TNF-α Promotor Polymorphisms to Predict TNFi Tx Responses in SpA

Tumor necrosis factor promoter polymorphisms were stronger predictors of response to etanercept than to infliximab or adalimumab in patients with spondyloarthritis.

Tumor necrosis factor (TNF)-α promoter polymorphisms in G alleles 308 and 238 were stronger predictors of response to etanercept than to infliximab or adalimumab in patients with spondyloarthritis (SpA), according to a study published in Scientific Reports.

TNF inhibitors are commonly used to treat SpA and can be classified into soluble receptors (including etanercept) and monoclonal antibodies (including adalimumab and infliximab). While TNF inhibitor therapy can lower disease activity or induce remission in some patients, up to 25% of patients do not respond to these agents. Several single nucleotide polymorphisms in the TNF-α promoter region have been linked to TNF inhibitor response in SpA, but data regarding this association have been inconsistent.

To evaluate the relationship between TNF-α promotor polymorphisms −308 A/G, −238 A/G, and −857 C/T to TNF inhibitor response in patients with SpA, the authors conducted a meta-analysis including 10 published studies and their own unpublished data set.

Analysis of data from 1016 patients showed that heterogeneity in response to TNF inhibitors could be accounted for by disease type, gender ratio, continent, and specific TNF blocker used.

Both TNF-α −308 A/G and −238 A/G polymorphisms were associated with good response to TNF inhibitors (−308 A/G: odds ratio [OR], 2.64; 95% confidence interval [CI], 1.48 to 4.73; −238 A/G: OR, 2.52; 95% CI, 1.46 to 4.37).

When TNF inhibitors were grouped by type, the −308 GG and −238 GG polymorphisms predicted response to soluble receptor etanercept (OR, 4.02 and 5.17, respectively), but no association was found with response to monoclonal antibodies infliximab or adalimumab.

Overall, −857 C/T polymorphisms did not predict response to TNF inhibitors. However, certain polymorphisms correlated with TNF blocker response when patients were grouped according to disease severity (more severe disease defined as longer disease duration plus mean Psoriasis Area and Severity Index score >20).

TNF-α −857 TT in patients with more severe disease and −857 CC in patients with less severe disease were associated with a better response to etanercept.

Summary and Clinical Applicability

In this meta-analysis, TNF-α promoter polymorphisms in −308 and −238 were sassociated with good response to TNF inhibitors, with a stronger correlation with etanercept response than with infliximab or adalimumab response. TNF-α −857 C/T polymorphisms predicted response to etanercept only when patients were grouped by disease severity.

“The results of our meta-analysis indicated that the common alleles of TNFα −238 and −308 could better predict the response to TNF blockers,” the authors concluded. “These results are in agreement with those of previous reports in a meta-analysis conducted in SpA patients.”

Limitations and Disclosures

  • Response criteria used to define response to TNF inhibitors were a source of heterogeneity, and stricter criteria weakened the association between TNF-α promoter polymorphisms and TNF blocker response while narrowing the confidence intervals in the cumulative meta-analysis in ankylosing spondylitis patients
  • Further analysis of ethnicity as a source of heterogeneity could not be performed since most patients were Caucasian and few studies included non-Caucasian patients

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Liu J, Dong Z, Zhu Q, et al. TNF-α Promoter Polymorphisms Predict the Response to Etanercept More Powerfully than that to Infliximab/Adalimumab in Spondyloarthritis. Sci Rep. 2016;6:32202. doi: 10.1038/srep32202.

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