Dataset Information

Independent Candidate Serum Protein Biomarkers of Response to Adalimumab and to Infliximab in Rheumatoid Arthritis: An Exploratory Study.

ABSTRACT: 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.

SUBMITTER: Ortea I

PROVIDER: S-EPMC4822871 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Independent Candidate Serum Protein Biomarkers of Response to Adalimumab and to Infliximab in Rheumatoid Arthritis: An Exploratory Study.

Ortea Ignacio I Roschitzki Bernd B López-Rodríguez Rosario R Tomero Eva G EG Ovalles Juan G JG López-Longo Javier J de la Torre Inmaculada I González-Alvaro Isidoro I Gómez-Reino Juan J JJ González Antonio A

PloS one 20160406 4

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 ...[more]

PMID: 27050469

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Project description:Rheumatoid arthritis is an autoimmune disorder of complex disease etiology. Currently available serological diagnostic markers lack in terms of sensitivity and specificity and thus additional biomarkers are warranted for early disease diagnosis and management. We aimed to screen and compare serum proteome profiles of rheumatoid arthritis serotypes with healthy controls in the Pakistani population for identification of potential disease biomarkers. Serum samples from rheumatoid arthritis patients and healthy controls were enriched for low abundance proteins using ProteoMinerTM columns. Rheumatoid arthritis patients were assigned to one of the four serotypes based on anti-citrullinated peptide antibodies and rheumatoid factor. Serum protein profiles were analyzed via liquid chromatography-tandem mass spectrometry. The changes in the protein abundances were determined using label-free quantification software ProgenesisQITM followed by pathway analysis. Findings were validated in an independent cohort of patients and healthy controls using an enzyme-linked immunosorbent assay. A total of 213 proteins were identified. Comparative analysis of all groups (false discovery rate < 0.05, >2-fold change, and identified with ≥2 unique peptides) identified ten proteins that were differentially expressed between rheumatoid arthritis serotypes and healthy controls including pregnancy zone protein, selenoprotein P, C4b-binding protein beta chain, apolipoprotein M, N-acetylmuramoyl-L-alanine amidase, catalytic chain, oncoprotein-induced transcript 3 protein, Carboxypeptidase N subunit 2, Apolipoprotein C-I and Apolipoprotein C-III. Pathway analysis predicted inhibition of liver X receptor/retinoid X receptor activation pathway and production of nitric oxide and reactive oxygen species pathway in macrophages in all serotypes. A catalogue of potential serum biomarkers for rheumatoid arthritis were identified. These biomarkers can be further evaluated in larger cohorts from different populations for their diagnostic and prognostic potential.

Project description:IntroductionThe treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor alpha (TNF?) biological drugs has dramatically improved the prognosis of these patients. However, a third of the treated patients do not respond to this therapy. Thus, the search for biomarkers of clinical response to these agents is currently highly active. Our aim is to analyze the number and distribution of circulating monocytes, and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16+ subsets in methotrexate (MTX) non-responder patients with RA, and to determine their value in predicting the clinical response to adalimumab plus MTX treatment.MethodsThis prospective work investigated the number of circulating monocytes, and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets, in 35 MTX non-responder patients with RA before and after three and six months of anti-TNF? treatment using multiparametric flow cytometry. The number of circulating monocytes in an age- and sex-matched healthy population was monitored as a control.ResultsNon-responder patients with RA show an increased number of monocytes and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets after three months of adalimumab plus MTX treatment that remained significantly increased at six months. In contrast, significant normalization of the numbers of circulating monocytes was found in responders at three months of adalimumab plus MTX treatment that lasts up to six months. CX3CR1 expression is increased in monocytes in non-responders. At three months of anti-TNF? treatment the number of circulating monocytes and their subsets was associated with at least 80% sensitivity, 84% specificity and an 86% positive predictive value (PPV) in terms of discriminating between eventual early responders and non-responders.ConclusionsThe absolute number of circulating monocytes and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets at three months of adalimumab plus MTX treatment, have a predictive value (with high specificity and sensitivity) in terms of the clinical response after six months of anti-TNF? treatment in patients with RA.

Dataset Information

Independent Candidate Serum Protein Biomarkers of Response to Adalimumab and to Infliximab in Rheumatoid Arthritis: An Exploratory Study.

Publications

Independent Candidate Serum Protein Biomarkers of Response to Adalimumab and to Infliximab in Rheumatoid Arthritis: An Exploratory Study.

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