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ID PMID Title PublicationDate abstract
17918635 [Endothelial dysfunction and early atherosclerosis in non-differentiated collagenosis]. 2005 Apr 24 INTRODUCTION: The most common systemic autoimmune diseases, as the rheumatoid arthritis (RA) and the systemic lupus erythematosus (SLE) are associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. The authors' aim was to determine the endothelial dysfunction and the accelerated atherosclerosis in patients with undifferentiated connective tissue disease (UCTD), in a preliminary phase of defined connective tissue diseases. PATIENTS AND METHODS: Twenty-two UCTD patients and twenty age and sex-matched controls were included. Using high-resolution B-mode ultrasound, the authors' measured the intima-media thickness (IMT) of the common carotid artery (CCA), and the diameter of brachial artery at rest, during reactive hyperemia, and after sublingual glyceryl trinitrate administration. The clinical, the demographical status and the serological profile of UCTD patients were also assessed. RESULTS: There was no significant difference between the groups considered to the traditional risk factors. The endothelium dependent vasodilatation was significantly impaired in UCTD patients as compared to the controls (5.3 +/- 3.03% vs. 8.85 +/- 4.02%, P < 0.002). The authors' have not found significant difference between the two groups either at the endothelium independent vasodilatation or at the CCA-IMT. CCA-IMT correlated significantly with the age (R = 0.819, p < 0.001) and with the anti-DNA antibody levels (R = 0.563, P < 0.008). CONCLUSIONS: The endothelium-dependent vasodilatation of patients with UCTD is reduced before development of a defined connective tissue disease and the potential anti-atherogenic treatment. The endothelium dependent vasodilatation is a more sensitive method to determine an early atherosclerotic process. The authors' found moderate correlation between the CCA-IMT and the anti-DNA antibody levels.
17185418 IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear f 2007 Jan 2 Recent studies indicate that IL-1alpha functions intracellularly in pathways independent of its cell surface receptors by translocating to the nucleus and regulating transcription. Similarly, the chromatin-associated protein HMGB1 acts as both a nuclear factor and a secreted proinflammatory cytokine. Here, we show that IL-33, an IL-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, is an endothelium-derived, chromatin-associated nuclear factor with transcriptional repressor properties. We found that IL-33 is identical to NF-HEV, a nuclear factor preferentially expressed in high endothelial venules (HEV), that we previously characterized. Accordingly, in situ hybridization demonstrated that endothelial cells constitute a major source of IL-33 mRNA in chronically inflamed tissues from patients with rheumatoid arthritis and Crohn's disease. Immunostaining with three distinct antisera, directed against the N-terminal part and IL-1-like C-terminal domain, revealed that IL-33 is a heterochromatin-associated nuclear factor in HEV endothelial cells in vivo. Association of IL-33 with heterochromatin was also observed in human and mouse cells under living conditions. In addition, colocalization of IL-33 with mitotic chromatin was noted. Nuclear localization, heterochromatin-association, and targeting to mitotic chromosomes were all found to be mediated by an evolutionarily conserved homeodomain-like helix-turn-helix motif within the IL-33 N-terminal part. Finally, IL-33 was found to possess transcriptional repressor properties, associated with the homeodomain-like helix-turn-helix motif. Together, these data suggest that, similarly to IL1alpha and HMGB1, IL-33 is a dual function protein that may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties.
17289553 Autoimmune inflammation from the Th17 perspective. 2007 Jan Recent studies demonstrated an IL-17-producer CD4+ T cell subpopulation, termed Th17, distinct from Th1 and Th2. It represents a different pro-inflammatory Th-cell lineage. This notion is supported by gene-targeted mice studies. Mice lacking IL-23 (p19-/-) do not develop experimental autoimmune encephalomyelitis (EAE) or collagen-induced arthritis (CIA), while knockout mice for the Th1 cytokine IL-12 (p35-/-) strongly develop both autoimmune diseases. Disease resistance by IL-23 knockout mice correlates well with the absence of IL-17-producing CD4(+) T lymphocytes in target organs despite normal presence of antigen-specific-IFN-gamma-producing Th1 cells. This finding may thus explain previous contradictory reports showing that anti-IFN-gamma-treated mice, IFN-gamma- or IFNR-deficient mice develop CIA or EAE. TGF-beta, IL-6 and IL-1 are the differentiation factors of Th17 cells. IL-23 is dispensable for this function, but necessary for Th17 expansion and survival. The master regulator that directs the differentiation program of Th17 cells is the orphan nuclear receptor RORgammat. IL-27, a member of the IL-12/IL-23 family, potently inhibits Th17 development. Evidence suggesting rheumatoid arthritis and multiple sclerosis as primarily IL-17 autoimmune inflammatory-mediated diseases is rapidly accumulating. The IL-17/23 axis of inflammation and related molecules may rise as therapeutic targets for treating these and perhaps other autoimmune diseases.
15674912 Rofecoxib for rheumatoid arthritis. 2005 Jan 25 BACKGROUND: Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. Further information is available at www.vioxx.com. Rheumatoid arthritis (RA) is a systemic auto-immune disorder, in which the synovial lining of many joints and tendon sheaths are persistently inflamed. OBJECTIVES: To assess the efficacy and toxicity of rofecoxib for treating RA. SEARCH STRATEGY: We searched the following electronic databases up to December 2000: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment database. The bibliographies of retrieved papers were scanned for additional references. The manufacturers of rofecoxib, MSD, were also approached by the UK National Institute for Clinical Excellence to submit additional evidence to inform it's appraisal on the use of cyclo-oxygenase inhibitors for arthritis. SELECTION CRITERIA: We included randomised controlled trials of parallel group design evaluating the efficacy and/or toxicity of rofecoxib in RA, both placebo based and comparative trials were eligible. Relevant outcome criteria had to be available to evaluate efficacy and/or toxicity, such as the OMERACT outcomes. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers and the results were compared for the degree of agreement. A validated tool (Jadad 1996) was used to score the quality of the randomised controlled trials. The planned analysis was to pool, where appropriate, continuous outcome measures using mean or standardized mean differences, and dichotomous outcome measures using relative risk ratios. MAIN RESULTS: Two randomised controlled trials evaluating rofecoxib for the treatment of RA were identified and met the inclusion criteria. One compared rofecoxib to placebo and was designed to assess the safety and efficacy of several doses of rofecoxib. The second trial compared rofecoxib to naproxen and was primarily designed to assess the safety of rofecoxib so did not include all the recommended RA efficacy measures. The overall number of ACR 20 responders who had received 25mg (82/ 171 = 48%) or 50mg (86/161 = 53%) was statistically significantly more than those receiving placebo (58/168 = 35% ) (RR 1.39 CI: 1.07, 1.80 and RR 1.55 CI: 1.20, 1.99 respectively) with no statistically significant differences between the 25 and 50 mg doses. The safety profile of rofecoxib was similar to that of placebo. In the comparative trial, rofecoxib at a dosage of 50 mg/day demonstrated similar efficacy to naproxen at a dosage of 500 mg twice daily. However, the combined rate of clinically significant complicated gastro-intestinal events (GI) (perforations, ulcers, bleeds, or obstructions) was lower with rofecoxib than with naproxen (RR 0.46, 95% CI, 0.34 to 0.63) due to a reduction in the number of ulcers and bleeds. Compared to patients taking naproxen, patients taking rofecoxib had a greater risk of having any cardiovascular event (45/4047 = 1.1% vs 19/4029 =0.47%) (RR 2.36 CI 1.38 to 4.02) and had greater risk of having a non-fatal myocardial infarction (MI) (18/4047 =0 .44% and 4/4029 =0.1%) (RR 4.48, 95% CI, 1.52 to 13.23). AUTHORS' CONCLUSIONS: In patients with RA, rofecoxib demonstrates a greater degree of efficacy than placebo, while having a comparable safety profile. Rofecoxib demonstrates a similar degree of efficacy as naproxen, but with a significantly lower rate of ulceration and gastrointestinal bleeding. Rofecoxib was associated with a greater risk for MI, but the exact significance and pathophysiology of this possible relationship is unclear. Rofecoxib was voluntarily withdrawn from global markets in October 2004. It cannot therefore be prescribed and therefore there are no implications for practice concerning its use. None the less when considering which NSAID to use, it must be borne in mind that the toxicity of NSAIDs is variable amongst patients and drugs and it tends to be dose related and associated with variation in the mode of action, absorption, distribution and metabolism. There remains a number of questions over both the benefits and risks associated with Cox II selective agents and further work is ongoing. It is likely that this issue will not be resolved until research has enabled a fuller understanding of the complex mechanism by which the Cox system operates.
16309988 Total knee arthroplasty for profound varus deformity: technique and radiological results i 2005 Aug One hundred seventy-three knees in 117 patients with varus deformity exceeding 20 degrees were prospectively evaluated. Using selective posteromedial release, reduction osteotomy of posteromedial tibial flare, and extra-articular tibial osteotomy, with the preservation of medial collateral ligament integrity, mean tibiofemoral angle of 22.7 degrees varus preoperatively (range, 15 degrees-62 degrees) was corrected to 5.3 degrees valgus (range, 2 degrees-9 degrees) postoperatively. Eighty-six percent of the knees were in 4 degrees to 10 degrees valgus postoperatively. Mean Knee Society score improved from 22.8 (range, 0-64) to 91.1 (range, 52-99), and function score from 22.8 (range, 0-64) to 72.1 (range, 5-100) at 2.6 years (range, 2-9 years). Mean femoral component valgus was 95.5 degrees (range, 92 degrees-98 degrees), and mean tibial component valgus was 89.8 degrees (range, 86 degrees-94 degrees). Of 30 grafts for posteromedial tibial defects, 28 were successfully incorporated. No patient reported significant instability. Three knees (1.7%) showed tibial component loosening with recurrence of deformity. Correction of severe varus deformity by the technique reported can successfully restore alignment, pain-free motion, and stability.
16331802 An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canad 2006 Jan OBJECTIVE: To revisit our previous evidence-based recommendations on the appropriate prescription of nonsteroidal antiinflammatory drugs (NSAID) with particular emphasis on cyclooxygenase-2 selective inhibitors (coxibs). METHODS: Needs assessments were conducted among Canadian physicians to determine their educational needs surrounding NSAID/coxibs. A survey of patients with arthritis was also conducted. Consensus participants reviewed articles relating to NSAID/coxibs in peer-reviewed journals between January 2000 and December 2004. At the consensus meeting, held January 21-23, 2005, participants discussed selected topics, after which recommendations were formulated and debated. Results. At the time of the meeting, it was agreed that emerging cardiovascular data were not clear enough to decide whether unanticipated cardiovascular events associated with coxibs represent a class effect or an effect of an individual drug. However, publications that appeared shortly after the meeting, as well as data presented at both the Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the US Food and Drug Administration, February 16-18, 2005, and Health Canada's Expert Advisory Panel on the Safety of Cox-2 Selective NSAID, June 9-10, 2005, clarified that all available coxibs do carry some degree of cardiovascular risk, denoting a class effect. Our consensus group made the following specific recommendations: (1) Patients should be fully informed about treatment options, including the need to balance between cardiovascular risks and gastrointestinal (GI) benefits of NSAID/coxibs. (2) Coxibs are as effective as nonselective NSAID and superior to acetaminophen for the symptoms of arthritis. Topical NSAID may also be beneficial. (3) Coxibs are associated with fewer severe GI complications than nonselective NSAID. A proton pump inhibitor (PPI) should be prescribed if an NSAID must be used in a patient at increased GI risk. (4) The renal/blood pressure (BP) impact of coxibs is similar to that of NSAID. (5) In individuals at risk, creatinine clearance and BP should be determined at baseline and shortly after treatment begins. (6) In the geriatric population, use of nonpharmacological therapies should be maximized, and special caution is required before prescribing oral NSAID/coxibs. (7) Patients taking rofecoxib have been shown to have an increased risk of cardiovascular events. Current data suggest that this increased cardiovascular risk may be an effect of the NSAID/coxib class. (8) Although the data are limited, coxibs may be more cost-effective for patients at high GI risk than nonselective NSAID plus proprietary PPI. CONCLUSION: Coxibs continue to be an option in the treatment armamentarium. Given the evolving cardiovascular information, physicians and patients should weigh the benefits and risks of NSAID/coxib treatment. This concern emphasizes the need to routinely reassess patients' risks. These recommendations, which were formulated according to the Appraisal of Guidelines for Research and Evaluation, are intended to be used as guidelines to supplement, but not replace, the physician's judgment in clinical decision-making.
17369772 [IgA, an essential part of the immune system: selected issues]. 2006 Immunoglobulin class A is the main protein of the mucosal immune system. The daily production of this isotype exceeds the synthesis of all other classes of immunoglobulins. Because the mucosal surface area of the human organism is about 400 m2, the role of IgA in the defense of this surfaces from harmful agents from the external environment is extremely essential. Any changes connected with a lack or an overproduction of this immunoglobulin can manifest as different clinical diseases. In this paper some selected issues on the heterogeneity of the IgA are presented, its structure and significance for the human organism, the formation of IgA immunity during ontogenesis on one hand and antigenic stimulation on the other, as well as disorders connected with abnormal synthesis or structure of these molecules.
17034427 Major histocompatibility complex class II (DR) antigen and costimulatory molecules on in v 2006 Dec We have previously shown that normal human peripheral blood polymorphonuclear neutrophils (PMNs) contain cytoplasmic 'stores' of three key molecules normally associated with antigen presentation and T-cell costimulation, i.e. major histocompatibility complex class II (DR) antigen, CD80 (B7-1) and CD86 (B7-2). These cytoplasmic molecules were found to translocate to the cell surface within a few minutes following cross-linking (X-L) of Mac-1: an early neutrophil activation signal. In this study we have compared X-L of Mac -1 in parallel with four other well documented in vitro neutrophil activators: phorbol myristate acetate, N-formyl methionyl leucyl phenylalanine, lipopolysaccharide, and phagocytosis of immunoglobulin G-Latex particles. In addition, we have used paired samples of neutrophils obtained from peripheral blood (as a control) and synovial fluid from patients with rheumatoid arthritis as a source of in vivo activated cells. With the exception of phagocytosis, all activators resulted in the rapid (within 30 min) generation of two populations of activated neutrophils (designated P1 and P2) based on flow-cytometry measurements of size, granularity and phenotype. Significant up-regulation of DR and costimulatory molecules was observed, predominantly on P2 cells, with all activators except phagocytosis. CD80 and CD86 were noted to respond to the various activation signals in a different pattern suggesting that their intracellular granule location may be different. Dual-staining confocal laser microscopy studies showed that CD80 is largely confined to secretory vesicles (SVs) while CD86 appears to have a much wider distribution being found in SVs and within secondary (specific) and primary (azurophilic) granules. Increased surface expression of these antigens was also observed on P2 synovial fluid neutrophils appearing as large heterogeneous clusters on the cell surface when visualized by confocal laser microscopy.
16984635 Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via c 2006 Sep 19 BACKGROUND: The T cell attracting chemokine CCL18 is produced by antigen presenting cells and a role for CCL18 has been suggested in the pathogenesis of a variety of diseases. Rheumatoid arthritis (RA) is one of these conditions, in which abundant CCL18 production is present. Although Th2 cytokines and IL-10 are known to have an effect on CCL18 production, there are several gaps in our knowledge regarding the exact regulation of CCL18 secretion, both in general and in RA. In this study we provide new insights in the regulation of CCL18 secretion by monocytes and dendritic cells. RESULTS: In contrast to a large panel of pro-inflammatory stimuli (IL-1beta, TNF-alpha, IL-10, IL-13, IL-15, IL-17, IL-18, IFN-gamma), T cell mimicking molecules (RANKL, CD40L) or TLR driven maturation, the anti-inflammatory IL-10 strongly stimulated DC to secrete CCL18. On freshly isolated monocytes, CCL18 secretion was induced by IL-4 and IL-13, in strong synergy with IL-10. This synergistic effect could already be observed after only 24 hours, indicating that not only macrophages and dendritic cells, but also monocytes secrete CCL18 under these stimulatory conditions. A high CCL18 expression was detected in RA synovial tissue and incubation of monocytes with synovial fluid from RA patients clearly enhanced the effects of IL-4, IL-13 and IL-10. Surprisingly, the effect of synovial fluid was not driven by IL-10 of IL-13, suggesting the presence of another CCL18 inducing factor in synovial fluid. CONCLUSION: In summary, IL-10 synergistically induces CCL18 secretion in combination with IL-4 of IL-13 on monocytes and monocyte derived cells. The effects of IL-14, IL-13 and IL-10 are strongly enhanced by synovial fluid. This synergy may contribute to the high CCL18 expression in RA.
16951119 Revision total elbow arthroplasty for prosthetic fractures. 2006 Sep BACKGROUND: Fractures of total elbow arthroplasty components are uncommon, and the literature provides little guidance regarding the management and outcomes of treatment of these complications. The goal of this report was to investigate the prevalence and management of fractures of ulnar and humeral components following total elbow arthroplasty and to review our experience with cement-within-cement reconstruction for revision following such fractures. METHODS: Between 1979 and 2003, twenty-four patients with a total of twenty-seven fractured total elbow arthroplasty components (seventeen ulnar and ten humeral) of different designs presented to our institution. Twenty-six implants underwent subsequent revision elbow arthroplasty at our institution. Fourteen of those revisions were done with a cement-within-cement technique, and twelve, with traditional methods. Twenty-one patients (twenty-three implants) were available for final follow-up, and data that had been acquired prospectively and entered into the institutional arthroplasty database were reviewed retrospectively. At the time of final follow-up, the Mayo Elbow Performance Score (MEPS) was calculated and preoperative, postoperative, and most recent radiographs were examined for bone loss, bushing wear, and integrity of the bone-cement interface. RESULTS: The prevalences of humeral and ulnar component fracture following primary total elbow arthroplasties performed at our institution were 0.65% and 1.2%, respectively. At a mean of 5.1 years following revisions for those fractures, the MEPS was excellent for eight patients, good for five, fair for six, and poor for two. The average MEPS was 82 points following the revision total elbow arthroplasties done with the cement-within-cement technique and 78 points following the revisions done with the traditional method of cement removal and insertion of a revision component. Complications included seven intraoperative cortical perforations; five nerve injuries, two of which were permanent; three triceps avulsions; and one deep infection. CONCLUSIONS: Implant fractures following total elbow arthroplasty are uncommon. They occur for several reasons, such as notch sensitivity, component design, and high stresses due to bone deficiency. Revision techniques, such as cement-within-cement reimplantation, are reliable for relieving pain and restoring function; however, the rate and spectrum of complications are a cause for concern. LEVEL OF EVIDENCE: Therapeutic Level IV.
16508941 CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph 2006 Mar OBJECTIVE: Rheumatoid arthritis (RA) is characterized by profound mononuclear cell (MNC) recruitment into synovial tissue (ST), thought to be due in part to tumor necrosis factor alpha (TNFalpha), a therapeutic target for RA. Although chemokines may also be involved, the mechanisms remain unclear. We undertook this study to examine the participation of CXCL16, a novel chemokine, in recruitment of MNCs to RA ST in vivo and to determine the signal transduction pathways mediating this process. METHODS: Using a human RA ST-SCID mouse chimera, immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, flow cytometry, and in vitro chemotaxis assays, we defined the expression and function of CXCL16 and its receptor, CXCR6, as well as the signal transduction pathways utilized by them for MNC homing in vitro and in vivo. RESULTS: CXCL16 was markedly elevated in RA synovial fluid (SF) samples, being as high as 145 ng/ml. Intense macrophage and lining cell staining for CXCL16 in RA ST correlated with increased CXCL16 messenger RNA levels in RA ST compared with those in osteoarthritis and normal ST. By fluorescence-activated cell sorting analysis, one-half of RA SF monocytes and one-third of memory lymphocytes expressed CXCR6. In vivo recruitment of human MNCs to RA ST implanted in SCID mice occurred in response to intragraft injection of human CXCL16, a response similar to that induced by TNFalpha. Lipofection of MNCs with antisense oligodeoxynucleotides for ERK-1/2 resulted in a 50% decline in recruitment to engrafted RA ST and a 5-fold decline in recruitment to regional lymph nodes. Interestingly, RA ST fibroblasts did not produce CXCL16 in response to TNFalpha in vitro, suggesting that CXCL16 protein may function in large part independently of TNFalpha. CONCLUSION: Taken together, these results point to a unique role for CXCL16 as a premier MNC recruiter in RA and suggest additional therapeutic possibilities, targeting CXCL16, its receptor, or its signaling pathways.
16766364 Interleukin-1beta influences the effect of infliximab on temporomandibular joint pain in r 2006 May OBJECTIVES: The aim of this study was to investigate the influence of plasma and synovial fluid tumour necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), IL-6, soluble TNF receptor II (TNF-sRII), IL-1 receptor antagonist (IL-1ra), soluble IL-1 receptor II (IL-1sRII) and IL-10 on the effect of the TNFalpha antibody infliximab on temporomandibular joint (TMJ) pain in patients with active rheumatoid arthritis (RA). METHODS: Fifteen patients with TMJ pain taking methotrexate were included in the study. The effect of intravenous infusions of infliximab was assessed after 14 or 22 weeks. TMJ resting and movement pain was assessed by a visual analogue scale (VAS) (0-100 mm) and samples of venous blood and TMJ synovial fluid were collected before and after treatment. RESULTS: The effect of infliximab on TMJ pain was influenced by pretreatment plasma levels of IL-1beta, IL-1ra, and IL-10 as well as pretreatment levels of TMJ synovial fluid IL-1sRII. High pretreatment levels of these cytokines and receptors as well as the presence of rheumatoid factor (RF) were associated with no or minor reduction in TMJ pain after treatment. CONCLUSIONS: Systemic treatment of RA with a combination of infliximab and methotrexate seems to be insufficient to alleviate TMJ pain in patients with RF or high pretreatment plasma levels of IL-1beta.
16432689 [Instability of the upper cervical spine due to rheumatism]. 2006 Mar Rheumatic manifestation at the cervical spine occurs in more than 50% of all cases in the natural course of this disease. The first cervical manifestation takes place in the upper cervical spine. The initial involvement of the C1/C2 segment leads to atlantodental subluxation. Progressive destruction can result in vertical instability, which is characterized by cranial subluxation of the odontoid process with the danger of resulting stenosis and cervical myelopathy. The goal of diagnosis has to be the early recognition of these changes to establish an effective treatment protocol. Persistent pain, neurological deficits, and progressive radiological signs for instability are indications for operative stabilizing procedures. These procedures avoid progressive destruction and improve the prognosis regarding pain decrease, regression of neurological deficits, and life expectancy.
15708884 Treatment continuation in patients receiving biological agents or conventional DMARD thera 2005 Sep OBJECTIVE: To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug (DMARD) treatment after previous DMARD failure. METHODS: Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study. Data were available for 511 patients treated with etanercept, 343 with infliximab, 70 with anakinra, and 599 controls. Propensity scores were used to select a subsample of patients from the control group who were likely to be treated with biological agents because of their disease severity, as well as comparable infliximab and etanercept cases. RESULTS: Treatment continuation after 12 months was similar for etanercept (68.6% (95% confidence interval, 62% to 75%)) and infliximab (65.4% (58% to 73%)) but lower for anakinra (59% (41% to 77%)). Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone. Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures. After adjustment for baseline differences, the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate. CONCLUSIONS: Treatment continuation of biological agents in clinical practice is less likely than in randomised clinical trials but more likely than in comparable controls treated with conventional DMARDs.
16794815 Determination of ceruloplasmin in human serum by SEC-ICPMS. 2006 Sep This paper describes an analytical method for the determination of ceruloplasmin (Cp) in human serum. The method uses immunoaffinity chromatography and size-exclusion chromatography (SEC) to "purify" the serum sample prior to analysis of 63Cu and 65Cu by inductively-coupled plasma mass spectrometry (ICPMS). By removing the six most abundant proteins from serum with immunoaffinity chromatography and by using SEC to separate Cu bound by Cp from any free Cu that might be present in the serum sample, we demonstrated that SEC-ICPMS can accurately and reproducibly measure Cp in the ERM DA470 reference serum. Cp identification is based on retention time match of the unknown in the serum sample with the Cp external standard and the presence of 63Cu and 65Cu at a ratio of 2.2+/-0.1. This method was used to analyze a reference serum certified for Cp, 47 serum samples from four different diseases and a set of normal controls. The reference serum and a serum sample from a patient with myocardial infarction, as well as a Cp standard, were also analyzed by electrospray mass spectrometry to confirm the presence of Cp in the SEC fraction known to contain 63Cu.
15751061 Joint inflammation and chondrocyte death become independent of Fcgamma receptor type III b 2005 Mar OBJECTIVE: It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)-mediated arthritis depend on Fcgamma receptor type III (FcgammaRIII). Local adenoviral overexpression of interferon-gamma (IFNgamma) in the knee joint prior to onset of IC-mediated arthritis aggravated severe cartilage destruction. In FcgammaRI(-/-) mice, however, chondrocyte death was not enhanced by IFNgamma, whereas matrix metalloproteinase (MMP)-mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating FcgammaRIII in the latter process. We undertook this study to determine the role of FcgammaRIII in joint inflammation and severe cartilage destruction in IFNgamma-stimulated IC-mediated arthritis, using FcgammaRIII(-/-) mice. METHODS: FcgammaRIII(-/-) and wild-type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFNgamma (AdIFNgamma) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC-mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMP-mediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and FcgammaR expression levels were determined in synovial washouts and synovium, respectively. RESULTS: Injection of AdIFNgamma in naive knee joints markedly increased levels of messenger RNA for FcgammaRI, FcgammaRII, and FcgammaRIII. Upon IFNgamma overexpression prior to induction of IC-mediated arthritis, joint inflammation was similar in FcgammaRIII(-/-) and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1alpha. Furthermore, IFNgamma induced 2-fold and 3-fold increases in chondrocyte death in WT controls and FcgammaRIII(-/-) mice, respectively. Notably, VDIPEN expression also remained high in FcgammaRIII(-/-) mice. CONCLUSION: IFNgamma bypasses the dependence on FcgammaRIII in the development of IC-mediated arthritis. Furthermore, both FcgammaRI and FcgammaRIII can mediate MMP-dependent cartilage matrix destruction.
17195044 Rosmarinic acid induces apoptosis of activated T cells from rheumatoid arthritis patients 2007 Jan T cells play an important role in the initiation and the progression of rheumatoid arthritis (RA) and depletion of potentially pathogenic T cells was suggested as an important therapeutic protocol. We determined if rosmarinic acid (RosA), known as a secondary metabolite from herbal plants, had apoptotic activity toward T cells from RA patients and further verified target T-cell subsets. CD3(+)CD25(+) activated T-cell subsets from most of the RA patients displayed significantly higher apoptosis rates than did the PBMCs and total CD3(+) T cells. Furthermore, activated and effector CD4(+) T cells, including CD4(+)CD25(+) and CD4(+)CD45RO(+) T cells, had a tendency of being more susceptible to RosA-induced apoptosis than that of resting and naïve T-cell subsets. RosA induced the release of cytochrome c from mitochondria and the blockage of mitochondrial depolarization inhibited apoptosis. Taken together, these results suggest that RosA induces apoptosis of activated T-cell subsets from RA patients via a mitochondrial pathway.
16703558 Endogenous endophthalmitis by Propionibacterium acnes associated with leflunomide and adal 2006 Mar PURPOSE: To report a case of unusual endogenous endophthalmitis associated with the use of leflunomide and adalimumab. METHODS: A 48-year-old woman on treatment with leflunomide and adalimumab for rheumatoid arthritis developed an endogenous endophthalmitis caused by Propionibacterium acnes. Diagnosis was confirmed by polymerase chain reaction and positive cultures. The patient underwent surgical treatment and intravitreal vancomycin, but the eye developed retinal fibrosis and untreatable retinal detachment. RESULTS: This report of endogenous endophthalmitis associated with the use of anti-tumor necrosis factor alpha (anti -TNF-a) drugs is consistent with those in the literature. P. acnes may induce pathologic reactions in compromised patients and cause endophthalmitis, but only after ocular surgery or in intravenous drug users. The Naranjo probability scale indicated a probable relationship between the drugs and the infection. CONCLUSIONS: Awareness of atypical infectious conditions in patients on anti-TNF-a drugs is critical for early diagnosis and good outcome.
15539415 Analysis of the CD8+ T cell response to the G1 domain of aggrecan in ankylosing spondyliti 2005 May BACKGROUND: CD4+ T cell responses to the G1 domain of aggrecan in patients with ankylosing spondylitis (AS) were recently reported. Whether such an immune response can be seen in the CD8+ subpopulation has not yet been determined. OBJECTIVE: To determine if HLA-B27 restricted G1-specific CD8+ T cells are present in AS and to analyse immunodominant CD8+ T cell epitopes. METHODS: Peripheral blood mononuclear cells of 45 patients with AS were stimulated with overlapping 18-mer peptides covering the whole G1 protein. Results were compared with those for patients with rheumatoid arthritis (RA) and healthy controls. For epitope analysis, G1-specific interferon gamma positive (IFNgamma+) T cells were isolated by magnetic activated cell sorting. After in vitro expansion, CD8+ T cells were restimulated with 14 subpools of G1 peptides. T cells responding to G1 peptide subpools were quantified by flow cytometry according to IFNgamma secretion. Predicted peptides were subsequently confirmed by stimulation with single peptides. RESULTS: G1-specific CD8+ T cell responses were found in 29/45 (64%) patients with AS, 18/35 (51%) patients with RA, but not in healthy controls. Five CD8+ T cell epitopes were identified as immunodominant in five patients. However, the T cell response was not HLA-B27 restricted. Nonamer peptides with an HLA-B27 binding motif did not induce a T cell response. CONCLUSION: A G1 peptide-specific CD8+ T cell response is present in AS but also in patients with RA. It does not seem to be HLA-B27 restricted. Whether such a response has a role in the pathogenesis of AS needs clarification.
16440745 [Effective treatment for a methotrexate-associated lymphoproliferative disorder with R-CHO 2005 Jul A 65-year-old male had a two-month history of fever and fatigue. He had been receiving low dose MTX administration for about 2 years for rheumatoid arthritis. The blood chemistry findings showed elevated liver function including lactic dehydrogenase (LDH) levels. The quantified serum EBV-DNA level was 200 copies/105 peripheral blood mononuclear cells. Computed tomographic scan demonstrated splenomegaly and intraperitoneal mass lesions. One of the masses was biopsied. Some tumor cells showed a large Hodgkin cell-like appearance. These were CD3e-, CD20 +, CD30 +, CD15-, LMP1 +, EBNA2-, EBER-ISH + without imbalance of the kappa/lambda ratio. A diagnosis of MTX-associated B-lymphoproliferative disorder was made. Although the patient's fever subsided and the serum LDH levels were normalized after withdrawal of the MTX, the masses showed almost no change. Therefore, we administered rituximab weekly for a total of four doses, resulting in normalization of the serum EBV-DNA load and serum CD4/CD8 ratio. The masses persisted, however, so we carried out eight courses of R-CHOP therapy, which induced complete response without any episode of serious infection.