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-tumor necrosis factor but can also bind lymphotoxin-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- genes. 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 protein 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.