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

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.

Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis

“…Further studies should address this issue, as polymorphisms of IL‐10 may alter transcription factors affecting IL‐10 production and the disease itself. Patients carrying putative IL‐10 low‐producer genotypes showed a reduced survival and activation of autoreactive B cells and a favourable response to anti‐tumour necrosis factor (TNF) treatment . For the first time, we have observed a trend for an association of rs30187 in ERAP1 gene and RA susceptibility.…”

“…This gene codes for IL‐10, an intriguing cytokine with pleiotropic effects that has anti‐inflammatory property, stimulates B cell proliferation, differentiation and survival and promotes antibody isotype switching . Genetic variants in certain ethnic groups may over‐produce or lower IL‐10 production, with potential effects on the disease . Association with genes, such as tumour necrosis factor receptor‐associated 3 interacting protein 2 (TRAF3IP2), psoriasis susceptibility 1 candidate 1 (PSORS1C1) and protein tyrosine phosphatase, non‐receptor type 2 (PTPN2), was investigated in this study as they are involved in either Th17‐ or Th1‐mediated immune responses that are typical of RA .…”

Antiarthritis Effect of Morin is Associated with Inhibition of Synovial Angiogensis

“…Besides direct inflammatory effects, TNF-a and IL-6 can induce secondary activation of many genes involved in the pathogenesis of inflammatory diseases [Venkatesha et al, 2014]. In contrast to proinflammatory cytokines, IL-10 mediates downregulation of the inflammation cascade by enhancing the production of anti-inflammatory cytokines, attenuating the production of proinflammatory cytokines, and exerting inhibitory effects on the activation and function of T cells, macrophages, and monocytes [Wanidworanun et al, 1993;Moore et al, 2001;Schotte et al, 2015]. In this study, morin reduced serum levels of TNF-a and IL-6, but elevated serum IL-10 in CIA rats, consistent with the antiarthritis effect of morin.…”

Forsythoside A Modulates Zymosan-Induced Peritonitis in Mice

“…IL-6, a pleiotropic cytokine produced by various cells such as T cells, macrophages and fibroblast, is involved in the regulation of the vascular inflammation and immune response [ 29 ]. IL-10 is an anti-inflammatory cytokine and suppresses inflammatory response by increasing anti-inflammatory factors and reducing proinflammatory factors, as well as inhibiting the activation and function of T cells, macrophages, and monocytes [ 30 , 31 , 32 ]. Moreover, such cytokines are associated with the neutrophil infiltration in zymosan-inflamed peritoneum [ 21 ].…”