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Abstract

Since the approval of the first anti-tumor necrosis factor (anti-TNF) therapy in late 1998, the treatment for Crohn’s disease (CD) has been revolutionized. Anti-TNF therapy has been consistently shown in numerous clinical trials to be effective for patients with more aggressive perianal, internal penetrating, and fistulizing CD. However, the loss of clinical remission is frequent and only one-third of patients remain in clinical remission at 1 year. The pharmacokinetics of anti-TNF is highly variable among patients and could be influenced by many factors including serum albumin, gender, body weight, systemic inflammation and route of administration. The main factor impacting anti-TNF pharmacokinetics and efficacy is the development of immunogenicity where antidrug antibodies accelerate anti-TNF drug clearance. In this review paper, we evaluate the role of combination therapy with anti-TNF drugs and immunomodulators, the role of therapeutic drug monitoring, and strategies to recapture loss of clinical response in order to improve both short- and long-term outcomes in CD patients.

Keywords

anti-TNF inflammatory bowel disease ulcerative colitis Crohn’s disease

Introduction

Crohn’s disease (CD) is a chronic inflammatory disorder involving the entire gastrointestinal tract. Although not fully understood, the proposed pathogenesis for the development of CD is from environmental triggers resulting in chronic inflammation in the genetically susceptible patient. Until the advent of the first US Food and Drug Administration (FDA) approved tumor necrosis factor antagonist (anti-TNF) therapy in late 1998, patients with CD were usually treated with conventional therapy such as corticosteroids, 5-aminosalicylates, thiopurines (azathioprine/6-mercaptopurine) and enteral nutrition. Though these conventional therapies have been shown to be effective at inducing and maintaining clinical remission in patients with mild to moderate disease, only anti-TNF therapies have been consistently shown in numerous clinical trials to be effective for patients with more aggressive perianal, internal penetrating, and fistulizing CD.

Anti-TNF therapies have the potential to decrease the need for surgery, but loss of clinical remission is frequent and only one-third of patients remain in clinical remission at 1 year [Peyrin-Biroulet and Lemann, 2011]. Clinical response, durable steroid-free remission and mucosal healing have been correlated with drug trough levels [Maser et al. 2006; Nanda et al. 2013]. However, the pharmacokinetics of anti-TNF varies dramatically between individuals and antidrug antibodies have been proposed as one of the major factors affecting the clearance of the drug [Nanda et al. 2013]. In this review paper, we evaluate the role of combination therapy with anti-TNF and immunomodulators, the role of therapeutic drug monitoring, and strategies to recapture loss of clinical response in order to improve both short- and long-term outcomes in CD patients.

Monotherapy versus combination therapy

Infliximab, a chimeric monoclonal antibody that binds specifically to human TNFα was approved by the FDA for the treatment of moderately to severely active CD in 1998 [Nguyen et al. 2014]. It was found to also be effective in maintaining steroid-free remission (ACCENT I) [Hanauer et al. 2002] and fistula closure (ACCENT II) [Sands et al. 2004]. In 2007, its fully humanized sister drug – adalimumab – a recombinant, immunoglobulin G1 monoclonal antibody to TNF, was approved by the FDA for the induction (CLASSIC I) [Hanauer et al. 2006] and remission (CLASSIC II, CHARM) [Colombel et al. 2007; Sandborn et al. 2007b] of moderate to severe CD. Shortly afterwards in 2008 certolizumab, a pegylated humanized FAB fragment that binds to TNFα, was approved (PRECISE I and II) [Sandborn et al. 2007a; Schreiber et al. 2007]. Many of the patients enrolled in these trials were on or previously exposed to immunomodulators including azathioprine/6-mercaptopurine (AZA/6MP), and methotrexate (MTX).

With the addition of this new class of anti-TNF drugs, the question posed was whether combination therapy with immunomodulators was more effective than either drug alone [Baert et al. 2013]. The first randomized studies found that combination therapy with AZA/6MP plus induction dosing infliximab was superior to AZA/6MP alone in steroid-dependent patients who were both naïve and experienced with immunomodulators [Lemann et al. 2006; D’Haens et al. 2008]. The groundbreaking SONIC trial, which randomized 508 steroid exposed CD patients to either azathioprine alone, infliximab alone, or azathioprine plus infliximab combination therapy, found that steroid-free clinical remission as well as endoscopic mucosal healing at 6 months was greater among patients in combination therapy, followed by monotherapy infliximab, and monotherapy azathioprine (43.9% versus 30.1% versus 16.5%, respectively) [Colombel et al. 2010].

Interestingly, the COMMIT trial, which included 126 steroid exposed CD patients, found that combination therapy with infliximab plus MTX was not statistically better than monotherapy with infliximab for the primary endpoint (lack of prednisone-free remission at week 14 or failure to maintain remission through week 50) [Feagan et al. 2014]. The conflicting results of this study might be in part explained by the fact that, unlike SONIC, a minimum Crohn’s Disease Activity Index (CDAI) score was not used for inclusion criteria, resulting in a ‘less severe’ study population that might never have reached the endpoint of time to failure regardless of the treatment group they were allocated to. Additionally, the study did not evaluate endoscopic remission as a primary endpoint. Furthermore, the COMMIT study did not explore the potential benefit of combination therapy of MTX with anti-TNF long term (i.e. beyond 6–12 months). Nevertheless, this result has caused confusion and leaves clinicians to interpret whether they believe the treatment efficacy of combination therapy is limited to immunomodulators other than MTX.

To date there have not been any similar randomized controlled trials (RCTs) directly comparing adalimumab or certolizumab pegol combination therapy with monotherapy. There was a meta-analysis including 11 RCTs of anti-TNF agents in CD that found combination therapy with adalimumab or certolizumab was not more efficacious than monotherapy; however these data were not prospective and should be interpreted with caution [Jones et al. 2013; Dulai et al. 2014].

One of the biggest concerns with combination therapy is the potential for increased adverse outcomes, notably severe infection and malignancies. However, no incremental increase in the odds of serious infections was actually seen with any dual therapy combinations over monotherapy in a study querying the FDA Adverse Event Reporting System (FAERS) [Deepak et al. 2013]. It is more difficult to truly calculate the risk of lymphoma with combination therapy since most studies are not powered to detect this relatively rare event. A meta-analysis including 9 RCTs, 3 cohort studies and 14 case series with 66% of patients concomitantly taking anti-TNFs and immunomodulators calculated a rate of non-Hodgkin’s lymphoma of 6.1 per 10,000 patient-years in patients taking combination therapy compared with a baseline 1.9 per 10,000 patient-years, with a standardized incidence ratio of 3.23 [Siegel et al. 2009]. In 2006, the FAERS was alerted to eight cases of the aggressive and usually fatal hepatosplenic T-cell lymphoma (HSTCL) associated with infliximab use in young patients receiving treatment for inflammatory bowel disease (IBD), prompting the FDA to add a boxed warning [Mackey et al. 2007]. Since then nearly 40 cases have been reported in CD patients, the majority occurring in young males (mean age at diagnosis was 30). Of the patients who were treated with anti-TNFs, 96% had been exposed to anti-metabolites [Selvaraj et al. 2013]. To date, no cases of HSTCL have been identified in patients on combination therapy with MTX.

Reducing immunogenicity with combination therapy

Although anti-TNF agents are effective drugs initially for many patients with severe CD, 23–46% of patients will lose response to infliximab and adalimumab after 12 months of anti-TNF therapy, requiring either dose escalation or drug discontinuation [Ben-Horin et al. 2011]. Antibodies to infliximab (ATIs), also known as human anti-chimeric antibodies (HACAs), form immune complexes that are cleared by the reticuloendothelial system and are associated with decreased drug levels, higher risk of infusion reactions and shorter duration of response [Baert et al. 2003; Ben-Horin et al. 2014]. Although adalimumab and certolizumab are fully humanized anti-TNF antibodies, they too are susceptible to antidrug antibodies, i.e. antibodies to adalimumab (ATAs), that reduce drug levels and treatment response. [Schreiber et al. 2007; West et al. 2008; Karmiris et al. 2009]. Approximately 7–17% of patients treated with scheduled infliximab develop ATIs with a higher incidence of antibody formation occurring in patients receiving episodic treatment (30%) [Hanauer et al. 2004; Sands et al. 2004]. ATIs are thought to promote drug clearance and reduce trough levels; however, the presence of ATIs also correlates with higher markers of inflammation [C-reactive protein (CRP)] independent of infliximab trough level [Feagan et al. 2012]. Interestingly, the presence of ATIs may be transient or sustained, with sustained ATIs associated with a higher rate of infliximab discontinuation due to loss of response or hypersensitivity reactions [Vande Casteele et al. 2013].

There are several assays available to detect ATIs and ADAs as well as serum drug levels. The enzyme-linked immunosorbent assay (ELISA) was the first assay used in early clinical trials; however, it is limited in that the presence of drug in the serum masks the detection of antibodies [Kopylov et al. 2012]. Other assays include the functional cell-based reporter gene assay (RGA), radioimmunoassay (RIA) and homogenous mobility shift assay (HMSA) using high pressure liquid chromatography (HPLC) (AnserIFX^TM) [Steenholdt et al. 2014a]. All assays agree on whether drug is detectable, but concentrations cannot be directly compared between the assays [Kopylov et al. 2012].

Multiple clinical trials have shown decreased anti-TNF antibody formation with concurrent use of immunosuppression. Premedication with intravenous (IV) corticosteroids (200 mg hydrocortisone) prior to infliximab infusion was found to decrease antibody formation to 26% of patients compared with 42% at 16 weeks post first infusion [Farrell et al. 2003]. In the COMMIT trial, patients treated with MTX were less likely to develop ATIs (4% compared with 20%) than those who received infliximab alone [Feagan et al. 2014]. AZA and 6MP when used in combination with anti-TNF have been found to consistently decrease anti-TNF antibody formation and increase drug levels [Dulai et al. 2014]. As monotherapy, 6-MP has been found to have its optimal therapeutic effect in achieving clinical remission at a cutoff concentration of 230–260 pmol/8 × 10⁸ red blood cells (RBC) and is thus the suggested target level, rather than the former weight-based dosing [Dubinsky et al. 2000; Osterman et al. 2006] However, a recent study by Yaryr and colleagues found that a cutoff 6-TG level of 125 pmol/8 × 10⁸ RBC may be sufficient at promoting higher anti-TNF levels, and this lower target may maximize infliximab levels while minimizing toxicity in IBD patients on combination therapy [Yaryr et al. 2014]. It is possible that the addition of thiopurines may deplete antigen-specific T cells, or drug-specific memory clones, thus reducing the titers of ATIs and ADAs [Yaryr et al. 2014].

The optimal length of time for combination therapy has yet to be decided. The median time to ATI formation is after 4 infusions corresponding to 16 weeks after start of infliximab [Vande Casteele et al. 2013]. Two-thirds of patients who lose response to anti-TNFs do so within the first 12 months with the remainder of patients losing response at a much slower rate several years after the first year. With the risk of immunogenicity being the greatest in the first few months of treatment with anti-TNF, it may be possible to minimize exposure to long-term combination therapy and the benefits of decreased anti-TNF antibody formation by limiting combination therapy to the initiation of anti-TNF therapy and then subsequently withdrawing the immunomodulator. A study of 80 patients in clinical remission after 6 months of combination therapy, randomized to either continue on both drugs or discontinue their immunomodulator while continuing infliximab monotherapy, found that patients who discontinued their immunomodulator did not have to shorten their dosing interval or stop infliximab at 2 years any more than patients who continued on dual therapy [Van Assche et al. 2008]. However, patients that discontinued their immunomodulator were found to have lower trough levels of infiximab and higher CRP, suggesting that clinical relapse may occur at higher rates in the anti-TNF monotherapy group in long-term follow up. Longer prospective studies are needed to know if this will result in a meaningful difference in clinical outcomes.

In our clinical practice, we typically initiate combination therapy with either AZA/6MP or MTX for minimum of 12 months to bring patients with active disease into deep clinical, biochemical [normalization of CRP, erythrocyte sedimentation rate (ESR), fecal calprotectin] and endoscopic remission. Once deep remission has been achieved, a full discussion of risks and benefits will be conducted with the patient to determine if the patient should remain on combination therapy versus tapering to monotherapy of anti-TNF. We typically favor MTX combination therapy in young men because of potentially higher risk for HSTLC in this group with long-term use of AZA/6MP. Among women of child-bearing age, we offer combination therapy with 6-MP/AZA.

Therapeutic drug monitoring and recapturing loss of clinical response

The annual risk for loss of clinical response, as defined by need for dose intensification, to infliximab and adalimumab is 13 and 24%, respectively [Gisbert and Panes, 2009; Billioud et al. 2011]. Thus, the optimization of TNF antagonists has become extremely important. Therapeutic drug monitoring is often used in medications with a narrow therapeutic window, where caution is used to not exceed a certain toxic concentration or fall below a threshold beyond which the drug may lose its efficacy. Multiple studies have shown that achieving a certain drug level of infliximab directly impacts response to therapy in IBD patients [Reinisch et al. 2012; Murthy et al. 2012; Feagan et al. 2012]. The ACCENT 1 study showed that attaining an infliximab level of >3.5 µg/ml at week 14 was associated with sustained clinical outcomes at week 54 [Hanauer et al. 2002]. A meta-analysis of 2021 serum samples from 532 CD patients included in 4 prospective RCTs or cohort studies examined the correlation between infliximab concentration, ATI and CRP, and showed that an infliximab concentration of >3 µg/ml was predictive of significantly lower disease activity, reflected in decreased CRP [Hanauer et al. 2004]. The data for adalimumab are similar, with data from CLASSIC 1 trial, ULTRA 2 and two recent prospective cross-sectional studies showing that a trough concentration of >5 µg/ml was predictive of clinical response and remission [Chiu et al. 2013; Mostafa et al. 2013; Velayos et al. 2013b; Yarur et al. 2013].

Therapeutic drug monitoring has also proven to be beneficial during the induction phase. The results of the randomized controlled TAXIT (Trough-level Adapted Infliximab Treatment) showed that increasing the infliximab dose in CD patients with suboptimal drug levels (<3 µg/ml) leads to better disease control reflected in a significant decrease in the Harvey–Bradshaw index and CRP [Vande Casteele et al. 2012]. In addition, dose de-escalation in CD patients at supra-optimal drug levels (>7 µg/ml) was also successful, and led to lower drug exposure and lower cost without significantly impacting disease activity [Vande Casteele et al. 2012].

In the case of re-induction of infliximab therapy after a long drug holiday, adequate drug levels and absence of antidrug antibodies early after the restart of therapy has shown to correlate with both short- and long-term clinical outcomes [Baert et al. 2013]. Recently, a meta-analysis including 1378 patients with IBD revealed that patients who develop ATIs have a risk ratio of 3.2 [95% confidence interval (CI) 2.0–4.9] of losing clinical response to the drug compared with patients who did not develop antibodies [Nanda et al. 2013]. These patients also tend to have lower infliximab trough concentrations. Additionally, a recent cross-sectional study including 66 IBD patients treated with maintenance adalimumab showed that detectable antibodies were associated with an adalimumab trough concentration of <5 µg/ml [odds ratio (OR) 8.6; 95% CI: 2.3–31.8], macroscopic mucosal inflammation (OR 3.8; 95% CI: 1.1–13.2) and need for corticosteroids (OR 3.7; 95% CI: 1.1–12.9) [Yarur et al. 2013].

The Mayo Clinic experience demonstrated that measuring serum trough levels to detect subtherapeutic concentrations and identification of antidrug antibodies impacted clinical decision making in 73% of patients. This study showed that, when antidrug antibodies were detected, the switch to another anti-TNF molecule allowed for partial or complete response in 92% versus 17% for dose escalation of the initial anti-TNF [Afif et al. 2010]. In contrast, dose escalation through shortening the infusion interval or increasing the dose in patients with subtherapeutic infliximab concentrations was found to be the most efficient strategy whereby 86% achieved partial of complete response versus 33% who had no dosing changes. This study suggests that increasing the dose of anti-TNF is ineffective in patients who have developed high levels of antibodies to the drug and switching to a different anti-TNF agent should be considered. Furthermore nonresponders, who have adequate drug level without the development of antibodies to anti-TNF therapy, may benefit from a different class of medication.

Velayos and colleagues compared the effectiveness of empiric dose escalation versus testing-based strategy over 1 year period. Though both strategies resulted in similar clinical remissions rates of approximately 60%, the testing-based strategy was less expensive than empiric dose escalation ($31,870 versus $34,266) [Velayos et al. 2013a]. Similar findings were also demonstrated by Steenholdt and colleagues in an RCT that also favored a testing-based strategy of drug monitoring [Steenholdt et al. 2014b]. Although more studies are needed to analyze the cost benefit of therapeutic drug monitoring in IBD, initial data support therapeutic drug monitoring is a viable strategy in the treatment of patients with IBD.

In clinical practice, we recommend using therapeutic drug monitoring during the initial induction dosing of anti-TNF therapy to see if accelerated dosing is necessary to bring patients into clinical remission. Among patients who required dose intensification to achieve clinical remission, once they have achieved deep clinical and biochemical remission, monitoring drug levels may allow for de-escalation of anti-TNF dosing to minimize drug-related adverse reactions (i.e. lupus-like drug reactions). Additionally, for patients who have subsequent loss of clinical response, therapeutic drug monitoring may allow clinicians to decide between need for dose escalation versus making a therapeutic change to a new anti-TNF versus switching to a different biologic class.

Conclusion

Since the advent of anti-TNF therapy more than a decade ago, these drugs have been consistently shown to alter the natural history of CD through induction and maintenance of clinical responses, achievement of mucosal healing, improvement in quality of life, and reduced need for surgery and hospitalizations. Unfortunately, despite a good initial response found in 60–80% of patients, only one-third of patients are able to achieve clinical remission at 1 year. The pharmacokinetics of anti-TNF is highly variable among patients and could be influenced by many factors including serum albumin, gender, body weight, systemic inflammation and route of administration. The main factor impacting anti-TNF pharmacokinetics and efficacy is the development of immunogenicity where antidrug antibodies accelerate anti-TNF drug clearance.

We have provided the most up-to-date review of our current understanding on how to maximize anti-TNF therapy in CD patients, including a review of the most up-to-date information from emerging pilot studies. Several considerations should be taken into account when managing CD with anti-TNF therapy. First, to optimize the efficacy of anti-TNF therapy, consideration should be given for combination therapy of anti-TNF with an immunomodulator, particularly during the first 6–12 months of therapy. Second, among patients who have failed to respond or subsequently loss response to anti-TNF therapy, therapeutic drug monitoring is absolutely necessary to rationalize medication adjustments. Lastly, it is important to monitor the patient’s clinical, biochemical and endoscopic response to anti-TNF and tailor therapy to achieve deep endoscopic remission so as to improve long-term outcomes of CD patients.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

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Hauenstein

Barkin

Sussman

. (2014) Higher 6-thioguanine nucleotide concentrations are associated with higher trough levels of infliximab in patients on combination therapy. Gastroenterology 146: S134–S135.

Optimizing the use of anti-tumor necrosis factor in the management of patients with Crohn’s disease

Abstract

Keywords

Introduction

Monotherapy versus combination therapy

Reducing immunogenicity with combination therapy

Therapeutic drug monitoring and recapturing loss of clinical response

Conclusion

Footnotes

Funding

Conflict of interest statement

References