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ID PMID Title PublicationDate abstract
16078319 Training and calibration improve inter-reader reliability of joint damage assessment using 2005 Aug OBJECTIVE: To assess the inter-reader reliability of 3 rheumatologist readers before and after training using 2 methods of assessment: magnetic resonance imaging (MRI) computerized erosion volume assessment and MRI scoring using the OMERACT-5 Rheumatoid Arthritis MRI Score (OM-5 RAMRIS) criteria. METHODS: Erosion volumes were measured in 10 patients [5 wrist and 5 metacarpophalangeal (MCP) joint studies] with rheumatoid arthritis. Erosion scores were derived from this group and 8 additional subjects to provide a total of 18 subjects (10 wrist and 8 MCP joint studies) with MRI scores for comparison. Subjects were selected from existing MRI databases to provide a spectrum of joint damage for assessment. Initial reading was undertaken after the 2 inexperienced readers were provided with instructions regarding OSIRIS computer software and definitions of the OMERACT score; no other formal training was undertaken. One month after the initial reading, the 2 inexperienced readers undertook a 3 hour training session and all 3 readers then took part in 2 subsequent 2 hour calibration sessions. Each reader then reread the original MRI studies using the computerized erosion volume method and the OMERACT MRI RA score. The interval between the baseline and post-training reading was 2 months. All reading was undertaken on a computer workstation and readers were blinded to other readers' results. RESULTS: For the wrist MRI studies, inter-reader agreement improved considerably after training for both the computerized MRI volume method and the OMERACT MRI score [intraclass correlation coefficients (ICC) 0.21 and 0.46, respectively, pre-training; 0.92 and 0.85 post-training]. The correlation between all readers' scores and volumes was excellent at baseline and post-training. For the MCP joint studies, inter-reader agreement was moderate at baseline for the erosion volume and score (ICC 0.51 and 0.61). While there was some improvement in agreement post-training for the scoring method (ICC 0.75), there was no significant improvement for the erosion volumes (ICC 0.58). CONCLUSION: Overall, inter-reader agreement for erosion scoring and volume measurement was higher for the wrist joint. The lack of improvement in the MCP joint region for the erosion volume measurements appears to relate primarily to difficulties in estimating the erosion border in the proximal MCP joints using the manual outlining tool. This limits the usefulness of erosion volume measurements in this joint region.
16163373 PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. 2005 Oct A functional single nucleotide polymorphism (SNP) C1858T in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene encoding an intracellular phosphatase with negative regulatory effects on T-cell activation is associated with some autoimmune diseases in Caucasians. Taking into account firstly, that SNP frequencies may vary across populations and, secondly, that replication studies are important to confirm previous associations, we examined the influence of PTPN22 polymorphism in 621 Colombian patients with four autoimmune diseases. Accordingly, 298 patients with rheumatoid arthritis (RA), 143 with systemic lupus erythematosus (SLE), 70 with primary Sjogren's syndrome (pSS) and 110 with Type 1 diabetes (T1D) were studied. The control group consisted of 308 matched healthy individuals. Genotyping of PTPN22 was performed by the real-time polymerase chain reaction technology, using the Taq Man 5'-allele discrimination assay. The 1858 T allele was found to be a risk factor for pSS (odds ratio (OR)=2.42), SLE (OR=2.56), and T1D (OR=1.83). A lower but nonsignificant trend was observed for RA (OR=1.26). These results confirm the influence of PTPN22 in autoimmunity and indicate that autoimmune phenotypes could represent pleiotropic outcomes of nonspecific disease genes that underlie similar immunogenetic mechanisms.
17014006 Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthr 2006 Nov OBJECTIVE: Abatacept, a soluble selective costimulation modulator, selectively modulates T cell activation via the CD80/CD86:CD28 costimulation pathway. Data from a Phase II trial showed efficacy in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate when treated with abatacept (10 mg/kg or 2 mg/kg). To determine the mechanism of action of abatacept, we analyzed changes in the serum levels of inflammatory biomarkers in the patients enrolled in this trial. RESULTS: Following 12 months' treatment, serum levels of interleukin 6 (IL-6), soluble IL-2 receptor, C-reactive protein, soluble E-selectin, and soluble intercellular adhesion molecule-1 were significantly lower in patients receiving abatacept 10 mg/kg versus placebo. Smaller reductions in tumor necrosis factor-a and rheumatoid factor were also observed in the abatacept 10 mg/kg group compared with the placebo group. Although there was no evidence for efficacy of the 2 mg/kg dose, small reductions in inflammatory biomarkers at this dosage support the biologic effect of this therapy. CONCLUSION: These findings reveal the antiinflammatory and immunomodulatory effects of abatacept in patients with RA, and are consistent with the concept that modulating T cell activation improves clinical signs and symptoms and inhibits the progression of structural damage. These data suggest that selective modulation of the CD80/CD86:CD28 pathway with abatacept may affect several inflammatory cell types and cytokines that are involved in the proinflammatory cascade.
16178860 Reduced blood BDCA-2+ (lymphoid) and CD11c+ (myeloid) dendritic cells in systemic lupus er 2005 Oct Type 1 IFN is thought to be implicated in the autoimmune process of SLE. Plasmacytoid dendric cells (DC), which are natural IFN-alpha producing cells, play a pivotal epipathogenic role in SLE. The present study was undertaken to investigate the phenotypic characteristics of peripheral blood DC in SLE patients in comparison with those of healthy controls. Samples from 20 SLE patients and 18 healthy controls were studied. Three-colour flow cytometry was performed to identify myeloid DC, as CD11c(+) lineage marker(-), and HLA-DR(+) cells and plasmacytoid DC, as BDCA-2(+) linage marker(-), and HLA-DR(+) cells. We used the whole blood 'lyse/no-wash' procedure, which allows precise counting of peripheral blood DC. BDCA-2(+) plasmacytoid DC and CD11c(+) myeloid DC were reduced in SLE patients compared with controls. Similarly, BDCA-3(+) DC were reduced in SLE patients. These results indicated that SLE patients had a reduced number of both BDCA-2(+) plasmacytoid DC and CD11c(+) myeloid DC. These alternations of the DC subset may drive the autoimmune response in SLE.
16603583 Safety of anti-TNF-alpha therapy in rheumatoid arthritis and spondylarthropathies with con 2006 Oct OBJECTIVE: To assess the safety of anti-tumour necrosis factor (TNF)-alpha therapy in patients with rheumatoid arthritis (RA) or spondylarthropathies (SA) and concurrent chronic hepatitis B or C. METHODS: Records concerning 480 outpatients attending the Rheumatology Department of the University Hospital of Nice (France) for RA or SA were retrospectively reviewed for the duration of disease, treatment, serological status and biological data. RESULTS: Six relevant cases were identified: two of RA with chronic hepatitis B; one of SA with chronic hepatitis B and three of RA with chronic hepatitis C. Five patients had received etanercept and one infliximab; two had been given adalimumab after an unsuccessful trial of etanercept. Patients with concurrent chronic hepatitis B were also given lamivudine. In none of the cases had changes in serum aminotransferases or viral load been reported. CONCLUSION: The use of anti-TNF-alpha therapy (plus lamivudine in the presence of concurrent underlying hepatitis B viral infection) appeared to be safe in that it had no effect on serum aminotransferases and/or viral load. However, repeated monitoring is necessary throughout the treatment period.
15699168 Regulation of S100A8 by glucocorticoids. 2005 Feb 15 S100A8 (A8) has roles in inflammation, differentiation and development and is associated with oxidative defense. Murine A8 (mA8) is up-regulated in macrophages, fibroblasts, and microvascular endothelial cells by LPS. Glucocorticoids (GCs) amplified LPS-induced mA8 in these cells. Relative to stimulation by LPS, GCs increased mA8 gene transcription and mRNA half-life. Enhancement required new protein synthesis, IL-10 and products of the cyclooxygenase-2 pathway, and both ERK1/2 and p38 MAPK. Protein kinase A positively and protein kinase C negatively regulated this process. Promoter analysis indicated element(s) essential for LPS and dexamethasone enhancement colocated within the region -178 to 0 bp. In the absence of glucocorticoid response elements, NF1 motif at -58 is a candidate for mediation of enhancement. Gel shift analysis detected no differences between LPS- and LPS/dexamethasone-treated complexes within this region. GCs increased constitutive levels of A8 and S100A9 (A9) mRNA in human monocytes. The synovial membrane of rheumatoid patients treated with high dose i.v. methylprednisolone contained higher numbers of A8/A9-positive macrophages than pre- or posttreatment samples. Results support the proposal that A8 has anti-inflammatory properties that may be independent of hetero-complex formation with A9 and may also enable localized defense in the absence of overriding deleterious host responses.
15790351 Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. 2005 Apr Rheumatoid arthritis (RA), like other autoimmune diseases, has a complex genetic basis. Rapid technical advances in high-throughput genotyping and analysis have now reached a point where genes of low-to-moderate risk can be identified using a variety of study designs, including whole genome association studies. The availability of large, well-characterized populations of cases and controls are critical to the success of these efforts. A functional variant (R620W) of the intracellular protein tyrosine phosphatase N22 (PTPN22) has now been conclusively shown to confer approximately two-fold risk for seropositive RA as well as several other autoimmune disorders. PTPN22 appears to act primarily by setting thresholds for T-cell receptor signaling, and the current data suggest that the PTPN22 620W allele is likely to be a general risk factor for the development of humoral autoimmunity. PTPN22 is expressed widely in hematopoietic cells, but other than in T cells, its role is unknown. These results provide strong evidence for the longstanding hypothesis that common genes underlie different autoimmune phenotypes and emphasize that finding genes of only moderate risk can provide important insights into disease pathogenesis.
16371767 Acute coronary syndrome after infliximab infusion. 2006 Jan The TNFalpha inhibitor infliximab is widely used in the treatment of rheumatoid arthritis and Crohn disease. Mild infusion reactions consisting of low-grade fever, headache, nausea, and fatigue are common, but we describe for the first time the occurrence of an acute coronary syndrome during infliximab administration. This case alerts infusion centers to consider the possibility that chest pain and dyspnea during infliximab infusion can represent a myocardial infarction, even in younger patients without a history of cardiac disease.
17178671 Application of flow cytometry in detection of red-cell-bound IgG in Coombs-negative AIHA. 2006 Aug Coombs negative autoimmune hemolytic anemia (AIHA) is characterized by laboratory evidence of in vivo hemolysis along with a negative direct antiglobulin test (DAT) performed by conventional tube technique (CTT) in clinically suspected AIHA patients. The sensitive gel test (GT) and flow cytometry (FC) can effectively diagnose such patients where CTT does not detect low level of red cell autoantibodies. We investigated the use of FC in the serological evaluation of CTT DAT negative AIHA and its comparison with GT DAT. Of the 50 patients with suspected AIHA, CTT DAT was negative in 5 patients (Coombs negative AIHA). GT DAT could detect red cell autoantibodies in 4 of these 5 patients. Monospecific GT DAT showed IgG and/or C3d as the responsible autoantibody. FC was considered as reactive when MFI was >3.6 (mean of 20 healthy negative volunteers +2SD). FC was reactive in all five Coombs negative AIHA patients. The mean MFI in five known CTT DAT positive samples taken for comparison was significantly higher compared to 5 DAT negative AIHA (18.3 +/- 7.78 vs. 7.88 +/- 1.35, p < 0.05). There was poor correlation between strength of GT DAT and MFI by FC. We conclude that FC is more sensitive test than the CTT and helps in the serological diagnosis of Coombs negative AIHA. However, in resource poor settings, GT DAT can be a good alternative to FC.
16177927 Prognostic significance of CD40 expression in malignant lymphoma developing in rheumatoid 2005 Dec PURPOSE: CD40, a member of tumor necrosis factor receptor superfamily, is expressed in synovial fluid B cells in rheumatoid arthritis (RA) and is postulated to contribute to RA progression. In this study, prognostic significance of CD40 expression was analyzed in B cell lymphoproliferative disorders (LPD) developing in RA. METHOD: CD40 expression was immunohistochemically examined in 35 cases of B-cell LPD developing in RA and in 32 of sporadic B-cell LPD as control. CD40 expression at mRNA level evaluated by quantitative reverse transcription-PCR and at protein level evaluated by immunohistochemistry correlated. RESULTS: Frequency of diffuse large B-cell lymphoma (DLBCL) in RA- and sporadic-LPD was 71.4 and 59.3%, respectively. CD40 positive rate in RA-LPD (62.9%) was significantly higher than that in sporadic LPD (37.5%) (P = 0.015). Interval between onset of RA and LPD development was shorter in CD40 positive cases than in negative cases (median 120 and 204 months, respectively) (P < 0.07). Five-year survival rate in CD40 positive DLBCL cases (75%) was significantly better than that in negative cases (25%) (P < 0.05). CONCLUSION: RA-LPD is characterized by the higher frequency of CD40 expression compared to sporadic LPD and CD40 positive cases which showed more favorable prognosis than those without CD40 expression.
15949333 [Serum levels of several chemokines in patients with rheumatoid arthritis]. 2005 Mar 2 OBJECTIVE: To explore the role of several chemokines in rheumatoid arthritis (RA) and their clinical significance. METHOD: ELISA was used to detect the serum levels of interleukin (IL)-8, interferon-gamma inducible protein (IP)-10, and RANTES in 58 active RA patients, 29 clinically remissive RA patients, 21 osteoarthritis (OA) patients, and 30 healthy volunteers. Clinical data of these patients were compared between different groups. RESULTS: The serum levels of IL-8, IP-10 and RANTES in the active RA patients were significantly higher than those of the healthy controls and OA patients. The serum level of IP-10 of the active patients was higher than that of the clinically remissive patients. The index IL-8/IP-10 x RANTES/IP-10 of the active patients was higher than that of the healthy controls (P = 0.01). The serum RANTES level was positively correlated with erythrocyte sedimentation rate, C-reactive protein, platelet count, and numbers of swollen joints, and was negatively correlated with the hemoglobin level. The serum level of IP-10 was negatively correlated with X-ray image grade of hand and wrist joints. CONCLUSION: The serum levels of IL-8, IP-10 and RANTES significantly increase in active RA. The level of RANTES may be a useful additional marker for disease activity and the level of IP-10 can be used as an index of prognosis.
16483568 Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. 2006 Mar 8 Stem cell factor (SCF), the ligand of the c-Kit receptor, is expressed by various structural and inflammatory cells in the airways. Binding of SCF to c-Kit leads to activation of multiple pathways, including phosphatidyl-inositol-3 (PI3)-kinase, phospholipase C (PLC)-gamma, Src kinase, Janus kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) and mitogen activated protein (MAP) kinase pathways. SCF is an important growth factor for mast cells, promoting their generation from CD34+ progenitor cells. In vitro, SCF induces mast cells survival, adhesion to extracellular matrix and degranulation, leading to expression and release of histamine, pro-inflammatory cytokines and chemokines. SCF also induces eosinophil adhesion and activation. SCF is upregulated in inflammatory conditions both in vitro and in vivo, in human and mice. Inhibition of the SCF/c-Kit pathway leads to significant decrease of histamine levels, mast cells and eosinophil infiltration, interleukin (IL)-4 production and airway hyperresponsiveness in vivo. Taken together, these data suggest that SCF/c-Kit may be a potential therapeutic target for the control of mast cell and eosinophil number and activation in inflammatory diseases.
16960897 Prevalence of antiphospholipid antibodies in Chilean patients with rheumatoid arthritis. 2006 Antiphospholipid (aPL) antibodies found in patients with autoimmune diseases are also detected in those with inflammatory diseases. The purpose of this study was to examine the prevalence of these antibodies in patients with rheumatoid arthritis (RA), and to evaluate the association of these antibodies with thrombosis and/or other clinical characteristics of this inflammatory disorder. Eighty-four patients with RA and 82 normal controls were studied. Anticardiolipin (aCL), anti-beta(2) glycoprotein I (anti-beta(2)GPI), and antiprothrombin (aPT) antibodies and the lupus anticoagulant (LA) activity were determined. Seven out of 84 (8.3%) patients were positive for aCL, six out of 84 (7.2%) for anti-beta(2)GPI, and six out of 84 (7.2%) for aPT, while in controls the overall prevalence of aPL antibodies was 3.6% (3 out of 82). All patients and controls were LA negative. There was no correlation between the presence of aPL with thrombosis and/or other clinical features of the antiphospholipid syndrome. We found aPL antibodies in 19.1% (16 out of 84) of the patients with rheumatoid arthritis and this prevalence was statistically higher than in normal controls (P<0.003). In this study, the presence of aPL antibodies was not associated with the development of thrombosis and/or thrombocytopenia. Whether the presence of aPL antibodies implies an increased risk for thrombosis and atherosclerosis in these patients should be studied further.
16146738 Beneficial autoimmunity participates in the regulation of rheumatoid arthritis. 2006 Jan 1 Antigen specific T cells and B cells recognize their target determinants by antigen specific receptors that are being rearranged in a random manner. These cells then undergo negative and positive selection processes that limit, albeit not eliminate, the escape of self-reactive T and B cells capable of eliciting autoimmune responses. The above processes are referred to as "central selection", and their outcome is the "central tolerance". Auto-reactive T and B cells escaping central tolerance are then subjected to peripheral mechanisms that restrain their auto-aggressive behavior. Different types of regulatory T cells are key players in maintaining actively induced peripheral tolerance. In patients suffering from various autoimmune disorders autoreactive T and/or B cells that escaped central tolerance also circumvented regulatory T cells that could, potentially, eradicate their pathogenicity in the periphery. We have found an additional regulatory mechanism that restrains the harmful activity of these cells at that time. It includes autoimmune B cells that produce neutralizing autoantibodies against numerous inflammatory mediators, mostly cytokines and chemokines, which participate in destructive autoimmunity. These autoantibodies restrain the harmful consequences of inflammatory autoimmune conditions such as in rheumatoid arthritis. Interestingly, this antibody production is elicited during autoimmune diseases, and to a much lesser extent during local inflammation. The specificity of this response is highly restricted to determinants with minimal cross reactivity to other known gene products. Thus, the immune system allows selective breakdown of tolerance in autoimmune conditions. The findings that this beneficial response is turned on by the autoimmune condition, and then regulated by its progression further imply for the existence of a programmed regulatory response of "beneficial autoimmunity". In the current review we describe how this mechanism was discovered in experimental models of rheumatoid arthritis and multiple sclerosis, demonstrate its importance in the natural regulation of these diseases, and finally explore its relevance to human diseases.
15597212 Mini-open approach combined with percutaneous transarticular screw fixation for C1-C2 fusi 2005 Jan This paper describes a limited exposure for posterior C1-C2 arthrodesis aided by percutaneous transarticular fixation. The purpose of this study was to report the fusion rate using the aforementioned method. Fifty-seven patients (54 females and three males) with C1-C2 instability due to rheumatoid disease constituted the material of this study. The exposure was restricted to C0-C3 levels. The drilling and insertion of the screws was done through two mini stab wounds. A special sleeve and screwdriver were developed to facilitate this step. An autogenous iliac bone graft was fixed between the decorticated posterior arch of the atlas and the lamina of the axis vertebra. The mean of the atlantodental interval decreased from 8.5 mm (SD 2.3 mm) to 2.6 mm (SD 0.6 mm) at the immediate postoperative periods and reached 2.7 mm (SD 0.7 mm) after a mean follow-up of 30.4 months (SD 5.6 months). Malposition of the screws was observed in two patients and warranted a second operation in one. Fusion was evident in 98% of the cases. Percutaneous insertion of the screws in posterior C1-C2 transarticular fixation reduces the size of the exposure and the surgical trauma to the cervical segments below the fixation.
15811282 [Applications of monoclonal antibodies and biotechnology products in the treatment of chro 2005 Mar In recent years we have noticed the arrival of biological drugs for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD), psoriasis, and other chronic inflammatory diseases. Those drugs are produced with biotechnology methods and are defined as biologicals because of they work on the immune system. Different cellular groups and inflammation mediators participate in the inflammatory process, all of them susceptible of a therapeutic approach; they are so-called biological targets. Inhibition of TNF and interleukina 1 (IL-1) has proven effective for the control of inflammation in diseases as RA or CD. At present we have two types of inhibitors of TNF, specific monoclonal antibodies (infliximab, adalimumab) and cellular receptors (etanercept) and an IL-1 inhibitor (anakinra). The use of TNF inhibitors has given rise to a substantial change in the treatment of RA and CD because of its effectiveness. Together with this beneficial effect, an increase of infections (some of them severe) has occurred, especially tuberculosis. Other side effects that can be considered infrequent include demyelinization, heart failure, blood dyscrasias and lymphomas, which means that a thorough knowledge of these drugs is necessary for their use. Other potential biological drugs still in investigational phase are mentioned.
16632481 Inhibitory characteristics of citrullinated telopeptides of type I and II collagens for au 2006 Nov OBJECTIVE: To study how soluble citrullinated telopeptides of type I and II collagens inhibit the binding of autoantibodies to the respective antigens immobilized onto solid phase, and to use modifications of previous methods to re-analyse rheumatoid arthritis (RA) and control serum samples. METHODS: Autoantibody binding was inhibited with normal or citrullinated carboxytelopeptides using enzyme-linked immunosorbent assay (ELISA) methods. Serum samples were available from 120 patients with RA and 81 controls. RESULTS: Autoantibodies that bind normal C-telopeptides were not inhibited with soluble normal or citrullinated telopeptides. However, the antibodies that bind only citrullinated telopeptides could be inhibited with corresponding citrullinated telopeptides. Thus, it is not necessary to study the binding of autoantibodies to normal collagens if the specificity of their binding is assessed by immunological inhibition. For type I telopeptide, there are two arginines, the latter of which, when citrullinated, is important for binding. For type II telopeptide, there is one arginine, which is important when citrullinated. The other amino acids, e.g. the last alanine, have only a slight effect on binding. These improved methods differentiate better between RA patients, who have specific citrullinated autoantibodies, and controls than previous ELISA methods. CONCLUSIONS: Based on inhibition assay, it is possible to measure the autoantibodies binding specifically to citrullinated telopeptides of type I and II collagens. When only one assay is involved, variance is decreased and the overall performance is easier than before.
16799778 Anti-tumour necrosis factor-alpha therapy over conventional therapy improves endothelial f 2006 Oct Rheumatoid arthritis (RA) is associated with cardiovascular morbidity and mortality and inflammation contributes to related endothelial dysfunction. We aimed to investigate the effect of anti-TNFalpha therapy on endothelial function in subjects with rheumatoid arthritis. We measured flow-mediated (FMD) and GTN-mediated dilation of the brachial artery before and following 36 weeks of anti-TNFalpha therapy in nine RA patients and in a group of RA patients on conventional therapy. Thirty-six weeks of anti-TNFalpha therapy improved FMD relative to those on conventional therapy (8.65 +/- 1.50 vs. 1.70 +/- 1.36%, P = 0.02). No significant changes in GTN responses were evident. Significant improvements in tender (P = 0.03) and swollen (P = 0.02) joint counts, patients' global self-assessment (P = 0.01) and DAS-28 scores (P = 0.04) were observed in the anti-TNFalpha treated group. The addition of anti-TNFalpha treatment to conventional therapy, in those with severe RA, reduces inflammatory symptoms and improves endothelial function, potentially lowering future atherosclerotic risk.
15642148 Mast cells in inflammatory arthritis. 2005 Mast cells are present in limited numbers in normal human synovium, but in rheumatoid arthritis and other inflammatory joint diseases this population can expand to constitute 5% or more of all synovial cells. Recent investigations in a murine model have demonstrated that mast cells can have a critical role in the generation of inflammation within the joint. This finding highlights the results of more than 20 years of research indicating that mast cells are frequent participants in non-allergic immune responses as well as in allergy. Equipped with a diversity of surface receptors and effector capabilities, mast cells are sentinels of the immune system, detecting and delivering a first response to invading bacteria and other insults. Accumulating within inflamed tissues, mast cells produce cytokines and other mediators that may contribute vitally to ongoing inflammation. Here we review some of the non-allergic functions of mast cells and focus on the potential role of these cells in murine and human inflammatory arthritis.
16431306 Gastrointestinal tolerability of lumiracoxib in patients with osteoarthritis and rheumatoi 2006 Jan BACKGROUND & AIMS: The aim of this study was to evaluate the gastrointestinal safety of lumiracoxib, a novel selective cyclooxygenase-2 inhibitor. METHODS: Results from 15 Phase II and III randomized studies of lumiracoxib in osteoarthritis and rheumatoid arthritis were pooled. Patients received lumiracoxib (200/400 mg/day), celecoxib (200/400 mg/day), rofecoxib (25 mg once daily), diclofenac (75 mg twice daily), ibuprofen (800 mg 3 times daily), naproxen (500 mg twice daily), or placebo. Outcome measures included the incidence of definite or probable ulcer complications (perforations, obstructions, or bleedings as confirmed by an adjudication committee) and symptomatic upper gastrointestinal ulcers, the incidence of prespecified gastrointestinal adverse events, and the discontinuation rate caused by adverse events. All suspected ulcer complications in these 15 studies were adjudicated prospectively. Data from 2 endoscopic studies were pooled separately to assess the cumulative incidence of gastroduodenal ulcers >or=3 mm in diameter. RESULTS: Symptomatic upper gastrointestinal ulcers and ulcer complications were reduced nearly 10-fold with lumiracoxib (1.7 events per 100 patient-years [95% confidence interval, 1.09-2.39]) compared with nonselective nonsteroidal anti-inflammatory drugs (13.7 events per 100 patient-years [95% confidence interval, 9.47-18.82]). Symptomatic ulcer frequency was markedly lower with lumiracoxib (0.4%) than with nonselective nonsteroidal anti-inflammatory drugs (2.5%). Discontinuation rates due to gastrointestinal adverse events were higher for nonselective nonsteroidal anti-inflammatory drugs (8.4%) than for lumiracoxib (3.3%). In the endoscopy analysis, the cumulative frequency of ulcers >or=3 mm in diameter was reduced by >70% for lumiracoxib versus ibuprofen. CONCLUSIONS: Lumiracoxib exhibited a gastrointestinal safety profile superior to nonselective nonsteroidal anti-inflammatory drugs.