Objective. To estimate the incidence rates of serious and nonserious infections in patients with rheumatoid arthritis (RA) who start treatment with a biologic agent, and to compare these rates with those in patients with RA who receive conventional treatment.Methods. Patients enrolled in the German biologics register between May 2001 and September 2003 were included. Treating rheumatologists assessed adverse events and serious adverse events. All adverse events and serious adverse events experienced within 12 months after study entry were analyzed. Propensity score methods were applied to estimate which part of a rate increase was likely to be attributable to differences in patient characteristics.Results. Data were available for 512 patients receiving etanercept, 346 patients receiving infliximab, 70 patients receiving anakinra, and 601 control patients treated with disease-modifying antirheumatic drugs.The total number of adverse events per 100 patientyears was 22.6 (95% confidence interval [95% CI] 18.7-27.2) among patients receiving etanercept, 28.3 (95% CI 23.1-34.7) among patients receiving infliximab, and 6.8 (95% CI 5.0-9.4) among controls (P < 0.0001). Significant differences in the rate of serious adverse events were also observed. For patients receiving etanercept, those receiving infliximab, and controls, the total numbers of serious adverse events per 100 patient-years were 6.4 (95% CI 4.5-9.1), 6.2 (95% CI 4.0-9.5), and 2.3 (95% CI 1.3-3.9), respectively (P ؍ 0.0016). After adjusting for differences in the case patient mix, the relative risks of serious adverse events were 2.2 (95% CI 0.9-5.4) for patients receiving etanercept and 2.1 (95% CI 0.8-5.5) for patients receiving infliximab, compared with controls.Conclusion. Patients treated with biologic agents have a higher a priori risk of infection. However, our data suggest that this risk is increased by treatment with tumor necrosis factor inhibitors.
ObjectivesTo investigate the impact of disease activity, the course of the disease, its treatment over time, comorbidities and traditional risk factors on survival.MethodsData of the German biologics register RABBIT were used. Cox regression was applied to investigate the impact of time-varying covariates (disease activity as measured by the DAS28, functional capacity, treatment with glucocorticoids, biologic or synthetic disease modifying antirheumatic drugs (DMARDs)) on mortality after adjustment for age, sex, comorbid conditions and smoking.ResultsDuring 31 378 patient-years of follow-up, 463 of 8908 patients died (standardised mortality ratio: 1.49 (95% CI 1.36 to 1.63)). Patients with persistent, highly active disease (mean DAS28 > 5.1) had a significantly higher mortality risk (adjusted HR (HRadj)=2.43; (95% CI 1.64 to 3.61)) than patients with persistently low disease activity (mean DAS28 < 3.2). Poor function and treatment with glucocorticoids > 5 mg/d was significantly associated with an increased mortality, independent of disease activity. Significantly lower mortality was observed in patients treated with tumour necrosis factor α (TNFα) inhibitors (HRadj=0.64 (95% CI 0.50 to 0.81), rituximab (HRadj=0.57 (95% CI 0.39 to 0.84), or other biologics (HRadj=0.64 (95% CI 0.42 to 0.99), compared to those receiving methotrexate. To account for treatment termination in patients at risk, an HRadj for patients ever exposed to TNFα inhibitors or rituximab was calculated. This resulted in an HRadj of 0.77 (95% CI 0.60 to 0.97).ConclusionsPatients with long-standing high disease activity are at substantially increased risk of mortality. Effective control of disease activity decreases mortality. TNFα inhibitors and rituximab seem to be superior to conventional DMARDs in reducing this risk.
Objective. To determine the hazard risk of developing or worsening heart failure in rheumatoid arthritis (RA) patients treated with tumor necrosis factor ␣ (TNF␣) inhibitors.Methods. RA patients ages 18-75 years who started treatment with infliximab, etanercept, or adalimumab (n ؍ 2,757), or conventional disease-modifying antirheumatic drugs (controls; n ؍ 1,491) at the time of enrollment in a German biologics register were studied. Cox proportional hazards models were applied to investigate the influence of disease-related and treatmentspecific risk factors on the incidence or worsening of heart failure.Results. The 3-year incidence rates of heart failure in patients with and patients without cardiovascular disease at the start of treatment were 2.2% and 0.4%, respectively. After adjustment for traditional cardiovascular risk factors, an increased risk of developing heart failure was found in patients who had a higher 28-joint Disease Activity Score at followup (hazard ratio Conclusion. The findings of this study indicate that TNF␣ inhibitor treatment that effectively reduces the inflammatory activity of RA is more likely to be beneficial than harmful with regard to the risk of heart failure, especially if there is no concomitant therapy with glucocorticoids or cyclooxygenase 2 inhibitors. Furthermore, the data suggest that TNF␣ inhibition does not increase the risk of worsening of prevalent heart failure.[
The adhesion of K21a, K26, K36, and K50 capsulated Klebsiella strains to ileocecal (HCT-8) and bladder (T24) epithelial cell lines was significantly lower than that of their corresponding spontaneous noncapsulated variants K21a/3, K26/1, K36/3, and K50/3, respectively. Internalization of the bacteria by both epithelial cell lines was also significantly reduced. Similarly, a capsule-switched derivative, K2(K36), that exhibited a morphologically larger K36 capsule and formed more capsular material invaded the ileocecal epithelial cell line poorly compared to the corresponding K2 parent strain. None of the capsulated strains exhibited significant mannose-sensitive type 1 fimbriae, whereas two of the noncapsulated variants K21a/3 and K50/3 exhibited potent mannose-sensitive hemagglutinating activity. Although hemagglutinating activity that could be attributed to mannose-resistant Klebsiella type 3 fimbriae was weak in all strains, in several cases the encapsulated parent strains exhibited lower titers than their corresponding noncapsulated variants. Although the level of adhesion to the ileocecal cells is not different from adhesion to bladder cells, bacterial internalization by bladder cells was significantly lower than internalization by ileocecal cells, suggesting that bladder cells lack components required for the internalization of Klebsiella.Klebsiella pneumoniae is an opportunistic pathogen involved in outbreaks of nosocomial infections, such as bacteremia and sepsis, mainly in immunocompromised individuals (36). Due to the emergence of multidrug resistance among Klebsiella strains, the search for new approaches for the prevention or treatment of Klebsiella infections is now under intensive investigation (34). To be successful, these efforts will require a better understanding of the infectious process.Multiple Klebsiella components (e.g., fimbriae, siderophores, O antigens, and capsular antigens) have been considered to be potential virulence factors (34). Of these factors, capsular antigens are probably considered the major determinants of pathogenicity (4,9,17,21). As a consequence, new therapeutic approaches have been targeted against the capsule. A polysaccharide-based vaccine has been tested (5). Based on the structural variability of its capsular polysaccharides (CPS), Klebsiella has been classified into 77 serotypes (27), which differ markedly in pathogenicity potential and epidemiological relevance (3,28,29,35). Epidemiological findings showed that over 70% of all cases of Klebsiella bacteremia were caused by only 25 of the 77 different serotypes (6).
This study examines the contribution of transforming growth factor 13
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