ROME – Tumor necrosis factor–alpha (TNF-alpha) inhibitors are well established as a treatment for psoriatic arthritis patients, but efficacy can vary greatly within that population. New work from Canadian researchers demonstrates that the global DNA methylation pattern differs between TNF-alpha–inhibitor responders and secondary failures, which could help explain the variability in medication success rates.
“Although TNF inhibitors [TNFi] work very well in certain individuals with psoriatic arthritis [PsA], up to 40% of individuals receiving this treatment fail to achieve a therapeutic response, and 20%-50% of individuals who have an initial response to treatment become refractory weeks or months after receiving therapy.” lead study author Darren O’Rielly, Ph.D., said at the European Congress of Rheumatology.
The preliminary study findings eventually could lead to the identification of biomarkers that would indicate patients who are not good candidates for TNFi medications, said Dr. O’Rielly of Memorial University, St. John’s, Nfld.
Dr. Darren O'Rielly
Given recent advances in epigenetics and that the epigenetic signature is affected by environmental factors, the investigators set out to determine if methylation alterations could help explain why PsA patients respond or fail with TNFi. The researchers performed genome-wide DNA methylation profiling on blood samples from 41 PsA patients, using machinery that measures about 480,000 CpG sites per sample and covers 96% of RefSeq genes. A total of 21 patients were considered TNFi responders, of whom 13 were treated with etanercept and 8 with adalimumab; median follow-up duration was 18 months. Twenty patients were considered secondary TNFi failures, of whom 15 were treated with etanercept and 5 with adalimumab; median follow-up duration was 36 months.
Dr. O’Rielly, a senior research scientist at Memorial and director of the Molecular Genetics Laboratory at Eastern Health in St. John’s, and his associates measured the methylation level at CpG sites using a genome-wide approach and selected regions of interest based on functional relevance to TNF-mediated signaling pathways with methylation level differences of 5% or greater and an adjusted P-value less than .05.
After quality-control filtering, investigators evaluated 384,599 CpG sites for TNFi responders and 368,863 CpG sites for TNFi failures. Researchers found 72 CpG sites of interest in the TNFi responder group and 91 CpG sites of interest in the TNFi failure group. Top candidate genes for TNFi responders included TRAPPC9 (which functions as an activator of NF-kB), CCR6 (which regulates the migration and recruitment of dendritic and T cells), and PSORS1C3 (psoriasis susceptibility 1 candidate 3), while top candidate genes for TNFi secondary failures included CD70 (an encoded protein that is a ligand for TNFRSF27/CD27) and TNFRSF1B (a member of the TNF receptor ‘superfamily’ that mediates most of the metabolic effects of TNF-alpha).
“We are very encouraged by these findings,” Dr. O’Rielly said. “We were a little surprised that several of our best candidate genes, such as TNFRSF1B and CD70, appear to play a role in TNF-alpha signaling, and that their methylation change occurs in a gene region that is consistent with a possible functional effect. We were expecting to find some methylation changes in genes but not necessarily in pathways with a direct connection with TNF-alpha–mediated signaling.”
The group plans to confirm these findings for the best candidate genes using other methylation-specific polymerase chain reaction technology, he said, and will investigate additional CpG sites adjacent to the region of interest, including promoters and enhancers, in the best candidate genes to better characterize the full extent of methylation changes in these regions. They also would like to replicate the findings in a prospective, independent cohort.
Dr. O’Rielly reported no relevant financial conflicts.