Rheumatoid Arthritis: Rubbert A

Cohen SB, Rubbert A. · St Paul University Medical Center, Dallas, Texas, USA. · Rheumatology (Oxford). · Pubmed #12817094 links to  free full text

Abstract: The recombinant interleukin-1 receptor antagonist, anakinra (Kineret; Amgen Inc., Thousand Oaks, CA), has been approved by the US Food and Drug Administration and the European Commission for the treatment of patients with active rheumatoid arthritis (RA). Approval was granted following the extensive evaluation of anakinra in five pivotal clinical trials that assessed its efficacy and safety in RA patients. These studies have indicated that anakinra has a favourable risk-benefit profile, producing rapid and sustained reductions in the signs and symptoms of RA, as measured by improvements in the American College of Rheumatology response criteria, particularly in patient-reported indicators of function and disability. The data from these trials suggest that anakinra is likely to provide a useful therapeutic option to clinicians and also meet the treatment expectations of patients with RA; however, further studies are underway to investigate additional benefits that anakinra may offer, particularly in patients with existing co-morbidities.

Rubbert A, Diehl V. · Medizinische Klinik I, Universität Köln, Joseph-Stelzmann Strasse 9, 50924 Köln. · Internist (Berl). · Pubmed #11449631 No free full text.

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Le Loët X, Nordström D, Rodriguez M, Rubbert A, Sarzi-Puttini P, Wouters JM, Woolley JM, Wright N, Lawrence C, Appleton B. · Rouen University Hospital, Rouen, France. · J Rheumatol. · Pubmed #18634163 No free full text.

Abstract: OBJECTIVE: To assess changes in functional status in patients with rheumatoid arthritis (RA) receiving the interleukin-1 receptor antagonist anakinra in addition to a disease modifying antirheumatic drug (DMARD). METHODS: In this large, multicenter, open-label, single-arm study, adult patients with RA receiving methotrexate, sulfasalazine, or hydroxychloroquine for > or = 3 months were given anakinra 100 mg once daily for up to 36 weeks. The primary objective was to evaluate changes from baseline to week 36 in the Health Assessment Questionnaire (HAQ) disability index and subscales. Changes in the 28-joint Disease Activity Score (DAS28), proportion of patients meeting European League Against Rheumatism (EULAR) response criteria, and the safety of each combination regimen were also assessed. RESULTS: A total of 1207 patients were enrolled, received > or = 1 dose of anakinra, and were included in the efficacy and safety analyses. A statistically significant change in the HAQ disability index was observed (p = 0.0001); no significant differences were seen among the 3 DMARD groups. A clinically meaningful improvement in HAQ (> 0.22) was observed in 51% of patients. Mean improvement in DAS28 was 1.5 (p < 0.0001), and 64% of patients achieved a good or moderate EULAR response score. Injection site reaction was the most frequently (62%) reported adverse event. The incidence of infections (24%), most commonly respiratory infection, was similar across treatment groups. No notable changes were observed in laboratory findings and vital signs. CONCLUSION: These findings indicate that anakinra 100 mg/day in combination with DMARD therapy safely improved functional status in patients with active RA.

Taubert D, Lazar A, Grimberg G, Jung N, Rubbert A, Delank KS, Perniok A, Erdmann E, Schömig E. · Department of Pharmacology, University Hospital of Cologne, D-50931 Cologne, Germany. · J Rheumatol. · Pubmed #17086603 No free full text.

Abstract: 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.

Hartmann P, Franzen C, Rubbert A, Rogowski J, Kailus M, Salzberger B. · Department of Internal Medicine I, Division of Infectious Diseases, University of Regensburg, 93042 Regenburg, Germany. · Immunobiology. · Pubmed #15804045 No free full text.

Abstract: Clinical trials evaluating tumor necrosis factor alpha (TNF-alpha) binding agents in patients with rheumatoid arthritis (RA) have demonstrated significant efficacy in reducing symptoms of disease and slowing radiographic progression. However, infectious complications are the most severe and common adverse effects of anti-TNF therapy. The functional capacities of neutrophils (PMNs) as the first line of defense in bacterial and fungal infections are enhanced by soluble TNF as a potent neutrophil primer. The aim of this study was to assess the influence of in vivo TNF blockade on oxygen burst (OB) and phagocytosis of human neutrophils. PMNs were derived from 20 patients with RA on anti-TNF-alpha therapy and 13 patients using conventional DMARDs. By flow cytometry we measured OB upon stimulation with Escherichia coli and N-formyl-1-methionyl-1-leucyl-phenylalanine (FMLP) with and without priming with granulocyte-colony stimulating factor (G-CSF) and/or TNF-alpha using dihydrorhodamine (DHR) 123. Phagocytosis of fluorescein isothiocyanate (FITC)-labeled E. coli was also assessed by flow cytometry. Thirty-three healthy volunteers served as controls. Upon stimulation with E. coli and FMLP, there was no significant difference in OB between the two patient groups and healthy controls. Priming was effective in all groups. Phagocytosis of E. coli by PMNs was equally effective in controls and patients independent from the treatment regimen. These data show that OB, phagocytosis and responsiveness to priming with TNF and G-CSF of PMNs are not impaired in patients with RA treated with anti-TNF agents in comparison with patients on conventional DMARDs or healthy controls. Thus, the infectious complications observed in patients with TNF blockade cannot be explained by functional impairment of PMNs; however, the neutralization of TNF as a potent primer of neutrophil response may increase the susceptibility for infections in these patients.

Gründemann D, Harlfinger S, Golz S, Geerts A, Lazar A, Berkels R, Jung N, Rubbert A, Schömig E. · Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany. · Proc Natl Acad Sci U S A. · Pubmed #15795384 links to  free full text

Abstract: Variants of the SLC22A4 gene are associated with susceptibility to rheumatoid arthritis and Crohn's disease. SLC22A4 codes for an integral membrane protein, OCTN1, that has been presumed to carry organic cations like tetraethylammonium across the plasma membrane. Here, we show that the key substrate of this transporter is in fact ergothioneine (ET). Human OCTN1 was expressed in 293 cells. A substrate lead, stachydrine (alias proline betaine), was identified by liquid chromatography MS difference shading, a new substrate search strategy. Analysis of transport efficiency of stachydrine-related solutes, affinity, and Na+ dependence indicates that the physiological substrate is ET. Efficiency of transport of ET was as high as 195 microl per min per mg of protein. By contrast, the carnitine transporter OCTN2 from rat did not transport ET at all. Because ET is transported >100 times more efficiently than tetraethylammonium and carnitine, we propose the functional name ETT (ET transporter) instead of OCTN1. ET, all of which is absorbed from food, is an intracellular antioxidant with metal ion affinity. Its particular purpose is unresolved. Cells with expression of ETT accumulate ET to high levels and avidly retain it. By contrast, cells lacking ETT do not accumulate ET, because their plasma membrane is virtually impermeable for this compound. The real-time PCR expression profile of human ETT, with strong expression in CD71+ cells, is consistent with a pivotal function of ET in erythrocytes. Moreover, prominent expression of ETT in monocytes and SLC22A4 polymorphism associations suggest a protective role of ET in chronic inflammatory disorders.

Rubbert A. · Medizin Klinik I der Universität zu Köln. · MMW Fortschr Med. · Pubmed #12380139 No free full text.

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Owczarczyk K, Hellmann M, Fliedner G, Röhrs T, Maizus K, Passon D, Hallek M, Rubbert A. · No affiliation provided · Ann Rheum Dis. · Pubmed #18854518 No free full text.

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Jung N, Owczarczyk K, Hellmann M, Lehmann C, Fätkenheuer G, Hallek M, Rubbert A. · No affiliation provided · Rheumatology (Oxford). · Pubmed #18417524 No free full text.

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Hellmann M, Jung N, Owczarczyk K, Hallek M, Rubbert A. · No affiliation provided · Rheumatology (Oxford). · Pubmed #18411212 No free full text.

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Hirche D, Rubbert A, Lunau L, Krieg T, Eming SA. · No affiliation provided · Br J Dermatol. · Pubmed #15888173 No free full text.

This publication has no abstract.