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Anti-TNF levels and anti-drug antibodies, immunosuppressants and clinical outcomes in inflammatory bowel disease Expert Rev. Gastroenterol. Hepatol. 9(4), 497–505 (2015)

Christina Ha1, Jagrati Mathur2 and Asher Kornbluth*3 1 Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA 2 Department of Medicine, University of California San Francisco, Fresno, CA, USA 3 Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, 1751 York Avenue, New York, NY 10128, USA *Author for correspondence: [email protected]

The anti-tumor necrosis factor-a (TNF) antibodies have revolutionized the management of ulcerative colitis and Crohn’s disease. The development of assays to allow for the measurements of serum drug levels and anti-drug antibodies have provided a more objective means of therapeutic decision making, particularly among patients losing response to treatment. Additionally, more evidence is emerging that indicates the relationship between drug levels and response to therapy including clinical response, mucosal healing and sustained remission. The use of combination therapies of the anti-TNF agents and the thiopurine immunosuppressants may also decrease immunogenicity to the anti-TNF agents and potentiate response to therapy. With more evidence emerging evidence of the importance of therapeutic drug levels and anti-drug antibodies, clinicians may be able to better optimize the current arsenal of inflammatory bowel disease therapeutics to achieve greater rates of durable remission and improved quality of life. KEYWORDS: anti-drug antibodies • anti-tumor necrosis factor agents • Crohn’s disease • immunogenicity • immunosuppressants • therapeutic drug levels • ulcerative colitis

The introduction of the biologic family of anti-tumor necrosis factor-a (anti-TNF) monoclonal antibodies has been a major breakthrough in the treatment of inflammatory bowel disease (IBD) refractory to conventional therapies. Immunosuppressants (IS) such as the thiopurines (azathioprine [AZA] and 6-mercaptopurine) and methotrexate have been used as IBD treatments for decades, but less than half of patients achieve remission and relapse rates are frequent [1–4]. Although patients on anti-TNF monotherapy achieve higher remission rates when compared to IS alone, patients can either fail to respond to biologic treatment (primary nonresponders) or become nonresponsive over time (secondary loss of response). Thus, several studies have investigated the utility of using combination therapy with both biologics and IS for the treatment of moderate-to-severe IBD [5,6]. The SONIC trial provided evidence that patients informahealthcare.com

10.1586/17474124.2015.983079

with moderate-to-severe Crohn’s disease (CD) naı¨ve to AZA and infliximab (IFX), a combination of both these drugs was superior for inducing and maintaining steroid-free remission and mucosal healing when compared to monotherapy with either drug [6]. The UCSUCCESS trial similarly demonstrated improved week 16 steroid-free remission rates with combination therapy compared to IFX or AZA monotherapy [7]. While the addition of IS to biologic therapy may decrease the immunogenicity of biologics and improve the drug levels, the durable impact of this strategy remains inconclusive and exposes patients to the risks associated with combination therapy [8,9]. These primarily include serious infections including opportunistic infections and a potentially increased risk of lymphoma with sustained use [10–12]. Weighing the risks and benefits of combination therapy with IS and biologics for the treatment of moderate to severe IBD is

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challenging for many clinicians. The aim of this review is to summarize the data available on the effects of combining IS with biologics on drug levels and immunogenicity.

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Immunomodulators

The thiopurines, AZA and 6-mercaptopurine have been used for the treatment of CD and ulcerative colitis for decades but primarily to maintain a steroid-induced response or remission as this class of medications has not demonstrated consistent efficacy for induction of remission. AZA and 6MP are purine analogs that inhibit nucleic acid metabolism arresting cell proliferation and thus have immunomodulating properties [13]. These immunomodulators are currently indicated for the treatment of active steroid-dependent CD or UC [14,15]. The thiopurines may maintain a steroid-induced remission for CD and UC, with demonstrated potential for longer-term steroid sparing, particularly with longer duration of treatment [2,3,16]. Recently published prospective studies, however, suggest their role as a primary maintenance therapy may be limited. Among newly diagnosed adult CD patients starting thiopurine therapy within 8 weeks of diagnosis, there were no differences in sustained steroid-free remission rates between AZA (44%) compared to placebo (36%) at 76 weeks [17]. Cosnes et al. comparing steroid-free and anti-TNF-free periods between newly diagnosed CD with early-initiation of AZA versus conventional management, reserving AZA use for steroiddependent patients only, found no differences in periods of remission with both treatment strategies. However, 61% of conventional-strategy patients received immunosuppression by the end of the follow-up period [18]. Of note, the majority of these newly diagnosed patients were in a steroid-induced remission at the start of these studies. Although a difference between treatment groups was not noted, a sizeable percentage of thiopurine-treated patients were maintained in a sustained remission, suggesting that there may be predictors of thiopurine response for a subset of these newly diagnosed patients. Pre-treatment testing of thiopurine methyltransferase (TPMT) enzyme activity or genotype is recommended to identify the subset of patients with normal activity or wild-type TPMT*1/TPMT*1 genotype (90%), who may be given standard dosing regimens of thiopurines (6MP 1–1.5 mg/kg/day or AZA 2–2.5 mg/kg/day). Other TPMT variants include persons with intermediate activity or heterozygous TPMT*1 plus a non-functional TPMT *2, *3A, *3B, *3C or *4 allele genotype (11%), who require adjusted thiopurine dosing of approximately one-third the conventional weight-based dose or persons with low/absent activity who possess two non-functional TPMT alleles (0.3% in whom thiopurines are contraindicated due to risk of leukopenia) [19,20]. Additionally, TPMT enzyme activity level may also identify patients more likely to respond to thiopurine therapy. AZA-treated patients with a TPMT enzyme activity below 35 pmol/h/mg/Hb had an 81% clinical response rate compared to only 43% response rate among patients with TPMT enzyme activity above 35 pmol/h/mg/Hb [21]. 498

Dose optimization strategies based on measurement of thiopurine metabolites, 6-thioguanine and 6-thioguanine nucleotide (6-TGN), may also improve thiopurine treatment efficacy. A meta-analysis of 12 studies of thiopurine-treated IBD patients with metabolite measurements concluded patients with 6-TGN levels about the threshold value of 230–260 were three times more likely to be in clinical remission than patients with subtherapeutic values [22]. Thiopurine dosing adjustments, based on metabolite levels of 6-TGN, the ‘therapeutic’ metabolite and 6-methylmercaptopurine, associated with hepatotoxicity, have been well described in the literature. Assessments of these metabolites may help identify non-adherent patients, patients who require increased thiopurine dosing, thiopurine ‘refractory’ patients with therapeutic 6-TGN levels or patients who may benefit from the addition of allopurinol to augment 6-TGN levels [23]. Allopurinol, a xanthine-oxidase inhibitor, augments thiopurine response by preferentially shunting thiopurine metabolism from 6-methylmercaptopurine production toward the 6-TGN pathway. Using a combined thiopurine– allopurinol approach led to improved therapeutic outcomes, including decreased disease activity index scores, reductions in steroid requirements and decreased hepatotoxicity [24–26]. However, caution must be exercised with the combined thiopurine– allopurinol strategy to avoid severe leukopenia. Lower doses of the thiopurine are used (e.g., 25 mg of 6-MP) in combination with lower doses of allopurinol (i.e., 50–100 mg daily), and complete blood counts and 6-TGN are followed very closely. With the thiopurines, loss of response due to drug-related immunogenicity does not occur. Therefore, among primary responders to thiopurines with appropriate dose optimization, sustained remission is possible [27]. However, the adverse event potential, including hypersensitivity, headache, nausea, hepatotoxicity, marrow suppression and pancreatitis, may lead to early discontinuation or withdrawal of thiopurines [28]. Up to 25% of thiopurine-treated patients may experience a medication-related adverse event, with close to 20% of patients discontinuing therapy [29]. Fear of more serious adverse events, including lymphoproliferative disorders, may also limit their longer-term utility as increased age and duration of thiopurine therapy are associated with increased adverse event risk [30,31]. Therefore, the present utility of thiopurines as a primary therapy for the treatment of IBD appears to be limited. However, based on more recent studies of combination anti-TNF therapies with immunomodulators, they remain an important part of the IBD therapeutic armamentarium with roles as an adjunct to biologics or possibly maintenance therapy after an anti-TNF-induced remission. Dose optimization of the thiopurines may further augment a clinical response to a primarily anti-TNF-based treatment strategy. Biologics

TNF-a is a key pro-inflammatory cytokine produced by macrophages and T-lymphocytes, which bind to receptors p55 and p75 causing inflammation in IBD. TNF-a activates other Expert Rev. Gastroenterol. Hepatol. 9(4), (2015)

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Anti-TNF levels & anti-drug antibodies, IS & clinical outcomes in IBD

pro inflammatory cytokines including IL-1 and IL-16 enhancing leukocyte migration and inducing acute-phase reactants, thus leading to vicious circle of ongoing inflammation [32]. Biologics in the anti-TNF family used for the treatment of moderate-to-severe IBD include IFX, adalimumab (ADA), for both UC and CD, certolizumab pegol (CZP) for CD and golimumab for UC. Currently, over 150,000 IBD patients are treated with these anti-TNF therapies, which have been a major breakthrough for the management of CD and ulcerative colitis, reducing the rate of hospitalizations and the need for surgery [8,33,34]. Prior to the era of biologics, treatment with IS resulted in an overall 2-year relapse-free rate of only 42% and the 10-year relapse free rates were 12% [35]. IFX is a chimeric mouse–human monoclonal IgG1 antibody to TNF-a and is administered intravenously. It exerts its therapeutic effects by binding to soluble bioactive TNF-a in the intestinal mucosa to neutralize its effects and by binding to membrane-bound TNF-a on activated T cells to induce apoptosis [36]. The ACCENT I trial of IFX for moderate-to-severe CD patients demonstrated greater rates of clinical remission among patients responding to an initial dose of IFX at week 2 who subsequently received scheduled maintenance IFX dosing. After an initial dose of IFX, 58% patients responded by week 2 and 29% had steroid-free remission at week 54 compared to 9% in the placebo group [37]. Post hoc subgroup analyses also revealed greater week 10 and 54 mucosal healing rates among IFX treated-patients receiving maintenance therapy [38]. For fistulizing CD, IFX 5mg/kg given for three doses at- 0, 2 and 6 weeks resulted in complete fistula closure in 55–88%, and the median duration of response was 90 days, 4 weeks after the last dose [39]. The efficacy of IFX for moderate-tosevere ulcerative colitis was demonstrated in the ACT 1 and 2 trials with greater week 8, 30 and 54 clinical response, remission and mucosal healing rates among UC patients treated with either IFX 5 or 10 mg/kg compared to placebo [40]. ADA is a self-injected fully humanized recombinant antibody indicated for use in the induction and maintenance of remission in CD and recently in refractory UC. The pivotal maintenance trial for ADA was Crohn’s trial of the fully human antibody ADA for remission maintenance (CHARM) [41]. ADA-treated patients with moderate-to-severe CD refractory to conventional therapy had a 60% clinical response rate by week 4 with clinical remission rates of 40–47% at week 26 and 36–41% at week 56, which were significantly superior to placebo [41]. The two key randomized controlled trials of ADA for ulcerative colitis were the ULTRA 1 and 2 studies. ULTRA 1 for ADA in ulcerative colitis included only anti-TNF-naı¨ve patients, with the aim to identify optimal induction dosing regimens for week 8 remission. Three groups of patients were randomized to receive either ADA 160 mg followed by 80 mg at weeks 0 and 2; 80 mg followed by 40 mg at weeks 0 and 2; or placebo injections. Only the 160/80 mg induction therapy arm demonstrated significantly greater week 8 remission rates (19%) compared to placebo (9%, p = 0.03). The ULTRA 2 study, which included a informahealthcare.com

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maintenance phase, included anti-TNF exposed patients (40% of study patients) who were secondary nonresponders or had experienced adverse effects (AEs) with prior anti-TNF therapies [42,43]. In the ULTRA 2 trial, week 4 and 52 remission rates (16.5 and 17.3%, respectively) were superior to placebo (9.3 and 8.5%, respectively) for these moderate-to-severe UC patients with an inadequate response to steroid or immunosuppressant therapy [42]. CZP is a pegylated recombinant humanized antigen-binding fragment of a TNF monoclonal antibody. It lacks the Fc portion of the antibody responsible for complement binding and cell lysis [44]. In the PRECISE trials for CZP, moderate-tosevere CD patients received CZP 400 mg at weeks 0, 2 and 4; responders were then randomized to continue CZP 400 mg every 4 weeks or placebo. The CZP-treated patients had a 64% response rate following induction and, at week 26, 63% of CZP maintenance-treated patients had evidence of continued response compared to only 36% of placebo-treated patients. Similarly, remission rates at week 26 were higher among CZPtreated patients (48%) compared to placebo (29%). Response to CZP was no different for those with an elevated C-reactive protein (CRP), concomitant immunomodulators or previous anti-TNF therapy [45–47]. Golimumab, the latest anti-TNF therapy approved by the US FDA in 2013 for moderate-to-severe ulcerative colitis, is another fully humanized monoclonal anti-TNF antibody that is subcutaneously administered. Results from the PURSUIT studies demonstrated superior efficacy for inducing and maintaining clinical response, remission and achieving mucosal healing with improved quality of life compared to placebo at weeks 6 and 54 [48,49]. Although the anti-TNF agents have demonstrated efficacy for moderate-to-severe IBD, these agents are not without associated AEs, with approximately 10% of biologic-treated patients discontinuing therapy due to medication-related AEs [50]. Notable AEs of the anti-TNFs include serious infections, including opportunistic infections (3%), hypersensitivity, hepatotoxicity, hepatitis B reactivation, bone marrow suppression, neurologic complications, drug-related lupus, skin cancers and lymphoma [12,30,51,52]. Anti-TNF drug levels

With the introduction of the anti-TNF therapies, the potential to modify the natural history of IBD with sustained remission, mucosal healing and improved quality of life has increased. However, the durability of these therapies remains a major problem as up to 40% of patients classified as primary responders to anti-TNF therapies lose response over time [53]. This secondary nonresponse to anti-TNFs may be due to subtherapeutic drug levels, the development of anti-drug antibodies or the emergence of alternative mediators and pathways of inflammation. In addition to anti-drug antibodies, anti-TNF levels may be influenced by a variety of other factors affecting pharmacokinetics such as disease activity, decreased albumin and elevations 499

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in CRP and baseline TNF concentration increase drug clearance, resulting in lower serum levels of anti-TNF therapy. Other factors such as increased body mass index and UC disease type may also influence drug levels; therefore, dosing adjustments may be considered based on patient characteristics [9]. Therefore, the potential for loss of response may be anticipated based on the measurements of drug levels during therapy. Multiple studies have demonstrated improved response rates relative to anti-TNF drug levels. Baert et al. reported a 71% response rate among refractory luminal and fistulizing CD patients receiving IFX induction with either a single infusion or three infusions of IFX. There was a direct correlation between higher IFX levels (>12 mg/dl) and duration of response, particularly among patients receiving concomitant IS as they were more likely to have IFX levels >12 mg/dl [54]. Compared to nonresponders, primary IFX responders in the ACCENT-1 study had higher IFX trough levels (4.0 vs 1.9 mg/dl) [55]. Patients enrolled in the ACT 1 and 2 trials for UC with the highest quartiles of IFX levels had significantly greater week 8, week 30 and week 54 remission rates compared to patients with the lower quartiles of IFX levels [56]. Maser et al. showed higher rates of clinical remission, endoscopic improvement and lower CRP among CD patients receiving maintenance IFX with detectable IFX levels, while Van Assche et al. noted lower IFX levels were associated with higher CRP levels and disease activity scores [57,58]. Similarly, Seow et al. reported 69% remission rates and 75% endoscopic improvement rates among UC patients with detectable serum trough IFX levels compared to only 15% remission and 28% endoscopic improvement rates for patients with undetectable trough levels [59]. Preliminary results from the trough level adapted IFX treatment (TAXIT) trial also found a correlation between lower IFX trough levels and CRP elevations among patients on maintenance IFX therapy. Patients with sustained IFX trough levels between 3 and 7 mg/ml had better response and remission rates, more mucosal healing and lower loss of response rates [60]. Higher rates of mucosal healing were also noted among patients with higher IFX trough levels, suggesting a potential role for dose optimization for patients with lower drug levels [61]. In another study, IFX dose optimization among IBD patients with subtherapeutic levels resulted in a complete or partial response among 86% of patients without requiring a switch to a different agent [62]. While the majority of the anti-TNF therapeutic level-based studies have investigated IFX, similar findings have been noted with the other anti-TNF agents. Among ADA-treated CD patients receiving maintenance therapy, 65% of patients required dose escalation. Clinical responders had greater incremental trough levels following dose escalation (5.9 mg/dl) compared to nonresponders (0.0 mg/dl), and patients with lower trough levels were more likely to discontinue therapy due to nonresponse [63]. Roblin et al. conducted a cross-sectional study of IBD patients on maintenance ADA to determine if ADA levels correlated with mucosal healing and remission. Trough 500

levels of ADA were significantly higher among patients with mucosal healing (6.5 mg/dl) compared to patients with endoscopic activity (4.2 mg/dl) [64]. They concluded that ADA levels less than 4.9 mg/dl were associated with endoscopic disease activity [65]. Post hoc data from the MUSIC trial, a 54-week open-label study to assess endoscopic improvement among CZP-treated CD patients, revealed greater endoscopic response and remission rates at week 10 and 54 among patients with the highest quartiles of CZP levels [66]. Increasing rates of clinical response and remission at week 6 were also positively correlated with higher quartiles of golimumab levels among patients receiving induction therapy for moderate-to-severe UC [49]. Although additional prospective dose optimization studies are needed to support the therapeutic efficacy of level-based strategies for clinical practice, particularly factoring in the additive cost with incrementally higher anti-TNF dosing, the current data suggest a potential role for a test-based strategy, particularly among patients with features indicative of rapid drug clearance. Immunogenicity

Immunogenicity occurs when biotechnology-derived therapeutic proteins generate antibodies against themselves, as they contain unique sequences that can elicit an immune response. Antidrug antibodies can be of different isotopes (IgG, IgE or IgM) and are directed against different isotopes of the anti-TNF agents. These antibodies can act on different sites and impede the drug activity by blocking the binding of the monoclonal antibody to TNF or be directed against the fragment antigenbinding domain of the medication. Any of the anti-TNF agents, including the chimeric and fully humanized agents, can trigger immunogenic responses [67,68]. Patients at risk for developing anti-drug antibodies include patients receiving episodic anti-TNF therapy (i.e., without scheduled maintenance dosing), patients with undetectable levels of anti-TNF and patients with a prior history of anti-drug antibodies to a different anti-TNF agent [8]. Baert et al. showed that 61% of patients receiving episodic IFX developed antibodies to IFX (ATI) compared to ATI rates of approximately 6–17% among patients receiving scheduled maintenance IFX [54]. Similarly, in the ACCENT I study, ATI formation was approximately 30% for episodic IFX-dosed patients compared to only 7–10% for patients receiving routine maintenance IFX [69]. Anti-drug antibodies bind to the drug and form a complex, which can be cleared faster and leads to a shortened half-life of the drug and lower drug trough levels, thus decreasing their efficacy [70]. Among ACT 1 and 2 study participants with moderate-to-severe UC, patients who were positive for antibodies to IFX had IFX clearance that was 47% higher than antibody negative patients [71]. Analysis of CD patients enrolled in the ACCENT 1 and REACH (pediatric CD IFX study) also demonstrated increased drug clearance in the presence of ATIs [72]. Similarly, 92% of ADA-treated CD patients with undetectable serum trough levels were positive for antiADA antibodies [63]. Expert Rev. Gastroenterol. Hepatol. 9(4), (2015)

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Anti-TNF levels & anti-drug antibodies, IS & clinical outcomes in IBD

Immunogenicity has been associated with an increased likelihood of hypersensitivity reactions, including infusion or injection site reactions, shorter durations of response and higher nonresponse rates to subsequent therapies [73]. Baert et al. reported approximately 20% of ADA-treated patients had antiADA antibodies present with a positive correlation between antibody formation and increased CRP levels [74]. In addition, based on small retrospective and cross-sectional studies, antibodies to ADA may be associated with nonresponse to therapy and lower rates of mucosal healing [64,75]. The presence of antibodies to ADA was associated with lower serum drug levels (2.1 mg/dl) compared to antibody-negative patients (6.1 mg/dl) and greater medication discontinuation [63]. Lower rates of antibody formation, ranging from 6 to 12%, were reported with CZP studies; however, the presence of antibodies has not consistently been shown to impact therapeutic efficacy [47,76]. Multiple studies have reported decreased immunogenicity potential of the anti-TNF agents with the addition of IS such as the thiopurines or methotrexate [48,69,77–79]. Farrell et al. reported lower rates of ATI formation among patients pretreated with intravenous hydrocortisone prior to IFX infusion (26%) than placebo-treated IFX patients (42%) after 16 weeks of therapy. ATIs were present among 73% of the IFX patients who lost response, whereas none of the patients with sustained response to IFX had detectable antibodies [73]. Immunosuppressant therapy with thiopurines or methotrexate reduced antibody formation among IFX-treated patients (24%) compared to IFX-monotherapy (63%) [73]. In the SONIC trial comparing IFX or AZA monotherapy to combination therapy, only one patient (0.9%) in the combined treatment arm (n = 116) developed ATIs compared to 15% of the IFX monotherapy arm. Additionally, the presence of ATIs was associated with lower rates of steroid-free remission at week 30 [6]. Similarly, in the COMMIT trial of combination IFX and methotrexate therapy, patients treated with both medications were less likely to develop ATIs and more likely to have detectable trough levels compared to patients on monotherapy [80]. Antibody testing may also predict the likelihood of successful re-initiation of anti-TNF therapy after a period of discontinuation. Baert et al. describe the outcomes of 128 IBD patients with prior episodic anti-TNF exposure, who had discontinued therapy for a median of 15 months, but had resumed antiTNF maintenance therapy. The absence of ATIs after the reinitiation dose of IFX and concomitant IS use were associated with better short-term outcomes, and higher IFX trough levels yielded better longer-term outcomes. However, detectable ATIs following the re-initiation dose led to a nearly eightfold increased risk of infusion reactions and nonresponse to rechallenge with anti-TNF [81]. Also, interesting recent evidence suggests that drug antibodies may be transient. Vande Casteele et al. reported that among 53 patients who developed ATIs, 28% of patients’ antibodies, particularly those patients with ‘lower’ ATI levels, were transient and disappeared over time. While patients with ‘higher’ ATI levels were more likely to require treatment discontinuation, informahealthcare.com

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optimization of anti-TNF therapy, including the addition of an immunosuppressant therapy, may overcome these low titer ATIs, although further investigation is certainly warranted [82]. Therefore, therapeutic drug monitoring for the presence of antiTNF antibodies may be useful to identify which patients may benefit from a change in medications, either between classes or within classes or with the combination therapy to further enhance the likelihood of sustained response. The original antibody testing used to detect ATI was the ELISA test, which detected antibodies only in the absence of circulating serum anti-TNF levels. In the presence of circulating drug levels, the antibody testing is inconclusive [83]. Recently, however, the commercially available testing for antiTNF antibodies has changed to a mobility shift assay capable of quantitating both circulating drug levels and antibodies [84]. With this newer assay, positive antibody levels may be subject to additional interpretation as antibody formation may potentially be transient among a subset of patients receiving maintenance or combination therapy with IS. ATIs were present in 46% of IFX-treated patients; however, with repeat assessment during maintenance therapy, 67% of clinical responders had no detectable antibodies but detectable IFX levels (median 3.7 mg/ dl) on repeat assessment after a median of four infusions. On the other hand, nonresponders had persistent ATI levels [85]. In another study, although 59% of IFX-treated patients had confirmed ATI using the new assay, 28% of patients had only transiently detectable ATIs and were able to continue IFX with dose escalation. These patients were more likely to be on concomitant IS therapy and have lower levels of ATIs (median 18.7 mg/dl). Patients with persistent ATIs had higher median levels, 22.1 mg/dl, and were more likely to discontinue therapy or have infusion reactions [82]. These data suggest variable responses to anti-TNF therapies based on the complex interplay of therapeutic drug levels and antibody titers. Additionally, with the new assays, the presence of antibody appears to be more predictive of loss of response or nonresponse to antiTNF therapy as clinical efficacy is impacted even in the presence of therapeutic levels of IFX or ADA [86,87]. The combined use of anti-TNF levels and anti-drug antibody levels may be clinically useful for secondary nonresponders to anti-TNFs, that is, patients with an initial response to treatment but with gradual loss of response. The presence of undetectable trough levels of anti-TNFs and positive anti-drug antibodies is highly sensitive (81%) and specific (94%) for determining loss of response to therapy [88]. Based on these findings, clinical algorithms for patients losing response to anti-TNF therapy, using the presence or absence of anti-drug antibodies and detectable anti-TNF levels, have been published. In the presence of antidrug antibodies, switching to a different anti-TNF agent, particularly if the trough drug levels are low or undetectable may recapture clinical response or remission [62,65]. Therapeutic drug monitoring

With commercially available assays capable of detecting antibodies as well as serum drug levels for both IFX and ADA, the 501

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clinical applicability of a test-based strategy using trough levels and antibody positivity needs to be determined in daily clinical practice. The completion of the ongoing TAXIT trial, comparing the efficacy of a conventional strategy of dose adjustment or therapeutic switch based on clinical symptoms and laboratory values versus empiric dose optimization to achieve IFX levels within a presumed therapeutic window of 3–7 mg/dl, will add insight regarding the need for a level-based clinical standard [60]. However, in addition to the potential for improved efficacy and longevity of the anti-TNF agents, a level-based strategy must also be safe and cost–effective before being widely implemented into practice paradigms. Combination immunosuppression has been consistently demonstrated to impact immunogenicity for the anti-TNF agents. However, risk of serious and opportunistic infections increase with added immunosuppression [11,12]. The duration of combination therapy has not been clearly defined with respect to its impact on therapeutic levels and immunogenicity. In a study looking for predictors of IFX failure after withdrawal of thiopurine, a duration of combination therapy less than 27 months was associated with an increased risk of IFX failure in addition to elevations in CRP and platelet count [89]. Further investigation regarding the potential for medication discontinuation, particularly with the thiopurines, are needed. There are limited data presently available looking at the cost–effectiveness of using trough levels for medical decisionmaking compared to empiric dose escalations or switches. In a recent randomized, controlled, single-blind, multicenter study using an IFX level and antibody-based treatment algorithm compared to empiric dose intensification for secondary IFX nonresponders, Steenholdt et al. reported a 34% cost savings using a test-based approach with similar overall response rates between the two strategies [90]. Similarly, Velayos et al. reported similar response and remission rates as well as quality-adjusted life years gained when comparing an empiric dose-escalation strategy to a test-based strategy using a decision–analysis model for secondary IFX nonresponders with CD. However, the testbased strategy was more cost–effective, with approximately US$5000 savings per quality-adjusted life years [91]. While anti-TNF-based dose optimization strategies may prove to be cost–effective, little is also known about the potential additive benefit of thiopurine optimization during combination therapy. Conventional weight-based dosing of thiopurines may not yield therapeutic levels, especially for patients who are preferential 6 MMP metabolizers or may have higher TPMT enzyme activity [27]. Although thiopurines may not be as effective as anti-TNFs as a primary strategy, immunogenicity is decreased with concomitant immunomodulator use and optimization of thiopurines may be more cost–effective than dose escalation of biologics. Although there are currently no available studies investigating this option, a test-based strategy using thiopurine optimization with combination biologic therapy may also be a reasonable

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approach to consider prior to empiric dose escalation of the anti-TNF agent based on levels. Expert commentary & five-year view

Although the anti-TNF-based therapies have been a remarkable breakthrough for the treatment of moderate-to-severe IBD, it has been repeatedly demonstrated that our current practices using anti-TNF therapy result in suboptimal response and remission rates. We now have a clearer understanding of the factors that influence the pharmacokinetics of these anti-TNF agents and increasing evidence that clinical outcomes among patients treated with anti-TNFs are directly correlated with the presence of adequate drug levels and absence of anti-drug antibodies. The use of concomitant thiopurines reduces the development of these antibodies, thereby increasing anti-TNF drug levels. This knowledge can potentially allow clinicians to use these disease-modifying agents more appropriately and with a more adapted dosing style based on patient and disease-specific features rather than set dosing schemes. Optimizing therapy for the IBD patients involves careful patient selection based on objective and timely assessments of disease activity and severity. Earlier initiation of anti-TNF therapies relative to disease activity leads to better longer-term outcomes, decreased need for steroids, dose escalation, medication changes and surgery [92]. The goals of treatment for the IBD patients are to induce and maintain a steroid-free remission over time, restore normal bowel function and improve quality of life with fewer hospitalizations, surgeries and disability. Using appropriate induction dosing of anti-TNF therapies, with consideration of combination therapies for patients with greater disease activity, and emphasizing the importance of medication adherence may improve outcomes due to higher therapeutic levels and lower risks of antibody formation. Objective assessments for continued response or early signs of nonresponse can identify secondary nonresponders who may benefit from anti-drug antibody testing to guide therapeutic decision making. Ongoing and future prospective studies will yield more specific information regarding pharmacokinetics to help target ideal drug levels during both induction and maintenance periods. Refinement of strategies to reduce immunogenicity with concomitant IS will likely further improve the likelihood of durable steroid-free remission. Financial & competing interests disclosures

A Kornbluth has acted as consultant, advisory board, received research support and/or speaker’s bureau from Janssen, Abbvie, Prometheus, Takeda / Millennium, Pfizer, Bristol-Myers Squibb, Salix Pharmaceuticals and Warner-Chilcott. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Key issues • A sizeable percentage of initially anti-TNF responsive IBD patients lose response to these therapies over time typically due to subtherapeutic drug levels, development of anti-drug antibodies, or the emergence of alternative pathways that lead to persistent inflammation. • Clinical factors such as disease activity, hypoalbuminemia, elevated inflammatory markers and body mass impact may impact the Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

pharmacokinetics of the anti-TNF agents and, subsequently, drug clearance and efficacy. • The presence of anti-drug antibodies is predictive of loss of response or nonresponse to anti-TNF therapy. • The clinical availability of assays to check anti-TNF levels and anti-drug antibodies may assist with therapeutic decision making among patients whom have lost response to their initial anti-TNF agent. • A test-based strategy for therapeutic monitoring of anti-TNF treated IBD patients may be a cost-effective tool to aid in the decision between dose escalation versus medication substitution. • The addition of a thiopurine to anti-TNF therapy increases drug levels and decreases immunogenicity, however, the optimal duration of combination therapy factoring infection and other adverse event risk remains to be determined.

necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol 2012;10:1079-87.quiz e85-6

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