Potential Biomarkers for Etanercept and Adalimumab Response in Rheumatoid Arthritis

Children with type 1 diabetes have high rates of vitamin D deficiencies.
Children with type 1 diabetes have high rates of vitamin D deficiencies.
Findings suggest that different TNF inhibitor (TNFi) therapies function by alternative mechanisms that affect patient outcomes.

Findings presented at the 2017 Annual European Congress of Rheumatology Meeting (EULAR) held June 14-17 in Madrid, Spain show a wide range of blood-based transcriptomic profiles of responses to etanercept and adalimumab, suggesting that different TNF inhibitor (TNFi) therapies function by alternative mechanisms that affect patient outcomes.

While these potential biomarkers require replication in future studies, they may provide a way to determine early on which patients would respond to which therapy, and could inform early switching to a different therapy.

To compare transcriptomic changes between patients receiving etanercept and adalimumab, and to identify blood-based biomarkers that could predict or monitor patients’ response, Anne Barton, FRCP, PhD, from the Centre for Musculoskeletal Research at the University of Manchester and the NIHR Manchester Musculoskeletal BRU, Central Manchester Foundation Trust in Manchester, United Kingdom and colleagues selected 37 good-responders in clinical remission (GR) to etanercept and 18 non-responders (NR) to etanercept, as well as 50 GR and 20 NR to adalimumab, from the BRAGGSS (Biologics in RA Genetics and Genomics Study Syndicate).

At baseline and at 3 months, total RNA was isolated from Tempus™-stabilized whole blood samples using the MagMAX™ RNA extraction kit. Using the Affymetrix WT PLUS kit, the researchers amplified and converted the RNA into biotinylated sense-strand DNA for hybridization onto Affymetrix GeneChip® Human Transcriptome arrays. Quality control and differential expression/splice analysis were assessed with the Affymetrix Expression and Transcriptome Analysis Console™ and appropriate Bioconductor packages. The researchers adjusted differential transcript expression for baseline disease activity score (DAS), age, gender, and concurrent disease modifying antirheumatic drug (DMARD) therapy, and performed pathway analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA) tools.

The researchers found that in the adalimumab GR group, 636 genes were downregulated and 253 were upregulated at 3 months (FDR P <.05, fold-change >1.2).

“There was significant upregulation of immune cell components, most notably HLA genes including HLA-DRB1, other [RA] susceptibility genes [SLC2A4, PADI4, and CD28], and many B and T cell signaling genes,” the researchers wrote.

Alternative splice changes in RA-relevant genes such as MMP9 were also apparent in adalimumab GR at 3 months, but not in etanercept GR.

In the etanercept GR group, the participants showed a milder transcriptomic change overall that shared little overlap with adalimumab GR: 395 genes were downregulated and 27 upregulated at 3M (FDR P <.05, fold-change >1.2).

“Downregulated genes included downstream TNF components such as mitogen activated protein (MAP) kinases, as well as genes involved in NOD-like receptor, Toll-like receptor, and NF-κB signalling,” the researchers wrote.

Summary & Clinical Applicability

“The heterogeneity in the blood-based transcriptomic profiles of tanercept and adalimumab response observed herein suggests that different TNFi therapies function by alternative mechanisms that impact patient outcomes. It also calls into question the reliability of response studies that consider TNFi therapies as a homogenous group,” the researchers wrote. “The candidate biomarkers identified require replication in independent datasets but may provide early and objective response biomarkers to inform timely therapeutic switching in patients who are not responding to their current TNFi drug,” they concluded.

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Oliver J, Plant D, Orozco G, et al. Etanercept and adalimumab exhibit heterogeneous early signatures of response in rheumatoid arthritis therapy. Presented at: The Annual European Congress of Rheumatology Meeting (EULAR). June 14-17, 2017. Madrid, Spain. Abstract THU0002. doi:10.1136/annrheumdis-2017-eular.1739