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

PLoS One. 2016 Apr 6;11(4):e0153140. doi: 10.1371/journal.pone.0153140. eCollection 2016.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab / therapeutic use*
  • Adult
  • Aged
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy*
  • Biomarkers / blood*
  • Blood Proteins / metabolism*
  • Female
  • Humans
  • Infliximab / therapeutic use*
  • Male
  • Middle Aged


  • Antirheumatic Agents
  • Biomarkers
  • Blood Proteins
  • Infliximab
  • Adalimumab

Grants and funding

This work was supported by the Instituto de Salud Carlos III (Spain) [grants PI14/01651, PI11/01048, PI12/01909; and RETICS Program (RIER) grants RD08/0075/0019, RD12/0009/0008; which are partially financed by the European Regional Development Fund of the European Union]; and the 7th Framework Program of the European Union [PRIME-XS project grant agreement number 262067]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.