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Anti-Drug Antibodies, Drug Levels, Interleukin-6 and Soluble TNF Receptors in Rheumatoid Arthritis Patients during the First 6 Months of Treatment with Adalimumab or Infliximab: A Descriptive Cohort Study.

ABSTRACT: OBJECTIVES:With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-? -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs). METHODS:Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab. Samples were analyzed for levels of TNFi, interleukin (IL)-6, and soluble TNF-receptors 1 and -2 (sTNF-R1 and -2) and for presence of anti-TNFi Abs. Clinical and demographic data were recorded as well. RESULTS:During the initial 6 months treatment, DAS28(CRP) (Disease activity score in 28 joints using C-reactive protein) and levels of IL-6 and sTNF-R2 decreased significantly in patients without anti-TNFi Abs and in patients retaining detectable drug levels. The levels of other tested cytokines (TNF-?, TNF-?, IL-1ra, IL-1b, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, IL-17F, and IL-33) were generally below detection limits. Higher baseline levels of IL-6 associated with undetectable levels of TNFi at follow-up. Anti-TNFi Abs were associated with decreased drug levels, but no predictors for anti-TNFi Ab development could be found. CONCLUSION:The effect of treatment with TNFi on RA disease activity depends on levels of active drug, and by presence of anti-TNFi Abs. In patients who retain detectable drug levels, and in the absence of anti-TNFi Abs, clinical outcome is improved during treatment, and circulating levels of IL-6 and sTNF-R2 decrease. Baseline levels of IL-6 may predict depletion of TNFi and may identify patients at risk of treatment failure.

SUBMITTER: Eng GP

PROVIDER: S-EPMC5016088 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Anti-Drug Antibodies, Drug Levels, Interleukin-6 and Soluble TNF Receptors in Rheumatoid Arthritis Patients during the First 6 Months of Treatment with Adalimumab or Infliximab: A Descriptive Cohort Study.

Eng Grith Petersen GP Bouchelouche Pierre P Bartels Else Marie EM Bliddal Henning H Bendtzen Klaus K Stoltenberg Michael M

PloS one 20160908 9

<h4>Objectives</h4>With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs).<h4>Methods</h4>Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab. Samples were analyzed for leve ...[more]

PMID: 27606615

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Project description:Response to treatment of rheumatoid arthritis shows large inter-individual variability. This heterogeneity is observed with all the anti-rheumatic drugs, including the commonly used TNF inhibitors. It seems that drug-specific and target-specific factors lead individual patients to respond or not to a given drug, although this point has been challenged. The search of biomarkers distinguishing responders from non-responders has included shotgun proteomics of serum, as a previous study of response to infliximab, an anti-TNF antibody. Here, we have used the same study design and technology to search biomarkers of response to a different anti-TNF antibody, adalimumab, and we have compared the results obtained for the two anti-TNF drugs. Search of biomarkers of response to adalimumab included depletion of the most abundant serum proteins, 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) labeling, two-dimensional liquid chromatography fractionation and relative quantification with a hybrid Orbitrap mass spectrometer. With this approach, 264 proteins were identified in all the samples with at least 2 peptides and 95% confidence. Nine proteins showed differences between non-responders and responders (P < 0.05), representing putative biomarkers of response to adalimumab. These results were compared with the previous study of infliximab. Surprisingly, the non-responder/responder differences in the two studies were not correlated (rs = 0.07; P = 0.40). This overall independence with all the proteins showed two identifiable components. On one side, the putative biomarkers of response to either adalimumab or infliximab, which were not shared and showed an inverse correlation (rs = -0.69; P = 0.0023). On the other, eight proteins showing significant non-responder/responder differences in the analysis combining data of response to the two drugs. These results identify new putative biomarkers of response to treatment of rheumatoid arthritis and indicate that they are notably drug-specific.

Project description:INTRODUCTION: There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor ? (IL-18R?). In this study, we evaluated the levels and characteristics of soluble IL-18R? (sIL-18R?) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations. METHODS: The sIL-18R? complex was isolated from pooled human blood serum using an anti-IL-18R? monoclonal antibody affinity column. The purified sIL-18R? was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0. An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-?. Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18R? complex. RESULTS: The isolated sIL-18R? complex can be associated with IL-18 and the soluble form of the IL-18R? chain. The sIL-18R? complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-? production by the cells. The serum levels of sIL-18R? complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39). The serum level of sIL-18R? complex was not significantly different between RA and adult-onset Still's disease patients. The serum levels of IL-18, IL-13 and IFN-? in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls. ROC-AUC analysis of the serum concentration of sIL-18R? indicated that it was significantly diagnostic of RA. Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18R? in the sera of 29 RA patients 6 months after treatment. CONCLUSIONS: The sIL-18R? complex could be a potentially useful biomarker for the diagnosis of RA.

Project description:This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.

Project description:In 15 patients with rheumatoid arthritis the baseline expression (t=0) of type I IFN-regulated genes was determined in peripheral blood cells (PAXgene) using cDNA-microarrays and compared to levels one month after (t=1) anti-TNF treatment (infliximab). Therefore, we used 43K cDNA microarrays from the Stanford Functional Genomics Facility (http://microarray.org/sfgf/) printed on aminosilane-coated slides containing ~20.000 unique genes. Only one batch of arrays was used for all experiments. First DNA spots were UV-cross linked to the slide using 150-300 mJoules. Sample preparation and microarray hybridization were performed as described previously (1,2). Data storage and filtering was performed using the Stanford Microarray Database (http://genome-www5.stanford.edu//) as described previously. 1. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM et al.: Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 2007, 66: 1008-1014. 2. van der Pouw Kraan TC, van Baarsen LG, Rustenburg F, Baltus B, Fero M, Verweij CL: Gene expression profiling in rheumatology. Methods Mol Med 2007, 136: 305-327. Abbreviations: - Bnrs are the different patients analyzed - PAX or Paxgene indicates the total RNA was isolated from peripheral blood obtained in PAXgene tubes - CRS: common reference sample: We made a common reference that consisted of a mixture of mRNAs isolated from 11 different cell lines (Perou CM, Jeffrey SS, van de RM et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A. 1999; 96:9212-9217) supplemented with RNA from rheumatoid synovial tissue, fibroblasts, and activated peripheral blood mononuclear cells (PBMCs). - PMT: photomultiplier tube: the sensitivity/intensity of the scanner can be adjusted to prevent spot saturation. Compound Based Treatment: anti-TNF (infliximab)

Dataset Information

Anti-Drug Antibodies, Drug Levels, Interleukin-6 and Soluble TNF Receptors in Rheumatoid Arthritis Patients during the First 6 Months of Treatment with Adalimumab or Infliximab: A Descriptive Cohort Study.

Publications

Anti-Drug Antibodies, Drug Levels, Interleukin-6 and Soluble TNF Receptors in Rheumatoid Arthritis Patients during the First 6 Months of Treatment with Adalimumab or Infliximab: A Descriptive Cohort Study.

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