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Gene Polymorphisms That Can Predict Response to Anti-TNF Therapy in Patients with Psoriasis and Related Autoimmune Diseases

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Gene Polymorphisms That Can Predict Response to Anti-TNF Therapy in Patients with Psoriasis and Related Autoimmune Diseases The Pharmacogenomics Journal (2013) 13, 297–305 & 2013 Macmillan Publishers Limited All rights reserved 1470-269X/13 www.nature.com/tpj REVIEW Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases R Prieto-Pe´ rez1, T Cabaleiro1, E Daude´n2 and F Abad-Santos1 Psoriasis (Ps) is a chronic inflammatory disease with an important genetic component. It shares pathophysiological mechanisms with other autoimmune diseases such as psoriatic arthritis (PsA), rheumatoid arthritis (RA) and Crohn’s disease (CD). These conditions can be treated using biological drugs such as infliximab, adalimumab and etanercept, which selectively block the proinflammatory cytokine tumor necrosis factor (TNF)-a. Although these agents have greatly improved the prognosis of Ps, PsA, RA and CD, they do not cure the disease and are expensive; in addition, significant proportions of patients do not respond or develop serious adverse effects. Therefore, it is important to investigate biomarkers, such as gene polymorphisms, that can predict which patients will respond best to a specific drug. Some polymorphisms in genes TNF, TNF receptor superfamily 1B (TNFR1B) and TNFa-induced protein 3 gene (TNFAIP3) have been associated with response to anti-TNF therapy in patients with Ps. The present article reviews other polymorphisms that could also play a role in prediction of response to these treatments. The Pharmacogenomics Journal (2013) 13, 297–305; doi:10.1038/tpj.2012.53; published online 22 January 2013 Keywords: gene polymorphisms; psoriasis; etanercept; adalimumab; infliximab INTRODUCTION Medicines Agency, an 8-to-12-weeks study is generally sufficient 11,12 Psoriasis (Ps) is a chronic inflammatory disease with a multi- to show short-term efficacy. factorial origin that has a considerable impact on health-care. The anti-TNF agents are effective in the treatment of Ps (XPASI- Cytokines have an important role in the pathogenesis of the 75 in 50–80% of patients at 12 weeks). However, these drugs are disease by mediating intercellular communication between not effective in all patients and do not cure the disease. Moreover, 13,14 immune cells that infiltrate the skin and keratinocytes.1 The they are expensive and can also produce long-term toxicity. prevalence of Ps varies with geographic location and has been Consequently, it is necessary to further investigate the reported to range from 1%–3%.2,3 pathogenesis of Ps to find new therapeutic targets that enable Family and twin studies show that genetic predisposition the development of more effective drugs. It is also important to has a major role in the development of Ps.4 In addition, several search for new biomarkers, in particular, genetic polymorphisms studies have reported that environmental factors can trigger that can predict which patients will respond to a specific drug. the disease.5 Identification of pharmacogenetic markers that allow us to treat Genome-wide association studies (GWAS) have uncovered only those patients who will respond without the risk of adverse several Ps-related chromosomal regions, such as the receptors events would significantly optimize the efficiency of therapy and for interleukin (IL)-23 and IL-12B.6,7 The major histocompatibility reduce costs. complex human leukocyte antigen-Cw6 region, however, has This review is based on current knowledge of the genetic basis been consistently associated with Ps (present in 67% of patients of the pathogenesis of Ps and of the relationship between Ps and versus 15% of the general population).8 other autoimmune diseases (PsA, RA and CD). We examined the Ps is a complex disease that can occur simultaneously with association between these diseases and response to biological other inflammatory disorders such as psoriatic arthritis (PsA) in treatments. We propose to identify genetic biomarkers that could 10–30% of cases.2 In addition, Ps shares pathophysiological possibly be associated with response to the treatment of Ps with mechanisms with PsA, rheumatoid arthritis (RA) and Crohn’s anti-TNF. disease (CD). These disorders involve a strong genetic component and can be treated with the drugs used to treat Ps.9,10 Several agents are available for the treatment of Ps, including biologics that selectively block tumor necrosis factor (TNF)-a (infliximab, IMMUNOPATHOGENESIS AND GENETICS OF PS AND RELATED adalimumab and etanercept). AUTOIMMUNE DISEASES The regular tool for assessing efficacy of treatment of Ps in Failure of the immune system to recognize autologous tissues or clinical trials is Ps area and severity index (PASI) score. The components of the immune system as self leads to inflammation, European Medicines Agency has recognized PASI-75 response injury and death of healthy cells, as well as onset of autoimmune (75% improvement from baseline PASI) as an indicator for severe diseases such as Ps, PsA, RA and CD. The exact cause of loss of Ps response to treatment in clinical trials. According to European recognition of self is not well known. 1Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teo´ filo Hernando, Universidad Auto´noma de Madrid, Instituto de Investigacio´ n Sanitaria Princesa (IP), Madrid, Spain and 2Service of Dermatology, Hospital Universitario de la Princesa, Instituto de Investigacio´n Sanitaria Princesa (IP), Madrid, Spain. Correspondence: R Prieto- Pe´rez Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teo´filo Hernando, Instituto de Investigacio´n Sanitaria Princesa (IP), C/Diego de Leo´n, 62, Madrid 28006, Spain. E-mail: [email protected] Received 6 August 2012; revised 24 October 2012; accepted 16 November 2012; published online 22 January 2013 Gene polymorphisms in response to anti-TNF therapy R Prieto-Pe´rez et al 298 Several studies have associated Ps, PsA, RA and CD with an activation into Th1 that produce IFN-g. Other cytokines produced immune response involving the helper T cells Th1 and Th17 that is by APCs include IL-19, IL-20 and IL-24, which cause alteration of triggered by bacterial infection or an environmental stimulus.15 keratinocytes in psoriatic skin.1 Antigens cross the epithelium through cells and are phagocytized IL-18 maintains the response of Th1, whose production is by antigen-presenting cells (APCs) such as macrophages and increased in CD.23 Th1 cells develop mainly as a result of cytokine dendritic cells. Naive CD4 þ T cells become activated by cytokines IL-12 production by macrophages and increased production such as TNF-a, IL-1, IL-6 and chemokines and inflammatory of IFN-g by T cells.16 Recent studies have associated polymor- molecules released by APCs after an environmental stimulus or phisms in IL-12B (rs6887695 and rs3212227) with Ps in Caucasian infection (Figure 1). patients.7 These findings have been confirmed elsewhere,6,24–26 The influx of activated leukocytes and monocytes leads to the and single-nucleotide polymorphisms (SNPs) have been detected production of inflammatory mediators that amplify inflammation in Caucasian patients with CD,27,28 PsA29,30 and RA.31 However, and cause tissue injury.16 IL-1, IL-6 and TNF-a are the major APCs Varade et al.32 found no association between these SNPs and RA, derived from the cytokines present in the rheumatoid joint. All of although their data suggest that IL-23R contributes to the etiology these agents cause aberrant activation of osteoclasts and joint of RA (Table 1). erosion in patients with RA.15,17,18 Activated Th1 also increase production of TNF-a, which acts on Increased levels of proinflammatory cytokines (TNF-a, IL-6 and intestinal fibroblasts and leads to the release of IL-13 and IL-1b), favoring the recruitment of leukocytes intensify the transforming growth factor-b (TGF-b), which causes fibrosis and inflammatory response.19 These cytokines have a major role in stricture formation in CD.33 the perpetuation of intestinal inflammation in CD, resulting in an The role of IL-13 and IL-4 is unclear, although genetic variations imbalance between proinflammatory and anti-inflammatory may result in deregulation of the Th1 and Th17 pathways.34 SNPs in cytokines.20 They also have an important role in the mechanism the IL-13 gene (rs2054, rs848 and rs1800925) have been associated of arthritic bone destruction, because they induce the receptor with Ps31,35,36 and PsA.37 Eder et al.38 associated these polymorphisms activator of NF-kB (RANK) in synovial fibroblasts, which require with increased susceptibility to PsA in patients with Ps. RANK ligand (RANKL) to trigger the differentiation of osteoclast The SNPs rs20541 and rs1800925 were found to be closely precursor cells into activated osteoclasts. This process results in associated with susceptibility to PsA. However, Bowes et al.39 bone resorption and the eventual manifestation of PsA.21 T cells found that neither was significantly associated with susceptibility also express RANKL. In contrast, levels of interferon-g (IFN-g), a to Ps vulgaris. Li et al.40 suggested that the most significant 5q31 potent RANKL inhibitor produced by T cells, are very low. This variants (including rs1800925 in the IL-13 gene) associated with Ps imbalance may be responsible for the aberrant activation of were not significant in CD. Therefore, association with CD and Ps osteoclast formation in arthritis.22 in this region seems to result from the presence of different Activated APCs release other proinflammatory cytokines such as variants. As for RA, the results of Marinou et al.41 indicated that IL-12, IL-18, IL-15, IL-6 and IL-8, and, together with TNF-a and IL-1, common variants of the IL-4/IL-13 pathway did not significantly they acquire the ability to drive T-cell differentiation and contribute to susceptibility to this disease. Environmental factors, Bacteria Epithelium -Defensin-2 Joint inflammation, enthesitis, cytokine-induced + Antigen osteoclastogenesis, bone resorption by CD68 IL-4, IL-13 osteoclast in PsA.
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