Putative IL-10 Low Producer Genotypes Are Associated with a Favourable Etanercept Response in Patients with Rheumatoid Arthritis.

Heiko Schotte,Bernhard Schlüter,Hartmut Schmidt,Susanne Drynda,Peter Willeke,Markus Gaubitz,Jörn Kekow,Masataka Kuwana

doi:10.1371/journal.pone.0130907

Abstract

Outcome predictors of biologic therapeutic drugs like TNF inhibitors are of interest since side effects like serious infections or malignancy cannot be completely ruled out. Response rates are heterogeneous. The present study addressed the question whether in patients with rheumatoid arthritis (RA) interleukin-10 (IL-10) promoter genotypes with potential relevance for IL-10 production capacity are associated with response to long-term treatment with etanercept. Caucasian RA patients that, according to the EULAR criteria, responded well (n = 25), moderately (n = 17) or not (n = 8) to etanercept therapy (median 36 months, range 4–52), and 160 matched controls were genotyped for the IL-10 promoter SNPs -2849 G>A (rs6703630), -1082 G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872). Haplotypes were reconstructed via mathematic model and tested for associations with disease susceptibility and therapy response. We identified the four predominant haplotypes AGCC, GATA, GGCC, and GACC in almost equal distribution. Patients that responded well carried the putative IL-10 low producer allele -2849 A or the haplotypes AGCC and GATA (RR 2.1 and 4.0, respectively; 95% CI 1.1–4.0 and 1.1–14.8), whereas an unfavourable response was associated with carriage of the putative high producer haplotype GGCC (RR 1.9, 95% CI 1.1–3.3). No significant associations of alleles or haplotypes with disease susceptibility were observed. In RA, a low IL-10 production which is genetically determined rather by haplotypes than by SNPs may favour the response to etanercept treatment. Iatrogenic blockade of TNF may reveal proinflammatory effects of its endogeneous antagonist IL-10. Further studies are needed to correlate these genetic findings to direct cytokine measurements.

Highlights

The introduction of tumor necrosis factor (TNF) blocking agents into the therapy of rheumatoid arthritis (RA) is a story of remarkable success [1]
Based on theoretical considerations and experimental findings that attribute IL-10 a pathogenetic role in RA, the present study addressed the question whether genetic polymorphisms associated with the constitutional IL-10 production could be related to anti-TNF therapy response in RA
The introduction of TNF blocking agents like the soluble TNF receptor-Fc fusion protein etanercept has been a milestone in the treatment of patients with chronic inflammation such as RA

Summary

Introduction

The introduction of tumor necrosis factor (TNF) blocking agents into the therapy of rheumatoid arthritis (RA) is a story of remarkable success [1]. The efficacy of anti-TNF is comparable to or even better than methotrexate, and today, we are not aware of startling safety concerns. Antagonizing cytokines provided us with detailed insights into the pathophysiology of chronic inflammation [2]. About 30–40% of the patients fail to respond. Compared to patients on conventional DMARD therapy, patients treated with anti-TNF seem to have a higher risk of serious infections, of tuberculosis, of infections by herpes zoster, and the risk of melanoma seems to be slightly increased [3]. Reliable predictors of therapy outcome are expedient, allowing for the rational selection of eligible patients

Methods

Results

Conclusion