptosis, but when recruited into tissues, their apoptosis is delayed, and they survive for much longer time periods. In inflammatory diseases, such as rheumatoid arthritis (RA), this delayed apoptosis may lead to increased tissue damage and a failure of the inflammation to resolve. However, there are conflicting reports in the literature as to whether neutrophil apoptosis is delayed or accelerated in rheumatoid joints. In this report, we show that neutrophils isolated from the synovial fluid (SF) of patients with RA show accelerated rates of apoptosis when incubated ex vivo and that SF, despite containing a variety of antiapoptotic cytokines, is proapoptotic. Paradoxically, levels of the key neutrophil survival protein Mcl-1 are elevated in freshly isolated SF neutrophils compared with matched peripheral blood samples from the same patients, indicating that delayed neutrophil apoptosis has been signaled in vivo as the cells enter the joints. However, when SF was added to neutrophils and incubated under hypoxia (1% O(2)), conditions known to exist in vivo within joints, the SF was antiapoptotic. These data reveal that the rheumatoid synovial joint contains a complex mixture of pro- and antiapoptotic factors and that the low, local oxygen tensions that exist within these joints can exert profound effects on neutrophil survival. These experiments also highlight the importance of performing in vitro experiments under laboratory conditions that closely mimic those that occur in vivo; otherwise, misleading conclusions may be drawn.
16705109 Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and m 2006 May 17 CONTEXT: Tumor necrosis factor (TNF) plays an important role in host defense and tumor growth control. Therefore, anti-TNF antibody therapies may increase the risk of serious infections and malignancies. OBJECTIVE: To assess the extent to which anti-TNF antibody therapies may increase the risk of serious infections and malignancies in patients with rheumatoid arthritis by performing a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of anti-TNF therapy. DATA SOURCES: A systematic literature search of EMBASE, MEDLINE, Cochrane Library, and electronic abstract databases of the annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology was conducted through December 2005. This search was complemented with interviews of the manufacturers of the 2 licensed anti-TNF antibodies. STUDY SELECTION: We included randomized, placebo-controlled trials of the 2 licensed anti-TNF antibodies (infliximab and adalimumab) used for 12 weeks or more in patients with rheumatoid arthritis. Nine trials met our inclusion criteria, including 3493 patients who received anti-TNF antibody treatment and 1512 patients who received placebo. DATA EXTRACTION: Data on study characteristics to assess study quality and intention-to-treat data for serious infections and malignancies were abstracted. Published information from the trials was supplemented by direct contact between principal investigators and industry sponsors. DATA SYNTHESIS: We calculated a pooled odds ratio (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections (infection that requires antimicrobial therapy and/or hospitalization) in anti-TNF-treated patients vs placebo patients. We estimated effects for high and low doses separately. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher doses compared with patients who received lower doses of anti-TNF antibodies. For patients treated with anti-TNF antibodies in the included trials, the number needed to harm was 154 (95% CI, 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (95% CI, 39-125) within a treatment period of 3 to 12 months. CONCLUSIONS: There is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy. The formal meta-analysis with pooled sparse adverse events data from randomized controlled trials serves as a tool to assess harmful drug effects.
18289073 Carbon monoxide-releasing molecules: a pharmacological expedient to counteract inflammatio 2008 Carbon monoxide (CO) mediates many of the biological effects that are attributed to heme oxygenase (HO), the enzyme responsible for CO production in mammals. Antioxidant and anti-inflammatory activities of HO-1, the inducible isoform of heme oxygenase, have been demonstrated in a variety of disease models and a therapeutic exploitation of this pathway is currently under scrutiny. In this context, the liberation of CO from CO-releasing molecules (CO-RMs) is extremely attractive as these compounds may form the basis of a new class of pharmaceuticals. Recent investigations indicate that HO-1 and CO modulate important processes in chronic inflammation; these include the control of immune responses, the production of inflammatory mediators and the mitigation of cartilage or bone destruction. As HO-1 is highly expressed in the joint tissues of patients affected by arthritic diseases, it is plausible to suggest that this pathway may play a protective role against joint degenerative diseases. Studies aimed at identifying the signaling pathways responsive to endogenous CO and CO-RMs in rheumatoid arthritis and other inflammatory states are currently in progress. This research will help to elucidate the molecular mechanisms underlying the pharmacological effects of CO-RMs and may lead to the development of novel therapeutic strategies for the treatment of acute and chronic inflammatory conditions.
17378701 AHRQ's Effective Health Care Program: its impact on managed care. 2007 Jan OBJECTIVE: To describe some of the managed care perspectives regarding the data development and coverage issues. BACKGROUND: Section 1013 of the Medicare Modernization Act of 2003 has initiated the formation of the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program, which is evaluating the treatments for rheumatoid arthritis (RA) in the Medicare population. The results of these studies have the potential to impact future drug utilization. It is not known whether this data could be applied to the commercial population. SUMMARY: Payers (e.g., managed care organizations, pharmacy benefit managers) make decisions about which drugs will be covered and to which formulary "tier" the drug will be assigned. These decisions are made by evaluating current evidence based on safety, effectiveness, outcomes, and cost. Patients believe in a "warranty" of care, meaning that there will always be a treatment option whether they are compliant with their treatment regimen or not. All treatments are measured by a "value," and each stakeholder may see this value differently. A return on medical investment is one way to assess this value. CONCLUSIONS: Different stakeholders view treatment value in different ways. The evidence that will be identified through AHRQ's Effective Health Care Program will partially define this value. If this model succeeds, it has the potential to significantly affect health care.
18625055 Lack of association or interactions between the IL-4, IL-4Ralpha and IL-13 genes, and rheu 2008 INTRODUCTION: A feature of rheumatoid arthritis (RA) is an imbalance between proinflammatory and anti-inflammatory cytokines. Several recent studies have implicated polymorphism in the IL-4 signalling pathway in the development of erosive RA. The aim of the present study was to investigate the role of polymorphism in the IL-4, IL-4Ralpha and IL-13 genes in RA, including an examination of epistasis. METHODS: A total of 965 Caucasian patients with RA (cases) and 988 healthy control individuals (controls) were genotyped for five variants in the IL-4/IL-13 gene cluster (5q31.1) and two functional variants IL-4Ralpha (16p12.1). Individual genotype and haplotype frequencies were compared between cases and controls. The odd ratios were calculated with asymptotic 95% confidence intervals, and P values less than 0.05 were considered statistically significant. The potential association with radiological joint damage was also examined. Potential gene interactions were assessed using both stratified analysis and the linkage disequilibrium-based statistic. RESULTS: Genotype, allele and haplotype frequencies were equally distributed between RA cases and controls. Similarly, no association was detected between these variants and modified Larsen scores. Furthermore, no evidence of epistasis was detected between IL-4 or IL-13 genotypes and IL-4Ralpha. CONCLUSION: These results indicate that common variants of the IL-4/IL-13 pathway do not significantly contribute to RA susceptibility and radiological severity.
18641439 Primary total hip replacement in childhood, adolescence and young patients: quality and ou 2008 OBJECTIVE: The present meta-analysis illustrates relevant information about hip replacement in young patients that has been published during the past 3 decades. MATERIAL AND METHODS: Based on a MedLine literature review a total of 95 studies were evaluated. Parameters for evaluation of study quality and outcome were implant survival rates (ISR),number of patients, indications, follow-up, surgical approaches and number of surgeons. RESULTS: Most studies consider patient numbers <50. In 33 studies one implant system was applied compared to 65 studies in which more than one system was used. Most studies include different surgical approaches. 20% of all studies contained neither the number of surgeons,nor the type of surgical approach. The overall ISR could be evaluated in 67 studies. Sufficient data about the ISR of stem and/or sockets were available in 50 papers. CONCLUSIONS: Most published studies analyzed inhomogeneous study populations; study variables vary as do the implants used for treatment.
17416344 A possible role for TSLP in inflammatory arthritis. 2007 May 25 Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that triggers dendritic cell-mediated Th2-type inflammatory responses and is considered as a master switch for allergic inflammation. In this study, we found increased levels of TSLP and, also TNF-alpha as previously reported, in synovial fluid specimens derived from patients with rheumatoid arthritis (RA) when compared with those from patients with osteoarthritis (OA). In addition, TNF-alpha up-regulated TSLP expression in RA- and OA-derived synovial fibroblasts, which was inhibited by IFN-gamma. Furthermore, anti-TSLP neutralizing antibody ameliorated a TNF-alpha-dependent experimental arthritis induced by anti-type II collagen antibody in mice. Collectively, these results suggest that TSLP, as a downstream molecule of TNF-alpha, may be involved in the pathophysiology of inflammatory arthritis. TSLP might thus play a role not only in allergic diseases but also in inflammatory arthritis such as RA.
17977770 Exacerbation of interstitial lung disease during etanercept therapy: Two cases. 2008 Mar We report two cases of interstitial lung disease possibly related to TNF alpha antagonist therapy (etanercept) in patients with rheumatoid arthritis. In both cases, pre-existing interstitial lung disease worsened during etanercept therapy. We found 19 previously published cases of interstitial lung disease in patients who were taking TNF alpha antagonists and had no evidence of infection, raising the possibility of a causal link with the medication. The potential pathophysiological mechanisms remain unknown. Caution is in order when using TNF alpha antagonists in patients with pre-existing lung disease. The development or exacerbation of interstitial lung disease in a patient on TNF alpha antagonist therapy should lead to investigations for a cause. Should these investigations prove negative, the treatment must be discontinued.
17911596 Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the d 2007 Oct 15 Depletion of B cells in rheumatoid arthritis is therapeutically efficacious. Yet, the mechanism by which B cells participate in the inflammatory process is unclear. We previously demonstrated that Ag-specific B cells have two important functions in the development of arthritis in a murine model of rheumatoid arthritis, proteoglycan (PG)-induced arthritis (PGIA). PG-specific B cells function as autoantibody-producing cells and as APCs that activate PG-specific T cells. Moreover, the costimulatory molecule CD86 is up-regulated on PG-specific B cells in response to stimulation with PG. To address the requirement for CD80/CD86 expression on B cells in the development of PGIA, we generated mixed bone marrow chimeras in which CD80/CD86 is specifically deleted on B cells and not on other APC populations. Chimeras with a specific deficiency in CD80/CD86 expression on B cells are resistant to the induction of PGIA. The concentration of PG-specific autoantibody is similar in mice sufficient or deficient for CD80/86-expressing B cells, which indicates that resistance to PGIA is not due to the suppression of PG-specific autoantibody production. CD80/86-deficient B cells failed to effectively activate PG-specific autoreactive T cells as indicated by the failure of T cells from PG-immunized CD80/86-deficient B cell chimeras to transfer arthritis into SCID mice. In vitro secondary recall responses to PG are also dependent on CD80/86-expressing B cells. These results demonstrate that a CD80/86:CD28 costimulatory interaction between B cells and T cells is required for autoreactive T cell activation and the induction of arthritis but not for B cell autoantibody production.