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Toward a Personalized Medicine Approach to the Management of Inflammatory Bowel Disease Mahmoud H. Mosli, MBBS1–3, William J. Sandborn, MD2,4, Richard B. Kim, MD5, Reena Khanna, MD1,2, Bandar Al-Judaibi, MBBS1,6 and Brian G. Feagan, MD1,2

The medical management of inflammatory bowel disease (IBD) is evolving toward a personalized medicine-based model. Modern therapeutic algorithms that feature use of tumor necrosis factor (TNF) antagonists in combination with immunosuppressive are highly effective when initiated in high-risk patients early in the course of disease. Defined targets that guide intensification of therapy are critical interventions. In this model, therapy is optimized through appropriate pretreatment testing, therapeutic drug monitoring, and patient-based monitoring strategies. This review discusses the current application of personalized medicine to the management of IBD. Am J Gastroenterol 2014; 109:994–1004; doi:10.1038/ajg.2014.110; published online 20 May 2014

INTRODUCTION

The right drug: selection of initial therapy

Over the past decade, the concept of personalized medicine has evolved from the framework of “the right drug, the right dose, in the right patient, at the right time, using the right route (1)” to a standard of care for the management of chronic diseases. Personalized medicine has potential to optimize efficacy, decrease the risk of adverse events, and minimize costs through the integration of genetic and conventional laboratory testing, as well as clinical variables such as age, gender, and relevant renal and hepatic function to guide treatment decisions. As part of this paradigm, modern therapeutic algorithms have evolved for the management of inflammatory bowel disease (IBD) that feature use of tumor necrosis factor (TNF) antagonists in combination with immunosuppressives (azathioprine (AZA), 6mercaptopurine (6-MP), and methotrexate) early in the course of the disease in high-risk patients (2). The goal of this strategy is to avoid long-term complications, disability, and mortality by preventing permanent bowel damage. Defined targets are used to guide treatment intensification with mucosal healing as a primary goal. Therapeutic drug monitoring (TDM) is an essential component of personalized medicine wherein serum drug concentrations or their metabolic by-products are measured and utilized to adjust dosing (3). Emerging evidence indicates that patients have a vital role in this model through active participation in monitoring disease activity. This review discusses the strategies currently available for selecting and monitoring IBD therapy and speculates on the future role of personalized medicine in disease management.

Laboratory testing before therapy can be used to select a treatment for a given patient that will have the greatest likelihood of maximizing efficacy and/or minimizing toxicity. Testing for single-nucleotide polymorphisms that are predictive of response to specific drug treatments has proven valuable in many clinical settings. For example, pretreatment tumor genomic analysis now plays a vital role in the management of lung cancer, as oncogene homolog mutations are strongly linked to resistance to epidermal growth factor receptor antagonists (4). Accordingly, genetic testing in select patients who are likely to respond to these agents is an approach that maximizes treatment efficiency and spares patients who are unlikely to respond to targeted therapy or who possess germline pharmacogenetic variations that place such patients at risk of drug-related toxicity. However, preliminary experience with genomic predictors of response to therapy in IBD has been disappointing. Although multiple predictors of response to 5-aminosalicylic acid (5), methotrexate (5), TNF antagonists (6–20), and glucocorticoid therapy have been identified (21), they have not been consistently reproduced. Nevertheless, thiopurine methyl transferase (TPMT) testing before initiation of purine antimetabolite therapy is an excellent example of the value of personalized medicine in IBD.

TPMT testing in IBD: principles and practices. AZA and 6-MP are commonly used to treat both ulcerative colitis (UC) and Crohn’s disease (CD). Although traditionally prescribed

1 Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; 2Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada; 3Department of Medicine, Division of Gastroenterology, King Abdulaziz University, Jeddah, Saudi Arabia; 4Division of Gastroenterology, University of California San Diego, La Jolla, California, USA; 5Department of Medicine, Division of Clinical Pharmacology, Western University, London, Ontario, Canada; 6 Department of Medicine, Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia. Correspondence: Brian G. Feagan, MD, Robarts Clinical Trials, Robarts Research Institute, 100 Perth Drive, PO Box 5015, London, Ontario, Canada N6A 5K8. E-mail: [email protected] Received 9 January 2014; accepted 30 March 2014

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6-Thiouracil

XO

HPRT Azathioprine

6-TIMP

TPMT

HPRT 6-TGN

6-MP

ITPA

6-MMP

Figure 1. The metabolic pathway of thiopurines. GST, glutathionine S-transferase; HPRT, hypoxanthine phosphoribosyl transferase; ITPA, inosine triphosphatase (nucleoside triphosphate pyrophosphatase); 6-MMP, 6-methylmercaptopurine; 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; 6-TIMP, 6-thioinosine 5′-monophosphate; TPMT, thiopurine methyltransferase; XO, xanthine oxidase.

as monotherapy in patients with corticosteroid dependence or resistance, thiopurines are now extensively utilized with TNF antagonists as integral components of combination therapy regimens (22,23). However, a critical limitation of these agents is severe myelosuppression, a potentially fatal complication that occurs in ~1 in 300 patients (24). This risk is genetically determined (25). Thiopurines undergo complex metabolism to active 6-thioguanine nucleotides (6-TGs). Steady-state intracellular metabolite concentrations are attained within ~4 weeks based on multiple enzymatic steps (Figure 1). Heterogeneity of TPMT activity is a critical determinant of myelotoxicity. Approximately 90% of Caucasians have normal TPMT activity (homozygous wild type), 10% have intermediate activity (heterozygotes), and 0.3% has negligible enzymatic activity. The latter patients are at risk for potentially fatal bone marrow suppression (26) because they have minimal ability to deactivate 6-MP and preferentially shunt its metabolism to 6-TGs that then results in an excess myelosuppression. Thirty TPMT gene variants have been identified (27–30). The most common mutant alleles are TPMT*2, *3B, and 3*C (31–33). A strong concordance exists between TPMT genotype and phenotype (i.e., enzyme activity) (34,35). However, severe myelosuppression has occurred in patients with either wild-type or heterozygous genotypes, and this calls into question the predictive value of genotyping and holds out the possibility that direct measurement of functional activity might be a preferable screening tool to genetic testing. Even though direct comparisons of TPMT genotyping and phenotyping show comparable sensitivity and specificity, the majority of studies evaluated small numbers of patients and lacked statistical power to identify important differences (35,36). Although rare cases of severe bone marrow suppression have occurred in patients with normal TPMT activity, it is not clear that these events are mechanistically related to this pathway. However, their occurrence underscores the need for continued monitoring of complete blood counts following initiation of thiopurine therapy irrespective of TPMT status (37,38). Therefore, the optimal method of testing remains unknown. © 2014 by the American College of Gastroenterology

Traditionally, AZA and 6-MP are initiated at a low dose and then gradually increased to a full therapeutic dose of 2.0–2.5 and 1.5 mg/kg/day, respectively, if the leukocyte count remains normal. This incremental strategy, which requires weeks of monitoring and potentially results in suboptimal results, can be replaced by an algorithmic approach based on assessment of TPMT status, whether using genotype or phenotype (activity).In this model, full-dose therapy can be initiated without delay in patients with normal enzyme activity (Figure 2). As a consequence, patients require less time to achieve steady-state concentration of 6-TGs, less frequent hematologic monitoring (39,40), and lower drug doses (in heterozygotes). This approach has only recently been introduced into clinical practice. Although ascertainment of TPMT status facilitates the early use of full-dose therapy, we acknowledge that some clinicians may continue to employ an incremental approach to dosing based on the belief that this approach may reduce the incidence of other side effects such as nausea and myalgia. In a previous placebo-controlled study, 96 patients with severely active CD were randomized to receive a 36-h intravenous infusion of AZA or placebo followed by oral AZA for 16 weeks. No significant difference in steroid-sparing effect or clinical remission was seen between the two groups at the end of follow-up despite a steady state in 6-TG concentration after 1 week for both groups (41). Interestingly, a recent Canadian survey of 216 IBD patients who were tested for TPMT before AZA treatment revealed that in many cases test results did not influence physician behavior. Only 40% of patients with normal TPMT activity initially received a full therapeutic dose of drug (42), indicating that physicians, who have not had prolonged experience with this strategy, remain wary about immediately proceeding with full-dose therapy on the basis of genetic testing. Given the available evidence regarding the predictability of TPMT testing, the hesitancy on the part of physicians to utilize this information suggests that additional continuing physician education, particularly in relation to pharmacogenetic testing and clinical relevance, is needed for greater adoption of TPMT testing and AZA dosing. The use of TPMT testing has been hindered to some degree by the reluctance of some insurance carriers to cover the cost of the testing (either in the United States as private insurance, or outside the United State), resulting in the test not being ordered. We acknowledge that definitive data are lacking for the optimal approach to thiopurine dosing but a randomized controlled trial is not practicable and existing observational data strongly support using full dosing with normal phenotypic profiles. The potential economic benefits of TPMT testing have been evaluated in multiple studies. A meta-analysis of seven costeffectiveness studies has concluded that the cost of TPMT testing to prevent one case of severe neutropenia was ~5,300 euros ($7,000 USD) (43), and this could be viewed as cost effective, particularly if a severe neutropenia is likely to result in hospitalization or risk for infection or sepsis, where the overall cost incurred could rapidly rise to well in excess of $10,000. Similarly, a population-based pharmacoeconomic model estimated that testing was a dominant strategy; i.e., it resulted in both better The American Journal of GASTROENTEROLOGY

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Indication for thiopurine treatment

TPMT genotype or phenotype testing

Low or absent TPMT

Normal or high TPMT

Intermediate TPMT

Alternative treatment (e.g., methotrexate, anti-TNF. surgery)

Full dose 6-MP (1–1.5 mg/kg) or AZA (2–3 mg/kg)

Reduce thiopurine dose by 50% and monitor CBC and liver enzymes (consider 6-TG and 6-MMP monitoring)

Response

Toxicity or nonresponse

Monitor CBC and liver enzymes’

Check 6-TG and 6-MMP levels

Low 6-TG and low 6MMP levels

Low dose

Response

Monitor CBC and liver enzymes*

Low 6-TG and High 6MMP levels (preferential 6-MMP producers)

High 6-TG levels or optimal 6-TG levels**

Non-compliance

Increase dose or check compliance

Alternative treatment

Figure 2. Proposed algorithm for treatment of inflammatory bowel disease with thiopurines. *Adjust the dose in cases of suspected drug toxicity. **Rule out infection, stricturing disease. Adapted from Papadakis (128). Anti-TNF, anti-tumor necrosis factor; AZA, azathioprine; CBC, complete blood count; 6-MP, 6-mercaptopurine; 6-MMP, 6-methyl mercaptopurine; 6-TG, 6-thioguanine; TPMT, thiopurine methyl transferase.

outcomes and reduced costs (44). Based on the totality of the existing data, many experts currently recommend measuring TPMT activity before initiating therapy (45). Although TPMT testing is not specifically endorsed in guidelines issued by European (European Crohn’s and Colitis Organization (ECCO)) or North American professional societies (American Gastroenterology Association (AGA)/Canadian Association of Gastroenterology (CAG)), the Food and Drug Administration (FDA) recommends TPMT genotyping or activity testing before initiation of AZA or 6-MP. Although the clinical and economic benefits of TPMT testing (46,47) is likely to remain controversial, the pace of development in genomics technology has meant that cost of genotyping will continue to decline, and thus cost–benefit ratio will likely favor TPMT testing within the next few years. The right patient at the right time: risk stratification in IBD

A personalized approach to therapy has great promise to improve disease outcomes. Selection of high-risk patients as candidates for the early introduction of highly effective therapy can both maxiThe American Journal of GASTROENTEROLOGY

mize treatment efficiency and prevent long-term complications. Multiple observational studies and subgroup analyses of controlled trials of TNF antagonist indicate that early initiation of therapy is associated with lower rates of surgery, hospitalization, and steroid requirements in CD (23,48). Clinical risk factors such as young age at disease onset, fistulizing/stricturing disease phenotype (49), perianal disease (50), cigarette smoking, foregut disease, first presentation with a penetrating complication, and early postoperative recurrence are associated with a poor prognosis (51). In addition, endoscopic severity of disease (52,53), genetic markers (e.g., nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations and autophagy pathway single-nucleotide polymorphisms) (50,54,55), and serological markers (56) have been proposed as objective indicators of risk that can be used to individualize therapy. Serological panels that include a wide range of genetic mutations and antibodies linked to IBD are commercially available, and although their clinical utility has not been clearly established, they are increasingly ordered in clinical practice despite their fairly high costs. Clinical VOLUME 109 | JULY 2014 www.amjgastro.com

predictors of severity and colectomy have also been identified in UC. Traditional predictive tools such as the Truelove and Witt’s criteria rely on clinical variables such as stool frequency, blood in the stool, pulse rate, temperature, and the erythrocyte sedimentation rate to prognosticate (57–63). Although these criteria (64) are widely used because of their clinical sensibility, they have not been validated. The “Oxford index” is a clinical prediction rule that evaluates the serum C-reactive protein concentration and the number of bloody bowel movements on the third day (57). As patients who are classified as severe have a high probability of requiring colectomy, this clinical prediction rule allows clinicians to select which patients are candidates for either cyclosporine or infliximab (IFX) therapy at a time when a change of therapy is likely to result in optimal results (57). Other biomarkers for an increased risk of colectomy include a low serum albumin concentration and an elevated fecal calprotectin concentration (58,65,66). Endoscopic disease severity may be a dominant predictor of outcome in severe colitis. Specifically, in one retrospective study, the presence of deep ulceration was associated with colectomy in 44 of 46 patients (96%) with severe UC (67). The endoscopic activity index is used to evaluate patients presenting with severely active UC and can be useful in selecting treatments. This index, which closely correlates with clinical activity, scores patients based on size of ulcers, depth of ulcers, redness, bleeding, mucosal edema, and mucosal exudates, with higher scores indicating more severe disease (68). More recently, persistence of microscopic inflammation in patients with endoscopic healing has been identified as an independent risk factor for poor outcomes including hospitalization, colectomy, and colorectal cancer (70–73). Despite the large number of candidate predictors available in IBD, no validated model exists for risk stratification in either CD or UC. Given the variability in prognosis of both diseases and the evolving complexities of medical treatment algorithms, development of such instruments remains a research priority. In the interim, the best evidence currently available supports the use of combined TNF antagonist/immunosuppressive therapy in high-risk patients based on the previously described clinical and endoscopic predictors. The right dose: TDM

Following initial selection of treatment, TDM with dose adjustment and titration of serum drug concentrations has the potential to minimize toxicity and maximize efficacy. This approach, which is routinely used for many drugs such as antibiotics (69,70) and calcineurin inhibitors (71), is gaining support in IBD.

Therapeutic drug monitoring and thiopurine therapy. Thiopurines are frequently discontinued because of inadequate efficacy despite the use of recommended doses (72). One potential cause of this problem is the previously described variability in the metabolism of these agents. Therefore, measuring serum concentrations of 6-TG with subsequent dose adjustment to a target metabolite concentration has the potential to increase © 2014 by the American College of Gastroenterology

efficacy. In an important observational study, Dubinsky et al. (73) determined that patients with a 6-TG concentration of > 235 pmol/10(8) red blood cells (RBCs) had a substantially greater chance of responding to treatment than those with lower metabolite concentrations (odds ratio 5.0; 95% confidence interval, 2.6–9.7; P value < 0.001). Choice of this cut point is supported by several other retrospective studies (74). In another small study, 57 CD patients treated with standard AZA dosing (2.5 mg/kg) for maintenance were randomized to usual therapy or dose adjustments based upon targeted 6-TG concentrations for 16 weeks. At 16 weeks, the remission rate (Crohn’s Disease Activity Index < 150) in patients assigned to TDM was 40% compared with 44% in those assigned to usual therapy (P value = 0.99) (75). A meta-analysis by Osterman et al. (76), which included 12 clinical studies, showed that a 6-TG concentration of > 230 pmol/10(8) RBCs correlates with clinical remission (pooled difference between patients in remission and patients not in remission = 66 pmol/8×10(8) RBCs; 95% confidence interval, 18–113; P value = 0.006). A double-blind randomized controlled trial sponsored by the National Institutes of Health that compared standard dosing and test (TPMT genotype before and 6-TG levels after induction dose)-based dosing of AZA in CD attempted to definitively assess the value of metabolite testing. However, this trial was terminated prematurely because of poor recruitment after enrolment of only 50 patients. A trend in favor of the testing group for the outcome of clinical remission at week 16 (40 vs. 16%, P value = 0.11) (77) was observed; however, definitive conclusions were not possible. However, it is noteworthy that the sensitivity and specificity of thiopurine metabolite testing is relatively low. Furthermore, the most supportive data come from a study that evaluated a small sample of children and used a nonvalidated clinical end point as a response measure (78). This concern was later on addressed in the meta-analysis of Osterman et al. (76) that included data from adult studies that used clinical remission as an end point. Based on the totality of data, more studies are needed to justify the use of 6-TG concentration based dosing of thiopurines. TDM may also play a role in minimizing the risk of adverse events as elevated 6-methylmercaptopurine (6-MMP) concentrations have been linked to hepatotoxicity (79). In the previously described study by Dubinsky et al. (73), a 6-MMP concentration of 5,700 pmol/8×10(8) RBCs was associated with a threefold increase in the incidence of elevated liver enzymes. As a result, measurement of 6-MMP has been proposed as a means of minimizing hepatotoxicity secondary to thiopurines (80). Historically, thiopurines were discontinued if transaminase elevations occurred, resulting in discontinuation rates of up to 10%. Thiopurine dose adjustment based on measurement of erythrocyte 6-MMP concentrations has been suggested as a strategy to minimize this problem. However, the studies that have assessed the validity of this approach are relatively small and retrospective in design (81,82). Although monitoring of 6-TG concentrations has been advocated as a means of reducing the risk of myelotoxicity, this approach cannot replace serial monitoring of complete blood counts as myelosuppression is more often because of other causes (38,83). The American Journal of GASTROENTEROLOGY

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In summary, although strong observational data support the value of measuring thiopurine metabolites, prospective experimental evidence validating this approach is lacking. As a result, TDM has not been endorsed by the guidelines issued by ECCO, AGA, and CAG. The role of TDM for TNF antagonists

TNF antagonists are the most effective class of drugs currently available for the treatment of IBD (84–86). Nevertheless, approximately one-third of patients fail to respond to induction therapy and ~40% lose response over a year (87–89). Patients who lose response to IFX are typically managed by empiric dose intensification or switching to another agent (90–95). Treatment options for IBD are quite limited, and as a consequence, optimizing the use of biologic agents is essential. Multiple mechanisms are responsible for treatment failure including the presence of other pathologies (fibrostenotic disease; bile salts diarrhea, enteric infection), inflammation due to non-TNF-mediated pathways, and inadequate serum drug concentration with or without the development of antidrug antibodies (ADAs). The latter problem has gained considerable attention based on the recognition that the metabolism of monoclonal antibodies is highly variable. Development of ADAs can lead to neutralization of TNF antagonist effects by several mechanisms including accelerated clearance by the reticuloendothelial system that results in subtherapeutic drug concentrations. Multiple studies have shown a strong inverse correlation between the development of ADAs and clinical efficacy. In a cohort of 125 CD patients predominantly treated with intermittent therapy, Baert et al. (96) made the following observations: (i) the development of titer ADAs resulted in a shorter duration of response to IFX (71 days and 35 days, respectively, P value < 0.001); (ii) serum drug concentrations ≥12 μg/ml at week 4 following an infusion resulted in longer time to relapse compared with values below this threshold (81.5 days and 68.5 days, respectively, P value < 0.01); and (iii) concomitant use of AZAs was associated with higher drug concentrations at week 4 and a lower likelihood of ADAs (43% (24/56) vs. 75% (52/69), P value < 0.001). The benefit of combining biologic therapy with immunosuppression was made clear after the SONIC trial was published in 2010 (22). In this double-blind, randomized, placebocontrolled trial, 508 patients with immunosuppressive and biologic-naive moderate to severely active CD were randomized to one of three arms: IFX (5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks) combined with oral placebo, AZA (2.5 mg/kg/day) combined with intravenous placebo, or a combination of IFX and AZA for 30 weeks. More patients in the combination therapy group achieved corticosteroid-free remission (56.8% vs. 44.4 vs. 30%, P value ≥0.001 for comparison with combination therapy and 0.006 for IFX) and mucosal healing (43.9 vs. 30.1% vs. 16.5%, P value < 0.001 for the comparison with combination therapy and P value = 0.02 for the comparison with IFX) at week 26 compared with monotherapy with IFX or AZA combined with placebo. The greater efficacy observed in the combination therapy group can be partially attributed to lower rates of ADA formation (1% vs. 13%) and higher IFX trough concentrations (3.5 vs. 1.6 μg/ml, P value < 0.001 at week 30). These results have been replicated in The American Journal of GASTROENTEROLOGY

multiple large-scale studies (97–100). The “pros” of combination therapy including the reduction of ADA concentrations should however always be weighed against its “cons,” specifically risks of infection (101,102) and hepatosplenic T-cell lymphoma (103). “Humanization” of monoclonal antibodies has not overcome the problem of sensitization. ADAs occur in up to 38% of patients treated with adalimumab (69,104–107). In a cohort of 301 CD patients who had previously failed IFX and were subsequently treated with adalimumab for a median of 20.3 months, 61.5% of patients remained in clinical remission for the complete duration of follow-up. However, 40% of patients discontinued therapy because of loss of response. Dose escalation was required in ~15% of patients at 30 weeks, 42% at 60 weeks, and 80% at 120 weeks. Patients who discontinued adalimumab therapy were more likely to have lower trough drug concentration and ADAs. These results demonstrate that ADAs to adalimumab and low trough drug concentrations are strongly associated with treatment failure. Based on these cumulative findings, an important role for TDM has emerged in clinical practice. The three types of assay techniques currently available, the enzyme-linked immunosorbent assay (ELISA) (108,109), the high-pressure liquid chromatography-based homogeneous mobility shift assay, and the radioimmunoassay, share three fundamental steps for detection of ADA and serum drug levels: (i) identification of a capture molecule with affinity to bind the target; (ii) incubation of the capture molecule with serum containing the target; and (iii) quantification of the target. In ELISA-based assays, the drug is used to capture ADAs, whereas TNF-α serves at the capture moiety for the drug. Following capture-target binding, a color-producing antibody is incubated with the target. This molecule can be quantified by photometry to estimate the concentration of the target. If both ADAs and drugs are present in the serum sample, the interaction between these molecules prevents binding of the target to the capture moiety (110). Although ELISA assays are simple to perform, they are limited as they cannot detect ADA or drug in the presence of both molecules. Homogeneous mobility shift assay overcomes this limitation, by introducing an acid-dissociation step that separates ADA and drug in the serum, before incubation with a dye-labeled capture moiety. Quantification of the target is obtained by running the sample over a size-exclusion high-pressure liquid chromatography. The homogeneous mobility shift assay has the advantage of quantifying the total serum concentration of the target (both free target and target bound in ADA/drug complexes) (111). Radioimmunoassay utilizes a radiolabeled capture moiety. As IFX and adalimumab are immunoglobulin G constructs with κ light chains, an anti-Fc antibody is added to detect drug levels. This complex is precipitated with centrifugation and quantified by assessing the radioactivity. ADAs, however, are detected using chromatography columns lined with anti-λ light chains that bind the drug–ADA complex (112). One of the major concerns about the interpretation of drug antibody concentration results is the lack of comparability between biologic drug assays from different vendors. There is currently no standard for concentrations of IFX or adalimumab, and most of the published data (and cut points) are based on ELISA and more recently mobility shift assays VOLUME 109 | JULY 2014 www.amjgastro.com

Table 1. A guide to interpreting results of serum infliximab levels and antibodies to infliximab (ATIs) ATI negative Serum infliximab level < threshold

Serum infliximab level ≥ threshold

Infliximab dose escalation

Endoscopic evaluation vs. switch

ATI positive Low levels

High levels

Dose optimize

Switch drug

Mild disease activity

High disease activity

Monitor

Switch Drug

from Prometheus Laboratories (San Diego, CA), ELISA assays from Janssen (San Diego, CA), and an in-house ELISA assay from Leuven (Pharmaceutical Biology, KU Leuven, Belgium), which is not commercially available. At this juncture, it is not clear what to do with nonzero concentrations from other vendors where cut points have been established, or how they compare with the concentrations in published papers. Further efforts to evaluate differences among assays and validate the currently proposed target trough concentrations against clinically relevant outcomes are needed. Based on current understanding of the relationship between ADA and drug levels on clinical outcomes, TDM can be used to manage patients with a secondary loss of response to a TNF antagonist (113) (Table 1). Low drug concentrations in the absence of ADAs indicate a need for dose intensification. However, this strategy is not recommended for low serum drug concentrations in the presence of ADAs. This group is sensitized to the drug and will likely benefit from switching to another TNF antagonist agent (114,115). When ADAs are not detected and an adequate drug concentration is present, other causes of symptoms should be ruled out. If active inflammation is confirmed, consideration should be given to switching therapy to an “out of class” agent. Evidence for the benefit of TDM-based management approaches has begun to emerge. In a decision analysis model, a TDM-based algorithm resulted in improved outcomes and lower cost, compared with empiric management of patients with secondary loss of response to IFX (116). The cost effectiveness of a TDM-based management approach was compared with conventional empiric dose intensification in a randomized, double-blind, multicenter trial. Although efficacy was similar for the two strategies (response rates were 58% and 53% in the TDM and standard care group, respectively), TDM was more cost effective than empiric dose intensification ($7,736 and $11,760 USD per patient treated, P value < 0.001) (117). Conversely, in the large, single-center, double-blind, prospective clinical study (The Trough Concentration Adapted Infliximab Treatment Trial (TAXIT)), 270 consecutive IBD patients under long-term maintenance treatment with IFX infusions were optimized for IFX trough concentrations (3–7 μg/ml) and were randomly assigned to conventional follow-up using clinical parameters vs. IFX dosing using therapeutic trough concentrations as target and were evaluated for clinical and biochemical (C-reactive protein ( < 5 mg/l) remission after 1 year. Of the patients in clinical remission, 43% were found to have adequate trough concentrations, 9% had undetectable trough © 2014 by the American College of Gastroenterology

concentrations, and 26% had supratherapeutic trough concentrations. Patients with trough concentrations < 3 μg/ml had significantly higher C-reactive protein (2.75; 1.03–7.53 mg/l) compared with those with therapeutic (1.45; 0.60–3.28 mg/l; P value = 0.001) and supratherapeutic concentrations (1.20; 0.60–4.80 mg/l; P value = 0.01). This highlights the importance of clinical evaluation and that therapeutic drug monitoring can be used as supplement to clinical suspicion of activity. Given the highly selected and previously optimized nature of this patient population, these data cannot be readily extrapolated to other patient populations. It is notable that the cost per assay in TAXIT was 20 EUROS that is considerably lower than the costs of commercially available testing in North America that ranges between ~$250 and $2,500 USD per test. Nevertheless, a cost utility analysis demonstrated that even if the assay price was $2,500, use of TDM still resulted in cost savings (118). Another recently described method of TDM is measurement of fecal drug concentrations. This approach was reported in a small prospective pilot study that involved 9 IBD patients recently started on IFX treatment. Fecal IFX concentrations were highest in the first few days following initiation of therapy. Patients who responded to IFX had fecal drug concentrations that were lower than concentrations in nonresponders. This approach requires further research before it can be adopted in clinical practice (119). Treat to target

Contrary to the traditional approach, there is strong evidence that titrating drug therapy toward symptomatic relief in CD is not an effective strategy and can predispose patients to potential complications. The relatively new concept of “treat to target” is therefore becoming more popular. This strategy, which is largely extrapolated from treatment algorithms for other inflammatory disorders, particularly rheumatoid arthritis (120), revolves around serial objective evaluations of inflammatory burden through endoscopic, radiologic, and biochemical parameters. Endoscopic response “mucosal healing” is by far the most robust outcome based on many studies (121,122). As such, treatment algorithms for CD based on this strategy has been proposed (2). Validated scoring systems, uniformly accepted definitions, and reliable time frames are needed to optimize this approach (123). Patient-based monitoring of disease activity: the new frontier

In many jurisdictions, limited access to IBD specialists is a barrier to high-quality care. One means of managing this problem is to actively engage patients in monitoring their disease activity and response to treatment. Technological advances such as telemedicine, home biomarker testing, and internet-based patient management tools are now available to facilitate this approach, and these appear to be popular with patients. For example, self-management was favored by 87% of 147 IBD patients who assessed the relative value of an annual phone call by a nurse practitioner and a physician office visit (124). In another study, 27 patients with CD who were receiving IFX maintenance therapy participated in a web-based program that facilitated individualized care. Patients measured their disease activity and fecal calprotectin once a week. These results were used to adjust The American Journal of GASTROENTEROLOGY

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Diagnosis

Right Patient/Right Time (Risk Profiling)

Clinical Predictors Genetic Predictors Serological Markers

Right Drug (Selection of Therapy)

Right Dose (SNPs)

High Risk Features Early Onset Fistulizing/Stricturing Phenotype Cigarette Smoking Foregut Disease NOD2/CARD15 Mutations Complications at Diagnosis

Early “Top Down Therapy” Combination Therapy Second Line Agents Investigational Drugs Surgery

Low Risk Features Mild Localized Inflammatory Phenotype Preserved QOL

Conventional “Step Up Therapy” Steroids 5-ASA Immunosuppressants

Normal Metabolizers Full Dose

Low Metabolizers Lower Dosages with caution

Optimal Response Drug Levels for Withdrawal of Therapy

Suboptimal Response Drug Levels (Anti-TNF) Anti Drug Antibodies (HACA and HAHA) Thiopurines Metabolites (6-TG/6-MMP levels and ratio)

5-ASA Genetic Profiling MTX Genetic Profiling TPMT Genotype/Phenotype TNF Genetic Profiling Glucocorticoid Genetic Profiling Therapeutic Drug Monitoring (Assessing Response)

Dose Adjustment

Therapeutic Drug Monitoring (Assessing Toxicity)

Switch to Other Class

Use Other Drugs for Metabolic Shifting (e.g 5-ASA Agents or Allopurinol)

Drug Levels (Anti-TNF) Anti Drug Antibodies (HACA and HAHA) Thiopurines Metabolites (6-TG/6-MMP levels and ratio)

Figure 3. An algorithmic-based approach incorporating the use of personalized medicine in inflammatory bowel disease management. 5-ASA, 5-aminosalicylic acid; CARD15, caspase recruitment domain-containing protein 15; HACA, human anti-chimeric antibody; HAHA, human anti-human antibody; 6-MMP, 6-methyl mercaptopurine; MTX, methotrexate; NOD2, nucleotide-binding oligomerization domain-containing protein 2; QOL, quality of life; SNP, single-nucleotide polymorphism; 6-TG, 6-thioguanine; TNF, tumor necrosis factor; TPMT, thiopurine methyl transferase.

their IFX dose scheduling. Patients who were identified as being poorly controlled were triaged to receive clinic appointments and a physician evaluation. Of the infusions, 10% were administered as scheduled at the usual 8-week intervals, but 30% were given at shorter intervals and 50% at longer intervals. No significant difference was seen between the two groups in inflammatory burden, based on Harvey–Bradshaw index scores or quality of life. The authors concluded that self-management strategy was both safe and effective (125). However, it is noteworthy that this study was not randomized or blinded and did not assess serum ADA and drug concentrations. Lengthening the dosing interval of IFX has the potential to result in subtherapeutic drug concentrations at trough and sensitization (100). Accordingly, the addition of TDM into the monitoring phase may offer vital information that could be used to guide dosing. Additional support for the concept of patient participation in disease management comes from the results of a randomized controlled trial that compared conventional physician-guided management and webbased patient-centered management in 333 patients treated with The American Journal of GASTROENTEROLOGY

5-aminosalicylic acid therapy for moderate to severely active UC in Denmark and Ireland. Participants were assigned to either a web-based management group that received disease-specific education and self-treatment or a control group that continued usual physician-directed care for 12 months. The median time to relapse was substantially longer in the web-management group (8 vs. 77 days, P value < 0.001) than for those who received conventional management. Fewer outpatient visits and lower costs of care were also observed in the experimental group (126). In the web-based arm, 80% of the patients preferred web-based patient-centered management. In another prospective trial, 203 UC patients were randomly assigned to a self-care strategy that consisted of follow-up on demand or to conventional scheduled outpatient monitoring by a physician. Relapses were treated more promptly in the self-management group than the conventional group (14.8 vs. 49.6 h, P value < 0.0001) (127). Fewer visits to the hospital and to the primary care physician were seen in the self-care group compared with conventionally managed group (0.9 vs. 2.9 per patient per year, difference 2.0 (1.6–2.7) and 0.3 vs. VOLUME 109 | JULY 2014 www.amjgastro.com

0.9 per patient per year, difference 0.6 (0.2–1.1, P value < 0.006), respectively). Collectively, these data suggest that use of a personalized, patient-directed approach to management has potential to improve outcomes and reduce costs. In conclusion, given our current understanding of the treatment of IBD, personalized medicine has great potential to improve patient care. Although a comprehensive, integrated model of personalized IBD care does not currently exist (Figure 3), multiple components of this paradigm have emerged. Risk profiling is a fundamental concept that should be used to guide initial selection of treatment. High-risk patients should receive the best treatment available that, currently, is a TNF antagonist in combination with a thiopurine. TPMT testing before initiation of treatment with thiopurines reduces the risk of potentially fatal myelosuppression. Measurement of 6-TG/6-MMP metabolite concentrations in RBCs may optimize both the efficacy and safety of these agents. Measurement of serum dug concentrations and ADAs is highly valuable for patients who have lost response to TNF antagonists. Treatment to the target of mucosal healing may improve clinical outcomes. Web-based electronic tools that allow patients to monitor their disease activity and response to treatment based on clearly defined targets may improve both efficacy and safety. CONFLICT OF INTEREST

Guarantor of the article: Brian G. Feagan, MD. Specific author contributions: M.H.M.: contributed to the paper’s concept and intellectual content, performed the literature review, drafted, critiqued, and revised the article; B.J., R.B.K., R.K., W.J.S., and B.G.F.: contributed to the paper’s concept and intellectual content, critiqued, and revised the article. Financial support: None. Potential competing interests: Reena Khanna has received speaker’s fees from Takeda. Professor Sandborn has received consulting fees from AbbVie, ActoGeniX NV, AGI Therapeutics, Alaven Pharmaceuticals, Alba Therapeutics, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Atlantic Healthcare, Axcan Pharma, BioBalance, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Centocor, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research, ELAN, EnGene, Eli Lilly, Enteromedics, Exagen Diagnostics, Ferring, Flexion Therapeutics, Funxional Therapeutics, Genzyme, Genentech, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera, Merck Research Laboratories, MerckSerono, Millennium, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Receptos, Relypsa Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, ScheringPlough, Shire Pharmaceuticals, Sigmoid Pharma, Sirtris Pharmaceuticals, SLA Pharma (UK), Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics, Warner Chilcott and Wyeth. He has received lecture fees from

© 2014 by the American College of Gastroenterology

AbbVie, Bristol-Myers Squibb, and Janssen. He has received research support from AbbVie, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Biotech, Millennium Pharmaceuticals, Novartis, Pfizer, Procter & Gamble, Shire Pharmaceuticals, and UCB Pharma. Brian G. Feagan has received payment for development of educational presentations, including service on the speakers’ bureau for Abbott/ AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma. He has received travel/accommodation compensation from Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Axcan, Baxter Healthcare Corp., Boehringer-Ingelheim, BristolMyers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Merck, Millennium, Nektar, Novonordisk, Prometheus Therapeutics and Diagnostics, Pfizer, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, Tillotts, UCB Pharma, Vertex Pharma, WarnerChilcott, Wyeth, Zealand, and Zyngenia. He has received compensation for his membership on the scientific advisory boards of Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Salix Pharma, Takeda, Teva, Tillotts Pharma AG, and UCB Pharma. The remaining authors declare no conflict of interest.

Study Highlights WHAT IS CURRENT KNOWLEDGE

3Personalized medicine is an evolving concept. 3Therapeutic drug monitoring can be used to enhance inflammatory bowel disease (IBD) patient care. 3Thiopurine methyltransferase enzyme activity plays an important role while deciding to use thiopurines for managing IBD patients.

3Measuring thiopurine metabolites is helpful during the follow-up of IBD patients treated with thiopurines. 3The measurement of serum levels and detection of antibodies toward tumor necrosis factor (TNF) antagonists are valuable tools that can be used to assess secondary nonresponse to this class of drugs.

WHAT IS NEW HERE

3There is a great need of risk stratification models and tools for IBD patients as part of a personalized medicine approach to patient care.

3The cost effectiveness of thiopurine methyl transferase

(TPMT) activity assessment before thiopurine therapy and the measurement of thiopurine metabolites during the course of treatment with thiopurines needs further research evaluation.

3Integrated therapeutic algorithms for the management of patients with IBD are needed. 3Treat to target is an evolving concept used for the treatment of IBD that has significant potential. 3Patient self-monitoring using interactive and electronic measures is being introduced as a personalized method of IBD patient care that may improve compliance and reduce the burden of outpatient care.

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