Rheumatology Reports 2009; volume 1:e1

Genetic predictors of response of the human immunoglobulin Ig-G1. It works by binding to soluble TNF and neutralizing it Correspondence: Anne Barton, to anti- but can also bind -α (LTA). Arthritis Research Campaign Epidemiology Unit, drugs in rheumatoid arthritis Adalimumab and infliximab are monoclonal University of Manchester, M13 9PT, UK antibodies directed against membrane-bound E-mail: [email protected] Rachael Tan and Anne Barton and soluble TNFα.1 Whilst DMARDs may slow radiological progression, studies using anti- Key words: genetics, rheumatoid arthritis, ARC Epidemiology Unit, Stopford response, etanercept, infliximab, adalimumab. Building, The University of Manchester, TNF drugs have shown their superiority in suppressing structural change.2 However, anti- Manchester, UK Conflict of interest: the authors reported no potential TNFs are not without their drawbacks. As well conflict of interests. as being expensive, studies have shown links with malignancy and serious infections.3 Received for publication: 24 March 2009. Furthermore, for unknown reasons, up to 30% Revision received: 18 May 2009. Abstract of patients fail to respond to treatment with Accepted for publication: 18 May 2009. anti-TNFs.4 In many countries, these concerns This work is licensed under a Creative Commons limit the wholesale use of these drugs. In the The introduction of anti-tumor necrosis fac- Attribution 3.0 License (by-nc 3.0). tor (anti-TNF) agents has dramatically UK, for example, the National Institute for improved the outlook for many patients with Health and Clinical Excellence (NICE) advises ©Copyright R. Tan and A. Barton, 2009 rheumatoid arthritis (RA). However, 30% of that anti-TNF therapies can be prescribed for Licensee PAGEPress, Italy patients fail to respond to treatment for RA patients who: Hematology Reports 2009; 1:e1 unknown reasons. While research has identi- • have a 28-joint count disease activity score doi:10.4081/rr.2009.e1 fied clinical markers of response, including (DAS28) of >5.1 on 2 occasions; baseline disease activity, disability and the • have previously tried two DMARDs which ing towards identifying other markers that concurrent use of disease modifying therapy, have failed, one being methotrexate.5 may predict response to anti-TNF therapy. these account for only a small proportion of the These guidelines were developed based on Positivityonly for either rheumatoid factor or anti- variation in treatment response. A number of the cost-benefit analysis but may mean that CCP antibody tests have been reported to be groups, therefore, have started to investigate patients destined to require anti-TNF therapy associated with a poorer response to therapy genetic markers of response to anti-TNF ther- experience undue delays in receiving treat- but, even combined with clinical predictors, apies. To date, many of these studies have ment, with the consequent burden of sus- only 17% in the variation of treatment been small, underpowered and have largely tained disease activity. If it were possibleuse to response was explained in one study.8 been restricted to the analysis of candidate identify those patients most, or indeed least, A number of investigators have hypothe- . The only replicated and validated genet- likely to respond to treatment, the altered cost- sized that genetic variation may affect ic predictor of anti-TNF response is the benefit ratio may allow better targeting of response to anti-TNF therapies. Support for 308G>A SNP in the TNF promoter region, but these expensive treatments. this theory comes from studies of response to the amount of variation in response accounted other drugs in which genetic variation has for by this marker is modest. It is unknown been shown to play an important role. For whether variation in treatment response is example, up to 50% of the variation in warfarin determined by several genes each with a small Discussion dose required between individuals can be effect size or small numbers of genes with explained by single nucleotide polymorphisms large effect sizes but what is certain is the There are currently few clinical or biological (SNPs) within 2 genes, cytochrome P450 C29 need for a non-hypothesis driven approach in predictors of response to anti-TNF drugs. (CYP2C9) and VKORC1.9 order to identify further genetic markers of Hyrich et al. conducted a large study investi- A number of genetic studies have been anti-TNF response. The identification of gating clinical predictors of response in undertaken using different study designs. In genetic predictors of response to anti-TNF patients receiving either etanercept or inflix- designing studies to investigate genetic pre- therapies would enable clinicians to tailor imab.6 Patients were recruited from the British dictors of response to anti-TNF therapies, treatment of these expensive and potentially Society for Rheumatology (BSR) Biologics there has been debate as to whether studies harmful agents to patients most likelyNon-commercial to bene- Register, an observational cohort study which should investigate the anti-TNF agents indi- fit from them. aims to recruit and follow up 4,000 patients on vidually or as a class. Evidence that infliximab each of the 3 currently licensed anti-TNF is effective in Crohn’s disease while etaner- drugs. The study concluded that current use of cept and adalimumab are not fuels the argu- NSAIDs and methotrexate improved response ment that the different anti-TNFs work via dif- Introduction while poorer response was achieved in smok- ferent pathways.10,11 Similarly, patients who ers and those with higher baseline disability have failed to respond to one anti-TNF drug The introduction of anti-tumor necrosis fac- scores.6 Subsequently, Kristensen et al. con- may benefit from a second supporting the idea tor (TNF) drugs revolutionized the treatment firmed that concomitant treatment with that response to each of the anti-TNF drugs of rheumatoid arthritis (RA) particularly for methotrexate improved response to anti-TNF should be analyzed separately. However, a patients who showed little or no response to therapies. They also concluded that gender large study showed that the reason for stop- disease modifying anti-rheumatic drugs was not a predictor of response, but disease ping the second anti-TNF was often the same (DMARDs). There are currently three anti-TNF activity and poor functional ability at baseline as for the first, reinforcing the argument that drugs licensed for treatment of RA in the UK. were.7 However, these clinical factors only anti-TNFs work in a similar manner and, They are etanercept (Enbrel®), adalimumab explained a minority of the variation in therefore, that there may be a class effect in (Humira®) and infliximab (Remicade®). response to therapy. treatment response.12 Table 1 lists the studies Etanercept is a fusion of two p75 TNF With the disappointing results from studies in which response to anti-TNF drugs has been receptors that are linked to the Fc component investigating clinical factors, research is mov- analyzed as a class effect for a number of can-

[Rheumatology Reports 2009; 1:e1] [page 1] Review didate genes. tested when investigating susceptibility genes. making it difficult to interpret statistically Many authors, however, have analyzed Plenge et al. highlighted in a recent review insignificant results. Where positive associa- response to the anti-TNF drugs separately, as that to detect a SNP with an odds ratio (OR) of tions have been reported, there are few exam- outlined in Tables 2-4, in order to reduce het- 3 (equivalent to the effect of the shared epi- ples where the findings have been subsequent- erogeneity in the patient population. It should tope) recruitment of several hundred partici- ly validated in independent cohorts. One be noted that only one study to date has inves- pants would be required.33 Therefore, investi- notable exception is the TNF-308G>A SNP tigated polymorphisms associated with gation of SNPs with much smaller OR may (rs1800629), association with which has been response to adalimumab therapy alone (Table require studies with thousands of participants replicated in independent studies and been 4). This most likely reflects the fact that this to give statistical power to the results. It is not shown to be a weak predictor of anti-TNF treat- drug was the one most recently licensed and, clear at the moment whether a small number ment response. Previous functional studies therefore, there will be fewer patients receiv- of genes with large effect sizes or a large num- have suggested that patients carrying -308 A ing this therapy at the current time. ber of genes with small effect sizes will deter- allele express higher levels of TNF.24,26,27 These studies raise a number of points for mine response to these therapies but, even so, Secondly, the response criteria vary between discussion. Firstly, the sample sizes included the majority of reported studies have been the different studies conducted. Some studies to date are small in comparison with those underpowered to detect even large effects have used American College of Rheumatology

Table 1. Studies investigating association between genes and response to combinations of anti-TNFs. The table below summarises the studies to date investigating genes and response to anti-TNF therapies in which the studies did not separate the three anti-TNF drugs but investigated a class effect of treatment response. Study Anti-TNF N. recruited Response criteria Genes investigated Conclusion Ref. Toonen et al. 2008 Infliximab 234 DAS28 TNFS1b Not significant (13) Adalimumab Seitz et al. 2007 Etanercept 54 DAS28 TNFA -308only GG associated with (14) Infliximab improved response Adalimumab Fabris et al. 2002 Etanercept 66 Not stated TNFR2 +676 G allele associated (15) Infliximab use with reduced response Tutunca et al. 2005 Etanercept 30 Physician decided Fc γ-receptor type IIIA F/F genotype associated (16) Infliximab according to criteria with improved response Adalimumab Kastbom et al. 2007 Etanercept 282 ACR20 Fc γ-receptor type IIIA No association found (17) Infliximab ACR50 ACR70 DAS28 Potter et al. 2008 Etanercept 642 DAS28 Shared Epitope No association found (8) Infliximab PTPN22 Adalimumab

Table 2. Studies investigating predictors of etanercept response. Study N. recruited Response criteria Genes investigated Conclusion Ref. Padyukov et al. 2003 123 ACR20 TNFA, IL10, TGFB1, IL1RN No allele significant on its own but (18) Non-commercialDAS28 a combination of TNF-308GG and TNF-1087GG improved response to etanercept (p<0.05) as did a combination of alleles at IL1RN and TGFB1(p<0.05) Kang et al. 2005 70 ACR20 TNFA TNF-857 T alleles associated (9) ACR70 LTA with better response Schotte et al. 2005 50 EULAR IL10.R IL10.R3 allele associated with improved response IL10.G (OR 5.46, p= 0.01) while IL10-G13 allele associated with moderate or no response (OR 0.18, p=0.01) (20) Guis et al. 2007 86 DAS28 TNFA TNF-308 GG associated with improved response (21) Criswell et al. 2004 457 ACR50 HLA-DRB1 Carriage of *0404 and *0101 shared epitope alleles (22) TNF associated with better response LTA TNFRSF1A TNFRSF1B FCGR3A FCGR3B Maxwell et al. 2008 455 DAS28 TNF TNF-308AA associated with poor response (23)

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Table 3. Studies investigating predictors of response to infliximab. Study N. recruited Response criteria Genes investigated Conclusion Ref. Mugnier et al. 2003 59 DAS28 TNFA TNF-308 GG associated with improved response (24) Martinez et al. 2004 78 DAS28 HLA TNFa11;b4 minihaplotype and D6S273_4/BAT2_2 haplotype (25) MICA associated with improved response. TNF BAT2 Cuchacovich et al. 2004 20 ACR20 TNFA TNF-308 G>A associated with improved response (26) ACR50 Balog et al. 2004 9 DAS28 TNFA Carriage of A allele at TNF-308 associated with decreased (27) response Marotte et al. 2008 198 ACR20 HLA No association found (28) DAS28 IL1B IL1RN TNFA Fonseca et al. 2005 22 DAS28 TNFA TNF-308 GG associated with improved response (29) Tolusso et al. 2006 49 DAS28 IL1B Non-responders have higher IL1RN*3 frequency (30) IL1RN Chatzikyriakidou 58 DAS28 TNFR1 No allele significant alone but a combination of TNFR2 (31) et al. 2007 TNFR2 TNFR2 676T>G with either TNFA -857C>T or 489 G>A TNFA (which are in LD with one another) was associated with improved response Maxwell et al. 2008 450 DAS28 TNF TNF-308AA associatedonly with poorer response (23)

Table 4. Study investigating predictors of response to adalimumab. Study N. recruited Response criteria Genes investigated Conclusionuse Ref. Cuchacovich et al. 2006 70 ACR20DAS28 TNFA TNF-308 GG associated with improved response (32)

(ACR) response criteria while others have loci that had not previously been identified as Tumor Necrosis Factor Trial in used DAS 28 (Tables 1-4).13,20,21,23 Although pre- important in the pathogenesis of RA.35 This Rheumatoid Arthritis with Concomitant vious work has validated the sensitivity and highlights the need for a hypothesis-free Therapy Study Group. N Engl J Med 2000; specificity of these measures, they are some- approach to pharmacogenetics. At the 343:1594-602. what subjective and potentially open to manip- moment, the availability of large, well-pheno- 3. Bongartz T, Sutton AJ, Sweeting MJ, et al. ulation. For example, it has been shown that typed cohorts of anti-TNF treated patients and Anti-TNF antibody therapy in rheumatoid the DAS28 is greatly influenced by the tender suitable resources for undertaking GWA stud- arthritis and the risk of serious infections joint count, which is a very subjective meas- ies limit progress in this field. However, initia- and malignancies: systematic review and ure.34 Hence, it may be argued that more objec- tives to bring together researchers in order to meta-analysis of rare harmful effects in tive measures of response, such as the per- pool resources and samples are underway. randomized controlled trials.[see com- centage improvement in the erythrocyte sedi- Such national and international collaboration ment][erratum appears in JAMA. 2006; mentation rate (ESR) or C- reactive protein will be necessary to advance this clinically 295:2482]. JAMA 2006;295:2275-85. (CRP) may be more robust. Non-commercialimportant research. Ultimately, the identifica- 4. Coenen MJ, Toonen EJ, Scheffer H, et al. Thirdly, the different studies have taken dif- tion of predictors of response, whether they Pharmacogenetics of anti-TNF treatment ferent approaches when trying to account for are genetic or otherwise, has the potential to in patients with rheumatoid arthritis. baseline co-variables. Smoking, baseline make an enormous impact on clinical practice Pharmacogenomics 2007;8:761-73. DAS28, age, concurrent DMARD therapy and by helping physicians to target the right thera- 5. National Institute for Health and Clinical disability [as measured by the health assess- pies to the right patients. Excellence. Adalimumab, etanercept and ment questionnaire (HAQ)] influence infliximab for the treatment of rheumatoid absolute change in DAS28 but not all studies arthritis. http://www.nice.org uk/Guidance/ have adjusted for these potential confounders. TA130 2007 October. Available from: URL: This leads to difficulties when trying to con- References http://www.nice.org.uk/Guidance/TA130 duct a meta-analysis incorporating all avail- 6. Hyrich KL, Watson KD, Silman AJ, able data. 1. Ranganathan P. Pharmacogenomics of Symmons DPM. Predictors of response to Finally, all of these pharmacogenetic studies tumor necrosis factor antagonists in anti-TNF-alpha therapy among patients have investigated SNPs that map to obvious RA rheumatoid arthritis. Pharmacogenomics with rheumatoid arthritis: results from the candidate genes such as the TNFα . 2005;6:481-90. British Society for Rheumatology However, as has been demonstrated by 2. Lipsky PE, van der Heijde DM, St Clair EW, Biologics Register. Rheumatology 2006;45: genome wide association (GWA) studies of RA et al. Infliximab and methotrexate in the 1558-65. susceptibility, associated variants often map to treatment of rheumatoid arthritis. Anti- 7. Kristensen LE, Kapetanovic MC, Gulfe A,

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et al. Predictors of response to anti-TNF patients with inflammatory arthritis treat- levels and influence of -308 TNF-alpha pro- therapy according to ACR and EULAR crite- ed with tumor necrosis factor alpha-block- moter polymorphism on the responsive- ria in patients with established RA: results ing agents. Arthritis Rheum 2005;52:2693- ness to infliximab in patients with from the South Swedish Arthritis 6. rheumatoid arthritis. Scand J Rheumatol Treatment Group Register. Rheumatology 17. Kastbom A, Bratt J, Ernestam S, et al. 2004;33:228-32. 2008;47:495-9. Fcgamma receptor type IIIA genotype and 27. Balog A, Klausz G, Gal J, Molnar T, et al. 8. Potter C, Hyrich KL, Tracey A, et al. response to tumor necrosis factor alpha- Investigation of the prognostic value of Association of rheumatoid factor and anti- blocking agents in patients with rheuma- TNF-alpha gene polymorphism among cyclic citrullinated peptide positivity, but toid arthritis. Arthritis Rheum 2007;56: patients treated with infliximab, and the not carriage of shared epitope or PTPN22 448-52. effects of infliximab therapy on TNF-alpha susceptibility variants, with anti-tumour 18. Padyukov L, Lampa J, Heimburger M, et al. production and apoptosis. Pathobiology necrosis factor response in rheumatoid Genetic markers for the efficacy of tumour 2004;71:274-80. arthritis. Ann Rheum Dis 2009;68:69-74. necrosis factor blocking therapy in 28. Marotte H, Arnaud B, Diasparra J, et al. 9. Bodin L, Verstuyft C, Tregouet DA, et al. rheumatoid arthritis. Ann Rheum Dis Association between the level of circulat- Cytochrome P450 2C9 (CYP2C9) and vita- 2003;62:526-9. ing bioactive tumor necrosis factor alpha min K epoxide reductase (VKORC1) geno- 19. Kang CP, Lee KW, Yoo DH, et al. The influ- and the tumor necrosis factor alpha gene types as determinants of acenocoumarol ence of a polymorphism at position -857 of polymorphism at -308 in patients with sensitivity. 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The tor-alpha and tumour necrosis factor Results from a Large UK National Cohort influence of genetic variation in the HLA- receptor genotypes could predict rheuma- Study. Arthritis Rheum 2007;56:13-20. DRB1 and LTA-TNF regions on the toid arthritis patients' response to anti- 13. Toonen EJ, Coenen MJ, Kievit W, et al. The response to treatment of early rheumatoid TNF-alpha therapy and explain controver- tumour necrosis factor receptor superfam- arthritis with methotrexate or etanercept. sies of studies based on a single polymor- ily member 1b 676T>G polymorphism in Arthritis Rheum 2004;50:2750-6. phism. Rheumatology (Oxford) 2007;46: relation to response to infliximab and 23. Maxwell JR, Potter C, Hyrich KL, et al. 1034-5. adalimumab treatment and disease sever- Association of the tumour necrosis factor- 32. Cuchacovich M, Soto L, Edwardes M, et al. ity in rheumatoid arthritis. Ann Rheum 308 variant with differential response to Tumour necrosis factor (TNF)alpha -308 G/G Dis 2008;67:1174-7. anti-TNF agents in the treatment of promoter polymorphism and TNFalpha levels 14. Seitz M, Wirthmuller U, Moller B, Villiger rheumatoid arthritis. Hum Mol Genet correlate with a better response to adali- PM. The -308 tumour necrosis factor-alpha 2008;17:3532-8. mumab in patients with rheumatoid arthri- gene polymorphism predicts therapeutic 24. Mugnier B, Balandraud N, Darque A, et al. tis. Scand J Rheumatol 2006;35:435-40. response to TNFalpha-blockers in rheuma- Polymorphism at position -308 of the 33. Plenge RM, Criswell LA. Genetic variants toid arthritis and spondyloarthritisNon-commercialtumor necrosis factor alpha gene influ- that predict response to anti-tumor necro- patients. Rheumatology (Oxford) 2007;46: ences outcome of infliximab therapy in sis factor therapy in rheumatoid arthritis: 93-6. rheumatoid arthritis. 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