Genetic and Genomic Predictors of Anti-TNF Response

Abstract

The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; however, variation in genes or their expression may identify those most likely to respond. By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have replicated consistently between studies. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect. Other potential serum biomarkers of response have also been explored including cytokines and autoantibodies, with antibodies developing to the anti-TNF drugs themselves being correlated with treatment failure.

Anti–tumor necrosis factor-α therapy in uveitis

“…Pharmacogenetics A substantial proportion of patients (approximately 30-40%) fail to respond to anti-TNF-α therapy for non-uveitis indications. 103 The largest studies in uveitis report a non-response rate of approximately 20%. 76,131 Treatment response is likely dependent on many factors, including age, location and severity of uveitis, and type of TNF-α blocker employed.…”

“…Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect; 103 Infliximab is currently the anti-TNF-α agent used more often for the treatment of immunemediated uveitis. 80 The number of studies is particularly large for uveitis associated with two underlying conditions: Behçet disease and JIA.…”

The tumor necrosis factor receptor superfamily member 1B polymorphisms predict response to anti-TNF therapy in patients with autoimmune disease: A meta-analysis

“…1). After the full-text review, 10 of these 18 articles were excluded because 2 of them were review articles [16,24], 3 articles had no exact statistics about polymorphisms [25][26][27], 1 reported duplicate data [28], 1 was irrelevant to biological agent [29], 3 were not related to TNFRSF polymorphisms [2,30,31]. Finally, in the current study, 8 eligible studies [32][33][34][35][36][37][38][39] that meet the inclusion criteria were included in our biologic-specific meta-analysis.…”

“…This issue could be addressed by pharmacogenetic studies which are analysis of genetic variations and may be used to predict how a patient may react to a drug, from both a safety and an efficacy points of view. Large-scale genetic analysis is revealing key gene associations with responsiveness and side effects to TNF inhibitors [16]. For example, Lee et al showed that individuals carrying the IL-6-174 C allele show a poorer response to anti-TNF therapy for RA [17].…”

Pharmacogenomics in pediatric rheumatology

“…The mechanism of action of anti-TNF-a drugs is through interruption of the interaction between TNF-a and its receptors, with subsequent interference with downstream signaling; thus, the investigation of several potential pharmacogenomic targets reviewed extensively by Prajapati et al includes the candidate gene encoding TNF-a, genes in the TNF-a signaling pathway, susceptibility genes associated with disease development and Genome Wide Association Studies (GWAS) [49].…”