Rheumatoid Arthritis: Wagner C

Visvanathan S, Wagner C, Rojas J, Kay J, Dasgupta B, Matteson EL, Mack M, Baker DG, Rahman MU. · Centocor Research and Development, Inc., Malvern, Pennsylvania, USA. · J Rheumatol. · Pubmed #19487269 No free full text.

Abstract: OBJECTIVE: To assess the effect of golimumab (human monoclonal antibody to tumor necrosis factor-alpha) plus methotrexate (MTX) on selected inflammatory biomarkers, and to determine if these effects predict clinical response in rheumatoid arthritis (RA). METHODS: Sera from adults with active RA despite MTX therapy, who received subcutaneous injections of placebo + MTX (MTX alone, n = 34) or golimumab 50 or 100 mg every 2 or 4 weeks + MTX (n = 137), were analyzed for levels of C-reactive protein (CRP), serum amyloid A (SAA), interleukin 18 (IL-18), E-selectin, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). RESULTS: Golimumab + MTX treatment significantly decreased serum CRP, SAA, IL-18, E-selectin, TIMP-1, and MMP-9 levels (median percent changes of -4.1% to -74.3% across treatment groups) versus MTX alone (-5.8% to 9.7%) when first measured at Week 4; decreases were sustained through Week 16. Larger magnitudes of decrease in all biomarkers were observed for clinical responders versus nonresponders. For golimumab + MTX, regression analyses including all biomarkers and select clinical measures showed that reductions in levels of several markers (SAA, E-selectin, MMP-9) as early as Week 4 correlated significantly with improvement in swollen joint count (SJC) at Week 16, as did reductions in E-selectin with improvement in tender joint count at Week 16. After accounting for the biomarkers, however, treatment group was no longer significant for SJC. CONCLUSION: Significant decreases in several inflammatory biomarkers were associated with golimumab + MTX therapy. Decreases in serum levels of SAA, E-selectin, and MMP-9 at Week 4 may be useful in predicting clinical response at Week 16.

Kay J, Matteson EL, Dasgupta B, Nash P, Durez P, Hall S, Hsia EC, Han J, Wagner C, Xu Z, Visvanathan S, Rahman MU. · Rheumatology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114, USA. · Arthritis Rheum. · Pubmed #18383539 links to  free full text

Abstract: OBJECTIVE: To assess the efficacy, safety, and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX). METHODS: Patients were randomly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48. Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo. RESULTS: The primary end point was attained. Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37% of patients in the placebo plus MTX group (P=0.010). In addition, 79% of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response (P<0.001 versus placebo). Through week 20 (after which patients receiving placebo were switched to active infliximab therapy), serious adverse events were reported in 9% of patients in the combined golimumab groups and in 6% of patients in the placebo group. CONCLUSION: Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX.

Toedter G, Hayden K, Wagner C, Brodmerkel C. · Department of Clinical Pathology and Experimental Medicine, Centocor R&D, 145 King of Prussia Road, Radnor, PA 19087, USA. · Clin Vaccine Immunol. · Pubmed #18003817 links to  free full text

Abstract: The accurate detection and quantitation of cytokines in serum are important in the study of disease mechanisms, pathogenesis, and treatment. Serum cytokines can reflect processes that are occurring at the cellular or tissue level and thus provide a means of indirectly monitoring these processes. Multiplex detection of cytokines allows the simultaneous measurement of multiple cytokines in a sample, increasing the efficiency of measuring the cytokines while reducing the serum sample volumes required for the testing. Two commercially available multiplex platforms were evaluated (Pierce SearchLight and Meso Scale Discovery), using multiplexes capable of simultaneously detecting eight cytokines. The cytokines analyzed in this study were gamma interferon, vascular endothelial growth factor, tumor necrosis factor alpha, interleukin-6 (IL-6), macrophage inflammatory protein 1beta, monocyte chemoattractant protein 1, IL-12p40, and IL-4. The range of quantitation of the platforms, the recovery of spiked cytokines, and the detection of the cytokines in serum samples from subjects with ulcerative colitis, Crohn's disease, rheumatoid arthritis, and psoriasis were examined. The findings showed that the detection of the cytokines was highly dependent upon the platform, with the consistency of the detection of cytokines across platforms being dependent upon the cytokine being analyzed. A careful examination of platform assay performance must be made prior to utilizing multiplex platforms in a study. While some cytokines will give similar patterns of results across platforms, others will be highly variable. The use of the same platform within a study or across studies where data will be compared is advised.

Visvanathan S, Marini JC, Smolen JS, Clair EW, Pritchard C, Shergy W, Pendley C, Baker D, Bala M, Gathany T, Han J, Wagner C. · Centocor, Inc., Malvern, Pennsylvania, USA. · J Rheumatol. · Pubmed #17552048 No free full text.

Abstract: OBJECTIVE: To determine if changes in biomarkers of inflammation and bone turnover in response to treatment with infliximab plus methotrexate (MTX) versus MTX alone are associated with improvement in clinical measures of signs, symptoms, and structural damage in early rheumatoid arthritis. METHODS: Sera were collected from patients in the ASPIRE study who received 3 mg/kg (n = 48) or 6 mg/kg infliximab plus MTX (n = 55), or MTX alone (n = 41). Several baseline biomarker levels correlated with changes in median percentage of American College of Rheumatology improvement (ACR-N), 50% improvement in ACR response (ACR50), and van der Heijde-modified Sharp score (vdHSS) at Week 54. RESULTS: Infliximab plus MTX treatment resulted in more rapid decreases in levels of matrix metalloproteinase-3 (MMP-3), intercellular cell adhesion molecule-1, interleukin 8 (IL-8), and tumor necrosis factor-a than treatment with MTX alone. Baseline levels and decreases from baseline to Weeks 6 and 54 in MMP-3 correlated with improvement in ACR-N response at Week 54. An increase in IL-8 levels from baseline to Week 54 correlated with worsening in vdHSS at Week 54 in the MTX-alone group. Regression analysis of markers at baseline showed that MMP-3 was the only variable associated with ACR50 response and less worsening in vdHSS at Week 54. CONCLUSION: Treatment with infliximab plus MTX resulted in a rapid decrease in inflammation markers. MMP-3 levels at different timepoints were consistently associated with clinical improvements at Week 54 in the infliximab plus MTX group, while increases in IL-8 levels correlated with a worsening in vdHSS at Week 54 in the MTX-alone group.

Rahman MU, Strusberg I, Geusens P, Berman A, Yocum D, Baker D, Wagner C, Han J, Westhovens R. · Centocor Research and Development, Inc, Malvern, PA, USA. · Ann Rheum Dis. · Pubmed #17392352 No free full text.

Abstract: OBJECTIVE: To determine the efficacy, safety and pharmacokinetics of infliximab dose escalation in patients with rheumatoid arthritis (RA) who had an inadequate response to 3 mg/kg infliximab treatment or whose disease flared after initially responding. METHODS: Patients with active RA, despite receiving methotrexate, received infliximab 3 mg/kg at weeks 0, 2, 6 and 14 in one of the three arms of the START trial. Beginning at week 22, patients had their infliximab dose increased in a double-blind fashion in increments of 1.5 mg/kg if the total tender and swollen joint count did not improve by at least 20% from baseline (lack of response) or the improvement at week 22 or later worsened by 50% or more (criterion for flare). RESULTS: Of the 329 evaluable patients, 100 (30.4%) patients required dose escalation at or after week 22 because of flare or lack of response. The majority of patients (>80%) who received up to three dose escalations showed >/=20% improvement in the total tender and swollen joint count after their last dose escalation. Patients who required dose escalations generally had lower preinfusion serum infliximab concentrations than those who did not require them. The incidences of adverse events and serious adverse events for the patients who received dose escalation(s) were similar to those of patients who did not receive dose escalation. CONCLUSION: Fewer than one-third of patients required a dose escalation. The majority of patients showed improvement after receiving increased doses of infliximab, without an increased risk of adverse events.

Walsh S, Turner CM, Toye A, Wagner C, Jaeger P, Laing C, Unwin R. · Department of Physiology, Royal Free and University College Medical School, Rowland Hill Street, London, UK. · Nephrol Dial Transplant. · Pubmed #17205967 links to  free full text

This publication has no abstract.

Visvanathan S, Wagner C, Smolen J, St Clair EW, Hegedus R, Baker D, Keenan G. · Centocor, Inc., Malvern, Pennsylvania 19355, USA. · Arthritis Rheum. · Pubmed #16948115 links to  free full text

Abstract: OBJECTIVE: To assess the occurrence of anticardiolipin antibodies (aCL) in patients with early rheumatoid arthritis (RA) receiving treatment with infliximab plus methotrexate (MTX) versus MTX alone. METHODS: The first 299 patients enrolled in the randomized, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial who had baseline (week 0) samples available for aCL testing were included in this study. Sera were collected at weeks 0, 30, and 54 from 110 patients taking infliximab 3 mg/kg plus MTX, 98 patients taking infliximab 6 mg/kg plus MTX, and 91 patients taking placebo plus MTX. IgG and IgM aCL were measured using an anticardiolipin assay. RESULTS: IgG and IgM aCL positivity at baseline was similar in all treatment groups. Most patients were negative for IgG aCL at baseline and remained so at the last followup evaluation. One percent (2 of 208) of patients who received infliximab plus MTX and were negative for IgG aCL at baseline were positive for IgG aCL at weeks 30 and 54. A slightly higher proportion of patients who received infliximab plus MTX and were negative for IgM aCL at baseline were positive for IgM aCL at weeks 30 and 54 (4.8% [10 of 208]) as compared with patients who received placebo plus MTX (1.1% [1 of 91]), but the difference was not significant. CONCLUSION: There was a low incidence of the development of aCL in patients with early RA who received infliximab in combination with MTX, and the difference was not significant compared with patients who received placebo plus MTX.

Iking-Konert C, Ostendorf B, Sander O, Jost M, Wagner C, Joosten L, Schneider M, Hänsch GM. · Centre for Rheumatology, Department of Endocrinology, Diabetology and Rheumatology, Heinrich-Heine-University Duesseldorf, Düsseldorf, Germany. · Ann Rheum Dis. · Pubmed #15778239 links to  free full text

Abstract: OBJECTIVES: To investigate infiltrated cells in the synovial fluid (SF) of inflamed joints of patients with rheumatoid arthritis (RA), with special reference to polymorphonuclear neutrophils (PMN) and their interaction with T cells. METHODS: Expression on PMN of activation associated receptors CD14, CD64, CD83, and major histocompatibility complex (MHC) class II was examined in the SF of 15 patients with RA, as were the infiltrated T cells. SF cytokines were determined by enzyme linked immunosorbent assay (ELISA). To mimic the in vivo situation, co-culture experiments were carried out using PMN and T cells of healthy donors. RESULTS: The SF contained activated T lymphocytes and abundant PMN. SF PMN expression of CD14 and CD64 was enhanced compared with peripheral blood. Of special interest was the observation that only the SF PMN expressed MHC class II antigens and CD83. Exposure to SF, which contained considerable amounts of cytokines (for example, interferon gamma (IFNgamma), tumour necrosis factor alpha, and interleukin 2), induced a similar receptor pattern on blood derived PMN of healthy donors. Furthermore, PMN acquired MHC class II and CD83 within 24 to 48 hours, when co-cultured with autologous T cells or T cell lines. This effect was also achieved by T cell supernatants, was dependent on protein synthesis, and could be inhibited by antibodies against IFNgamma. CONCLUSIONS: SF PMN from patients with RA undergo major alterations, including transdifferentiation to cells with dendritic-like characteristics, probably induced by T cell derived cytokines. Because MHC class II positive PMN are known to activate T cells, the mutual activation of PMN and T cells might contribute to the perpetuation of the local inflammatory process, and eventually to the destructive process in RA.

Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C. · Research and Development, Centocor, Inc., Malvern, Pennsylvania 19355-1307, USA. · J Pharmacol Exp Ther. · Pubmed #11961039 links to  free full text

Abstract: Two tumor necrosis factor (TNF) antagonists infliximab (a chimeric monoclonal antibody) and etanercept (a p75 TNF receptor/Fc fusion protein) have been approved for treatment of rheumatoid arthritis. However, these agents have shown different degrees of clinical benefit in controlled clinical trials in other TNF-mediated diseases such as Crohn's disease (CD) and psoriasis. We investigated whether structural differences between these two antagonists translate into different binding and functional characteristics. To study the binding of infliximab and etanercept to both the soluble and cell-surface transmembrane forms of TNF, a variety of in vitro binding and cell-based assays were performed. Binding assays using (125)I-labeled TNF showed that infliximab binds to both monomer and trimer forms of soluble TNF (sTNF), whereas etanercept binding is restricted to the trimer form. Infliximab formed stable complexes with sTNF, whereas etanercept formed relatively unstable complexes, resulting in release of dissociated TNF. KYM-1D4 cell killing assays and human umbilical vein endothelial cell activation assays demonstrated that TNF that had dissociated from etanercept was bioactive. Infliximab also formed more stable complexes with the transmembrane form of TNF expressed on transfected cells relative to analogous complexes formed with etanercept. Additionally, more infliximab molecules bound to the transmembrane TNF with higher avidity than etanercept. Although both infliximab and etanercept inhibited transmembrane TNF-mediated activation of human endothelial cells, infliximab was significantly more effective. The differences between infliximab and etanercept in their TNF binding characteristics may help explain their differential efficacy in CD and psoriasis clinical trials.

Mangge H, Liebmann P, Tanil H, Herrmann J, Wagner C, Gallistl S, Schauenstein K, Erwa W. · Department of Laboratory Medicine (Blocklabor III) and Pediatric Immunology/Rheumatology, University of Graz, School of Medicine, A-8036, Graz, Austria. · Clin Chim Acta. · Pubmed #10958875 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic disease requiring potential nephrotoxic therapy with nonsteroidal antiinflammatory drugs (NSAIDs) and disease modifying antirheumatic drugs (DMARDs). The rationale of our study was to examine the renal status of patients suffering from prolonged RA by means of plasma cystatin C, a new parameter of renal function. Fifty-six patients affected with RA for more than 5 years, and treated with NSAIDs for more than 50 months, were included in the study. Besides conventional markers of renal function (i.e. plasma creatinine, estimated glomerular filtration rate, creatinine clearance), we analysed plasma cystatin C by an automated, nephelometric immunoassay on a Behring nephelometer. Sixty percent of the RA patients exhibited elevated levels of plasma cystatin C, whereas only three out of 56 patients showed an elevated plasma creatinine, even though the creatinine clearance was decreased in 57% of these patients. Cystatin C exhibited a by far better correlation with creatinine clearance than plasma creatinine. In conclusion, patients with prolonged RA for more than 50 months, show a disturbed renal function despite normal plasma creatinine. Elevated cystatin C indicates such incipient renal disease, and is, not least because of a simple, well reproducible technique, more recommendable for screening purposes than tedious clearance determinations.